bluuebunny/crossref_metadata_2025 huggingface dataset:
CHAOTIC SYNCHRONIZATION AND ANTISYNCHRONIZATION IN COUPLED SINE MAPS
Authors: MAISTRENKO V. L. , MAISTRENKO YU. L. , MOSEKILDE E.
Published: August 2005

This paper investigates different types of chaotic synchronization in a system of two coupled sine maps. Due to the bimodal nature of the individual map, there is a range of parameters in which two synchronized chaotic states coexist along the main diagonal. In certain parameter regions, various (regular or chaotic) asynchronous states coexist with the synchronized chaotic states, and the basins of attraction become quite complicated. We determine the regions of stability for the so-called principal cycles that arise through transverse period-doubling bifurcations of synchronized saddle cycles. Particular emphasis is paid to the occurrence of chaotic antisynchronization, the coexistence of antisynchronous chaotic states, and the presence of narrow regions of parameter space in which states of chaotic synchronization and antisynchronization exist simultaneously. For each of these cases we provide detailed pictures of the associated basin structures.
CONVERGENCE DYNAMICS OF STOCHASTIC REACTION–DIFFUSION RECURRENT NEURAL NETWORKS WITH DELAYS
Authors: SUN JIANHUA , WAN LI
Published: August 2005

Stochastic effects on convergence dynamics of reaction–diffusion recurrent neural networks (RNNs) with constant transmission delays are studied. Without assuming the boundedness, monotonicity and differentiability of the activation functions, nor symmetry of synaptic interconnection weights, by skillfully constructing suitable Lyapunov functionals and employing the method of variational parameters, M-matrix properties, inequality technique, stochastic analysis and non-negative semimartingale convergence theorem, delay independent and easily verifiable sufficient conditions to guarantee the almost sure exponential stability, mean value exponential stability and mean square exponential stability of an equilibrium solution associated with temporally uniform external inputs to the networks are obtained, respectively. The results are compared with the previous results derived in the literature for discrete delayed RNNs without diffusion or stochastic perturbation. Two examples are also given to demonstrate our results.
FUZZY PROGRAMMING WITH RECOURSE
Authors: LIU YIAN-KUI
Published: August 2005

In this study, we deal with the optimization methodology in fuzzy decision-making systems. The issue of convergence for sequences of integrable fuzzy variables is discussed. Based on credibility theory, a new class of fuzzy programming—two-stage fuzzy programming or fuzzy programming with recourse problem is introduced, and a discussion about basic properties of the recourse problems is included. To solve the two-stage fuzzy programming problems, a heuristic solution method, which combines fuzzy simulations, genetic algorithm and neural network, is proposed, and the convergence of approximating a recourse functions is proved. We provide three numerical examples to illustrate the feasibility and effectiveness of the designed algorithm.
THE EXPERT'S CONFIDENCE VERSUS FUZZY PROBABILITY IN THE MEAN ACTIVITY TIMES COMPUTATION
Authors: RAMBAUD SALVADOR CRUZ , PÉREZ JOSÉ GARCÍA
Published: August 2005

Traditionally the beta distribution has been used due to its ease for computing the mean of tasks, times, cash-flows, etc. because, in this case, the expected value is a weighted average of optimistic, most likely and pessimistic values. One of the critiques of PERT has been the difficulty of introducing the level of confidence that the expert has in his own estimate of the modal value. The Belief in Fuzzy Probability Estimations of Time (BIFPET) model uses human judgement instead of stochastic assumptions to determine the duration of a project. Thus, each supervisor responsible of an activity specifies the three values with their respective probabilities. The manager accepts these probabilities or may extend them within a certain range, according to his belief in these likelihoods or the degree of control exercised by himself in achieving the lower bound of the expected value. However, this approach can be implemented in the PERT methodology. Thus, in this paper, we introduce the confidence that the manager has in the most likely value supplied by the supervisor in order to determine the specific beta distribution to model the variable, showing the advantages of this intuitive procedure which moreover can be easily implemented.
SMETS-MAGREZ AXIOMS FOR R-IMPLICATORS IN INTERVAL-VALUED AND INTUITIONISTIC FUZZY SET THEORY
Authors: DESCHRIJVER GLAD , KERRE ETIENNE E.
Published: August 2005

Interval-valued fuzzy sets constitute an extension of fuzzy sets which give an interval approximating the "real" (but unknown) membership degree. Interval-valued fuzzy sets are equivalent to intuitionistic fuzzy sets in the sense of Atanassov which give both a membership degree and a non-membership degree, whose sum must be smaller than or equal to 1. Both are equivalent to L-fuzzy sets w.r.t. a special lattice L*. In fuzzy set theory, an important class of triangular norms is the class of those that satisfy the residuation principle. In a previous paper5 we gave a construction for t-norms on L* satisfying the residuation principle which are not t-representable. In this paper we investigate the Smets-Magrez axioms and some other properties for the residual implicator generated by such t-norms.
Hypoxic reperfusion of the ischemic heart and oxygen radical generation
Authors: Angelos Mark G. , Kutala Vijay K. , Torres Carlos A. , He Guanglong , Stoner Jason D. , Mohammad Marwan , Kuppusamy Periannan
Published: August 2005

Postischemic myocardial contractile dysfunction is in part mediated by the burst of reactive oxygen species (ROS), which occurs with the reintroduction of oxygen. We hypothesized that tissue oxygen tension modulates this ROS burst at reperfusion. After 20 min of global ischemia, isolated rat hearts were reperfused with temperature-controlled (37.4°C) Krebs-Henseleit buffer saturated with one of three different O2concentrations (95, 20, or 2%) for the first 5 min of reperfusion and then changed to 95% O2. Additional hearts were loaded with 1) allopurinol (1 mM), a xanthine oxidase inhibitor, 2) diphenyleneiodonium (DPI; 1 μM), an NAD(P)H oxidase inhibitor, or 3) Tiron (10 mM), a superoxide scavenger, and were then reperfused with either 95 or 2% O2for the first 5 min. ROS production and tissue oxygen tension were quantitated using electron paramagnetic resonance spectroscopy. Tissue oxygen tension was significantly higher in the 95% O2group. However, the largest radical burst occurred in the 2% O2reperfusion group ( P < 0.001). Recovery of left ventricular (LV) contractile function and aconitase activity during reperfusion were inversely related to the burst of radical production and were significantly higher in hearts initially reperfused with 95% O2( P < 0.001). Allopurinol, DPI, and Tiron reduced the burst of radical formation in the 2% O2reperfusion groups ( P < 0.05). Hypoxic reperfusion generates an increased ROS burst originating from multiple pathways. Recovery of LV function during reperfusion is inversely related to this oxygen radical burst, highlighting the importance of myocardial oxygen tension during initial reperfusion.
Matrix metalloproteinase-9 gene deletion facilitates angiogenesis after myocardial infarction
Authors: Lindsey Merry L. , Escobar G. Patricia , Dobrucki Lawrence W. , Goshorn Danielle K. , Bouges Shenikqua , Mingoia Joseph T. , McClister David M. , Su Haili , Gannon Joseph , MacGillivray Catherine , Lee Richard T. , Sinusas Albert J. , Spinale Francis G.
Published: August 2005

Matrix metalloproteinases (MMPs) are postulated to be necessary for neovascularization during wound healing. MMP-9 deletion alters remodeling postmyocardial infarction (post-MI), but whether and to what degree MMP-9 affects neovascularization post-MI is unknown. Neovascularization was evaluated in wild-type (WT; n = 63) and MMP-9 null ( n = 55) mice at 7-days post-MI. Despite similar infarct sizes, MMP-9 deletion improved left ventricular function as evaluated by hemodynamic analysis. Blood vessel quantity and quality were evaluated by three independent studies. First, vessel density was increased in the infarct of MMP-9 null mice compared with WT, as quantified by Griffonia ( Bandeiraea) simplicifolia lectin I (GSL-I) immunohistochemistry. Second, preexisting vessels, stained in vivo with FITC-labeled GSL-I pre-MI, were present in the viable but not MI region. Third, a technetium-99m-labeled peptide (NC100692), which selectively binds to activated αvβ3-integrin in angiogenic vessels, was injected into post-MI mice. Relative NC100692 activity in myocardial segments with diminished perfusion (0–40% nonischemic) was higher in MMP-9 null than in WT mice (383 ± 162% vs. 250 ± 118%, respectively; P = 0.002). The unique finding of this study was that MMP-9 deletion stimulated, rather than impaired, neovascularization in remodeling myocardium. Thus targeted strategies to inhibit MMP-9 early post-MI will likely not impair the angiogenic response.
Correlation between heart valve interstitial cell stiffness and transvalvular pressure: implications for collagen biosynthesis
Authors: Merryman W. David , Youn Inchan , Lukoff Howard D. , Krueger Paula M. , Guilak Farshid , Hopkins Richard A. , Sacks Michael S.
Published: August 2005

It has been speculated that heart valve interstitial cells (VICs) maintain valvular tissue homeostasis through regulated extracellular matrix (primarily collagen) biosynthesis. VICs appear to be phenotypically plastic, inasmuch as they transdifferentiate into myofibroblasts during valve development, disease, and remodeling. Under normal physiological conditions, transvalvular pressures (TVPs) on the right and left side of the heart are vastly different. Hence, we hypothesize that higher left-side TVPs impose larger local tissue stress on VICs, which increases their stiffness through cytoskeletal composition, and that this relation affects collagen biosynthesis. To evaluate this hypothesis, isolated ovine VICs from the four heart valves were subjected to micropipette aspiration to assess cellular stiffness, and cytoskeletal composition and collagen biosynthesis were quantified by using the surrogates smooth muscle α-actin (SMA) and heat shock protein 47 (HSP47), respectively. VICs from the aortic and mitral valves were significantly stiffer ( P < 0.001) than those from the pulmonary and tricuspid valves. Left-side isolated VICs contained significantly more ( P < 0.001) SMA and HSP47 than right-side VICs. Mean VIC stiffness correlated well ( r = 0.973) with TVP; SMA and HSP47 also correlated well ( r = 0.996) with one another. Assays were repeated for VICs in situ, and, as with in vitro results, left-side VIC protein levels were significantly greater ( P < 0.05). These findings suggest that VICs respond to local tissue stress by altering cellular stiffness (through SMA content) and collagen biosynthesis. This functional VIC stress-dependent biosynthetic relation may be crucial in maintaining valvular tissue homeostasis and also prove useful in understanding valvular pathologies.
Fluid shear stress stimulates incorporation of hyaluronan into endothelial cell glycocalyx
Authors: Gouverneur Mirella , Spaan Jos A. E. , Pannekoek Hans , Fontijn Ruud D. , Vink Hans
Published: August 2005

Vascular endothelial cells are shielded from direct exposure to flowing blood by the endothelial glycocalyx, a highly hydrated mesh of glycoproteins, sulfated proteoglycans, and associated glycosaminoglycans (GAGs). Recent data indicate that the incorporation of the unsulfated GAG hyaluronan into the endothelial glycocalyx is essential to maintain its permeability barrier properties, and we hypothesized that fluid shear stress is an important stimulus for endothelial hyaluronan synthesis. To evaluate the effect of shear stress on glycocalyx synthesis and the shedding of its GAGs into the supernatant, cultured human umbilical vein endothelial cells (i.e., the stable cell line EC-RF24) were exposed to 10 dyn/cm2 nonpulsatile shear stress for 24 h, and the incorporation of [3H]glucosamine and Na2[35S]O4 into GAGs was determined. Furthermore, the amount of hyaluronan in the glycocalyx and in the supernatant was determined by ELISA. Shear stress did not affect the incorporation of 35S but significantly increased the amount of glucosamine-containing GAGs incorporated in the endothelial glycocalyx [168 (SD 17)% of static levels, P < 0.01] and shedded into the supernatant [231 (SD 41)% of static levels, P < 0.01]. Correspondingly with this finding, shear stress increased the amount of hyaluronan in the glycocalyx [from 26 (SD 24) × 10−4 to 46 (SD 29) × 10−4 ng/cell, static vs. shear stress, P < 0.05] and in the supernatant [from 28 (SD 11) × 10−4 to 55 (SD 16) × 10−4 ng·cell−1·h−1, static vs. shear stress, P < 0.05]. The increase in the amount of hyaluronan incorporated in the glycocalyx was confirmed by a threefold higher level of hyaluronan binding protein within the glycocalyx of shear stress-stimulated endothelial cells. In conclusion, fluid shear stress stimulates incorporation of hyaluronan in the glycocalyx, which may contribute to its vasculoprotective effects against proinflammatory and pro-atherosclerotic stimuli.
An anti-NH2-terminal antibody localizes NBCn1 to heart endothelia and skeletal and vascular smooth muscle cells
Authors: Damkier Helle Hasager , Nielsen Søren , Praetorius Jeppe
Published: August 2005

The electroneutral sodium bicarbonate cotransporter NBCn1 or NBC3 was originally cloned from rat aorta and from human skeletal muscle. NBCn1 (or NBC3) has been localized to the basolateral membrane of various epithelia, but thus far it has been impossible to detect the protein in these tissues by using anti-COOH-terminal antibodies. Hence an antibody was developed against the NH2-terminus of NBCn1 and was validated by peptide recognition and immunoblotting on positive control tissues and by binding of an ∼180-kDa protein in the rat kidney, cerebrum, cerebellum, and duodenum. In addition, an ∼180-kDa immunoreactive band appeared using samples from the aorta, heart ventricles and atria, mesenteric arteries, lung, spleen, liver, pancreas, and epididymis. Immunohistochemical analysis confirmed the previously described labeling in the kidney, duodenum, and the choroid plexus. The anti-NH2-terminal antibody localized NBCn1 to the plasma membrane domains of endothelia and smooth muscle cells in small mesenteric and renal arteries, as well as the capillaries of the heart ventricles, spleen, and salivary glands. NBCn1 was also detected in neuromuscular junctions and vasculature in skeletal muscle. Analysis of variable NBCn1 splicing by RT-PCR revealed that an NH2-terminal sequence, the cassette III, seems absent from cardiovascular NBCn1 and that both cassettes I and III are variable in most epithelia, whereas cassette II is absent from epithelial NBCn1. Thus the development of the NH2-terminal antibody allowed the localization of NBCn1 protein to major cardiovascular tissues where NBCn1 mRNA was previously detected. The NBCn1 is a likely candidate for mediating the reported electroneutral Na+-HCO3−cotransport in vascular smooth muscle.
Overexpression of cardiac connexin45 increases susceptibility to ventricular tachyarrhythmias in vivo
Authors: Betsuyaku Tetsuo , Nnebe Nkiruka S. , Sundset Rune , Patibandla Sushmitha , Krueger Charles M. , Yamada Kathryn A.
Published: August 2005

Electrophysiological remodeling involving gap junctions has been demonstrated in failing hearts and may contribute to intercellular uncoupling, delayed conduction, enhanced arrhythmias, and vulnerability to sudden death in patients with heart failure. Recently, we showed that failing human hearts exhibit marked increases in connexin45 (Cx45) expression in addition to previously documented decreases in connexin43 (Cx43) expression. Each of these changes results in reduced gap junction coupling. The objective of the present study was to examine functional consequences of increased Cx45 in cardiac gap junctions. Transgenic mice with cardiac-selective overexpression of the developmentally downregulated cardiac connexin, connexin45 (Cx45OE mice) were subjected to in vivo electrophysiology studies in which an intracardiac catheter was used to induce ventricular arrhythmias in anesthetized mice, and in which ambulatory ECG monitoring was used to detect spontaneous arrhythmias in unanesthetized mice. Hearts were analyzed by TaqMan RT-PCR, immunostaining, immunoblotting, and echocardiography. Lucifer yellow and neurobiotin dye transfer was used to assess coupling in transgenic and control myocyte cultures. Cx45 mRNA was two orders of magnitude greater in Cx45OE mice. Cx45-immunoreactive signal at gap junctions increased twofold and total Cx45 protein by immunoblotting increased 25% in Cx45OE mice compared with nontransgenic littermate controls. Functionally, Cx45OE mice exhibited more inducible ventricular tachycardia than controls but did not exhibit any other functional or structural derangements as assessed by echocardiography. Ventricular myocytes isolated from Cx45OE mice exhibited diminished intercellular transfer of Lucifer yellow dye and increased transfer of neurobiotin, consistent with altered cell-to-cell communication. Thus increased myocardial expression of Cx45 results in remodeling of intercellular coupling and greater susceptibility to ventricular arrhythmias in vivo.
Cigarette smoke suppresses Th1 cytokine production and increases RSV expression in a neonatal model
Authors: Phaybouth Vatsana , Wang Shan-Ze , Hutt Julie A. , McDonald Jacob D. , Harrod Kevin S. , Barrett Edward G.
Published: August 2005

Respiratory syncytial virus (RSV) infects ∼90% of young children by the age of 2 yr, with peak rates occurring during 2–6 mo of age. Exposure to side-stream cigarette smoke (SS) may increase the incidence or manifestation of an RSV infection. We hypothesized that exposure to SS would alter the subsequent immune response to RSV infection in neonatal mice. BALB/c mice were exposed to air or 1.5 mg/m3of SS from day (d) 1 up to 35 d of age. A subset was intranasally infected with 4 × 104PFU of RSV/g body wt on d 7 and rechallenged at 28 d of age. Immune responses were assessed on d 4 and 7 after RSV rechallenge. Both air- and SS-exposed mice responded to RSV rechallenge with neutrophilia and decreased Clara cell secretory protein levels within the lung. However, an increase in bronchoalveolar lavage fluid eosinophils, in addition to reduced levels of Th1 cytokines (IFN-γ and IL-12), decreased lung tissue inflammation, and decreased mucus production was observed in SS-exposed mice compared with air-exposed mice after RSV rechallenge. Ultimately changes in cytokine and inflammatory responses due to SS exposure likely contributed to increased viral gene expression. These results suggest that SS exposure plays a significant role in shaping the neonatal response to RSV infection.
BMP-7 opposes TGF-β1-mediated collagen induction in mouse pulmonary myofibroblasts through Id2
Authors: Izumi Nobuhiro , Mizuguchi Shinjiro , Inagaki Yutaka , Saika Shizuya , Kawada Norifumi , Nakajima Yuji , Inoue Kiyotoshi , Suehiro Shigefumi , Friedman Scott L. , Ikeda Kazuo
Published: August 2005

Mesenchymal cells, primarily fibroblasts and myofibroblasts, are the principal matrix-producing cells during pulmonary fibrogenesis. Transforming growth factor (TGF)-β signaling plays an important role in stimulating the expression of type I collagen of these cells. Bone morphogenetic protein (BMP)-7, a member of the TGF-β superfamily, has been reported to oppose the fibrogenic activity of TGF-β1. Here, we have addressed the effects of BMP-7 on the fibrogenic activity of pulmonary myofibroblasts. We first established cell lines from the lungs of transgenic mice harboring the COL1A2 upstream sequence fused to luciferase. They displayed a spindle shape and expressed vimentin and α-smooth muscle actin, but not E-cadherin. COL1A2 promoter activity was dose dependently induced by TGF-β1, which was further augmented by adenoviral overexpression of Smad3, but was downregulated by Smad7. Under the identical condition, adenoviral overexpression of BMP-7 attenuated the TGF-β1-dependent COL1A2 promoter activity. By immunocytochemistry, the ectopic expression of BMP-7 led to the nuclear localization of phospho-Smad1/5/8 and suppressed that of Smad3. BMP-7 suppressed the expression of mRNAs for COL1A2 and tissue inhibitor of metalloproteinase-2 while increasing those of inhibitors of differentiation (Id) 2 and 3. Ectopic expression of Id2 and Id3 was found to decrease the COL1A2 promoter activity. Finally, BMP-7 and Id2 decreased TGF-β1-dependent collagen protein secretion. In conclusion, these data demonstrate that BMP-7 antagonizes the TGF-β1-dependent fibrogenic activity of mouse pulmonary myofibroblastic cells by inducing Id2 and Id3.
Antibody-antigen interaction in the airway drives early granulocyte recruitment through BLT1
Authors: Medoff Benjamin D. , Tager Andrew M. , Jackobek Ryan , Means Terry K. , Wang Lan , Luster Andrew D.
Published: August 2005

Antibody-antigen interactions in the airway initiate inflammation in acute asthma exacerbations. This inflammatory response is characterized by the recruitment of granulocytes into the airways. In murine models of asthma, granulocyte recruitment into the lung contributes to the development of airway hyperresponsiveness (AHR), mucus production, and airway remodeling. Leukotriene B4is a mediator released following antigen challenge that has chemotactic activity for granulocytes, mediated through its receptor, BLT1. We investigated the role of BLT1 in granulocyte recruitment following antigen challenge. Wild-type mice and BLT1−/−mice were sensitized and challenged with ovalbumin (OVA) to induce acute allergic airway inflammation. In addition, to explore the relevance to antibody-antigen interactions, we injected OVA bound to anti-OVA IgG1or anti-OVA IgE intratracheally into naïve wild-type and BLT1−/−mice. Cell composition of the lungs, cytokine levels, histology, and AHR were determined. After sensitization and challenge with ovalbumin, there was significantly reduced neutrophil and eosinophil recruitment into the airways of BLT1−/−mice compared with wild-type animals after one or two daily antigen challenges, but this difference was not seen after three or four daily antigen challenges. Mucus production and AHR were not affected. Intratracheal injection of OVA bound to IgG1or IgE induced neutrophil recruitment into the airways in wild-type mice but not in the BLT1−/−mice. We conclude that BLT1 mediates early recruitment of granulocytes into the airway in response to antigen-antibody interactions in a murine model of acute asthma.
S-nitrosoglutathione inhibits α1-adrenergic receptor-mediated vasoconstriction and ligand binding in pulmonary artery
Authors: Nozik-Grayck Eva , Whalen Erin J. , Stamler Jonathan S. , McMahon Timothy J. , Chitano Pasquale , Piantadosi Claude A.
Published: August 2005

Endogenous nitric oxide donor compounds ( S-nitrosothiols) contribute to low vascular tone by both cGMP-dependent and -independent pathways. We have reported that S-nitrosoglutathione (GSNO) inhibits 5-hydroxytryptamine (5-HT)-mediated pulmonary vasoconstriction via a cGMP-independent mechanism likely involving S-nitrosylation of its G protein-coupled receptor (GPCR) system. Because catecholamines, like 5-HT, constrict lung vessels via a GPCR coupled to Gq, we hypothesized that S-nitrosothiols modify the α1-adrenergic GPCR system to inhibit pulmonary vasoconstriction by receptor agonists, e.g., phenylephrine (PE). Rat pulmonary artery rings were pretreated for 30 min with and without an S-nitrosothiol, either GSNO or S-nitrosocysteine (CSNO), and constricted with sequential concentrations of PE (10−8–10−6 M). Effective cGMP-dependence was tested in rings pretreated with soluble guanylate cyclase inhibitors {either 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) or LY-83583} or G kinase inhibitor (KT-5823), and a thiol reductant [dithiothreitol (DTT)] was used to test reversibility of S-nitrosylation. Both S-nitrosothiols attenuated the PE dose response. The GSNO effect was not prevented by LY-83583, ODQ, or KT-5823, indicating cGMP independence. GSNO inhibition was reversed by DTT, consistent with S-nitrosylation or other GSNO-mediated cysteine modifications. In CSNO-treated lung protein, the α1-adrenergic receptor was shown to undergo S-nitrosylation in vitro using a biotin switch assay. Studies of α1-adrenergic receptor subtype expression and receptor density by saturation binding with 125I-HEAT showed that GSNO decreased α1-adrenergic receptor density but did not alter affinity for antagonist or agonist. These data demonstrate a novel cGMP-independent mechanism of reversible α1-adrenergic receptor inhibition by S-nitrosothiols.
Coronary artery bypass surgery in high-risk patients
Authors: Kunt Alper Sami , Darcın Osman Tansel , Andac Mehmet Halit
Published: August 2005

Background

In high-risk coronary artery bypass patients; off-pump versus on-pump surgical strategies still remain a matter of debate, regarding which method results in a lower incidence of perioperative mortality and morbidity. We describe our experience in the treatment of high-risk coronary artery patients and compare patients assigned to on-pump and off-pump surgery.

Methods

From March 2002 to July 2004, 86 patients with EuroSCOREs > 5 underwent myocardial revascularization with or without cardiopulmonary bypass. Patients were assigned to off-pump surgery (40) or on-pump surgery (46) based on coronary anatomy coupled with the likelihood of achieving complete revascularization.

Results

Those patients undergoing off-pump surgery had significantly poorer left ventricular function than those undergoing on-pump surgery (28.6 ± 5.8% vs. 40.5 ± 7.4%, respectively, p < 0.05) and also had higher Euroscore values (7.26 ± 1.4 vs. 12.1 ± 1.8, respectively, p < 0.05). Differences between the two groups were nonsignificant with regard to number of grafts per patient, mean duration of surgery, anesthesia and operating room time, length of stay intensive care unit (ICU) and rate of postoperative atrial fibrillation

Conclusion

Utilization of off-pump coronary artery bypass graft (CABG) does not confer significant clinical advantages in all high-risk patients. This review suggest that off-pump coronary revascularization may represent an alternative approach for treatment of patients with Euroscore ≥ 10 and left ventricular function ≤ 30%.
FiatFlux – a software for metabolic flux analysis from 13C-glucose experiments
Authors: Zamboni Nicola , Fischer Eliane , Sauer Uwe
Published: August 2005

Background

Quantitative knowledge of intracellular fluxes is important for a comprehensive characterization of metabolic networks and their functional operation. In contrast to direct assessment of metabolite concentrations, in vivo metabolite fluxes must be inferred indirectly from measurable quantities in 13C experiments. The required experience, the complicated network models, large and heterogeneous data sets, and the time-consuming set-up of highly controlled experimental conditions largely restricted metabolic flux analysis to few expert groups. A conceptual simplification of flux analysis is the analytical determination of metabolic flux ratios exclusively from MS data, which can then be used in a second step to estimate absolute in vivo fluxes.

Results

Here we describe the user-friendly software package FiatFlux that supports flux analysis for non-expert users. In the first module, ratios of converging fluxes are automatically calculated from GC-MS-detected 13C-pattern in protein-bound amino acids. Predefined fragmentation patterns are automatically identified and appropriate statistical data treatment is based on the comparison of redundant information in the MS spectra. In the second module, absolute intracellular fluxes may be calculated by a 13C-constrained flux balancing procedure that combines experimentally determined fluxes in and out of the cell and the above flux ratios. The software is preconfigured to derive flux ratios and absolute in vivo fluxes from [1-13C] and [U-13C]glucose experiments and GC-MS analysis of amino acids for a variety of microorganisms.

Conclusion

FiatFlux is an intuitive tool for quantitative investigations of intracellular metabolism by users that are not familiar with numerical methods or isotopic tracer experiments. The aim of this open source software is to enable non-specialists to adapt the software to their specific scientific interests, including other 13C-substrates, labeling mixtures, and organisms.
Variation in structural location and amino acid conservation of functional sites in protein domain families
Authors: Pils Birgit , Copley Richard R , Schultz Jörg
Published: August 2005

Background

The functional sites of a protein present important information for determining its cellular function and are fundamental in drug design. Accordingly, accurate methods for the prediction of functional sites are of immense value. Most available methods are based on a set of homologous sequences and structural or evolutionary information, and assume that functional sites are more conserved than the average. In the analysis presented here, we have investigated the conservation of location and type of amino acids at functional sites, and compared the behaviour of functional sites between different protein domains.

Results

Functional sites were extracted from experimentally determined structural complexes from the Protein Data Bank harbouring a conserved protein domain from the SMART database. In general, functional (i.e. interacting) sites whose location is more highly conserved are also more conserved in their type of amino acid. However, even highly conserved functional sites can present a wide spectrum of amino acids. The degree of conservation strongly depends on the function of the protein domain and ranges from highly conserved in location and amino acid to very variable. Differentiation by binding partner shows that ion binding sites tend to be more conserved than functional sites binding peptides or nucleotides.

Conclusion

The results gained by this analysis will help improve the accuracy of functional site prediction and facilitate the characterization of unknown protein sequences.
stam – a Bioconductor compliant R package for structured analysis of microarray data
Authors: Lottaz Claudio , Spang Rainer
Published: August 2005

Background

Genome wide microarray studies have the potential to unveil novel disease entities. Clinically homogeneous groups of patients can have diverse gene expression profiles. The definition of novel subclasses based on gene expression is a difficult problem not addressed systematically by currently available software tools.

Results

We present a computational tool for semi-supervised molecular disease entity detection. It automatically discovers molecular heterogeneities in phenotypically defined disease entities and suggests alternative molecular sub-entities of clinical phenotypes. This is done using both gene expression data and functional gene annotations.

We provide stam, a Bioconductor compliant software package for the statistical programming environment R. We demonstrate that our tool detects gene expression patterns, which are characteristic for only a subset of patients from an established disease entity. We call such expression patterns molecular symptoms. Furthermore, stam finds novel sub-group stratifications of patients according to the absence or presence of molecular symptoms.

Conclusion

Our software is easy to install and can be applied to a wide range of datasets. It provides the potential to reveal so far indistinguishable patient sub-groups of clinical relevance.
A new dynamical layout algorithm for complex biochemical reaction networks
Authors: Wegner Katja , Kummer Ursula
Published: August 2005

Background

To study complex biochemical reaction networks in living cells researchers more and more rely on databases and computational methods. In order to facilitate computational approaches, visualisation techniques are highly important. Biochemical reaction networks, e.g. metabolic pathways are often depicted as graphs and these graphs should be drawn dynamically to provide flexibility in the context of different data. Conventional layout algorithms are not sufficient for every kind of pathway in biochemical research. This is mainly due to certain conventions to which biochemists/biologists are used to and which are not in accordance to conventional layout algorithms. A number of approaches has been developed to improve this situation. Some of these are used in the context of biochemical databases and make more or less use of the information in these databases to aid the layout process. However, visualisation becomes also more and more important in modelling and simulation tools which mostly do not offer additional connections to databases. Therefore, layout algorithms used in these tools have to work independently of any databases. In addition, all of the existing algorithms face some limitations with respect to the number of edge crossings when it comes to larger biochemical systems due to the interconnectivity of these. Last but not least, in some cases, biochemical conventions are not met properly.

Results

Out of these reasons we have developed a new algorithm which tackles these problems by reducing the number of edge crossings in complex systems, taking further biological conventions into account to identify and visualise cycles. Furthermore the algorithm is independent from database information in order to be easily adopted in any application. It can also be tested as part of the SimWiz package (free to download for academic users at [1]).

Conclusion

The new algorithm reduces the complexity of pathways, as well as edge crossings and edge length in the resulting graphical representation. It also considers existing and further biological conventions to create a drawing most biochemists are familiar with. A lot of examples can be found on [2].
Improved prediction of critical residues for protein function based on network and phylogenetic analyses
Authors: Thibert Boris , Bredesen Dale E , del Rio Gabriel
Published: August 2005

Background

Phylogenetic approaches are commonly used to predict which amino acid residues are critical to the function of a given protein. However, such approaches display inherent limitations, such as the requirement for identification of multiple homologues of the protein under consideration. Therefore, complementary or alternative approaches for the prediction of critical residues would be desirable. Network analyses have been used in the modelling of many complex biological systems, but only very recently have they been used to predict critical residues from a protein's three-dimensional structure. Here we compare a couple of phylogenetic approaches to several different network-based methods for the prediction of critical residues, and show that a combination of one phylogenetic method and one network-based method is superior to other methods previously employed.

Results

We associate a network with each member of a set of proteins for which the three-dimensional structure is known and the critical residues have been previously determined experimentally. We show that several network-based centrality measurements (connectivity, 2-connectivity, closeness centrality, betweenness and cluster coefficient) accurately detect residues critical for the protein's function. Phylogenetic approaches render predictions as reliable as the network-based measurements, although, interestingly, the two general approaches tend to predict different sets of critical residues. Hence we propose a hybrid method that is composed of one network-based calculation – the closeness centrality – and one phylogenetic approach – the Conseq server. This hybrid approach predicts critical residues more accurately than the other methods tested here.

Conclusion

We show that network analysis can be used to improve the prediction of amino acids critical for protein function, when utilized in combination with phylogenetic approaches. It is proposed that such improvement is due to the complementary nature of these approaches: network-based methods tend to predict as critical those residues that are highly connected and internal (i.e., non-surface), although some surface residues are indeed identified as critical by network analyses; whereas residues chosen by phylogenetic approaches display a lower overall probability of being surface inaccessible.
Plexin B3 promotes neurite outgrowth, interacts homophilically, and interacts with Rin
Authors: Hartwig Christine , Veske Andres , Krejcova Sarka , Rosenberger Georg , Finckh Ulrich
Published: August 2005

Background

Plexins, known to date as receptors of semaphorins, are implicated in semaphorin-mediated axon repulsion and growth cone collapse. However, subtype-specific functions of the majority of the nine members of the mammalian plexin family are largely unknown. In order to investigate functional properties of B-plexins, we analyzed the expression of human and murine plexin B3 and expressed full-length human plexins B2 (B2) and B3 (B3) in NIH-3T3 cells.

Results

Unexpectedly, B3 strongly and B2 moderately stimulate neurite outgrowth of primary murine cerebellar neurons. Both plexins mediate Ca2+/Mg2+-dependent cell aggregation due to homophilic trans-interaction, which is strong in the case of B3 and moderate for B2. Using different deletion constructs we show that the sema domain of B3 is essential for homophilic interaction. Using yeast two-hybrid analysis, we identified the neuron-specific and calmodulin-binding Ras-related GTPase Rin as an interaction partner of the intracellular part of B3, but not of B2. Rin, also known for its neurite outgrowth-inducing characteristics, co-localizes and co-immunoprecipitates with B3 in co-transfected COS-7 cells.

Conclusion

Our data suggest an involvement of homophilic interaction of B3 in semaphorin-independent signaling mechanisms positively influencing neuronal morphogenesis or function. Furthermore the neuron-specific small GTPase Rin is involved in downstream signaling of plexin B3.
Organic acid toxicity, tolerance, and production in Escherichia coli biorefining applications
Authors: Warnecke Tanya , Gill Ryan T
Published: August 2005

Organic acids are valuable platform chemicals for future biorefining applications. Such applications involve the conversion of low-cost renewable resources to platform sugars, which are then converted to platform chemicals by fermentation and further derivatized to large-volume chemicals through conventional catalytic routes. Organic acids are toxic to many of the microorganisms, such asEscherichia coli, proposed to serve as biorefining platform hosts at concentrations well below what is required for economical production. The toxicity is two-fold including not only pH based growth inhibition but also anion-specific effects on metabolism that also affect growth.E. colimaintain viability at very low pH through several different tolerance mechanisms including but not limited to the use of decarboxylation reactions that consume protons, ion transporters that remove protons, increased expression of known stress genes, and changing membrane composition. The focus of this mini-review is on organic acid toxicity and associated tolerance mechanisms as well as several examples of successful organic acid production processes forE. coli.
Teratogenicity of depleted uranium aerosols: A review from an epidemiological perspective
Authors: Hindin Rita , Brugge Doug , Panikkar Bindu
Published: August 2005

Background

Depleted uranium is being used increasingly often as a component of munitions in military conflicts. Military personnel, civilians and the DU munitions producers are being exposed to the DU aerosols that are generated.

Methods

We reviewed toxicological data on both natural and depleted uranium. We included peer reviewed studies and gray literature on birth malformations due to natural and depleted uranium. Our approach was to assess the "weight of evidence" with respect to teratogenicity of depleted uranium.

Results

Animal studies firmly support the possibility that DU is a teratogen. While the detailed pathways by which environmental DU can be internalized and reach reproductive cells are not yet fully elucidated, again, the evidence supports plausibility. To date, human epidemiological data include case examples, disease registry records, a case-control study and prospective longitudinal studies.

Discussion

The two most significant challenges to establishing a causal pathway between (human) parental DU exposure and the birth of offspring with defects are: i) distinguishing the role of DU from that of exposure to other potential teratogens; ii) documentation on the individual level of extent of parental DU exposure. Studies that use biomarkers, none yet reported, can help address the latter challenge. Thoughtful triangulation of the results of multiple studies (epidemiological and other) of DU teratogenicity contributes to disentangling the roles of various potentially teratogenic parental exposures. This paper is just such an endeavor.

Conclusion

In aggregate the human epidemiological evidence is consistent with increased risk of birth defects in offspring of persons exposed to DU.
Non-infected preterm parturition is related to increased concentrations of IL-6, IL-8 and MCP-1 in human cervix
Authors: Törnblom Susanne Abelin , Klimaviciute Aurelija , Byström Birgitta , Chromek Milan , Brauner Annelie , Ekman-Ordeberg Gunvor
Published: August 2005

Background

Human cervical ripening is an inflammatory process. In labour at term the mRNA-levels and protein concentrations for interleukin-6 (IL-6) and IL-8 in cervix significantly increase. The aim of this study was to investigate if there are differences in the inflammatory process of preterm and term cervical ripening.

Methods

Cervical biopsies from 50 singleton pregnant women without clinical signs of infection were allocated to four groups: preterm labour, term labour, preterm not in labour and term not in labour. The protein levels of IL-8, IL-6, monocyte chemotactic protein-1 (MCP-1), regulated upon activation normal t cells expressed and secreted (RANTES) and tumour necrosis factor-alpha (TNF-alpha) were quantified in tissue homogenates by ELISA or Immulite. The mRNA expression of IL-8, MCP-1 and RANTES was studied using RT-PCR. White blood cell count (WBC) and C-reactive protein (CRP) in the blood were determined. For determination of statistically significant differences between study groups Mann-Whitney U test or Kruskal-Wallis test were applied.

Results

Protein concentrations of IL-8, IL-6, and MCP-1 were significantly increased during labour compared to non-labouring groups, whereas no changes were observed for RANTES and TNF-alpha. The mRNA levels of representative cytokines such as IL-8 and MCP-1 increased significantly during labour whereas RANTES mRNA expression remained unchanged. WBC and CRP were significantly higher in the labouring groups as compared to groups not in labour. For neither of the analysed cytokines, WBC or CRP levels were there any changes between preterm and term respective groups.

Conclusion

Our findings indicate that non-infected preterm cervical ripening is an inflammatory process, just as cervical ripening at term, with cytokines as important mediators.
The SARS Coronavirus S Glycoprotein Receptor Binding Domain: Fine Mapping and Functional Characterization
Authors: Chakraborti Samitabh , Prabakaran Ponraj , Xiao Xiaodong , Dimitrov Dimiter S
Published: August 2005

The entry of the SARS coronavirus (SCV) into cells is initiated by binding of its spike envelope glycoprotein (S) to a receptor, ACE2. We and others identified the receptor-binding domain (RBD) by using S fragments of various lengths but all including the amino acid residue 318 and two other potential glycosylation sites. To further characterize the role of glycosylation and identify residues important for its function as an interacting partner of ACE2, we have cloned, expressed and characterized various soluble fragments of S containing RBD, and mutated all potential glycosylation sites and 32 other residues. The shortest of these fragments still able to bind the receptor ACE2 did not include residue 318 (which is a potential glycosylation site), but started at residue 319, and has only two potential glycosylation sites (residues 330 and 357). Mutation of each of these sites to either alanine or glutamine, as well as mutation of residue 318 to alanine in longer fragments resulted in the same decrease of molecular weight (by approximately 3 kDa) suggesting that all glycosylation sites are functional. Simultaneous mutation of all glycosylation sites resulted in lack of expression suggesting that at least one glycosylation site (any of the three) is required for expression. Glycosylation did not affect binding to ACE2. Alanine scanning mutagenesis of the fragment S319–518 resulted in the identification of ten residues (K390, R426, D429, T431, I455, N473, F483, Q492, Y494, R495) that significantly reduced binding to ACE2, and one residue (D393) that appears to increase binding. Mutation of residue T431 reduced binding by about 2-fold, and mutation of the other eight residues – by more than 10-fold. Analysis of these data and the mapping of these mutations on the recently determined crystal structure of a fragment containing the RBD complexed to ACE2 (Li, F, Li, W, Farzan, M, and Harrison, S. C., submitted) suggested the existence of two hot spots on the S RBD surface, R426 and N473, which are likely to contribute significant portion of the binding energy. The finding that most of the mutations (23 out of 34 including glycosylation sites) do not affect the RBD binding function indicates possible mechanisms for evasion of immune responses.
The nuclear-envelope protein and transcriptional repressor LAP2β interacts with HDAC3 at the nuclear periphery, and induces histone H4 deacetylation
Authors: Somech Raz , Shaklai Sigal , Geller Orit , Amariglio Ninette , Simon Amos J. , Rechavi Gideon , Gal-Yam Einav Nili
Published: August 2005

Nuclear-envelope proteins have been implicated in diverse and fundamental cell functions, among them transcriptional regulation. Gene expression at the territory of the nuclear periphery is known to be repressed by epigenetic modifications such as histone deacetylation and methylation. However, the mechanism by which nuclear-envelope proteins are involved in such modifications is still obscure. We have previously shown that LAP2β, an integral nuclear-envelope protein that contains the chromatin-binding LEM domain, was able to repress the transcriptional activity of the E2F5-DP3 heterodimer. Here, we show that LAP2β's repressive activity is more general, encompassing various E2F members as well as other transcription factors such as p53 and NF-κB. We further show that LAP2β interacts at the nuclear envelope with HDAC3, a class-I histone deacetylase, and that TSA (an HDAC inhibitor) abrogates LAP2β's repressive activity. Finally, we show that LAP2β is capable of inducing histone-H4 deacetylation. Our data provide evidence for the existence of a previously unknown repressive complex, composed of an integral nuclear membrane protein and a histone modifier, at the nuclear periphery.