bluuebunny/crossref_metadata_2025 huggingface dataset:
Fatigue‐related depression of the feline monosynaptic gastrocnemius–soleus reflex
Authors: Kalezic Ivana , Bugaychenko Larisa A. , Kostyukov Alexander I. , Pilyavskii Alexander I. , Ljubisavljevic Milos , Windhorst Uwe , Johansson Håkan
Published: December 2003

In decerebrate cats, changes in the monosynaptic reflex (MSR) of gastrocnemius–soleus (G–S) motoneurones were studied after fatiguing stimulation (FST) of the G–S muscles. Monosynaptic reflexes were evoked by stimulation of Ia fibres in the G–S nerve and recorded from a filament of ventral root (VR) L7. FST (intermittent 40 s−1 stimulation for 10–12 min) was applied to the distal part of the cut VR S1. FST reduced MSR amplitudes to 0.64 ± 0.04 (mean ±s.e.m.) of the prefatigue values. The suppression remained stable for approximately 25 min and then MSR amplitudes gradually returned towards the normal. To test for the involvement of presynaptic and recurrent inhibition, MSRs were conditioned by stimulation of the nerve to the posterior biceps and semitendinosus (PBSt) muscles or a filament of VR L7, respectively. The intensity of presynaptic inhibition (reduction of the normalized value of MSR amplitude during conditioning) increased from 0.19 ± 0.02 in prefatigue to 0.44 ± 0.04 within a 5.3–18.2 min interval after FST, followed by a recovery. In contrast, the intensity of recurrent inhibition first diminished from 0.23 ± 0.02 in prefatigue to 0.15 ± 0.01 within 15.6–30.1 min after FST and then gradually recovered. Both primary afferent depolarization and the intensity of antidromic discharges in primary afferents increased with the presynaptic inhibition intensity. These results demonstrate a fatigue‐related suppression of Ia excitation of synergistic motoneurones, probably arising from the activation of group III and IV afferents. The effects could in part be due to increased presynaptic inhibition, while recurrent inhibition plays a minor role.
Structure and function of AMPA receptors
Authors: Gouaux Eric
Published: December 2003

The application of X‐ray diffraction has allowed the structure of the ligand‐binding core of AMPA receptors to be determined. Here I review the insights that this has given into the molecular mechanisms of activation and desensitization of these receptors.
Mice overexpressing the cardiac sodium‐calcium exchanger: defects in excitation–contraction coupling
Authors: Reuter Hannes , Han Tieyan , Motter Christi , Philipson Kenneth D. , Goldhaber Joshua I.
Published: December 2003

Homozygous overexpression of the cardiac Na+–Ca2+ exchanger causes cardiac hypertrophy and increases susceptibility to heart failure in response to stress. We studied the functional effects of homozygous overexpression of the exchanger at the cellular level in isolated mouse ventricular myocytes. Compared with patch‐clamped myocytes from wild‐type animals, non‐failing myocytes from homozygous transgenic mice exhibited increased cell capacitance (from 208 ± 16 pF to 260 ± 15 pF, P < 0.05). Intracellular Ca2+ oscillations were readily elicited in homozygous transgenic animals during depolarizations to +80 mV, consistent with rapid Ca2+ overload caused by reverse Na+–Ca2+ exchange. After normalization to cell capacitance, transgenic myocytes had significant increases in Na+–Ca2+ exchange activity (318%) and peak L‐type Ca2+ current (8.2 ± 0.7 pA pF−1 at 0 mV test potential) compared to wild‐type (5.8 ± 0.9 pA pF−1 at 0 mV, P < 0.02). The peak Ca2+ current amplitude and its rate of inactivation could be modulated by rapid reversible block of the exchanger. Thus, we describe an unexpected direct influence of Na+–Ca2+ exchange activity on the L‐type Ca2+ channel. Despite intact sarcoplasmic reticular Ca2+ content and larger peak L‐type Ca2+ currents, homozygous transgenic animals exhibited smaller Ca2+ transients (Δ[Ca2+]i= 466 ± 48 nm in transgenics versus 892 ± 104 nm in wild‐type, P < 0.0005) and substantially reduced gain of excitation–contraction coupling. These alterations in excitation–contraction coupling may underlie the tendency for these animals to develop heart failure following haemodynamic stress.
Selective antagonism of rat inhibitory glycine receptor subunits
Authors: Han Yi , Li Ping , Slaughter Malcolm M.
Published: December 2003

Retinal ganglion cells exhibit fast and slow inhibitory synaptic glycine currents that can be selectively inhibited by strychnine and 5,7‐dichlorokynurenic acid (DCKA), respectively. In this study we examined whether strychnine and DCKA selectivity correlated with the subunit composition of the glycine receptor. Homomeric α1, α2 or α2* glycine subunits were in vitro expressed in human embryonic kidney cells (HEK 293). In cells expressing the α1 subunit, responses to 200 μm glycine were blocked by 1 μm strychnine but not by 500 μm DCKA. In cells expressing the α2 subunit, both 1 μm strychnine and 500 μm DCKA were effective antagonists of 200 μm glycine. In cells expressing α2* subunits, which are much less glycine‐sensitive, 10 mm glycine was inhibited by 500 μm DCKA but not by 1 μm strychnine. A single amino acid mutation in the α1 subunit (R196G), converted this subunit from DCKA‐insensitive to DCKA‐sensitive. In conclusion, the comparative effectiveness of strychnine and DCKA can be used to distinguish between the α1, α2 and α2* receptor responses. Furthermore, a single amino acid near the glycine receptor's putative agonist binding site may account for differences in DCKA sensitivity amongst the α subunits.
Group II metabotropic glutamate receptors enhance NMDA receptor currents via a protein kinase C‐dependent mechanism in pyramidal neurones of rat prefrontal cortex
Authors: Tyszkiewicz Joanna P. , Gu Zhenglin , Wang Xun , Cai Xiang , Yan Zhen
Published: December 2003

The action of glutamate in CNS is mediated by the activation of metabotropic and ionotropic receptors. The metabotropic glutamate receptors (mGluRs) are highly enriched in prefrontal cortex (PFC) – a brain region critically involved in the regulation of cognition and emotion. Emerging evidence has suggested that mGluRs are viable drug targets for neuropsychiatric disorders associated with PFC dysfunction. However, the mGluR‐mediated signalling in PFC remains unclear. To understand the physiological functions of postsynaptic group II mGluRs (mGluR2/3) in PFC neurones, we investigated the molecular and cellular mechanisms underlying the regulation of NMDA receptor channels by group II mGluRs. We found that APDC, a highly selective and potent group II mGluR agonist, reversibly increased NMDAR currents in acutely dissociated PFC pyramidal neurones. Selective group II mGluR antagonists, but not group I mGluR antagonists, blocked APDC‐induced enhancement of NMDAR currents, suggesting the mediation by mGluR2/3 receptors. The APDC effect on NMDAR currents was independent of Mg2+ block or membrane voltages, and primarily targeted NR2A subunits containing NMDARs. While changing protein kinase A levels was without effect, inhibiting protein kinase C (PKC) or dialysis with Ca2+ chelators largely blocked the mGluR2/3 modulation of NMDAR currents. In contrast, inhibiting protein tyrosine kinases, cyclin‐dependent kinase 5, Ca2+/calmodulin‐dependent kinase II or the Ca2+/calmodulin‐dependent phosphatase calcineurin failed to do so. Moreover, treatment of PFC slices with APDC significantly increased the PKC activity and PKC phosphorylation of NMDA receptors. These findings suggest that activation of mGluR2/3 receptors potentiates NMDAR channel functions in PFC through a PKC‐dependent mechanism. This modulation may be relevant for developing novel mGluR‐related pharmacological agents for the treatment of mental illnesses.
Aligned Multiwalled Carbon Nanotube Membranes
Authors: Hinds Bruce J. , Chopra Nitin , Rantell Terry , Andrews Rodney , Gavalas Vasilis , Bachas Leonidas G.
Published: December 2003

An array of aligned carbon nanotubes (CNTs) was incorporated across a polymer film to form a well-ordered nanoporous membrane structure. This membrane structure was confirmed by electron microscopy, anisotropic electrical conductivity, gas flow, and ionic transport studies. The measured nitrogen permeance was consistent with the flux calculated by Knudsen diffusion through nanometer-scale tubes of the observed microstructure. Data on Ru(NH
3
)
6
3+
transport across the membrane in aqueous solution also indicated transport through aligned CNT cores of the observed microstructure. The lengths of the nanotubes within the polymer film were reduced by selective electrochemical oxidation, allowing for tunable pore lengths. Oxidative trimming processes resulted in carboxylate end groups that were readily functionalized at the entrance to each CNT inner core. Membranes with CNT tips that were functionalized with biotin showed a reduction in Ru(NH
3
)
6
3+
flux by a factor of 15 when bound with streptavidin, thereby demonstrating the ability to gate molecular transport through CNT cores for potential applications in chemical separations and sensing.
The Growth Advantage in Stationary-Phase PhenotypeConferred by
rpoS
Mutations Is Dependent on the pH andNutrientEnvironment
Authors: Farrell Michael J. , Finkel Steven E.
Published: December 2003

Escherichia
coli
cells that are aged in batch culture display an increased
fitness referred to as the growth advantage in stationary phase, or
GASP, phenotype. A common early adaptation to this culture environment
is a mutant
rpoS
allele, such as
rpoS819
, that
results in attenuated RpoS activity. However, it is important to note
that during long-term batch culture, environmental conditions are in
flux. To date, most studies of the GASP phenotype have focused on
identifying alleles that render an advantage in a specific environment,
Luria-Bertani broth (LB) batch culture. To determine what role
environmental conditions play in rendering relative fitness advantages
to
E. coli
cells carrying either the wild-type or
rpoS819
alleles, we performed competitions under a variety of
culture conditions in which either the available nutrients, the pH, or
both were manipulated. In LB medium, we found that while the
rpoS819
allele confers a strong competitive fitness advantage
at basic pH, it confers a reduced advantage under neutral conditions,
and it is disadvantageous under acidic conditions. Similar results were
found using other media.
rpoS819
conferred its greatest
advantage in basic minimal medium in which either glucose or Casamino
Acids were the sole source of carbon and energy. In acidic medium
supplemented with either Casamino Acids or glucose, the wild-type
allele conferred a slight advantage. In addition, populations were
dynamic under all pH conditions tested, with neither the wild-type nor
mutant
rpoS
alleles sweeping a culture. We also found that the
strength of the fitness advantage gained during a 10-day incubation is
pH
dependent.
Responses of theCentral Metabolism in
Escherichia coli
to PhosphoglucoseIsomerase and Glucose-6-Phosphate DehydrogenaseKnockouts
Authors: Hua Qiang , Yang Chen , Baba Tomoya , Mori Hirotada , Shimizu Kazuyuki
Published: December 2003

The
responses of
Escherichia coli
central carbon metabolism to
knockout mutations in phosphoglucose isomerase and glucose-6-phosphate
(G6P) dehydrogenase genes were investigated by using glucose- and
ammonia-limited chemostats. The metabolic network structures and
intracellular carbon fluxes in the wild type and in the knockout
mutants were characterized by using the complementary methods of flux
ratio analysis and metabolic flux analysis based on
[U-
13
C]glucose labeling and
two-dimensional nuclear magnetic resonance (NMR) spectroscopy of
cellular amino acids, glycerol, and glucose. Disruption of
phosphoglucose isomerase resulted in use of the pentose phosphate
pathway as the primary route of glucose catabolism, while flux
rerouting via the Embden-Meyerhof-Parnas pathway and the nonoxidative
branch of the pentose phosphate pathway compensated for the G6P
dehydrogenase deficiency. Furthermore, additional, unexpected flux
responses to the knockout mutations were observed. Most prominently,
the glyoxylate shunt was found to be active in phosphoglucose
isomerase-deficient
E. coli
. The Entner-Doudoroff pathway also
contributed to a minor fraction of the glucose catabolism in this
mutant strain. Moreover, although knockout of G6P dehydrogenase had no
significant influence on the central metabolism under glucose-limited
conditions, this mutation resulted in extensive overflow metabolism and
extremely low tricarboxylic acid cycle fluxes under ammonia limitation
conditions.
FimX, a Multidomain Protein Connecting EnvironmentalSignals to Twitching Motility in
Pseudomonasaeruginosa
Authors: Huang Bixing , Whitchurch Cynthia B. , Mattick John S.
Published: December 2003

Twitching
motility is a form of surface translocation mediated by the extension,
tethering, and retraction of type IV pili. Three independent
Tn
5
-B21 mutations of
Pseudomonas aeruginosa
with
reduced twitching motility were identified in a new locus which encodes
a predicted protein of unknown function annotated PA4959 in the
P.
aeruginosa
genome sequence. Complementation of these mutants with
the wild-type PA4959 gene, which we designated
fimX
, restored
normal twitching motility.
fimX
mutants were found to express
normal levels of pilin and remained sensitive to pilus-specific
bacteriophages, but they exhibited very low levels of surface pili,
suggesting that normal pilus function was impaired. The
fimX
gene product has a molecular weight of 76,000 and contains four
predicted domains that are commonly found in signal transduction
proteins: a putative response regulator (CheY-like) domain, a PAS-PAC
domain (commonly involved in environmental sensing), and DUF1 (or
GGDEF) and DUF2 (or EAL) domains, which are thought to be involved in
cyclic di-GMP metabolism. Red fluorescent protein fusion experiments
showed that FimX is located at one pole of the cell via sequences
adjacent to its CheY-like domain. Twitching motility in
fimX
mutants was found to respond relatively normally to a range of
environmental factors but could not be stimulated by tryptone and
mucin. These data suggest that
fimX
is involved in the
regulation of twitching motility in response to environmental
cues.
Suppression of Factor-Dependent TranscriptionTermination by AntiterminatorRNA
Authors: King Rodney A. , Weisberg Robert A.
Published: December 2003

Nascent
transcripts of the phage HK022
put
sites modify the
transcription elongation complex so that it terminates less efficiently
at intrinsic transcription terminators and accelerates through pause
sites. We show here that the modification also suppresses termination
in vivo at two factor-dependent terminators, one that depends on the
bacterial Rho protein and a second that depends on the HK022-encoded
Nun protein. Suppression was efficient when the termination factors
were present at physiological levels, but an increase in the
intracellular concentration of Nun increased termination both in the
presence and absence of
put. put
-mediated
antitermination thus shows no apparent terminator specificity,
suggesting that
put
inhibits a step that is common to
termination at the different types of
terminator.
YmoA Negatively Regulates Expression of Invasin fromYersiniaenterocolitica
Authors: Ellison Damon W. , Young Briana , Nelson Kristin , Miller Virginia L.
Published: December 2003

invencodes invasin, which is the primary invasion factor ofYersinia enterocolitica. invexpression in vitro is regulated in response to temperature, pH, and growth phase. In vitro,invis maximally expressed at 26°C and repressed at 37°C at neutral pH but, when the pH of the media is adjusted to 5.5, levels ofinvexpression at 37°C are comparable to those at 26°C. A previous genetic screen for regulators ofinvidentified RovA, which was found to be required for activation ofinvin vitro under all conditions tested as well as in vivo. Here we describe a screen that has identified a negative regulator ofinvexpression,ymoA. TheymoBAlocus was identified by transposon mutagenesis as a repressor ofinvexpression in vitro at 37°C at neutral pH. This mutant shows increasedinvexpression at 37°C. The mutant can be fully complemented forinvexpression by a plasmid expressingymoA. These results indicate that YmoA plays a role in the negative regulation ofinv.
Purification of the Formate-Tetrahydrofolate Ligasefrom
Methylobacterium extorquens
AM1 and Demonstrationof Its Requirement for MethylotrophicGrowth
Authors: Marx Christopher J. , Laukel Markus , Vorholt Julia A. , Lidstrom Mary E.
Published: December 2003

The
serine cycle methylotroph
Methylobacterium extorquens
AM1
contains two pterin-dependent pathways for C
1
transfers, the
tetrahydrofolate (H
4
F) pathway and the
tetrahydromethanopterin (H
4
MPT) pathway, and both are
required for growth on C
1
compounds. With the exception of
formate-tetrahydrofolate ligase (FtfL, alternatively termed
formyl-H
4
F synthetase), all of the genes encoding the
enzymes comprising these two pathways have been identified, and the
corresponding gene products have been purified and characterized. We
present here the purification and characterization of FtfL from
M.
extorquens
AM1 and the confirmation that this enzyme is encoded by
an
ftfL
homolog identified previously through transposon
mutagenesis. Phenotypic analyses of the
ftfL
mutant strain
demonstrated that FtfL activity is required for growth on C
1
compounds. Unlike mutants defective for the H
4
MPT pathway,
the
ftfL
mutant strain does not exhibit phenotypes indicative
of defective formaldehyde oxidation. Furthermore, the
ftfL
mutant strain remained competent for wild-type conversion of
[
14
C]methanol to
[
14
C]CO
2
. Collectively, these data
confirm our previous presumptions that the H
4
F pathway is
not the key formaldehyde oxidation pathway in
M. extorquens
AM1. Rather, our data suggest an alternative model for the role of the
H
4
F pathway in this organism in which it functions to
convert formate to methylene H
4
F for assimilatory
metabolism.
A New Pathway for Salvaging the CoenzymeB12Precursor Cobinamide in Archaea RequiresCobinamide-Phosphate Synthase (CbiB) EnzymeActivity
Authors: Woodson Jesse D. , Zayas Carmen L. , Escalante-Semerena Jorge C.
Published: December 2003

The ability of archaea to salvage cobinamide has been under question because archaeal genomes lack orthologs to the bacterial nucleoside triphosphate:5′-deoxycobinamide kinase enzyme (cobUinSalmonella enterica). The latter activity is required for cobinamide salvaging in bacteria. This paper reports evidence that archaea salvage cobinamide from the environment by using a pathway different from the one used by bacteria. These studies demanded the functional characterization of two genes whose putative function had been annotated based solely on their homology to the bacterial genes encoding adenosylcobyric acid and adenosylcobinamide-phosphate synthases (cbiPandcbiB, respectively) ofS. enterica. AcbiPmutant strain of the archaeonHalobacteriumsp. strain NRC-1 was auxotrophic for adenosylcobyric acid, a known intermediate of the de novo cobamide biosynthesis pathway, but efficiently salvaged cobinamide from the environment, suggesting the existence of a salvaging pathway in this archaeon. AcbiBmutant strain ofHalobacteriumwas auxotrophic for adenosylcobinamide-GDP, a known de novo intermediate, and did not salvage cobinamide. The results of the nutritional analyses of thecbiPandcbiBmutants suggested that the entry point for cobinamide salvaging is adenosylcobyric acid. The data are consistent with a salvaging pathway for cobinamide in which an amidohydrolase enzyme cleaves off the aminopropanol moiety of adenosylcobinamide to yield adenosylcobyric acid, which is converted by the adenosylcobinamide-phosphate synthase enzyme to adenosylcobinamide-phosphate, a known intermediate of the de novo biosynthetic pathway. The existence of an adenosylcobinamide amidohydrolase enzyme would explain the lack of an adenosylcobinamide kinase in archaea.
GacA Regulates Symbiotic Colonization Traits of
Vibrio fischeri
and Facilitates a Beneficial Association withan AnimalHost
Authors: Whistler Cheryl A. , Ruby Edward G.
Published: December 2003

The
GacS/GacA two-component system regulates the expression of bacterial
traits during host association. Although the importance of GacS/GacA as
a regulator of virulence is well established, its role in benign
associations is not clear, as mutations in either the
gacS
or
gacA
gene have little impact on the success of colonization in
nonpathogenic associations studied thus far. Using as a model the
symbiotic association of the bioluminescent marine bacterium
Vibrio
fischeri
with its animal host, the Hawaiian bobtail squid,
Euprymna scolopes
, we investigated the role of GacA in this
beneficial animal-microbe interaction. When grown in culture,
gacA
mutants were defective in several traits important for
symbiosis, including luminescence, growth in defined media, growth
yield, siderophore activity, and motility. However,
gacA
mutants were not deficient in production of acylated homoserine lactone
signals or catalase activity. The ability of the
gacA mutants to initiate squid colonization was
impaired but not abolished, and they reached lower-than-wild-type
population densities within the host light organ. In contrast to their
dark phenotype in culture,
gacA
mutants that reached
population densities above the luminescence detection limit had normal
levels of luminescence per bacterial cell in squid light organs,
indicating that GacA is not required for light production within the
host. The
gacA
mutants were impaired at competitive
colonization and could only successfully cocolonize squid light organs
when present in the seawater at higher inoculum densities than
wild-type bacteria. Although severely impaired during colonization
initiation,
gacA
mutants were not displaced by the wild-type
strain in light organs that were colonized with both strains. This
study establishes the role of GacA as a regulator of a beneficial
animal-microbe association and indicates that GacA regulates
utilization of growth substrates as well as other colonization
traits.
Role of
narK2X
and
narGHJI
inHypoxic Upregulation of Nitrate Reduction by
Mycobacteriumtuberculosis
Authors: Sohaskey Charles D. , Wayne Lawrence G.
Published: December 2003

Mycobacterium
tuberculosis
is one of the strongest reducers of nitrate in the
genus
Mycobacterium
. Under microaerobic
conditions, whole cells exhibit upregulation of activity, producing
approximately eightfold more nitrite than those of aerobic cultures of
the same age. Assays of cell extracts from aerobic cultures and hypoxic
cultures yielded comparable nitrate reductase activities.
Mycobacterium bovis
produced only low levels of nitrite, and
this activity was not induced by hypoxia.
M
.
tuberculosis
has two sets of genes,
narGHJI
and
narX
of the
narK2X
operon, that exhibit some degree
of homology to prokaryotic dissimilatory nitrate reductases. Each of
these were knocked out by insertional inactivation. The
narG
mutant showed no nitrate reductase activity in whole culture or in
cell-free assays, while the
narX
mutant showed wild-type
levels in both assays. A knockout of the putative nitrite transporter
narK2
gene produced a strain that had aerobic levels of
nitrate reductase activity but failed to show hypoxic upregulation.
Insertion of the
M. tuberculosis narGHJI
into a
nitrate reductase
Escherichia coli
mutant allowed anaerobic
growth in the presence of nitrate. Under aerobic and hypoxic
conditions, transcription of
narGHJI
was constitutive, while
the
narK2X
operon was induced under hypoxia, as measured with
a
lacZ
reporter system and by quantitative real-time reverse
PCR. This indicates that nitrate reductase activity in
M
.
tuberculosis
is due to the
narGHJI
locus with no
detectable contribution from
narX
and that the hypoxic
upregulation of activity is associated with the induction of the
nitrate and nitrite transport gene
narK2
.
InvBIs a Type III Secretion-Associated Chaperone for theSalmonella entericaEffector ProteinSopE
Authors: Ho Lee Sang , Galán Jorge E.
Published: December 2003

SopE is a bacteriophage-encoded effector protein ofSalmonella entericaserovar Typhimurium that is translocated into the cytosol of eukaryotic cells by a type III secretion system (TTSS) (W.-D. Hardt, H. Urlaub, and J. E. Galán, Proc. Natl. Acad. Sci. USA 95:2574-2579, 1998; M. W. Wood, R. Rosqvist, P. B. Mullan, M. H. Edwards, and E. E. Galyov, Mol. Microbiol. 22:327-338, 1996). In this study, we provide evidence that an unlinked gene carried within theSalmonellapathogenicity island 1 (SPI-1),invB(K. Eichelberg, C. Ginocchio, and J. E. Galán, J. Bacteriol. 176:4501-4510, 1994), is required for the secretion of SopE through the SPI-1 TTSS. Furthermore, far-Western blotting analysis shows that SopE directly interacts with InvB through a domain located at its amino terminus. We conclude that InvB is the TTSS-associated chaperone for SopE.
ColonialDifferentiation in
Streptomyces
coelicolor
Depends on Translation of a SpecificCodon within the
adpA
Gene
Authors: Nguyen Kien T. , Tenor Jennifer , Stettler Hansruedi , Nguyen Lieu T. , Nguyen Liem D. , Thompson Charles J.
Published: December 2003

We
identified
adpA
as an
araC
-like regulatory gene
needed for colonial morphogenesis in
Streptomyces
coelicolor
and showed that its activity depended on a unique
TTA triplet corresponding to the leucyl-tRNA gene (
bldA
).
These findings partially explained the dependence of aerial mycelium
formation on a rare tRNA that is postulated to have developmental
control
functions.
THE PAULI EXCLUSION PRINCIPLE AND SU(2) VERSUS SO(3) IN LOOP QUANTUM GRAVITY
Authors: SWAIN JOHN
Published: December 2003

Recent attempts to resolve the ambiguity in the loop quantum gravity description of the quantization of area has led to the idea that j=1 edges of spin-networks dominate in their contribution to black hole areas as opposed to j=1/2 which would naively be expected. This suggests that the true gauge group involved might be SO(3) rather than SU(2) with attendant difficulties. We argue that the assumption that a version of the Pauli principle is present in loop quantum gravity allows one to maintain SU(2) as the gauge group while still naturally achieving the desired suppression of spin-1/2 punctures. Areas come from j=1 punctures rather than j=1/2 punctures for much the same reason that photons lead to macroscopic classically observable fields while electrons do not.
PRECURSORS SEE INSIDE BLACK HOLES
Authors: HUBENY VERONIKA E.
Published: December 2003

We consider, within a string theoretic context, the accessibility of events inside a black hole horizon. We present a gedankenexperiment which uses the nonlocal nature of precursors in the AdS/CFT correspondence, as well as the global nature of event horizons, to argue that the dual field theory does contain information about physics inside black holes. This alleviates the causal obstacles to accessing behind-the-horizon physics, thereby rendering more tractable certain long-standing questions of quantum gravity, such as the information paradox and possibly even singularity resolution.
DISCRETE QUANTUM GRAVITY: A MECHANISM FOR SELECTING THE VALUE OF FUNDAMENTAL CONSTANTS
Authors: GAMBINI RODOLFO , PULLIN JORGE
Published: December 2003

Smolin has put forward the proposal that the universe fine tunes the values of its physical constants through a Darwinian selection process. Every time a black hole forms, a new universe is developed inside it that has different values for its physical constants from the ones in its progenitor. The most likely universe is the one which maximizes the number of black holes. Here we present a concrete quantum gravity calculation based on a recently proposed consistent discretization of the Einstein equations that shows that fundamental physical constants change in a random fashion when tunneling through a singularity.
RADIATION REACTION AND THE PRINCIPLE OF EQUIVALENCE
Authors: WHITING BERNARD F. , DETWEILER STEVEN
Published: December 2003

The principle of equivalence is shown to extend to situations involving radiation reaction. For example, the Lorentz force law governs the motion of an isolated charge undergoing radiation reaction. In the case of an isolated uncharged particle of small mass, it is the geodesic equation which governs the motion, even when radiation reaction is included. For a local observer to understand such motion he must subtract the singular field of the particle from the actual electromagnetic and gravitational fields he measures. The remaining source-free fields are then used in computing the motion of the particle. With only local measurements, the observer has no knowledge of the existence of radiation and sees no effect which he would be compelled to describe as radiation reaction.
CLASSICAL SCALE OF QUANTUM GRAVITY
Authors: KAZAKOV KIRILL A.
Published: December 2003

Characteristic length scale of the post-Newtonian corrections to the gravitational field of a body is given by its gravitational radius r g . The role of this scale in quantum domain is discussed in the context of the low-energy effective theory. The question of whether quantum gravity effects appear already at r g leads to the question of correspondence between classical and quantum theories, which in turn can be unambiguously resolved by considering the issue of general covariance. The O(ℏ0) loop contributions turn out to violate the principle of general covariance, thus revealing their essentially quantum nature. The violation is O(1/N), where N is the number of particles in the body. This leads naturally to a macroscopic formulation of the correspondence principle.
A DIALOG ON QUANTUM GRAVITY
Authors: ROVELLI CARLO
Published: December 2003

The debate between loop quantum gravity and string theory is sometime lively, and it is hard to present an impartial view on the issue. Leaving any attempt to impartiality aside, I report here, instead, a conversation on this issue, overheard in the cafeteria of a Major American University. The personae of the dialog are Professor Simp, a high energy physicist, and a graduate student, Sal. The Professor has heard that Sal has decided to work in loop gravity, and gently tries to talk her out. Here is what was heard.
A THEORETICAL CASE FOR NEGATIVE MASS-SQUARE FOR SUB-eV PARTICLES
Authors: AHLUWALIA-KHALILOVA D. V. , DYMNIKOVA IRINA
Published: December 2003

Electroweak gauge bosons have masses of the order of 102 GeV [/c2], while masses of additional bosons involved in gravito-electroweak unification are expected to be still higher. These are at least eleven orders of magnitude higher than sub-eV range indications for neutrino masses. Under these circumstances we suspect that the sub-eV particles are created in a spacetime where gravitational effects of massive gauge bosons may become important. The question that we thus ask is: What is the spacetime group around a gravito-electroweak vertex? Modeling it as de-Sitter we find that sub-eV particles may carry a negative mass square of the order of [Formula: see text]. Neutrino oscillation data then hints at 30–75 TeV scale for M unif. , where M unif. characterizes gravito-electroweak unification scale.
SOME CONSEQUENCES OF A GENERALIZATION TO HEISENBERG ALGEBRA IN QUANTUM ELECTRODYNAMICS
Authors: CAMACHO A.
Published: December 2003

In this essay it will be shown that the introduction of a modification to Heisenberg algebra (here this feature means the existence of a minimal observable length), as a fundamental part of the quantization process of the electrodynamical field, renders states in which the uncertainties in the two quadrature components violate the usual Heisenberg uncertainty relation. Hence in this context it may be asserted that any physically realistic generalization of the uncertainty principle must include, not only a minimal observable length, but also a minimal observable momentum.
ANALYZING THE AGENT-BASED MODEL AND ITS IMPLICATIONS
Authors: LEON SUEMATSU YUTAKA I. , TAKADAMA KEIKI , NAWA NORBERTO E. , SHIMOHARA KATSUNORI , KATAI OSAMU
Published: December 2003

Agent-based models (ABMs) have been attracting the attention of researchers in the social sciences, becoming a prominent paradigm in the study of complex social systems. Although a great number of models have been proposed for studying a variety of social phenomena, no general agent design methodology is available. Moreover, it is difficult to validate the accuracy of these models. For this reason, we believe that some guidelines for ABMs design must be devised; therefore, this paper is a first attempt to analyze the levels of ABMs, identify and classify several aspects that should be considered when designing ABMs. Through our analysis, the following implications have been found: (1) there are two levels in designing ABMs: the individual level, related to the design of the agents' internal structure, and the collective level, which concerns the design of the agent society or macro-dynamics of the model; and (2) the mechanisms of these levels strongly affect the outcomes of the models.
A SIMULATION OF THE IMPACT OF MEDIA ON SOCIAL COHESION
Authors: STOCKER ROB , CORNFORTH DAVID , GREEN DAVID G.
Published: December 2003

One impact of the introduction of television, according to widely held views, is an undermining of traditional values and social organization. In this study, we simulate this process by representing social communication as a Random Boolean Network in which the individuals are nodes, and each node's state represents an opinion (yes/no) about some issue. Television is modelled as having a direct link to every node in the network. Two scenarios were considered. First, we found that, except in the most well connected networks, television rapidly breaks down cohesion (agreement in opinion). Second, the introduction of Hebbian learning leads to a polarizing effect : one subgroup strongly retains the original opinion, while a splinter group adopts the contrary opinion. The system displays criticality with respect to connectivity and the level of exposure to television. More generally, the results suggest that patterns of communication in networks can help to explain a wide variety of social phenomena.
EFFECTS OF COMMUNICATION ON GROUP LEARNING RATES IN A MULTI-AGENT ENVIRONMENT
Authors: DARBYSHIRE PAUL
Published: December 2003

Distillations utilize multi-agent based modeling and simulation techniques to study warfare as a complex adaptive system at the conceptual level. The focus is placed on the interactions between the agents to facilitate study of cause and effect between individual interactions and overall system behavior. Current distillations do not utilize machine-learning techniques to model the cognitive abilities of individual combatants but employ agent control paradigms to represent agents as highly instinctual entities. For a team of agents implementing a reinforcement-learning paradigm, the rate of learning is not sufficient for agents to adapt to this hostile environment. However, by allowing the agents to communicate their respective rewards for actions performed as the simulation progresses, the rate of learning can be increased sufficiently to significantly increase the teams chances of survival. This paper presents the results of trials to measure the success of a team-based approach to the reinforcement-learning problem in a distillation, using reward communication to increase learning rates.
Interferon Regulatory Factor-1 Mediates PPARγ-Induced Apoptosis in Vascular Smooth Muscle Cells
Authors: Lin Yiming , Zhu Xiaojun , Mclntee Farron L. , Xiao Hailian , Zhang Jifeng , Fu Mingui , Chen Yuqing E.
Published: December 2003

Objective—

Peroxisome proliferator-activated receptor γ (PPARγ) possesses general beneficial effects on the cardiovascular system, such as inhibition of vascular lesion formation and atherosclerosis. However, molecular mechanisms for these effects are yet to be fully defined. The aim of this study is to elucidate whether interferon regulatory factor-1 (IRF-1), a transcriptional factor with anti-proliferative and pro-apoptotic properties, mediates PPARγ-induced apoptosis in vascular smooth muscle cells (VSMCs).

Methods and Results—

Using Northern and Western blot analyses, we documented that PPARγ ligands, including ciglitazone, troglitazone, and GW7845, significantly increased IRF-1 expression in VSMCs; however, the PPARα ligand (Wy14643) and PPARδ ligand (GW0742) did not affect its expression. PPARγ-induced IRF-1 expression was abrogated by pretreatment with the PPARγ antagonist GW9662. In contrast, adenoviral expression of PPARγ in VSMCs dramatically increased IRF-1 level. Furthermore, PPARγ activation increased IRF-1 promoter activity but did not affect IRF-1 mRNA stability. Finally, reducing IRF-1 expression by antisense technology attenuated PPARγ-induced VSMC apoptosis through decreasing cyclin-dependent kinase inhibitor p21

cip1

and caspase-3 activity.

Conclusion—

Our data demonstrate that IRF-1 is a novel PPARγ target gene and mediates PPARγ-induced VSMC apoptosis.
Coronary Microvascular Endothelial Stunning After Acute Pressure Overload in the Conscious Dog Is Caused by Oxidant Processes
Authors: Kinugawa Shintaro , Post Heiner , Kaminski Pawel M. , Zhang Xiaoping , Xu Xiaobin , Huang Harer , Recchia Fabio A. , Ochoa Manuel , Wolin Michael S. , Kaley Gabor , Hintze Thomas H.
Published: December 2003

Background—

Few studies have examined the effect of acute pressure overload on endothelial function in the coronary microcirculation.

Methods and Results—

In instrumented conscious dogs with heart rate held constant, veratrine caused a cholinergic nitric oxide (NO)–dependent increase in coronary blood flow by 23±3 mL/min (Bezold-Jarisch reflex). Ten minutes after release of constriction of the ascending aorta to increase left ventricular (LV) systolic pressure to 214±5 mm Hg for 30 minutes, the veratrine-induced increase in coronary blood flow (7±1 mL/min) was reduced by 66% and remained depressed for 2 hours (ie, endothelial stunning [ES]). Nitrite production from isolated coronary microvessels during ES was not different from normal. Ascorbic acid (AA), losartan, or apocynin prevented ES. Myocardial oxygen consumption (MV̇
o
2
) of LV tissue was measured in vitro in response to bradykinin with preincubation of angiotensin II for 30 minutes. Bradykinin (10
−4
mol/L)–induced reduction in MV̇
o
2
was reversed in a concentration-dependent manner by angiotensin II (38±1% versus 19±2% at 10
−8
mol/L) and restored by coincubation of AA (37±2%), tempol (33±2%), losartan (34±2%), or apocynin (36±1%). Exogenous NO-induced reduction in MV̇
o
2
was not altered by angiotensin II. Angiotensin II increased lucigenin-detectable superoxide anion in LV tissue in a manner that was inhibited by bradykinin, AA, tempol, losartan, or apocynin.

Conclusions—

Endothelial stunning is caused by oxidant processes inhibited by ascorbate, and the activation of NAD(P)H oxidase by increased angiotensin II plays an important role in this process.
Catheter Ablation of Ventricular Fibrillation in Rabbit Ventricles Treated With β-Blockers
Authors: Pak Hui-Nam , Oh Yong-Seog , Liu Yen-Bin , Wu Tsu-Juey , Karagueuzian Hrayr S. , Lin Shien-Fong , Chen Peng-Sheng
Published: December 2003

Background—

A therapeutic implication of the focal-source hypothesis of ventricular fibrillation (VF) is that VF can be terminated by focal ablation. We hypothesize that β-adrenergic receptor blockade converts multiple-wavelet VF to focal-source VF and that this focal source is located near the papillary muscle (PM).

Methods and Results—

We used optical mapping techniques to study the effects of propranolol (0.3 mg/L) on VF dynamics in Langendorff-perfused rabbit hearts. The left ventricular (LV) anterior wall was mapped and optical action potential duration restitution (APDR) was determined at 25 epicardial sites. We performed ablation during VF of the left anterior PM in hearts with (N=6) or without (N=6) cytochalasin infusion, the LV lateral epicardium (Epi group, N=3), and the LV endocardium (Endo group, N=3). The PM was also ablated in 3 hearts without propranolol (control group). Propranolol converted multiple-wavelet VF to slow VF with reentry localized to the PM. Propranolol decreased the maximal slope of the APDR curve (
P
<0.001) as well as its spatial heterogeneity (
P
<0.01) and conduction velocity (
P
=0.01) while increasing the VF cycle length (
P
<0.001). PM ablation terminated VF during propropranolol infusion with (6 of 6, 100%) or without (4 of 6, 67%) cytochalasin D and significantly reduced inducibility. VF did not terminate in the Epi, Endo, and control groups (
P
<0.001).

Conclusions—

Propranolol flattens the APDR curve and reduces conduction velocity, converting multiple-wavelet VF into VF with a focal source anchored to the PM. Ablation of this focal source may terminate VF.
Role of the Posterior Left Atrium and Pulmonary Veins in Human Lone Atrial Fibrillation
Authors: Todd Derick M. , Skanes Allan C. , Guiraudon Gerard , Guiraudon Colette , Krahn Andrew D. , Yee Raymond , Klein George J.
Published: December 2003

Background—

Surgery can eliminate atrial fibrillation (AF), but data confirming the rationale for specific lesion sets are lacking. We used postoperative electrophysiological studies to test the rationale and effects of operative pulmonary venous isolation.

Methods and Results—

Fourteen patients undergoing surgical pulmonary venous isolation for drug-refractory lone AF were studied. Successful isolation was confirmed postoperatively in 13 of 14 patients. Spontaneous sustained AF was recorded from the isolated pulmonary venous region (PVR) in 4 and was induced by extrastimulus testing in another. The remaining atrial region (RAR) was in sinus rhythm in 13 patients and nonsustained AF in 1. Atrial extrastimulus testing and burst pacing in the RAR failed to induce sustained AF. In follow-up, 1 patient developed paroxysmal AF, and electrical continuity between the PVR and RAR was confirmed. Isolation was achieved with radiofrequency ablation with no further AF. Another patient developed typical atrial flutter that required ablation. AF has not recurred in any patient at 25.1±11.9 months (range, 6 to 56 months) after surgery. Atrial histopathology was consistent with tachycardia-induced changes.

Conclusions—

Total electrical isolation of the PVR controlled AF with excellent clinical outcome and appeared necessary for success. The isolated PVR can sustain spontaneous or induced AF, whereas the considerably larger RAR does not. These data provide a sound rationale for PVR in eliminating AF.
Angiotensin-Converting Enzyme Inhibition Alters the Fibrinolytic Response to Cardiopulmonary Bypass
Authors: Pretorius Mias , Murphey Laine J. , McFarlane Julie A. , Vaughan Douglas E. , Brown Nancy J.
Published: December 2003

Background—

Increased plasminogen activator inhibitor-1 (PAI-1) concentrations after coronary artery bypass grafting (CABG) are associated with increased risk of vein graft occlusion. Because angiotensin II stimulates PAI-1 expression, we tested the hypothesis that preoperative angiotensin-converting enzyme (ACE) inhibition decreases PAI-1 expression after CABG.

Methods and Results—

We measured the effects of cardiopulmonary bypass (CPB) on PAI-1 antigen and tissue-type plasminogen activator (tPA) antigen and activity in 31 patients taking an ACE inhibitor (ACEI) who were randomized to continue ACEI until the morning of surgery (ACEI group, n=19) or to discontinue it 48 hours before surgery (No-ACEI group, n=12). Arterial blood samples were taken at baseline before CPB, twice during CPB, after separation from CPB, and on postoperative day 1 (POD1). CPB caused an early decrease in PAI-1 antigen, followed by an increase in PAI-1 antigen on POD1 (
P
<0.001 for effect of time). ACE inhibition attenuated the increase in PAI-1 antigen such that both PAI-1 antigen on POD1 (
P
=0.013) and the change in PAI-1 antigen from baseline to POD1 (
P
=0.009) were higher in the No-ACEI group (from 17.0±5.0 to 48.7±8.8 ng/mL) versus the ACEI group (from 19.9±3.4 to 33.1±6.2 ng/mL). There was no significant difference between the 2 groups in intraoperative tPA activity (
P
=0.259); however, the increase in tPA activity was significantly greater in the ACEI group than in the No-ACEI group (
P
=0.030).

Conclusions—

Preoperative ACEI attenuates the increase in PAI-1 after CABG, suggesting a role for ACE inhibition in reducing the risk of acute graft thrombosis.
Determinants of Platelet Activation in Human Essential Hypertension
Authors: Minuz Pietro , Patrignani Paola , Gaino Stefania , Seta Francesca , Capone Marta L. , Tacconelli Stefania , Degan Maurizio , Faccini Giovanni , Fornasiero Anna , Talamini Giorgio , Tommasoli Rosamaria , Arosio Enrico , Santonastaso Clara Lechi , Lechi Alessandro , Patrono Carlo
Published: December 2003

Experimental data suggest that oxidative stress might be enhanced in hypertension and contribute to platelet activation. We hypothesized that both oxidative stress and platelet activation could be related to the clinical characteristics of hypertensive patients. The urinary excretion of 11-dehydrothromboxane (TX) B
2
, reflecting in vivo platelet activation, was measured in 75 patients with mild to severe essential hypertension and 75 pair-matched, healthy controls. The urinary excretion of 8-iso-prostaglandin (PG) F
2α
was determined as an index of in vivo lipid peroxidation. Urinary 11-dehydro-TXB
2
was significantly higher in essential hypertensives compared with controls. Although no statistically significant difference in urinary 8-iso-PGF
2α
was observed between patients and controls, plasma vitamin C was lower and plasma homocysteine higher in hypertensive patients than in controls. Both urinary 11-dehydro-TXB
2
and 8-iso-PGF
2α
were higher in patients with advanced hypertensive retinopathy compared with patients without retinopathy. Multivariate linear regression analysis identified urinary 8-iso-PGF
2α
, plasma fibrinogen, homocysteine, and vitamin E as the only variables independently correlated with urinary 11-dehydro-TXB
2
. Logistic regression analysis showed that high urinary 8-iso-PGF
2α
, plasma fibrinogen, and homocysteine, as well as low plasma vitamin E, advanced retinopathy, elevated diastolic blood pressure, and the absence of antihypertensive treatment, were predictors of high urinary 11-dehydro-TXB
2
. We demonstrated increased oxidative stress and persistent platelet activation in essential hypertensives with advanced vascular lesions. These findings might help identify hypertensive patients who are at increased risk of cardiovascular events and who might benefit from long-term antiplatelet therapy.