bluuebunny/crossref_metadata_2025 huggingface dataset:
XopC and XopJ, Two Novel Type III Effector Proteinsfrom
Xanthomonas campestris
pv.vesicatoria
Authors: Noël Laurent , Thieme Frank , Gäbler Jana , Büttner Daniela , Bonas Ulla
Published: December 2003

Pathogenicity
of the gram-negative plant pathogen
Xanthomonas campestris
pv.
vesicatoria depends on a type III secretion (TTS) system which
translocates bacterial effector proteins into the plant cell. Previous
transcriptome analysis identified a genome-wide regulon of putative
virulence genes that are coexpressed with the TTS system. In this
study, we characterized two of these genes,
xopC
and
xopJ
. Both genes encode
Xanthomonas
outer proteins
(Xops) that were shown to be secreted by the TTS system. In addition,
type III-dependent translocation of both proteins into the plant cell
was demonstrated using the AvrBs3 effector domain as a reporter. XopJ
belongs to the AvrRxv/YopJ family of effector proteins from plant and
animal pathogenic bacteria. By contrast, XopC does not share
significant homology to proteins in the database. Sequence analysis
revealed that the
xopC
locus contains several features that
are reminiscent of pathogenicity islands. Interestingly, the
xopC
region is flanked by 62-bp inverted repeats that are also
associated with members of the
Xanthomonas avrBs3
effector
family. Besides
xopC
, a second gene of the locus, designated
hpaJ
, was shown to be coexpressed with the TTS system.
hpaJ
encodes a protein with similarity to transglycosylases
and to the
Pseudomonas syringae
pv. maculicola protein
HopPmaG. HpaJ secretion and translocation by the
X. campestris
pv. vesicatoria TTS system was not detectable, which is consistent with
its predicted Sec signal and a putative function as transglycosylase in
the bacterial
periplasm.
FarRRegulates thefarAB-Encoded Efflux Pump ofNeisseriagonorrhoeaevia an MtrR RegulatoryMechanism
Authors: Lee E.-H. , Rouquette-Loughlin C. , Folster J. P. , Shafer W. M.
Published: December 2003

ThefarABoperon ofNeisseria gonorrhoeaeencodes an efflux pump which mediates gonococcal resistance to antibacterial fatty acids. It was previously observed that expression of thefarABoperon was positively regulated by MtrR, which is a repressor of themtrCDE-encoded efflux pump system (E.-H. Lee and W. M. Shafer, Mol. Microbiol. 33:839-845, 1999). This regulation was believed to be indirect since MtrR did not bind to thefarABpromoter. In this study, computer analysis of the gonococcal genome sequence database,lacZreporter fusions, and gel mobility shift assays were used to elucidate the regulatory mechanism by which expression of thefarABoperon is modulated by MtrR in gonococci. We identified a regulatory protein belonging to the MarR family of transcriptional repressors and found that it negatively controls expression offarABby directly binding to thefarABpromoter. We designated this regulator FarR to signify its role in regulating thefarABoperon. We found that MtrR binds to thefarRpromoter, thereby repressingfarRexpression. Hence, MtrR regulatesfarABin a positive fashion by modulatingfarRexpression. This MtrR regulatory cascade seems to play an important role in adjusting levels of the FarAB and MtrCDE efflux pumps to prevent their excess expression in gonococci.
Competence-Induced Cells ofStreptococcuspneumoniaeLyse Competence-Deficient Cells of the SameStrain duringCocultivation
Authors: Steinmoen Hilde , Teigen Aina , Håvarstein Leiv Sigve
Published: December 2003

Several streptococcal species are able to take up naked DNA from the environment and integrate it into their genomes by homologous recombination. This process is called natural transformation. InStreptococcus pneumoniaeand related streptococcal species, competence for natural transformation is induced by a peptide pheromone through a quorum-sensing mechanism. Recently we showed that induction of the competent state initiates lysis and release of DNA from a subfraction of the bacterial population and that the efficiency of this process is influenced by cell density. Here we have further investigated the nature of this cell density-dependent release mechanism. Interestingly, we found that competence-induced pneumococci lysed competence-deficient cells of the same strain during cocultivation and that the efficiency of this heterolysis increased as the ratio of competent to noncompetent cells increased. Furthermore, our results indicate that the lysins made by competent pneumococci are not released into the growth medium. More likely, they are anchored to the surface of the competent cells by choline-binding domains and cause lysis of noncompetent pneumococci through cell-to-cell contact.
Legume Symbiotic Nitrogen Fixation byβ-Proteobacteria Is Widespread inNature
Authors: Chen Wen-Ming , Moulin Lionel , Bontemps Cyril , Vandamme Peter , Béna Gilles , Boivin-Masson Catherine
Published: December 2003

Following
the initial discovery of two legume-nodulating
Burkholderia
strains (L. Moulin, A. Munive, B. Dreyfus, and C.
Boivin-Masson, Nature 411:948-950, 2001), we identified as
nitrogen-fixing legume symbionts at least 50 different strains of
Burkholderia caribensis
and
Ralstonia
taiwanensis
, all belonging to the β-subclass of
proteobacteria, thus extending the phylogenetic diversity of the
rhizobia.
R. taiwanensis
was found to represent
93% of the
Mimosa
isolates in Taiwan, indicating thatβ
-proteobacteria can be the specific symbionts of a legume. The
nod
genes of rhizobial β-proteobacteria
(β-rhizobia) are very similar to those of rhizobia from theα
-subclass (α-rhizobia), strongly supporting the
hypothesis of the unique origin of common
nod
genes. Theβ
-rhizobial
nod
genes are located on a 0.5-Mb plasmid,
together with the
nifH
gene, in
R
.
taiwanensis
and
Burkholderia phymatum
.
Phylogenetic analysis of available
nodA
gene sequences
clustered β-rhizobial sequences in two
nodA
lineages
intertwined with α-rhizobial sequences. On the other hand, theβ
-rhizobia were grouped with free-living nitrogen-fixingβ
-proteobacteria on the basis of the
nifH
phylogenetic
tree. These findings suggest that β-rhizobia evolved from
diazotrophs through multiple lateral
nod
gene
transfers.
TheStreptomyces coelicolorPolynucleotide PhosphorylaseHomologue, and Not the Putative Poly(A) Polymerase, CanPolyadenylateRNA
Authors: Sohlberg Björn , Huang Jianqiang , Cohen Stanley N.
Published: December 2003

A protein containing a nucleotidyltransferase motif characteristic of poly(A) polymerases has been proposed to polyadenylate RNA inStreptomyces coelicolor(P. Bralley and G. H. Jones, Mol. Microbiol.40:1155-1164, 2001). We show that this protein lacks poly(A) polymerase activity and is instead a tRNA nucleotidyltransferase that repairs CCA ends of tRNAs. In contrast, aStreptomyces coelicolorpolynucleotide phosphorylase homologue that exhibits polyadenylation activity may account for the poly(A) tails found in this organism.
Differencesin Genetic and Transcriptional Organization of theglpTQOperons betweenHaemophilus influenzaeType b andNontypeableStrains
Authors: Song Xin-Ming , Janson Håkan
Published: December 2003

TheglpTQoperon ofHaemophilus influenzaetype b (Hib) and nontypeableH. influenzae(NTHi) strains is highly conserved, except for a 1.4-kbglpTQintergenic region that was found in most Hib strains. The presence of this intergenic region results in divergentglpTQtranscriptional profiles for Hib and NTHi where Hib strains appear to have evolved an alternative promoter forglpQexpression. Based on the intergenic region's low G+C content, we speculate that this DNA fragment was acquired by lateral transfer.
ACTION BASED APPROACH TO THE DYNAMICS OF EXTENDED BODIES IN GENERAL RELATIVITY
Authors: ANANDAN JEEVA , DADHICH NARESH , SINGH PARAMPREET
Published: December 2003

We present, for the first time, an action principle that gives the equations of motion of an extended body possessing multipole moments in an external gravitational field, in the weak field limit. From the action, the experimentally observable quantum phase shifts in the wavefunction of an extended object due to the coupling of its multipole moments with the gravitational field are obtained. Also, since the theory may be quantized using the action, the present approach is useful in the interface between general relativity and quantum mechanics.
COSMIC BLACK HOLES
Authors: AHN EUN-JOO , CAVAGLIÀ MARCO
Published: December 2003

Production of high-energy gravitational objects is a common feature of gravitational theories. The primordial universe is a natural setting for the creation of black holes and other nonperturbative gravitational entities. Cosmic black holes can be used to probe physical properties of the very early universe which would usually require the knowledge of the theory of quantum gravity. They may be the only tool to explore thermalization of the early universe. Whereas the creation of cosmic black holes was active in the past, it seems to be negligible at the present epoch.
VARIABILITY OF FUNDAMENTAL CONSTANTS
Authors: PERES ASHER
Published: December 2003

Are universal fundamental constants really constant over cosmological times? Recent observations of the fine structure of spectral lines in the early universe have been interpreted as due to a variation of the fine structure constant e2/4πε0ℏc. From the assumed validity of Maxwell equations in general relativity and well known experimental facts, it is proved that e and ℏ are absolute constants. On the other hand, the speed of light need not be constant.
THE BUBBLING UNIVERSE
Authors: VACHASPATI TANMAY
Published: December 2003

The scenario of an expanding universe envisioned in the early part of the 20th century has been replaced by one where we live in a chaotic, eternally bubbling universe. Every bubble has the potential for developing into a new habitable universe. In this essay I describe how large-scale quantum effects could be driving the chaotic bubbling universe.
PROPOSAL OF A SECOND GENERATION OF QUANTUM-GRAVITY-MOTIVATED LORENTZ-SYMMETRY TESTS: SENSITIVITY TO EFFECTS SUPPRESSED QUADRATICALLY BY THE PLANCK SCALE
Authors: AMELINO-CAMELIA GIOVANNI
Published: December 2003

Over the last few years the study of possible Planck-scale departures from classical Lorentz symmetry has been one of the most active areas of quantum-gravity research. We now have a satisfactory description of the fate of Lorentz symmetry in the most popular noncommutative spacetimes and several studies have been devoted to the fate of Lorentz symmetry in loop quantum gravity. Remarkably there are planned experiments with enough sensitivity to reveal these quantum-spacetime effects, if their magnitude is only linearly suppressed by the Planck length. Unfortunately, in some quantum-gravity scenarios even the strongest quantum-spacetime effects are suppressed by at least two powers of the Planck length, and many authors have argued that it would be impossible to test these quadratically-suppressed effects. I here observe that advanced cosmic-ray observatories and neutrino observatories can provide the first elements of an experimental programme testing the possibility of departures from Lorentz symmetry that are quadratically Planck-length suppressed.
THE NEW PLANCK SCALE: QUANTIZED SPIN AND CHARGE COUPLED TO GRAVITY
Authors: COOPERSTOCK F. I. , FARAONI V.
Published: December 2003

In the standard approach to defining a Planck scale where gravity is brought into the quantum domain, the Schwarzschild gravitational radius is set equal to the Compton wavelength. However, ignored thereby are the charge and spin, the fundamental quantized aspects of matter. The gravitational and null-surface radii of the Kerr–Newman metric are used to introduce spin and charge into a new extended Planck scale. The fine structure constant appears in the extended Planck mass and the recent discovery of the α variation with the evolution of the universe adds further significance. An extended Planck charge and Planck spin are derived. There is an intriguing suggestion of a connection with the α value governing high-energy radiation in Z-boson production and decay.
MASS, PARTICLES AND WAVES IN HIGHER DIMENSIONS
Authors: WESSON PAUL S.
Published: December 2003

Using 5D membrane/induced-matter theory as a basis, we derive the equations of motion for a novel gauge. The latter admits both particle and wave behaviour, as well as super-communication (wherein there is causal contact in the higher-dimensional manifold among points which are disjoint in spacetime). Possible ways to test this model are suggested, notably using particle mass.
ON THE VACUUM ENTROPY AND THE COSMOLOGICAL CONSTANT
Authors: CARNEIRO SAULO
Published: December 2003

It is generally accepted that the entropy of an asymptotically de Sitter universe is bounded by the area, in Planck units, of the de Sitter horizon. Based on an analysis of the entropy associated to the vacuum quantum fluctuations, we suggest that the existence of such a holographic bound constitutes a possible explanation for the observed value of the cosmological constant, theoretically justifying a relation proposed 35 years ago by Zel'dovich.
HOLOGRAPHIC BOUNDS ON HILBERT SPACE
Authors: CROWELL LAWRENCE B.
Published: December 2003

The size of Hilbert space for quantum gravity is examined in the light of the holographic principle. The fluctuation of lengths results in a bound on the amount of quantum information that may exist in a volume of space, and prevent divergences at the Planck energy.
WMAPing THE UNIVERSE: SUPERSYMMETRY, DARK MATTER, DARK ENERGY, PROTON DECAY AND COLLIDER PHYSICS
Authors: LAHANAS A. B. , MAVROMATOS N. E. , NANOPOULOS D. V.
Published: December 2003

In this review we critically discuss constraints on minimal supersymmetric models of particle physics as implied by the recent astrophysical observations of WMAP satellite experiment. Although the prospects of detecting supersymmetry increase dramatically, at least within the context of the minimal models, and 90% of the available parameter space can safely be reached by the sensitivity of future colliders, such as Tevatron, LHC and linear colliders, nevertheless we pay particular emphasis on discussing regions of the appropriate phase diagrams, which — if realized in nature — would imply that detection of supersymmetry, at least in the context of minimal models, could be out of colliders reach. We also discuss the importance of a precise determination of the radiative corrections to the muon anomalous magnetic moment, gμ-2, both theoretically and experimentally, which could lead to elimination of such "out of reach" regions in case of a confirmed discrepancy of gμ-2 from the standard model value. Finally, we briefly commend upon recent evidence, supported by observations, on a dark energy component of the Universe, of as yet unknown origin, covering 73% of its energy content. To be specific, we discuss how supergravity quintessence (relaxation) models can be made consistent with recent observations, which may lead to phenomenologically correct constrained supersymmetric models, accounting properly for this dark energy component. We also outline their unresolved problems.
BRANE-PRODUCTION AND THE NEUTRINO–NUCLEON CROSS SECTION AT ULTRAHIGH ENERGIES IN LOW SCALE GRAVITY MODELS
Authors: JAIN PANKAJ , KAR SUPRIYA , PANDA SUKANTA
Published: December 2003

The observed ultrahigh energy cosmic rays (UHECR) might require a modification of the basic laws of physics. In low scale gravity models, where the neutrino–nucleon cross section rises to typical hadronic values at energies above 1020 eV, the neutrino becomes a candidate for the primary that initiates these showers. We calculate the neutrino–nucleon cross section at ultrahigh energies by assuming that it is dominated by the production of p-branes. We show, using a generalized Randall–Sundrum model, that the neutrino–nucleon cross-section at neutrino energies of 1020 eV is of the order of 100 mb, which is required for explaining the UHECR events. Similar results also follow in other models such as the Lykken–Randall model.
COSMOLOGICAL MODELS GENERALIZING ROBERTSON–WALKER MODELS
Authors: ABDUSSATTAR
Published: December 2003

Considering the physical 3-space t= constant of the space–time metrics as spheroidal and pseudo-spheroidal, cosmological models which are generalizations of Robertson–Walker models are obtained. Specific forms of these general models as solutions of Einstein's field equations are also discussed in the radiation and the matter dominated era of the universe.
COMPLEX DYNAMICS AND FINANCIAL FRAGILITY IN AN AGENT-BASED MODEL
Authors: GALLEGATI MAURO , GIULIONI GIANFRANCO , KICHIJI NOZOMI
Published: December 2003

We model an agent-based economy in which heterogeneous agents (firms and a bank) interact in the financial markets. The heterogeneity is due to the balance sheet conditions and to size. In our simulations, at the aggregate level, output displays changes in trend and volatility giving rise to complex dynamics. The average solvency and liquidity ratios peak during recessions as empirical analysis shows. At the firm level the model generates: (i) firm sizes left-skewed distributed, (ii) growth rates Laplace distributed. Furthermore, small idiosyncratic shocks can generate large aggregate fluctuations.
EMPIRICAL LAWS OF A STOCK PRICE INDEX AND A STOCHASTIC MODEL
Authors: KAIZOJI TAISEI , KAIZOJI MICHIYO
Published: December 2003

Recent works by econo-physicists [5,8,15,19] have shown that the probability function of the share returns and the volatility satisfies a power law with an exponent close to 4. On the other hand, we investigated quantitatively the return and the volatility of the daily data of the Nikkei 225 index from 1990 to 2003, and we found that the distributions of the returns and the volatility can be accurately described by the exponential distributions [11]. We then propose a stochastic model of stock markets that can reproduce these empirical laws. In our model the fluctuations of stock prices are caused by interactions among traders. We indicate that the model can reproduce the empirical facts mentioned above. In particular, we show that the interaction strengths among traders are a key variable that can distinguish the emergence of the exponential distribution or the power-law distribution.
INTERACTING TV VIEWERS: A CASE OF EMPIRICAL AGENT-BASED MODELING AND SIMULATION FOR BUSINESS APPLICATION
Authors: MIZUNO MAKOTO , NISHIYAMA NAOKI
Published: December 2003

For business applications of agent-based modeling and simulation, we should formulate rules for individual agents that are more realistic than those required by the KISS principle. This idea could be referred to as "empirical agent-based modeling." In order to develop such models, the first step could possibly be to apply well-established behavioral modeling to individuals/organizations and then link them incorporating interactions between those agents. As an illustrative work, we will present the modeling of TV viewing behavior including interactions in each family, each demographic segment and each reference group.
RE-FORMATION OF MOBILE AGENTS STRUCTURE BY THE SYNCHRONIZATION OF COUPLED CHAOTIC OSCILLATORS
Authors: KUBO MASAO , SASAKABE YOSHIYUKI
Published: December 2003

A new equation system (based on synchronization of coupled chaotic oscillators) is proposed for bringing autonomous mobile agents into formation. Chaotic itinerancy of the oscillators is used to generate the re-formation. Sannomiya's fish simulator is applied to test the system behavior and the re-formation performance was verified using trajectory and quantitative measures.
A CAFÉ CHOICE PROBLEM AS AN EXTENDED ARTHUR'S EL FAROL PROBLEM
Authors: NAKAYAMA SHOICHIRO
Published: December 2003

In this study, a café choice problem, which is an extension of Arthur's El Farol problem, is formulated, and is examined by an agent-based simulation. In the café choice problem, N agents predict a café's "congestion," and determine which café to visit. The N agents prefer less congested cafés because they are more relaxing. The agent is assumed to know the state of congestion of only the café he visits, and he learns to predict the café's congestion. The simulation results can be summarized as follows: (i) the agent is not necessarily acquiring the correct cognition for the café's congestion, even though sufficient time goes by; (ii) the agents are bifurcated into two groups which consist of agents with cognitions that the congestion of the café they do not visit is significantly more congested than the actual congestion; and (iii) the system does not necessarily converge to a Nash equilibrium, which is a theoretical solution, when the system's structure changes.
Tissue-Specific Utilization of Menaquinone-4 Results in the Prevention of Arterial Calcification in Warfarin-Treated Rats
Authors: Spronk H.M.H. , Soute B.A.M. , Schurgers L.J. , Thijssen H.H.W. , De Mey J.G.R. , Vermeer C.
Published: December 2003

The effects of vitamin K (phylloquinone: K1 and menaquinone-4: MK-4) on vascular calcification and their utilization in the arterial vessel wall were compared in the warfarin-treated rat model for arterial calcification. Warfarin-treated rats were fed diets containing K1, MK-4, or both. Both K1 and MK-4 are cofactors for the endoplasmic reticulum enzyme γ-glutamyl carboxylase but have a structurally different aliphatic side chain. Despite their similar in vitro cofactor activity we show that MK-4 and not K1 inhibits warfarin-induced arterial calcification. The total hepatic K1 accumulation was threefold higher than that of MK-4, whereas aortic MK-4 was three times that of K1. The utilization of K1 and MK-4 in various tissues was estimated by calculating the ratios between accumulated quinone and epoxide species. K1 and MK-4 were both equally utilized in the liver, but the aorta showed a more efficient utilization of MK-4. Therefore, the observed differences between K1 and MK-4 with respect to inhibition of arterial calcification may be explained by both differences in their tissue bioavailability and cofactor utilization in the reductase/carboxylase reaction. An alternative explanation may come from an as yet hypothetical function of the geranylgeranyl side chain of MK-4, which is a structural analogue of geranylgeranyl pyrophosphate and could interfere with a critical step in the mevalonate pathway.
Influence of γ′ Fibrinogen Splice Variant on Fibrin Physical Properties and Fibrinolysis Rate
Authors: Collet J.P. , Nagaswami C. , Farrell D.H. , Montalescot G. , Weisel J.W.
Published: December 2003

Objective—

A splice variant of fibrinogen, γ′, has an altered C-terminal sequence in its gamma chain. This γA/γ′ fibrin is more resistant to lysis than γA/γA fibrin. Whether the physical properties of γ′ and γA fibrin may account for the difference in their fibrinolysis rate remains to be established.

Methods and Results—

Mechanical and morphological properties of cross-linked purified fibrin, including permeability (Ks, in cm
2
) and clot stiffness (G′, in dyne/cm
2
), were measured after clotting γA and γ′ fibrinogens (1 mg/mL). γ′/γ′ fibrin displayed a non-significant decrease in the density of fibrin fibers and slightly thicker fibers than γA/γA fibrin (12±2 fiber/10
−3
nm
3
versus 16±2 fiber/10
−3
nm
3
and 274±38 nm versus 257±41 nm for γ′/γ′ and γA/γA fibrin, respectively;
P
=NS). This resulted in a 20% increase of the permeability constant (6.9±1.7 10
−9
cm
2
versus 5.5±1.9 10
−9
cm
2
, respectively;
P
=NS). Unexpectedly, γ′ fibrin was found to be 3-times stiffer than γA fibrin (72.6±2.6 dyne/cm
2
versus 25.1±2.3 dyne/cm
2
;
P
<0.001). Finally, there was a 10-fold decrease of the fibrin fiber lysis rate.

Conclusions—

Fibrinolysis resistance that arises from the presence of γA/γ′ fibrinogen in the clot is related primarily to an increase of fibrin cross-linking with only slight modifications of the clot architecture.
Magnetic Resonance Fluoroscopy Allows Targeted Delivery of Mesenchymal Stem Cells to Infarct Borders in Swine
Authors: Dick Alexander J. , Guttman Michael A. , Raman Venkatesh K. , Peters Dana C. , Pessanha Breno S.S. , Hill Jonathan M. , Smith Scott , Scott Greig , McVeigh Elliot R. , Lederman Robert J.
Published: December 2003

Background—

The local environment of delivered mesenchymal stem cells (MSCs) may affect their ultimate phenotype. MR fluoroscopy has the potential to guide intramyocardial MSC injection to desirable targets, such as the border between infarcted and normal tissue. We tested the ability to (1) identify infarcts, (2) navigate injection catheters to preselected targets, (3) inject safely even into fresh infarcts, and (4) confirm injection success immediately.

Methods and Results—

A 1.5-T MRI scanner was customized for interventional use, with rapid imaging, independent color highlighting of catheter channels, multiple-slice 3D rendering, catheter-only viewing mode, and infarct-enhanced imaging. MRI receiver coils were incorporated into guiding catheters and injection needles. These devices were tested for heating and used for targeted MSC delivery. In infarcted pigs, myocardium was targeted by MR fluoroscopy. Infarct-enhanced imaging included both saturation preparation MRI after intravenous gadolinium and wall motion. Porcine MSCs were MRI-labeled with iron-fluorescent particles. Catheter navigation and multiple cell injections were performed entirely with MR fluoroscopy at 8 frames/s with 1.7×3.3×8-mm voxels. Infarct-enhanced MR fluoroscopy permitted excellent delineation of infarct borders. All injections were safely and successfully delivered to their preselected targets, including infarct borders. Iron-fluorescent particle–labeled MSCs were readily visible on delivery in vivo and post mortem.

Conclusions—

Precise targeted delivery of potentially regenerative cellular treatments to recent myocardial infarction borders is feasible with an MR catheter delivery system. MR fluoroscopy permits visualization of catheter navigation, myocardial function, infarct borders, and labeled cells after injection.
Endothelial Replacement and Angiogenesis in Arteriosclerotic Lesions of Allografts Are Contributed by Circulating Progenitor Cells
Authors: Hu Yanhua , Davison Fergus , Zhang Zhongyi , Xu Qingbo
Published: December 2003

Background—

Endothelial regeneration and angiogenesis in the intima of the arterial wall are key events in the pathogenesis of transplantation arteriosclerosis. The traditional hypothesis that damaged endothelial cells are replaced by remaining cells of the donor vessel has been challenged by recent observations, but the cell origins of large arteries and microvessels are still not well established.

Methods and Results—

Aortic segments were allografted between Balb/c and TIE2-LacZ (C57BL/6) mice expressing β-galactosidase (gal) in endothelial cells. β-gal+ cells in TIE2-LacZ vessels grafted to Balb/c mice completely disappeared, whereas the positive cells found in Balb/c aorta allografted into TIE2-LacZ mice 4 weeks after surgery indicated a host origin. En face analysis of allograft vessels displayed a unique distribution of β-gal+ cells on the surface at 3 days, 1 week, and 4 weeks. Interestingly, 35±19% β-gal+ cells were found in arterial segments allografted into chimeric mice with TIE2-LacZ bone marrows. Furthermore, endothelial cells of microvessels within allografts had a β-gal+ staining in the media at 1 week and in the neointimal lesions and adventitia at 4 weeks. Allograft studies in chimeric mice demonstrated that β-gal+ cells of microvessels in transplant arteriosclerosis were derived from bone marrow progenitors.

Conclusions—

We provide strong evidence that endothelial cells of neointimal lesions in allografts are derived from circulating progenitor cells and that bone marrow–derived progenitors are responsible for angiogenesis of the allograft, that is, the formation of microvessels in transplant arteriosclerosis.
Involvement of Tissue Factor Pathway Inhibitor in the Coronary Circulation of Patients With Acute Coronary Syndromes
Authors: Golino Paolo , Ravera Amelia , Ragni Massimo , Cirillo Plinio , Piro Orlando , Chiariello Massimo
Published: December 2003

Background—

Tissue factor pathway inhibitor (TFPI) is the endogenous inhibitor of the extrinsic coagulation pathway; however, its involvement during thrombus formation in patients with acute coronary syndromes (ACS) is still unknown.

Methods and Results—

Transcardiac (aorta/coronary sinus) free and total TFPI (free + lipoprotein-bound form) levels, as well as TFPI/factor Xa (FXa) complex levels, were measured in plasma samples obtained from patients with acute myocardial infarction undergoing primary PTCA and patients with unstable angina undergoing urgent PTCA. Patients with stable angina undergoing elective PTCA served as controls. In addition, prothrombin fragment 1+2 and fibrinopeptide A plasma levels were measured. Samples were collected at baseline, after PTCA, and after stent deployment. In patients with ACS, both total and free TFPI plasma levels in the coronary sinus were significantly lower than the corresponding levels measured in the aorta at any time point of the study; conversely, a significant increase in TFPI/FXa complex plasma levels was observed in the coronary sinus as compared with the aorta. In contrast, in patients with stable angina, no differences were observed in TFPI and TFPI/FXa levels at baseline in the coronary sinus as compared with the aorta.

Conclusions—

TFPI is involved in the process of thrombus formation in vivo in patients with ACS, which suggests a potential role for TFPI in modulating coronary thrombosis.
Transplantation of Bone Marrow–Derived Mononuclear Cells in Ischemic Apolipoprotein E–Knockout Mice Accelerates Atherosclerosis Without Altering Plaque Composition
Authors: Silvestre Jean-Sébastien , Gojova Andrea , Brun Valérie , Potteaux Stéphane , Esposito Bruno , Duriez Micheline , Clergue Michel , Le Ricousse-Roussanne Sophie , Barateau Véronique , Merval Régine , Groux Hervé , Tobelem Gérard , Levy Bernard , Tedgui Alain , Mallat Ziad
Published: December 2003

Background—

Bone marrow–derived mononuclear cells (BM-MNCs) enhance postischemic neovascularization, and their therapeutic use is currently under clinical investigation. We evaluated the safety of BM-MNC–based therapy in the setting of atherosclerosis.

Methods and Results—

Apolipoprotein E (apoE)–knockout (KO) mice were divided into 4 groups: 20 nonischemic mice receiving intravenous injection of either saline (n=10) or 10
6
BM-MNCs from wild-type animals (n=10) and 20 mice with arterial femoral ligature receiving intravenous injection of either saline (n=10) or 10
6
BM-MNCs from wild-type animals (n=10) at the time of ischemia induction. Animals were monitored for 4 additional weeks. Atherosclerosis was evaluated in the aortic sinus. BM-MNC transplantation improved tissue neovascularization in ischemic hind limbs, as revealed by the 210% increase in angiography score (
P
<0.0001), the 33% increase in capillary density (
P
=0.01), and the 65% increase in tissue Doppler perfusion score (
P
=0.0002). Hindlimb ischemia without BM-MNC transplantation or BM-MNC transplantation without ischemia did not affect atherosclerotic plaque size. However, transplantation of 10
6
BM-MNCs into apoE-KO mice with hindlimb ischemia induced a significant 48% to 72% increase in lesion size compared with the other 3 groups (
P
=0.0025), despite similar total cholesterol levels. Transplantation of 10
5
BM-MNCs produced similar results, whereas transplantation of 10
6
apoE-KO–derived BM-MNCs had neither proangiogenic nor proatherogenic effects. There was no difference in plaque composition between groups.

Conclusions—

BM-MNC therapy is unlikely to affect atherosclerotic plaque stability in the short term. However, it may promote further atherosclerotic plaque progression in an ischemic setting.
Alpha
2
-Adrenergic Receptor–Induced Vascular Constriction in Blacks and Whites
Authors: Muszkat Mordechai , Sofowora Gbenga G. , Wood Alastair J.J. , Stein C. Michael
Published: December 2003

Black Americans have a reduced hypotensive response to the α
2
-adrenergic receptor agonist clonidine compared with whites, despite similar central sympathoinhibition. This reduced hypotensive response might be explained by greater postsynaptic vascular α
2
-adrenergic receptor vasoconstrictive response. However, clonidine has a low α
2
/α
1
selectivity ratio. Therefore, to determine the role of altered α
2
-adrenergic receptor vascular sensitivity in ethnic differences in vascular response, we compared local vascular responses with the highly selective α
2
-adrenergic receptor agonist dexmedetomidine in healthy black (n=18) and white (n=19) subjects. Increasing doses of dexmedetomidine (0.001 to 1000 ng/min) were infused into a dorsal hand vein, and the local response was measured with a linear variable differential transformer. Dexmedetomidine caused pronounced venoconstriction, with an average (±SD) maximum response of 74.5±17.72% but with no difference between blacks and whites. There was substantial intersubject variability in the sensitivity to dexmedetomidine; the dose resulting in 50% (ED
50
) of maximum vasoconstriction ranged from 0.08 ng/min to 256 ng/min. The geometric mean ED
50
was 2.28 ng/min (95% CI, 0.02 to 271.6 ng/min) in blacks and 1.58 ng/min (95% CI, 0.11 to 24.55 ng/min) in whites (
P
=0.59). Our data indicate that α
2
-adrenergic receptor–induced venoconstriction is similar in blacks and whites. These findings do not support the hypothesis that altered α
2
-adrenergic receptor sensitivity is the explanation for the decreased blood pressure response to systemic administration of clonidine in blacks. The response to dexmedetomidine provides a model that will allow further study of the regulation of α
2
-adrenergic receptor–mediated vascular responses
Enhanced Vascular Activity of Endogenous Endothelin-1 in Obese Hypertensive Patients
Authors: Cardillo Carmine , Campia Umberto , Iantorno Micaela , Panza Julio A.
Published: December 2003

Hypertensive patients have increased endothelin-1–dependent vasoconstrictor tone. This abnormality, however, might not be uniformly present in all forms of hypertension, as suggested by experimental studies showing that endothelin-1 activity is enhanced predominantly in low-renin, high-volume models and in insulin-resistant states. Because hypertension in obesity is commonly associated with both expanded plasma volume and insulin resistance, this study sought to determine whether increased body mass index (BMI) in hypertensive patients relates to activation of the endothelin-1 system. Forearm blood flow (FBF) responses (plethysmography) to intra-arterial infusion of an ET
A
receptor blocker (BQ-123) were analyzed in hypertensive patients and normotensive control subjects according to BMI. The vasodilator response to BQ-123 was significantly higher in hypertensive patients than in control subjects (
P
<0.001). During BQ-123, a significant increase in FBF from baseline was observed in obese (BMI ≥30 kg/m
2
;
P
<0.001) and overweight (BMI, 27 to 29.9 kg/m
2
;
P
=0.04) but not in lean (BMI <27 kg/m
2
;
P
=0.83) hypertensive patients. In contrast, no significant change in FBF was observed during BQ-123 either in obese (
P
=0.53), overweight (
P
=0.76), or lean (
P
=0.93) normotensive subjects. Moreover, a significant correlation between BMI and the vasodilator response to ET
A
blockade was observed in hypertensive subjects (
R
=0.53;
P
=0.005) but not in control subjects (
R
=0.11;
P
=0.58). In human hypertension, increased BMI is associated with enhanced ET
A
-dependent vasoconstrictor activity, suggesting that this abnormality may play a role in the pathophysiology of obesity-related hypertension and that targeting the endothelin-1 system may be useful in the treatment of these patients.
Amino-Terminal Pro–C-Type Natriuretic Peptide in Heart Failure
Authors: Wright Sue P. , Prickett Tim C.R. , Doughty Robert N. , Frampton Chris , Gamble Greg D. , Yandle Tim G. , Sharpe Norman , Richards Mark
Published: December 2003

The levels and pathophysiological role of amino terminal C-type natriuretic peptide in heart failure are unknown. The potential of plasma amino-terminal C-type natriuretic peptide (N-CNP) as a marker of cardiac function was investigated in symptomatic patients. In 305 patients with recent-onset dyspnea and/or peripheral edema, presenting to primary care, assay of plasma amino-terminal C-type natriuretic peptide and other plasma vasoactive hormones was conducted together with echocardiography. Heart failure was diagnosed in 77 (of the 305) patients by rigorous application of predefined criteria. Plasma amino-terminal C-type natriuretic peptide concentrations were elevated in patients with heart failure, and by univariate analysis were related to age, renal function, and other hormones. On multivariate analysis, tertile of plasma N-CNP interacted with tertile of plasma amino-terminal B-type natriuretic peptide to predict heart failure independent of age, gender, renal function, or echocardiographic left ventricular fractional shortening. N-CNP showed significant relations to concurrent plasma CNP, atrial natriuretic peptide (ANP), N-ANP, B-type (or brain) natriuretic peptide (BNP), N-BNP, endothelin-1, and adrenomedullin but not to echocardiographic indicators of left ventricular systolic function. Plasma amino-terminal C-type natriuretic peptide is elevated in heart failure and is related to other plasma hormones in heart failure. These findings suggest a possible compensatory response from the peripheral vasculature to heart failure by an endothelium-based vasodilator peptide and mandate further exploration of the role of C-type natriuretic peptide in this condition.
Hypersensitivity of the Adrenal Cortex to Trophic and Secretory Effects of Angiotensin II in Lyon Genetically-Hypertensive Rats
Authors: Aguilar Frédérick , Lo Ming , Claustrat Bruno , Saez José Maria , Sassard Jean , Li Jacques Yuan
Published: December 2003

In Lyon hypertensive (LH) rats, a model of low-renin genetic hypertension, we investigated adrenal sensitivity to angiotensin II in terms of angiotensin II receptor (AT
1
and AT
2
receptors) regulation, morphological changes, and aldosterone and corticosterone secretion. Twelve-week-old LH rats, compared with normotensive LN and LL rats, were either untreated or treated for 4 weeks with AT
1
receptor antagonist irbesartan (50 mg/kg/d), angiotensin-converting enzyme inhibitor perindopril (3 mg/kg/d), or perindopril (3 mg/kg/d) plus angiotensin II infusion (200 ng/kg/min). At 16 weeks, untreated LH rats had high systolic blood pressure (
P
<0.05), low aldosterone (
P
<0.05), and increased corticosterone (
P
<0.05) plasma levels. AT
1
-receptor binding density in the zona glomerulosa was similar in the three strains. In LH rats, angiotensin II infusion increased the relative adrenal weight from 10.5±0.3 to 16.7±0.7 mg/100g (
P
<0.05), whereas this change was very modest in normotensive rats. Zona glomerulosa enlarged and plasma aldosterone increased after angiotensin II infusion in the 3 strains, but more markedly in LH versus normotensive rats (2.4- versus 1.3- and 1.6-fold, respectively; 20- versus 10-fold in normotensive rats,
P
<0.05). Surprisingly, after angiotensin II infusion, despite the absence of angiotensin II receptors in the three strains, the zona fasciculata-reticularis enlarged 1.5-fold and plasma corticosterone increased 1.7-fold only in LH rats (
P
<0.05), suggesting an indirect control of this compartment by angiotensin II. The hypertrophy and hypersecretory activity of both zona glomerulosa and zona fasciculata-reticularis in LH rats in response to angiotensin II point to the adrenal cortex as a pivotal tissue in the pathophysiology of hypertension in LH rats.
Relationship of Physical Activity and Body Mass Index to the Risk of Hypertension: A Prospective Study in Finland
Authors: Hu Gang , Barengo Noël C. , Tuomilehto Jaakko , Lakka Timo A. , Nissinen Aulikki , Jousilahti Pekka
Published: December 2003

Prospective studies on physical activity in relation to the risk for hypertension are scant, particularly in women. This study aimed at finding out whether regular physical activity can reduce the risk of hypertension in both men and women, and in subjects with and without overweight. We prospectively followed 8302 Finnish men and 9139 women aged 25 to 64 years without a history of antihypertensive drug use, coronary heart disease, stroke, and heart failure at baseline. Both single and joint associations of physical activity and body mass index with the risk of hypertension were examined using Cox proportional hazard models. During a mean followup of 11 years, there were 1600 incident cases of drug-treated hypertension. Multivariate-adjusted hazards ratios of hypertension associated with light, moderate, and high physical activity were 1.00, 0.63, and 0.59 in men (
P
trend
<0.001), and 1.00, 0.82, and 0.71 in women (
P
trend
=0.005), respectively. This association persisted both in subjects who were overweight and in those who were not. Multivariate-adjusted hazards ratios of hypertension based at different levels of body mass index (<25, 25 to 29.9, and ≥30) were 1.00, 1.18, and 1.66 for men (
P
trend
<0.001), and 1.00, 1.24, and 1.32 for women (
P
trend
=0.007), respectively. Further adjustment for baseline systolic blood pressure did not affect the protective effect associated with physical activity, but it weakened markedly the association between body mass index and hypertension. The present study indicates that regular physical activity and weight control can reduce the risk of hypertension. The protective effect of physical activity was observed in both sexes regardless of the level of obesity.
Agonist-Induced Activation of Matrix Metalloproteinase-7 Promotes Vasoconstriction Through the Epidermal Growth Factor–Receptor Pathway
Authors: Hao Li , Du Min , Lopez-Campistrous Ana , Fernandez-Patron Carlos
Published: December 2003

Matrix metalloproteinase (MMP)-dependent shedding of heparin-binding epidermal growth factor (HB-EGF) and subsequent activation of the EGF receptor (EGFR) in the cardiovasculature is emerging as a unique mechanism signaling growth effects of diverse G protein–coupled receptors (GPCRs). Among these GPCRs are adrenoceptors and angiotensin receptors that contribute to the pathogenesis of hypertension through their vasoconstrictive and growth effects. Focusing on α
1b
-adrenoceptors, we suggest here that MMP-dependent activation of the EGFR promotes vasoconstriction as well as growth. We identified MMP-7 as a major HB-EGF sheddase in rat mesenteric arteries and α
1b
-adrenoceptors, angiotensin receptors, and hypertension-stimulated MMP-7 activity. Adrenoceptors stimulated EGFR autophosphorylation in arteries, and this transactivation was opposed by the MMP-7 inhibitor GM6001 as well as MMP-7–specific antibodies. In isolated microperfused arteries, blockade of EGFR transactivation with inhibitors of the EGFR (AG1478 and PD153035), HB-EGF (CRM197 and neutralizing antibodies), or MMPs (doxycycline) inhibited adrenergic vasoconstriction. In spontaneously hypertensive rats but not in normotensive rats, the inhibition of MMPs with doxycycline (19.2 mg/d from week 7 until week 12) reduced systolic blood pressure and attenuated HB-EGF shedding in the mesenteric arteries. These findings suggest a previously unknown mechanism of vasoregulation whereby agonists of certain GPCRs (such as adrenoceptors and angiotensin receptors) activate MMPs (such as MMP-7) that shed EGFR ligands (such as HB-EGF), which then activate the EGFR, thereby promoting vasoconstriction as well as growth. Because this mechanism is triggered by agonists typically overexpressed in hypertension, its blockade may have therapeutic potential for simultaneously inhibiting pathological vasoconstriction and growth in hypertensive disorders.
Spontaneous Cardiomyocyte Differentiation From Adipose Tissue Stroma Cells
Authors: Planat-Bénard V. , Menard C. , André M. , Puceat M. , Perez A. , Garcia-Verdugo J.-M. , Pénicaud L. , Casteilla L.
Published: December 2003

Cardiomyocyte regeneration is limited in adult life. Thus, the identification of a putative source of cardiomyocyte progenitors is of great interest to provide a usable model in vitro and new perspective in regenerative therapy. As adipose tissues were recently demonstrated to contain pluripotent stem cells, the emergence of cardiomyocyte phenotype from adipose-derived cells was investigated. We demonstrated that rare beating cells with cardiomyocyte features could be identified after culture of adipose stroma cells without addition of 5-azacytidine. The cardiomyocyte phenotype was first identified by morphological observation, confirmed with expression of specific cardiac markers, immunocytochemistry staining, and ultrastructural analysis, revealing the presence of ventricle- and atrial-like cells. Electrophysiological studies performed on early culture revealed a pacemaker activity of the cells. Finally, functional studies showed that adrenergic agonist stimulated the beating rate whereas cholinergic agonist decreased it. Taken together, this study demonstrated that functional cardiomyocyte-like cells could be directly obtained from adipose tissue. According to the large amount of this tissue in adult mammal, it could represent a useful source of cardiomyocyte progenitors.
Sleep-Disordered Breathing as a Risk Factor for Cerebrovascular Disease
Authors: McArdle Nigel , Riha Renata L. , Vennelle Marjorie , Coleman Emma L. , Dennis Martin S. , Warlow Charles P. , Douglas Neil J.
Published: December 2003

Background and Purpose—

The evidence that obstructive sleep apnea/hypopnea (OSAH) is a risk factor for ischemic cerebrovascular disease is inconclusive. We explored this relationship in transient ischemic attack (TIA) patients because they are less likely than stroke patients to have OSAH as a consequence of cerebrovascular disease.

Methods—

We performed a case-control study among 86 patients with TIA from a hospital neurovascular clinic, matched for age (±5 years) and sex with controls from the referring local family practice registers.

Results—

Forty-nine of the 86 matched pairs were male and the body mass index was similar among cases and controls. The primary outcome measure, the apnea/hypopnea index [AHI=number of (apneas+hypopneas)/h slept, measured during overnight polysomnography and scored blind to case-control status], was the same for cases and controls (21/hour). However, the median number of 4% desaturations during sleep was slightly greater in the cases (12/hour) than controls (6/hour,
P
=0.04). There were the expected associations between TIA and higher fibrinogen levels (TIA 3.3, control 3.0 g/L,
P
=0.01), previous myocardial infarction (TIA 22, control 6%,
P
=0.007), a history of ever smoking (TIA 71, control 54%,
P
=0.01), hypertension (TIA 51, control 21%,
P
=0.001), and raised cholesterol (TIA 27, control 10%,
P
=0.01), with a weak trend for diabetes mellitus (TIA 10, control 6%,
P
=0.4).

Conclusion—

OSAH does not appear to be strongly associated with TIAs.