bluuebunny/crossref_metadata_2025 huggingface dataset:
Effective Symbiosis between
Rhizobium etli
and
Phaseolus vulgaris
Requires the Alarmone ppGpp
Authors: Moris Martine , Braeken Kristien , Schoeters Eric , Verreth Christel , Beullens Serge , Vanderleyden Jos , Michiels Jan
Published: July 2005

The symbiotic interaction between
Rhizobium etli
and
Phaseolus vulgaris
, the common bean plant, ultimately results in the formation of nitrogen-fixing nodules. Many aspects of the intermediate and late stages of this interaction are still poorly understood. The
R. etli relA
gene was identified through a genome-wide screening for
R. etli
symbiotic mutants. RelA has a pivotal role in cellular physiology, as it catalyzes the synthesis of (p)ppGpp, which mediates the stringent response in bacteria. The synthesis of ppGpp was abolished in an
R. etli relA
mutant strain under conditions of amino acid starvation. Plants nodulated by an
R. etli relA
mutant had a strongly reduced nitrogen fixation activity (75% reduction). Also, at the microscopic level, bacteroid morphology was altered, with the size of
relA
mutant bacteroids being increased compared to that of wild-type bacteroids. The expression of the σ
N
-dependent nitrogen fixation genes
rpoN2
and
iscN
was considerably reduced in the
relA
mutant. In addition, the expression of the
relA
gene was negatively regulated by RpoN2, the symbiosis-specific σ
N
copy of
R. etli
. Therefore, an autoregulatory loop controlling the expression of
relA
and
rpoN2
seems operative in bacteroids. The production of long- and short-chain acyl-homoserine-lactones by the
cinIR
and
raiIR
systems was decreased in an
R. etli relA
mutant. Our results suggest that
relA
may play an important role in the regulation of gene expression in
R. etli
bacteroids and in the adaptation of bacteroid physiology.
Functional Analysis of Conserved Gene Products Involved in Assembly ofEscherichia coliCapsules and Exopolysaccharides: Evidence for Molecular Recognition between Wza and Wzc for Colanic Acid Biosynthesis
Authors: Reid Anne N. , Whitfield Chris
Published: July 2005

Group 1 capsular polysaccharides (CPSs) ofEscherichia coliand some loosely cell-associated exopolysaccharides (EPSs), such as colanic acid, are assembled by a Wzy-dependent polymerization system. In this biosynthesis pathway, Wza, Wzb, and Wzc homologues are required for surface expression of wild-type CPS or EPS. Multimeric complexes of Wza in the outer membrane are believed to provide a channel for polymer export; Wzc is an inner membrane tyrosine autokinase and Wzb is its cognate phosphatase. This study was performed to determine whether the Wza, Wzb, and Wzc proteins for colanic acid expression inE. coliK-12 could function in theE. coliK30 prototype group 1 capsule system. When expressed together, colanic acid Wza, Wzb, and Wzc could complement awza-wzb-wzcdefect inE. coliK30, suggesting conservation in their collective function in Wzy-dependent CPS and EPS systems. Expressed individually, colanic acid Wza and Wzb could also function in K30 CPS expression. In contrast, the structural requirements for Wzc function were more stringent because colanic acid Wzc could restore translocation of K30 CPS to the cell surface only when expressed with its cognate Wza protein. Chimeric colanic acid-K30 Wzc proteins were constructed to further study this interaction. These proteins could restore K30 biosynthesis but were unable to couple synthesis to export. The chimeric protein comprising the periplasmic domain of colanic acid Wzc was functional for effective K30 CPS surface expression only when coexpressed with colanic acid Wza. These data highlight the importance of Wza-Wzc interactions in group 1 CPS assembly.
Histones in
Crenarchaea
Authors: Čuboňová L'ubomíra , Sandman Kathleen , Hallam Steven J. , DeLong Edward F. , Reeve John N.
Published: July 2005

Archaeal histone-encoding genes have been identified in marine
Crenarchaea
. The protein encoded by a representative of these genes, synthesized in vitro and expressed in
Escherichia coli
, binds DNA and forms complexes with properties typical of an archaeal histone. The discovery of histones in
Crenarchaea
supports the argument that histones evolved before the divergence of
Archaea
and
Eukarya
.
Global Regulation of Gene Expression by ArlRS, a Two-Component Signal Transduction Regulatory System of
Staphylococcus aureus
Authors: Liang Xudong , Zheng Li , Landwehr Christina , Lunsford Dwayne , Holmes David , Ji Yinduo
Published: July 2005

Staphylococcus aureus
expresses various cell wall-associated and extracellular virulence factors, coordinately controlled by different two-component signal transduction systems and transcriptional regulators. In this study, we used microarray technology to identify the genes regulated by ArlR. The microarray data indicate that ArlR functions as a positive regulator and also as a negative repressor to directly and/or indirectly mediate the expression of at least 114 genes involved in different functions, including autolysis, cell division, growth, and pathogenesis.
Phenotypic Alteration and Target Gene Identification Using Combinatorial Libraries of Zinc Finger Proteins in Prokaryotic Cells
Authors: Park Kyung-Soon , Jang Young-Soon , Lee Horim , Kim Jin-Soo
Published: July 2005

We have developed a method with prokaryotic organisms that uses randomized libraries of zinc finger-containing artificial transcription factors to induce phenotypic variations and to identify genes involved in the generation of a specific phenotype of interest. Combining chromatin immunoprecipitation experiments and in silico prediction of target DNA binding sequences for the artificial transcription factors, we identified
ubiX
, whose down-regulation correlates with the thermotolerance phenotype in
Escherichia coli
. Our results show that randomized libraries of artificial transcription factors are powerful tools for functional genomic studies.
SHANNON INFORMATION IN COMPLETE GENOMES
Authors: CHANG CHANG-HENG , HSIEH LI-CHING , CHEN TA-YUAN , CHEN HONG-DA , LUO LIAOFU , LEE HOONG-CHIEN
Published: July 2005

Shannon information in the genomes of all completely sequenced prokaryotes and eukaryotes are measured in word lengths of two to ten letters. It is found that in a scale-dependent way, the Shannon information in complete genomes are much greater than that in matching random sequences — thousands of times greater in the case of short words. Furthermore, with the exception of the 14 chromosomes of Plasmodium falciparum, the Shannon information in all available complete genomes belong to a universality class given by an extremely simple formula. The data are consistent with a model for genome growth composed of two main ingredients: random segmental duplications that increase the Shannon information in a scale-independent way, and random point mutations that preferentially reduces the larger-scale Shannon information. The inference drawn from the present study is that the large-scale and coarse-grained growth of genomes was selectively neutral and this suggests an independent corroboration of Kimura's neutral theory of evolution.
A THEORETICAL ANALYSIS OF THE SELECTION OF DIFFERENTIALLY EXPRESSED GENES
Authors: MUKHERJEE SACH , ROBERTS STEPHEN J.
Published: July 2005

A great deal of recent research has focused on the challenging task of selecting differentially expressed genes from microarray data ("gene selection"). Numerous gene selection algorithms have been proposed in the literature, but it is often unclear exactly how these algorithms respond to conditions like small sample sizes or differing variances. Choosing an appropriate algorithm can therefore be difficult in many cases. In this paper we propose a theoretical analysis of gene selection, in which the probability of successfully selecting differentially expressed genes, using a given ranking function, is explicitly calculated in terms of population parameters. The theory developed is applicable to any ranking function which has a known sampling distribution, or one which can be approximated analytically. In contrast to methods based on simulation, the approach presented here is computationally efficient and can be used to examine the behavior of gene selection algorithms under a wide variety of conditions, even when the number of genes involved runs into the tens of thousands. The utility of our approach is illustrated by comparing three widely-used gene selection methods.
SPIDER: SOFTWARE FOR PROTEIN IDENTIFICATION FROM SEQUENCE TAGS WITH DE NOVO SEQUENCING ERROR
Authors: HAN YONGHUA , MA BIN , ZHANG KAIZHONG
Published: July 2005

For the identification of novel proteins using MS/MS, de novo sequencing software computes one or several possible amino acid sequences (called sequence tags) for each MS/MS spectrum. Those tags are then used to match, accounting amino acid mutations, the sequences in a protein database. If the de novo sequencing gives correct tags, the homologs of the proteins can be identified by this approach and software such as MS-BLAST is available for the matching. However, de novo sequencing very often gives only partially correct tags. The most common error is that a segment of amino acids is replaced by another segment with approximately the same masses. We developed a new efficient algorithm to match sequence tags with errors to database sequences for the purpose of protein and peptide identification. A software package, SPIDER, was developed and made available on Internet for free public use. This paper describes the algorithms and features of the SPIDER software.
DETERMINING RELEVANT FEATURES TO RECOGNIZE ELECTRON DENSITY PATTERNS IN X-RAY PROTEIN CRYSTALLOGRAPHY
Authors: GOPAL KRESHNA , ROMO TOD D. , SACCHETTINI JAMES C. , IOERGER THOMAS R.
Published: July 2005

High-throughput computational methods in X-ray protein crystallography are indispensable to meet the goals of structural genomics. In particular, automated interpretation of electron density maps, especially those at mediocre resolution, can significantly speed up the protein structure determination process. TEXTALTM is a software application that uses pattern recognition, case-based reasoning and nearest neighbor learning to produce reasonably refined molecular models, even with average quality data. In this work, we discuss a key issue to enable fast and accurate interpretation of typically noisy electron density data: what features should be used to characterize the density patterns, and how relevant are they? We discuss the challenges of constructing features in this domain, and describe SLIDER, an algorithm to determine the weights of these features. SLIDER searches a space of weights using ranking of matching patterns (relative to mismatching ones) as its evaluation function. Exhaustive search being intractable, SLIDER adopts a greedy approach that judiciously restricts the search space only to weight values that cause the ranking of good matches to change. We show that SLIDER contributes significantly in finding the similarity between density patterns, and discuss the sensitivity of feature relevance to the underlying similarity metric.
MULTIPLE RNA STRUCTURE ALIGNMENT
Authors: WANG ZHUOZHI , ZHANG KAIZHONG
Published: July 2005

Ribonucleic Acid (RNA) structures can be viewed as a special kind of strings where characters in a string can bond with each other. The question of aligning two RNA structures has been studied for a while, and there are several successful algorithms that are based upon different models. In this paper, by adopting the model introduced in Wang and Zhang,19 we propose two algorithms to attack the question of aligning multiple RNA structures. Our methods are to reduce the multiple RNA structure alignment problem to the problem of aligning two RNA structure alignments. Meanwhile, we will show that the framework of sequence center star alignment algorithm can be applied to the problem of multiple RNA structure alignment, and if the triangle inequality is met in the scoring matrix, the approximation ratio of the algorithm remains to be [Formula: see text], where n is the total number of structures.
Transportation and deposition of magnetite and gold in Harris Creek, south-central British Columbia
Authors: Hou Z. , Fletcher W.K.
Published: July 2005

Although previous studies have indicated the importance of flood events in the mobilization, transport and deposition of gold by streams, there have been no estimates of actual transport rates of sediment and gold as discharge varies both within and between years. Here, we use Helley–Smith bed load samples from Harris Creek, a gold-rich gravel-cobble bed stream in British Columbia, to develop equations of the form

R
i

= a
Q
b
that relate transport rates (

R
i

) of sediment, magnetite and gold to discharge (
Q
). These equations have then been used to estimate the amounts of sediment, magnetite and gold transported by Harris Creek in 1991, 1992 and 1993.

Results show that the amount of material transported can vary by up to three orders of magnitude from year to year depending on the magnitude and duration of the snowmelt flood. Combined with the preferential deposition of Au at bar-head sites, it seems likely these large annual variations in the amount of Au transported result in similar year-to-year variations in the strength of stream sediment geochemical anomalies for Au.
Atypical and typical zinc geochemistry in a carbonate setting, Sä Dena Hes Mine, Yukon Territory, Canada
Authors: Day Stephen J. , Bowell Robert J.
Published: July 2005

The Sä Dena Hes Mine produced Pb and Zn concentrates from a polymetallic Manto deposit in 1991 and 1992. Ownership of the mine was assumed by Sä Dena Hes Operating Corporation (Teck Cominco Ltd and Pan-Pacific Metal Mining Corporation) in 1994. Sphalerite and galena ore bodies with negligible Fe sulphide were processed by conventional flotation methods resulting in carbonate-rich tailings. This paper presents evaluations of atypical and typical Zn geochemistry under non-acidic conditions using laboratory testing, mineralogy and simple modelling.

Atypical behaviour is shown by drainage containing 40 mg/l Zn from a short adit. The Zn load contained in the mine drainage is not apparent in a spring-fed stream a few hundred metres down-gradient. Results of an attenuation test to mimic field conditions showed that Zn was removed to concentrations of less than 0.001 mg/l. Spherical aggregates containing 40% Zn were found in the column residues using scanning electron microscopy. The aggregates are likely a Zn hydroxide or basic carbonate based on the Zn concentration, though the exact mineralogical form was not determined.

Similarly, elevated Zn concentrations (up to 56 mg/l) have been found in pH-neutral porewaters near the water table in the tailings deposit. Zinc concentrations generally decrease to below 1 mg/l just below the water table and below 0.1 mg/l in seepage from the tailings dam. However in this case, simple dilution modelling and thermodynamic equilibrium modelling of the tailings porewater chemistry showed that the decrease in Zn concentrations could be attributed to the formation of Zn carbonate. Electron microscopy confirmed the presence of smithsonite (ZnCO
3
) in the tailings; in addition Zn also occurred as a trace element in Mg–Mn–Ca carbonate phases.
INSECT ODOR AND TASTE RECEPTORS
Authors: Hallem Elissa A. , Dahanukar Anupama , Carlson John R.
Published: July 2005

▪ Abstract  Insect odor and taste receptors are highly sensitive detectors of food, mates, and oviposition sites. Following the identification of the first insect odor and taste receptors in Drosophila melanogaster, these receptors were identified in a number of other insects, including the malaria vector mosquito Anopheles gambiae; the silk moth, Bombyx mori; and the tobacco budworm, Heliothis virescens. The chemical specificities of many of the D. melanogaster receptors, as well as a few of the A. gambiae and B. mori receptors, have now been determined either by analysis of deletion mutants or by ectopic expression in in vivo or heterologous expression systems. Here we discuss recent advances in our understanding of the molecular and cellular basis of odor and taste coding in insects.
REAL JURIES
Authors: Diamond Shari Seidman , Rose Mary R.
Published: July 2005

▪ Abstract  The elaborate efforts of the legal system to control and channel jury behavior reveal a mistrust of an institution that also attracts extravagant praise. We look at the jury by examining research on real juries drawn from archival studies and post-trial surveys and interviews, as well as from the deliberations of real juries. We show how the methods used by courts to gather and select jurors affect the representativeness and legitimacy of the jury. We also examine the evidence underlying skepticism about jury verdicts and decision making, focusing on cases that pose special challenges to jurors, particularly those involving complex evidence, legal complexity, and the death penalty. We then consider how optimal jury trials can be achieved.

Even twelve experienced judges, deliberating together, would probably not function well under the conditions we impose on the twelve inexperienced laymen [Judge Jerome Frank, Courts on Trial (1949), p. 120].

Juror #4 (discussing the testimony of an expert physician in a medical malpractice case): What I would like to have is 40 [specialists] and show them the [test results] and okay, get a survey and is this significant or is this not significant and would they have [done what the defendant did]? [Deliberating juror from the Arizona Filming Project ( Diamond et al. 2003 )]
Muscle contractions, AICAR, and insulin cause phosphorylation of an AMPK-related kinase
Authors: Fisher Jonathan S. , Ju Jeong-Sun , Oppelt Peter J. , Smith Jill L. , Suzuki Atsushi , Esumi Hiroyasu
Published: July 2005

We hypothesized that AMP-activated protein kinase-related kinase 5 (ARK5)/novel kinase family 1 (NUAK1), an AMP-activated protein kinase (AMPK)-related kinase that has been found to be stimulated by protein kinase B (Akt), would be expressed in rat skeletal muscle and activated by electrically elicited contractions, 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), or insulin. We verified expression of ARK5 in muscle through RT-PCR and Western blot. Cross-reactivity of ARK5 immunoprecipitates with antibodies against phospho-AMPK was increased by ∼30% by muscle contractions and ∼60% by incubation of muscle with AICAR. AMPK was not detected in the ARK5 immunoprecipitates. Despite the apparent increase in phosphorylation of ARK5 at a site essential to its activation, neither contractions nor AICAR increased ARK5 activity. For muscles from animals injected with saline or insulin, we probed nonimmunoprecipitated samples in sequence for phosphotyrosine (P-Tyr), ARK5, and phosphorylated substrates of Akt (P-AS) and found that the ARK5 band could be precisely superimposed on phosphoprotein bands from the P-Tyr and P-AS blots. In the band corresponding to ARK5, insulin increased P-Tyr content by ∼45% and cross-reactivity with the antibody against P-AS by approximately threefold. We also detected ARK5 in phosphotyrosine immunoprecipitates. Our data suggest that increased phosphorylation of ARK5 by muscle contractions or exposure to AICAR is insufficient to activate ARK5 in skeletal muscle, suggesting that some other modification (e.g., phosphorylation on tyrosine or by Akt) may be necessary to its activity in muscle.
A discrete economic growth model with endogenous labor
Authors: Zhang Wei-Bin
Published: July 2005

This paper proposes an alternative approach to economic growth with endogenous labor supply. The production side is the same as the Solow model, the Ramsey model, and the Diamond model. But we deal with the behavior of consumers differently from the traditional approaches by proposing a concept of disposable income
(which is the sum of the wealth available for use, the current income from interest income, and the wage payment) and a utility function which depends on the current consumption, savings, and leisure. The model provides a mechanism of endogenous saving and labor supply which the Solow model lacks, avoids the assumption of adding up utility over a period of time upon which the Ramsey approach is based, and does not need the assumption of two‐period agents which the Diamond model and many of its extensions accept.
Multiscale behavior of a simple model for stock markets
Authors: Sánchez Juan R.
Published: July 2005

The multiscale behavior of a recently reported model for stock markets is presented. It has been shown that indexes of real‐world markets display absolute returns with memory properties on a long‐time range, a phenomenon known as cluster volatility. The
multiscale characteristics of an index are studied by analyzing the power‐law scaling of the volatility correlations which display nonunique scaling exponents. Here such analysis is done on an artificial time series produced by a simple model for stock markets. After comparison, excellent agreements with the multiscale behavior of real‐time series are
found.
Analytic solutions of nonlinear Cournot duopoly game
Authors: Matsumoto Akio , Suzuki Mami
Published: July 2005

We construct a Cournot duopoly model with production externality in which reaction functions are unimodal. We consider the case of a Cournot model which has a stable equilibrium point. Then we show the existence of analytic solutions of the model. Moreover, we seek general solutions of the model in the form of nonlinear second‐order difference equation.
Permanence and global stability of positive solutions of a nonautonomous discrete ratio‐dependent predator‐prey model
Authors: Huo Hai-Feng , Li Wan-Tong
Published: July 2005

We first give sufficient conditions for the permanence of nonautonomous discrete ratio‐dependent predator‐prey model. By linearization of the model at positive solutions and construction of Lyapunov function, we also obtain some conditions which ensure that a positive solution of the model is stable and attracts all positive solutions.
Two new approaches for construction of the high order of accuracy difference schemes for hyperbolic differential equations
Authors: Ashyralyev Allaberen , Sobolevskii Pavel E.
Published: July 2005

We consider the abstract Cauchy problem for differential equation of the hyperbolic type v″(t) + Av(t) = f(t) (0 ≤ t ≤ T), v(0) = v0, in an arbitrary Hilbert space H with the selfadjoint positive definite operator A. The high order of accuracy two‐step difference schemes generated by an exact difference scheme or by the Taylor decomposition on the three points for the numerical solutions of this problem are presented. The stability estimates for the solutions of these difference schemes are established. In applications, the stability estimates for the solutions of the high order of accuracy difference schemes of the mixed‐type boundary value problems for hyperbolic equations are obtained.
A remark on positive topological entropy of N‐buffer switchedflow networks
Authors: Yang Xiao-Song
Published: July 2005

We present a simpler elementary proof on positive topological entropy of the N‐buffer switched flow networks based on a new simple theorem on positive topological entropy of continuous map on compact metric space.
Cocoa Reduces Blood Pressure and Insulin Resistance and Improves Endothelium-Dependent Vasodilation in Hypertensives
Authors: Grassi Davide , Necozione Stefano , Lippi Cristina , Croce Giuseppe , Valeri Letizia , Pasqualetti Paolo , Desideri Giovambattista , Blumberg Jeffrey B. , Ferri Claudio
Published: July 2005

Consumption of flavanol-rich dark chocolate (DC) has been shown to decrease blood pressure (BP) and insulin resistance in healthy subjects, suggesting similar benefits in patients with essential hypertension (EH). Therefore, we tested the effect of DC on 24-hour ambulatory BP, flow-mediated dilation (FMD), and oral glucose tolerance tests (OGTTs) in patients with EH. After a 7-day chocolate-free run-in phase, 20 never-treated, grade I patients with EH (10 males; 43.7±7.8 years) were randomized to receive either 100 g per day DC (containing 88 mg flavanols) or 90 g per day flavanol-free white chocolate (WC) in an isocaloric manner for 15 days. After a second 7-day chocolate-free period, patients were crossed over to the other treatment. Noninvasive 24-hour ambulatory BP, FMD, OGTT, serum cholesterol, and markers of vascular inflammation were evaluated at the end of each treatment. The homeostasis model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), and insulin sensitivity index (ISI) were calculated from OGTT values. Ambulatory BP decreased after DC (24-hour systolic BP −11.9±7.7 mm Hg,
P
<0.0001; 24-hour diastolic BP −8.5±5.0 mm Hg,
P
<0.0001) but not WC. DC but not WC decreased HOMA-IR (
P
<0.0001), but it improved QUICKI, ISI, and FMD. DC also decreased serum LDL cholesterol (from 3.4±0.5 to 3.0±0.6 mmol/L;
P
<0.05). In summary, DC decreased BP and serum LDL cholesterol, improved FMD, and ameliorated insulin sensitivity in hypertensives. These results suggest that, while balancing total calorie intake, flavanols from cocoa products may provide some cardiovascular benefit if included as part of a healthy diet for patients with EH.
Melanocortin-4 Receptor–Deficient Mice Are Not Hypertensive or Salt-Sensitive Despite Obesity, Hyperinsulinemia, and Hyperleptinemia
Authors: Tallam Lakshmi S. , Stec David E. , Willis Mary A. , da Silva Alexandre A. , Hall John E.
Published: July 2005

The purpose of this study was to test whether the melanocortin-4 receptor (MC4R) is critical in the development of hypertension associated with obesity and its metabolic disorders. MC4R-deficient homozygous (−/−) and heterozygous (+/−) and wild-type (WT) C57BL/6J mice 17 to 19 weeks old (n=5 to 7 per group) were implanted with telemetry devices for monitoring 24-hour mean arterial pressure (MAP) and heart rate (HR). After 3-day stable control measurements on normal-salt diet (NSD; 0.4% NaCl), mice received a high-salt diet (HSD; 4% NaCl) for 7 days, followed by 3-day recovery on NSD. MC4R (−/−) mice were severely obese compared with MC4R (+/−) and WT mice (body weight 48±1.5 versus 31±0.6 and 30±0.5 g respectively). On NSD, MAP was similar in all groups of mice (MC4R (−/−) 110±3 mm Hg; MC4R (+/−) 109±2 mm Hg; WT 114±2 mm Hg), and HR in MC4R (−/−) was lower than in WT (604±5 versus 645±9 bpm;
P
<0.05) but not different from MC4R (+/−) (625±13 bpm) mice. HSD did not significantly alter MAP or HR in any of the groups. Epididymal and retroperitoneal fat weights and plasma leptin levels were several-fold greater in MC4R (−/−) compared with MC4R (+/−) and WT mice. Plasma insulin and glucose levels were also significantly greater in MC4R (−/−) than in MC4R (+/−) and WT mice. These data suggest that despite obesity, visceral adiposity, hyperleptinemia, and hyperinsulinemia, MC4R (−/−) mice are neither hypertensive nor salt sensitive, indicating that a functional MC4R may be necessary for the development of hypertension associated with obesity and its metabolic abnormalities.
Interactive Effects of Common β
2
-Adrenoceptor Haplotypes and Age on Susceptibility to Hypertension and Receptor Function
Authors: Bao Xuping , Mills Paul J. , Rana Brinda K. , Dimsdale Joel E. , Schork Nicholas J. , Smith Douglas W. , Rao Fangwen , Milic Milos , O’Connor Daniel T. , Ziegler Michael G.
Published: July 2005

Few studies have examined to what extent genetic variants of the β
2
-adrenoceptor (ADRB2) are involved in the development of hypertension with age, although β
2
-adrenergic receptor responsiveness declines in older subjects. To investigate this, 10 common single-nucleotide polymorphisms (SNPs) in the promoter and coding regions of the ADRB2 gene were genotyped in an unrelated population consisting of 2 ethnic groups: European American (EA; n=610) and African American (AA; n=420). ADRB2 haplotypes were estimated by expectation maximization (EM) algorithm–based methods. In the general population for EAs and AAs, the variants of the ADRB2 gene, including the individual SNPs and their haplotypes, were not associated with hypertension. However, there was a significant interaction between age and one of the common haplotypes (haplotype 1) in EAs (
P
=0.01). Haplotype 1 was associated with protection against hypertension in young (≤50 years of age) but not in old (>50 years of age) EAs (odds ratio, 0.5; 95% confidence interval, 0.27 to 0.91;
P
=0.02). This age-specific effect was further supported by the observations that young subjects carrying ≥1 copy of haplotype 1 had significantly lower diastolic blood pressure and nearly 2-fold higher ADRB2 binding density than the noncarriers (
P
<0.05). With aging, their ADRB2 numbers decreased to the level of the noncarriers, along with increased body mass index (7%;
P
<0.05) and decreased heart rate (7%;
P
<0.001). Our study suggests that age is an important modifier for the effects of ADRB2 polymorphisms on ADRB2 function and the development of hypertension.
Prognostic Value of Plasma N-Terminal Pro-Brain Natriuretic Peptide in Patients With Severe Sepsis
Authors: Brueckmann Martina , Huhle Guenter , Lang Siegfried , Haase Karl K. , Bertsch Thomas , Weiß Christel , Kaden Jens J. , Putensen Christian , Borggrefe Martin , Hoffmann Ursula
Published: July 2005

Background—

Increased plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) have been identified as predictors of cardiac dysfunction and prognosis in congestive heart failure and ischemic heart disease. In severe sepsis patients, however, no information is available yet about the prognostic value of natriuretic peptides. Therefore, the aim of the present study was to determine the role of the N-terminal prohormone forms of ANP (NT-proANP) and BNP (NT-proBNP) in the context of outcome of septic patients. Furthermore, the effect of treatment with recombinant human activated protein C [drotrecogin alfa (activated)] on plasma levels of natriuretic peptides in severe sepsis was evaluated.

Methods and Results—

Fifty-seven patients with severe sepsis were included. Levels of NT-proANP and NT-proBNP were measured on the second day of sepsis by ELISA. Septic patients with NT-proBNP levels >1400 pmol/L were 3.9 times more likely (relative risk [RR], 3.9; 95% CI, 1.6 to 9.7) to die from sepsis than patients with lower NT-proBNP values (
P
<0.01). NT-proANP levels, however, were not predictive of survival in our patient population. A highly significant correlation was found between troponin I levels and plasma concentrations of NT-proBNP in septic patients (
r
=0.68,
P
<0.0001). In addition, troponin I significantly accounted for the variation in NT-proBNP levels (
P
<0.0001), suggesting an important role for NT-proBNP in the context of cardiac injury and dysfunction in septic patients. Twenty-three septic patients who received treatment with drotrecogin alfa (activated) presented with significantly lower concentrations of NT-proANP, NT-proBNP, and troponin I compared with patients not receiving drotrecogin alfa (activated).

Conclusions—

NT-proBNP may serve as useful laboratory marker to predict survival in patients presenting with severe sepsis.
Increased Susceptibility to Pulmonary Hypertension in Heterozygous BMPR2-Mutant Mice
Authors: Song Yanli , Jones John E. , Beppu Hideyuki , Keaney John F. , Loscalzo Joseph , Zhang Ying-Yi
Published: July 2005

Background—

Bone morphogenetic protein receptor-2 (BMPR2)–heterozygous, mutant (
BMPR2
+/−
) mice have a genetic trait similar to that of certain patients with idiopathic pulmonary arterial hypertension (IPAH). To understand the role of BMPR2 in the development of IPAH, we examined the phenotype of
BMPR2
+/−
mice and their response to inflammatory stress.

Methods and Results—

BMPR2
+/−
mice were found to have the same life span, right ventricular systolic pressure (RVSP), and lung histology as those of wild-type mice under unstressed conditions. However, when treated with recombinant adenovirus expressing 5-lipoxygenase (Ad5LO),
BMPR2
+/−
mice exhibited significantly higher RVSP than wild-type mice. The increase of RVSP occurred in the first 2 weeks after Ad5LO delivery. Modest but significant muscularization of distal pulmonary arterioles appeared in
BMPR2
+/−
mice 4 weeks after Ad5LO treatment. Measurement of urinary metabolites of vasoactive molecules showed that cysteinyl leukotrienes, prostacyclin metabolites, and PGE
2
were all increased to a similar degree in both
BMPR2
+/−
and wild-type mice during 5LO transgene expression, whereas urinary endothelin-1 remained undetectable. Urinary thromboxane A
2
metabolites, in contrast, were significantly higher in
BMPR2
+/−
than in wild-type mice and paralleled the increase in RVSP. Platelet activation markers, serotonin, and soluble P-selectin showed a trend toward higher concentrations in
BMPR2
+/−
than wild-type mice. Cell culture studies found that BMP treatment reduced interleukin-1β–stimulated thromboxane A
2
production in the pulmonary epithelial cell line A549.

Conclusions—

BMPR2
+/−
mice do not develop pulmonary hypertension spontaneously; however, under inflammatory stress, they are more susceptible to an increase in RVSP, thromboxane A
2
production, and vascular remodeling than wild-type mice.
Transendocardial Autologous Bone Marrow Mononuclear Cell Injection in Ischemic Heart Failure
Authors: Dohmann Hans F.R. , Perin Emerson C. , Takiya Christina M. , Silva Guilherme V. , Silva Suzana A. , Sousa Andre L.S. , Mesquita Claudio T. , Rossi Maria-Isabel D. , Pascarelli Bernardo M.O. , Assis Isabella M. , Dutra Helio S. , Assad João A.R. , Castello-Branco Rodrigo V. , Drummond Cantidio , Dohmann Hans J.F. , Willerson James T. , Borojevic Radovan
Published: July 2005

Background—

Cell-based therapies for treatment of ischemic heart disease are currently under investigation. We previously reported the results of a phase I trial of transendocardial injection of autologous bone marrow mononuclear (ABMM) cells in patients with end-stage ischemic heart disease. The current report focuses on postmortem cardiac findings from one of the treated patients, who died 11 months after cell therapy.

Methods and Results—

Anatomicopathologic, morphometric, and immunocytochemical findings from the anterolateral ventricular wall (with cell therapy) were compared with findings from the interventricular septum (normal perfusion and no cell therapy) and from the inferoposterior ventricular wall (extensive scar tissue and no cell therapy). No signs of adverse events were found in the cell-injected areas. Capillary density was significantly higher (
P
<0.001) in the anterolateral wall than in the previously infarcted tissue in the posterior wall. The prominent vasculature of the anterolateral wall was associated with hyperplasia of pericytes, mural cells, and adventitia. Some of these cells had acquired cytoskeletal elements and contractile proteins (troponin, sarcomeric α-actinin, actinin), as well as the morphology of cardiomyocytes, and appeared to have migrated toward adjacent bundles of cardiomyocytes.

Conclusions—

Eleven months after treatment, morphological and immunocytochemical analysis of the sites of ABMM cell injection showed no abnormal cell growth or tissue lesions and suggested that an active process of angiogenesis was present in both the fibrotic cicatricial tissue and the adjacent cardiac muscle. Some of the pericytes had acquired the morphology of cardiomyocytes, suggesting long-term sequential regeneration of the cardiac vascular tree and muscle.
Cardiac Iron Determines Cardiac T2*, T2, and T1 in the Gerbil Model of Iron Cardiomyopathy
Authors: Wood John C. , Otto-Duessel Maya , Aguilar Michelle , Nick Hanspeter , Nelson Marvin D. , Coates Thomas D. , Pollack Harvey , Moats Rex
Published: July 2005

Background—Transfusional therapy for thalassemia major and sickle cell disease can lead to iron deposition and damage to the heart, liver, and endocrine organs. Iron causes the MRI parameters T1, T2, and T2* to shorten in these organs, which creates a potential mechanism for iron quantification. However, because of the danger and variability of cardiac biopsy, tissue validation of cardiac iron estimates by MRI has not been performed. In this study, we demonstrate that iron produces similar T1, T2, and T2* changes in the heart and liver using a gerbil iron-overload model.

Methods and Results—Twelve gerbils underwent iron dextran loading (200 mg · kg−1· wk−1) from 2 to 14 weeks; 5 age-matched controls were studied as well. Animals had in vivo assessment of cardiac T2* and hepatic T2 and T2* and postmortem assessment of cardiac and hepatic T1 and T2. Relaxation measurements were performed in a clinical 1.5-T magnet and a 60-MHz nuclear magnetic resonance relaxometer. Cardiac and liver iron concentrations rose linearly with administered dose. Cardiac 1/T2*, 1/T2, and 1/T1 rose linearly with cardiac iron concentration. Liver 1/T2*, 1/T2, and 1/T1 also rose linearly, proportional to hepatic iron concentration. Liver and heart calibrations were similar on a dry-weight basis.

Conclusions—MRI measurements of cardiac T2 and T2* can be used to quantify cardiac iron. The similarity of liver and cardiac iron calibration curves in the gerbil suggests that extrapolation of human liver calibration curves to heart may be a rational approximation in humans.
Human Atrial Ion Channel and Transporter Subunit Gene-Expression Remodeling Associated With Valvular Heart Disease and Atrial Fibrillation
Authors: Gaborit Nathalie , Steenman Marja , Lamirault Guillaume , Le Meur Nolwenn , Le Bouter Sabrina , Lande Gilles , Léger Jean , Charpentier Flavien , Christ Torsten , Dobrev Dobromir , Escande Denis , Nattel Stanley , Demolombe Sophie
Published: July 2005

Background—

Valvular heart disease (VHD), which often leads to atrial fibrillation (AF), and AF both cause ion-channel remodeling. We evaluated the ion-channel gene expression profile of VHD patients, in permanent AF (AF-VHD) or in sinus rhythm (SR-VHD), in comparison with patients without AF or VHD, respectively.

Methods and Results—

We used microarrays containing probes for human ion-channel and Ca
2+
-regulator genes to quantify mRNA expression in atrial tissues from 7 SR-VHD patients and 11 AF-VHD patients relative to 11 control patients in SR without structural heart disease (SR-CAD). From the data set, we selected for detailed analysis 59 transcripts expressed in the human heart. SR-VHD patients differentially expressed 24/59 ion-channel and Ca
2+
-regulator transcripts. There was significant overlap between VHD groups, with 66% of genes altered in SR-VHD patients being similarly modified in AF-VHD. Statistical differences between the AF- and SR-VHD groups identified the specific molecular portrait of AF, which involved 12 genes that were further confirmed by real-time reverse transcription–polymerase chain reaction. For example, phospholamban, the β-subunit MinK (
KCNE1
) and MIRP2 (
KCNE3
), and the 2-pore potassium channel
TWIK-1
were upregulated in AF-VHD compared with SR-VHD, whereas the T-type calcium-channel Cav3.1 and the transient-outward potassium channel Kv4.3 were downregulated. Two-way hierarchical clustering separated SR-VHD from AF-VHD patients. AF-related changes in L-type Ca
2+
-current and inward-rectifier current were confirmed at protein and functional levels. Finally, for 13 selected genes, SR restoration reversed ion-channel remodeling.

Conclusions—

VHD extensively remodels cardiac ion-channel and transporter expression, and AF alters ion-channel expression in VHD patients.
Percutaneous Versus Surgical Treatment for Patients With Hypertrophic Obstructive Cardiomyopathy and Enlarged Anterior Mitral Valve Leaflets
Authors: van der Lee Chris , ten Cate Folkert J. , Geleijnse Marcel L. , Kofflard Marcel J. , Pedone Chiara , van Herwerden Lex A. , Biagini Elena , Vletter Wim B. , Serruys Patrick W.
Published: July 2005

Background—

The purpose of this study was to compare percutaneous transluminal septal myocardial ablation (PTSMA) and septal myectomy combined with mitral leaflet extension (MLE) in symptomatic hypertrophic obstructive cardiomyopathy patients with an enlarged anterior mitral valve leaflet (AMVL). Both PTSMA and myectomy reduce septal thickness and left ventricular outflow tract (LVOT) gradient; however, an uncorrected enlarged AMVL may predispose to residual systolic anterior motion (SAM) after successful standard myectomy or PTSMA. Myectomy with MLE previously demonstrated superior hemodynamic results compared with standard myectomy, but its value relative to PTSMA is unknown.

Methods and Results—

Twenty-nine patients (aged 44±12 years) underwent myectomy with MLE, and 43 patients (aged 52±17 years) underwent PTSMA. Mitral leaflet area was similar in both groups (16.7±3.4 versus 15.9±2.7 cm
2
, respectively). After PTSMA, 2 patients died, 4 needed a reintervention, and 4 required a permanent pacemaker for complete heart block. After surgery, only 1 patient needed a reintervention. At 1-year follow-up, LVOT gradients did not differ between surgical and PTSMA patients (17±14 versus 23±19 mm Hg, respectively). Preinterventional mitral regurgitation grade was more severe in the surgical group, but with myectomy combined with MLE, the residual grade was similar to that of PTSMA. Mean SAM grade decreased significantly more after surgery (from 2.9±0.3 to 0.5±0.7 mm Hg versus from 2.8±0.5 to 1.3±0.9 mm Hg,
P
<0.05).

Conclusions—

PTSMA in these selected patients with hypertrophic obstructive cardiomyopathy had more periprocedural complications and resulted in more reinterventions. Hemodynamic results (SAM grade and reduction in mitral regurgitation) were better in surgical patients.
Biliverdin Administration Prevents the Formation of Intimal Hyperplasia Induced by Vascular Injury
Authors: Nakao Atsunori , Murase Noriko , Ho Chien , Toyokawa Hideyoshi , Billiar Timothy R. , Kanno Shinichi
Published: July 2005

Background—

Autologous vein grafts and balloon angioplasty are still commonly used for arterial reconstructive procedures. Their success is limited by the development of intimal hyperplasia (IH). Biliverdin (BVD), one of the by-products of heme degradation, has been shown to have potent antioxidant and antiinflammatory effects. We hypothesized that BVD administration would protect vascular tissue against vascular injury.

Methods and Results—

The effects of BVD administration against IH after vascular injury were analyzed in an arterialized vein graft model and a balloon injury model in rats. BVD treatment significantly suppressed the development of IH in both models compared with those without BVD. The mechanisms by which BVD treatment inhibits IH development might include decreasing
c
-Jun NH
2
terminal kinase activation and preventing apoptosis of endothelial cells. BVD also suppressed vascular smooth muscle cell migration in vitro.

Conclusions—

BVD administration prevented IH associated with arterialized vein graft vasculopathy or balloon angioplasty-induced vessel injury. These results suggest that a treatment regimen with exogenous BVD administration could provide an effective therapeutic adjunct to facilitate transfer of experimental treatments for vascular injury to the clinic.
Symbolic Dynamics of Heart Rate Variability
Authors: Guzzetti Stefano , Borroni Ester , Garbelli Pietro E. , Ceriani Elisa , Bella Paolo Della , Montano Nicola , Cogliati Chiara , Somers Virend K. , Mallani Alberto , Porta Alberto
Published: July 2005

Background—

Sympathetic and parasympathetic systems are considered the principal rapidly reacting systems that control heart rate.

Methods and Results—

We propose a symbolic analysis series to quantify the prevalence of sympathetic or parasympathetic cardiac modulation. This analysis decomposes the heart rate variability series in patterns lasting 3 beats and classifies them into 3 categories: nonvariable, variable, and very variable patterns referred to as 0V, 1V, and 2V patterns. First, we applied this method to experimental and pharmacological conditions characterized by sympathetic activation (tilt test, handgrip, nitroprusside, and high-dose atropine administration) or parasympathetic activation (phenylephrine and low-dose atropine administration) in 60 healthy subjects. An increase in sympathetic modulation and a vagal withdrawal elicited a significant increase in 0V patterns and a decrease in 2V patterns, whereas parasympathetic dominance induced the opposite, reflecting a reciprocal sympathovagal balance. The second part of the study considered a series of 300 beats before the onset of major arrhythmic events in patients with an implantable cardioverter-defibrillator. Symbolic analysis detected an increase in the percentage of 0V patterns before the onset of major arrhythmias compared with baseline (41.6±3.9% and 24.4±2.9%, respectively;
P
<0.01), indicating a sympathetic prevalence. On the other hand, the 2V patterns did not decrease before major arrhythmias, suggesting the presence of nonreciprocal autonomic modulations.

Conclusions—

Symbolic analysis of 3 beat sequences takes into account the different time course of sympathetic and parasympathetic cardiac modulations and seems appropriate for elucidating the neural pathophysiological mechanisms occurring during the short periods that precede acute cardiac events.
Elevated High-Density Lipoprotein Cholesterol Levels Are Protective Against Plaque Progression
Authors: Johnsen Stein Harald , Mathiesen Ellisiv B. , Fosse Einar , Joakimsen Oddmund , Stensland-Bugge Eva , Njølstad Inger , Arnesen Egil
Published: July 2005

Background—

There is an inverse relationship between HDL cholesterol and coronary heart disease. Experimental studies have indicated that HDL cholesterol may exert an antiatherogenic effect by inducing regression of atherosclerotic plaques and by turning lipid-rich plaques into more fibrotic lesions. In this prospective, population-based ultrasound study, we investigated how HDL cholesterol relates to carotid plaque progression.

Methods and Results—

The study included 1952 men and women aged 25 to 82 years who had at least 1 plaque present in the right carotid artery at baseline examination (1994). All plaque images were computer processed to yield a measure of plaque area in square millimeters and echogenicity, expressed as the gray-scale median. After 7 years of follow-up, a new ultrasound screening was performed, and the changes in plaque area and echogenicity were assessed. In a multivariable adjusted model, HDL cholesterol, age, systolic blood pressure, and current smoking were independent predictors of plaque growth. For a 1-SD (0.41 mmol/L) lower HDL cholesterol level, mean (SE) plaque area increased by 0.93 mm
2
(0.44 mm
2
;
P
=0.03). When users of lipid-lowering drugs were excluded from analysis, the HDL estimate was strengthened (β=1.46 mm
2
,
P
=0.002). Although plaque area increased in 70% of cases, and most plaques became more echogenic over the follow-up interval, the plaques that became more echolucent grew more in size than those that became more echogenic (
P
=0.002).

Conclusions—

This study shows that a high level of HDL cholesterol reduces plaque growth in subjects with preexisting carotid atherosclerosis. Transformation of the plaque mass into higher echogenicity is associated with reduced growth. Our findings may indicate that HDL cholesterol stabilizes plaques and counteracts their growth by reducing their lipid content and inflammation.