bluuebunny/crossref_metadata_2025 huggingface dataset:
Precaution in the harvest of Methuselah's clams  the difficulty of getting timely feedback from slow-paced dynamics
Authors: Orensanz JM (Lobo) , Hand Claudia M , Parma Ana M , Valero Juan , Hilborn Ray
Published: November 2004

Geoduck (Panopea abrupta) stocks are perceived as stable and their fisheries as sustainable, but this may reflect a mismatch between slow-paced dynamics (maximum recorded age 168 years) and short-term perception. Management is based on biological reference points, whose appropriateness as a means to ensure sustainability is limited by a sedentary lifestyle and long-term trends in productivity. Analysis of age frequency distributions for 19791983, postharvest recovery rates measured in Washington in tracts pulse-fished during the 1980s and 1990s, and age frequency distributions compiled in British Columbia during the 1990s consistently suggest that recruitment declined for decades (long before the onset of the fishery), reaching a minimum around 1975, and rebounded afterwards. In such scenario, reliance on biological-reference-point-based harvest rules without timely feedback could accelerate population declines, eventually driving an apparently sustainable fishery to collapse. The merits of approaches that rely on monitoring and feedback using data-driven decision rules are stressed. Transition from a biological-reference-point-based strategy to one based on monitoring and feedback will demand a shift in research focus to the design of practical monitoring programs and the evaluation of management procedures by means of simulations. For geoducks and other long-lived organisms, monitoring should integrate data informative at different temporal scales.
Biological reference points for American lobster (Homarus americanus) populations: limits to exploitation and the precautionary approach
Authors: Fogarty Michael J , Gendron Louise
Published: November 2004

Large-scale changes in American lobster (Homarus americanus) landings and abundance have been documented in both Canada and the United States over the last several decades. The spatial coherence of these changes suggests the importance of common environmental and fishery-related factors operating over broad areas in the western North Atlantic. Changes in both biotic and abiotic factors have been hypothesized to underlie the recent increases in lobster production. Area expansion of lobsters to previously unoccupied or low-density areas appears to be an important element of the population increase. Here, we review biological reference points applied to American lobster populations in the United States and Canada. Egg production per recruit models have been used to specify limit reference points (F10% in the United States) or target reference points (increasing egg production per recruit to twice its 1995 level in Canada). Surplus production and yield-per-recruit models have also been employed to provide qualitative management guidelines. We describe sources of uncertainty in the development of biological reference points for American lobster based on dynamic pool models in relation to the precautionary approach. Finally we consider auxiliary indicators and reference points with potential application to lobster stocks.
The titanocene-catalyzed reduction of acetamides to tertiary amines by PhMeSiH2
Authors: Selvakumar Kumaravel , Rangareddy Kesamreddy , Harrod John F
Published: November 2004

A variety of acetamide derivatives are reduced in excellent yields to tertiary amines by PhMeSiH2 in the presence of Cp2TiX2 (X = F or Me) catalysts. The reactions are very clean at 80 °C. At room temperature a secondary reaction, hydrogenolysis of the C(O)N bond, intervenes and reduces the chemoselectivity. Nevertheless, this chemistry provides a simple methodology for the amide/alkylamine transformation using inexpensive, commercially available reagents.Key words: amides, reduction, secondary amides, methylphenylsilane, titanocene, catalysis.
Synthesis and characterization of a series of 1-methyl-4-[2-aryl-1-diazenyl]piperazines and a series of ethyl 4-[2-aryl-1-diazenyl]-1-piperazinecarboxylates
Authors: Little Vanessa Renée , Vaughan Keith
Published: November 2004

1-Methylpiperazine was coupled with a series of diazonium salts to afford the 1-methyl-4-[2-aryl-1-diazenyl]piperazines (2), a new series of triazenes, which have been characterized by 1H and 13C NMR spectroscopy, IR spectroscopy, and elemental analysis. Assignment of the chemical shifts to specific protons and carbons in the piperazine ring was facilitated by comparison with the chemical shifts in the model compounds piperazine and 1-methylpiperazine and by a HETCOR experiment with the p-tolyl derivative (2i). A DEPT experiment with 1-methylpiperazine (6) was necessary to distinguish the methyl and methylene groups in 6, and a HETCOR spectrum of 6 enabled the correlation of proton and carbon chemical shifts. Line broadening of the signals from the ring methylene protons is attributed to restricted rotation around the N2-N3 bond of the triazene moiety in 2. The second series of triazenes, the ethyl 4-[2-phenyl-1-diazenyl]-1-piperazinecarboxylates (3), have been prepared by similar diazonium coupling to ethyl 1-piperazinecarboxylate and were similarly characterized. The chemical shifts of the piperazine ring protons are much closer together in series 3 than in series 2, resulting in distortion of the multiplets for these methylenes. It was noticed that the difference between these chemical shifts in 3 exhibited a linear free energy relationship with the Hammett substituent constants for the substituents in the aryl ring. Key words: triazene, piperazine, diazonium coupling, NMR, HETCOR, linear free energy relationship.
Identification of complexes involving toxic heavy metals with amino acid ligands by electrospray ionization mass spectrometry
Authors: Burford Neil , Eelman Melanie D , LeBlanc Wesley G
Published: November 2004

Electrospray ionization mass spectra (ESI-MS) of reaction mixtures containing ions of the heavy metals, cadmium, mercury, thallium, lead, and bismuth with each of the naturally occurring amino acids allows for definitive identification of monocationic complexes in the gas phase. Prominent m/z peaks are assigned to ions of the type [E(Am)  xH]+ (x = 0, 1, 2), [E(Am)2  xH]+ (x = 0, 1, 2), [E2(Am)  xH]+ (x = 1, 2, 3), and (or) [E2(Am)2  xH]+ (x = 1, 3, 5) for all amino acids studied (Am) with all metals studied (E = Cd, Hg, Tl, Pb) except bismuth, which shows complexes with only seven amino acids (Am = His, Thr, Met, Cys, Hcys, Asn, Gln). The results demonstrate the potential application of ESI-MS as a versatile and efficient approach to study toxic heavy metals in biological systems.Key words: heavy metals, amino acids, electrospray ionization mass spectrometry.
THE COMPLETE EXCITATION SPECTRUM OF THE ALKALI-METAL-DOPED SUPERCONDUCTING FULLERENES
Authors: DEGIORGI L.
Published: November 2004

The electrodynamic response in the normal and superconducting ground states of K 3 C 60 and Rb 3 C 60 is reviewed. The normal state optical properties are rather unconventional since they can be explained only by considering the interplay of a Drude-like and a mid-infrared absorption component. On the other hand, the superconducting state optical properties are more straightforward since they display clear fingerprints related to the conventional weak coupling limit of the BCS ground state. Our optical spectra clearly display a well developed excitation due to the superconducting gap. Moreover, the analysis of our optical results in the superconducting state within the standard Eliashberg electron–phonon theory of superconductivity strongly supports a pairing mechanism mediated by high frequency intramolecular phonon modes.
DIRAC DESCRIPTION OF ENERGY LEVELS OF POLARONS IN POLYANILINE
Authors: MAKARUK H.
Published: November 2004

In this paper an exact method for determining energy levels of polarons in systems with configuration spaces of the order parameter being the SU(2) group is presented. The base of the method being the evaluation of the spectrum for the Dirac operator on this manifold is shown. Conditions for a substance under which a polaron configuration space is SU(2) are formulated. Satisfaction of these conditions by polyaniline is proved. The representation of the UV-Vis polyaniline spectrum applying the Dirac operator spectrum is given. Applicability of the spectrum to other synthetic metals with SU(2) as the configuration space for the order parameter is discussed.
INSULATOR-TO-METAL TRANSITION IN LaRhO3 UNDER HIGH PRESSURE
Authors: ASOKAMANI R. , TRINADH CH. U.M. , PARI G. , NATARAJAN S.
Published: November 2004

The band structure calculations of perovskite transition metal compound LaRhO 3 performed using 'tight binding linear muffin tin orbital' (TB-LMTO) method within local density approximation (LDA) under ambient and high pressures are reported here. Our calculations are able to successfully explain the insulating nature of the system and the insulator-to-metal transition (IMT) is observed for the reduced volume of 0.90. The first electronic structure calculation reported here for LaRhO 3 enables us to compare it with that of LaCoO 3 which brings out the role played by the d bands. These studies lead to distinguish between these two insulating systems and LaCoO 3 is found to be a charge transfer (CT) insulator which is in agreement with the recent experimental observations whereas LaRhO 3 is a conventional band insulator. Further, the equilibrium lattice constant, bulk modulus, its first derivative, and metallization volume obtained from the total energy calculations for expanded and reduced cell volumes are also reported for LaRhO 3.
SAMARIUM DOPED Bi2−xSr2Ca2Cu3O10+δ HIGH TEMPERATURE SUPERCONDUCTOR
Authors: THOMAS PREETHI CICILY , KUMAR MANOJ K. , NAYAR V. UNNIKRISHNAN
Published: November 2004

Samarium is doped into Bi 2−x Sr 2 Ca 2 Cu 3 O 10+δ in the concentrations (x) 0.1, 0.2, and 0.3, and the resistivity, XRD patterns and Raman spectra are investigated. Samples do not exhibit superconductivity down to 77 K in the resistivity measurements. The characteristic peaks of the high T c 2223 phase are not observed in the XRD patterns, while a few peaks of the semiconducting 2201 phase are obtained. Raman spectra recorded at 296 K and 93 K do not reveal the characteristic bands of the superconducting phase.
ON NETWORK DISTANCE COEFFICIENTS AND NETWORK DYNAMICS
Authors: ROYER S.T. , MATHEWSON D.J. , HOFFMANN G.W.
Published: November 2004

We review and extend a method for measuring the amount of dissimilarity between N idiotypes of an immune network. We also show how the method can be used for a two-dimensional representation of the dynamics of the idiotypes of an immune network. To illustrate the method, dynamics of an N-dimensional immune network model are embedded in a shape-space called periodic Δ shape-space, which we introduce here.
TIME-DEPENDENT QUANTUM MECHANICAL TREATMENT OF He–CO INELASTIC SCATTERING
Authors: AKPINAR SINAN , BULUT NIYAZI , GOGTAS FAHRETTIN
Published: November 2004

The state-to-state and state-to-all reaction probabilities for He + CO (v,j)→ He + CO (v',j') reaction at zero total angular momentum have been calculated by using a time-dependent quantum wave packet method. The time-dependent method used is based on Fourier Grid and Discrete Variable Representation (DVR) techniques. The time-dependent propagation of the wave packet is accomplished by an expansion in terms of modified complex chebyshev polynomials. The results show that the He + CO reaction is not reactive in the studied energy range.
PROTEIN FORCE-FIELD PARAMETERS OPTIMIZED WITH THE PROTEIN DATA BANK II: COMPARISONS OF FORCE FIELDS BY FOLDING SIMULATIONS OF SHORT PEPTIDES
Authors: SAKAE YOSHITAKE , OKAMOTO YUKO
Published: November 2004

In Paper I of this series, the formulations of the optimization method of existing force-field parameters for protein systems have been presented. We then applied it to five sets of force-field parameters, namely, AMBER parm94, AMBER parm96, AMBER parm99, CHARMM version 22, and OPLS-AA. In order to test the validity of these force fields, the folding simulations of α-helical and β-hairpin peptides have been performed with each of the original and optimized force-field parameters. We found that all five modified force-field parameters gave both α-helical and β-hairpin structures more consistent with the experimental implications than the original force fields.
FORWARD-BACKWARD SEMICLASSICAL SIMULATION OF DYNAMICAL PROCESSES IN LIQUIDS
Authors: MAKRI NANCY , NAKAYAMA AKIRA , WRIGHT NICHOLAS J.
Published: November 2004

Forward-backward semiclassical dynamics (FBSD) provides a practical methodology for including quantum mechanical effects in classical trajectory simulations of polyatomic systems. FBSD expressions for time-dependent expectation values or correlation functions take the form of phase space integrals with respect to trajectory initial conditions, weighted by the coherent state transform of a corrected density operator. Quantization through a discretized path integral representation of the Boltzmann operator ensures a proper treatment of zero point energy effects and of imaginary components in finite-temperature correlation functions, and extension to systems obeying Bose statistics is possible. Accelerated convergence is achieved via Monte Carlo or molecular dynamics sampling techniques and through the construction of improved imaginary time propagators. The accuracy of the methodology is demonstrated on several model systems, including models of Bose and Fermi particles. Applications to liquid argon, neon and para-hydrogen are presented.
PHOTODISSOCIATION OF OZONE IN THE HARTLEY BAND: FRAGMENT ROTATIONAL QUANTUM STATE DISTRIBUTIONS
Authors: ZHAO MEI-YU , HAN KE-LI , HE GUO-ZHONG , ZHANG JOHN Z. H.
Published: November 2004

In this paper, we have calculated the rotational state distributions following the photodissociation of ozone in the Hartley band with total angular momentum J'=1. The calculated results are obtained by using time-dependent wave packet calculations on the Sheppard–Walker potential energy surface (PES). It is found that the physically more correct treatment with J'=1 semi-quantitatively reproduces the rotational state distributions of the CARS. Compared with the previous theoretical works, which had taken J=0 on both the ground and excited potential surface, J'=1 treatment makes the rotational distributions of the fragment closer to the experimental ones.
PREDICTION OF THE ENTHALPY OF FORMATION OF HYDROCARBONS USING SPARC
Authors: WHITESIDE TAD S. , CARREIRA LIONEL A.
Published: November 2004

Standard enthalpies of formation (ΔHf) were calculated with models developed using the computer program SPARC. SPARC uses computational algorithms based on chemical structure theory to calculate the ΔHf. Molecular structures are broken into simple functional units (reactophores) with intrinsic properties. Each reactophore is analyzed and the effects of appended molecular structures are quantified through perturbation theory. The ΔHf models have been developed using all known data for saturated and unsaturated hydrocarbons. The structures of these compounds vary from chains to conjugated rings to poly-benzoic aromatic hydrocarbons. The SPARC calculated RMS deviation of these 587 compounds is 4.50 kJ mol-1.
ADSORPTION AND DECOMPOSITION OF ClCN ON Si (100)-(2×1) SURFACE: A DENSITY FUNCTIONAL THEORY STUDY
Authors: HU JIAN MING , LI YI , ZHANG YONG FAN , LI JUN QIAN , CHEN YONG
Published: November 2004

The adsorption and decomposition of ClCN on Si (100)-(2×1) surface is studied by using density functional theory and the cluster model method. The Si 9 H 12 dimer cluster is used to simulate the surface. The present calculations show that ClCN may be adsorbed molecularly without a barrier onto the surface with both linear (L1) and parallel (S1) modes. L1 can isomerize to S1 with a small barrier of 5.6 kcal/mol. Both ClCN and ClNC end-on adsorbates were found to dissociate readily to produce Cl and CN species, which was in excellent agreement with the experiment.
Epidermal growth factor reduces intestinal apoptosis in an experimental model of necrotizing enterocolitis
Authors: Clark Jessica A. , Lane Robert H. , MacLennan Nicole K. , Holubec Hana , Dvorakova Katerina , Halpern Melissa D. , Williams Catherine S. , Payne Claire M. , Dvorak Bohuslav
Published: November 2004

Necrotizing enterocolitis (NEC) is a devastating intestinal disease of premature infants. Although end-stage NEC is characterized histopathologically as extensive necrosis, apoptosis may account for the initial loss of epithelium before full development of disease. We have previously shown that epidermal growth factor (EGF) reduces the incidence of NEC in a rat model. Although EGF has been shown to protect intestinal enterocytes from apoptosis, the mechanism of EGF-mediated protection against NEC is not known. The aim of this study was to investigate if EGF treatment elicits changes in expression of apoptotic markers in the ileum during the development of NEC. With the use of a well-established neonatal rat model of NEC, rats were divided into the following three experimental groups: dam fed (DF), milk formula fed (NEC), or fed with formula supplemented with 500 ng/ml EGF (NEC+EGF). Changes in ileal morphology, gene and protein expression, and histological localization of apoptotic regulators were evaluated. Anti-apoptotic Bcl-2 mRNA levels were markedly reduced and pro-apoptotic Bax mRNA levels were markedly elevated in the NEC group compared with DF controls. Supplementation of EGF into formula significantly increased anti-apoptotic Bcl-2 mRNA, whereas pro-apoptotic Bax was significantly decreased. The Bax-to-Bcl-2 ratio for mRNA and protein was markedly decreased in NEC+EGF animals compared with the NEC group. The presence of caspase-3-positive epithelial cells was markedly reduced in EGF-treated rats. These data suggest that alteration of the balance between pro-and anti-apoptotic proteins in the site of injury is a possible mechanism by which EGF maintains intestinal integrity and protects intestinal epithelium against NEC injury.
Luminal bacterial flora determines physiological expression of intestinal epithelial cytoprotective heat shock proteins 25 and 72
Authors: Arvans Donna L. , Vavricka Stephan R. , Ren Hongyu , Musch Mark W. , Kang Lisa , Rocha Flavio G. , Lucioni Alvaro , Turner Jerrold R. , Alverdy John , Chang Eugene B.
Published: November 2004

Heat shock proteins (HSP) 25 and 72 are expressed normally by surface colonocytes but not by small intestinal enterocytes. We hypothesized that luminal commensal microflora maintain the observed colonocyte HSP expression. The ability of the small intestine to respond to bacteria and their products and modulate HSPs has not been determined. The effects of luminal bacterial flora in surgically created midjejunal self-filling (SFL) vs. self-emptying (SEL) small-bowel blind loops on epithelial HSP expression were studied. HSP25 and HSP72 expression were assessed by immunoblot and immunohistochemistry. SFL were chronically colonized, whereas SEL contained levels of bacteria normal for the proximal small intestine. SFL creation significantly increased HSP25 and HSP72 expression relative to corresponding sections from SEL. Metronidazole treatment, which primarily affects anaerobic bacteria as well as a diet lacking fermentable fiber, significantly decreased SFL HSP expression. Small bowel incubation with butyrate ex vivo induced a sustained and significant upregulation of HSP25 and altered HSP72 expression, confirming the role of short-chain fatty acids. To determine whether HSPs induction altered responses to an injury, effects of the oxidant, monochloramine, on epithelial resistance and short-circuit current ( Isc) responses to carbachol and glucose were compared. Increased SFL HSP expression was associated with protection against oxidant-induced decreases in transmural resistance and Iscresponses to glucose, but not secretory responses to carbachol. In conclusion, luminal microflora and their metabolic byproducts direct expression of HSPs in gut epithelial cells, an effect that contributes to preservation of epithelial cell viability under conditions of stress.
Fat absorption in cystic fibrosis mice is impeded by defective lipolysis and post-lipolytic events
Authors: Bijvelds Marcel J. C. , Bronsveld Inez , Havinga Rick , Sinaasappel Maarten , de Jonge Hugo R. , Verkade Henkjan J.
Published: November 2004

Cystic fibrosis (CF) is frequently associated with progressive loss of exocrine pancreas function, leading to incomplete digestion and absorption of dietary fat. Supplementing patients with pancreatic lipase reduces fat excretion, but it does not completely correct fat malabsorption, indicating that additional pathological processes affect lipolysis and/or uptake of lipolytic products. To delineate the role of such (post) lipolytic processes in CF-related fat malabsorption, we assessed fat absorption, lipolysis, and fatty acid uptake in two murine CF models by measuring fecal fat excretion and uptake of oleate- and triolein-derived lipid. Pancreatic and biliary function was investigated by determining lipase secretion and biliary bile salt (BS) secretion, respectively. A marked increase in fecal fat excretion was observed in cftr null mice but not in homozygous ΔF508 mice. Fecal BS loss was enhanced in both CF models, but biliary BS secretion rates were similar. Uptake of free fatty acid was delayed in both CF models, but only in null mice was a specific reduction in lipolytic activity apparent, characterized by strongly reduced triglyceride absorption. Impaired lipolysis was not due to reduced pancreatic lipase secretion. Suppression of gastric acid secretion partially restored lipolytic activity and lipid uptake, indicating that incomplete neutralization of gastric acid impedes fat absorption. We conclude that fat malabsorption in cftr null mice is caused by impairment of lipolysis, which may result from aberrant duodenal pH regulation.
Molecular and phenotypic effects of heterozygous, homozygous, and compound heterozygote myosin heavy-chain mutations
Authors: Alpert Norman R. , Mohiddin Saidi A. , Tripodi Dorothy , Jacobson-Hatzell Jacqueline , Vaughn-Whitley Kelly , Brosseau Christine , Warshaw David M. , Fananapazir Lameh
Published: November 2004

Autosomal dominant familial hypertrophic cardiomyopathy (FHC) has variable penetrance and phenotype. Heterozygous mutations in MYH7 encoding β-myosin heavy chain are the most common causes of FHC, and we proposed that “enhanced” mutant actin-myosin function is the causative molecular abnormality. We have studied individuals from families in which members have two, one, or no mutant MYH7 alleles to examine for dose effects. In one family, a member homozygous for Lys207Gln had cardiomyopathy complicated by left ventricular dilatation, systolic impairment, atrial fibrillation, and defibrillator interventions. Only one of five heterozygous relatives had FHC. Leu908Val and Asp906Gly mutations were detected in a second family in which penetrance for Leu908Val heterozygotes was 46% (21/46) and 25% (3/12) for Asp906Gly. Despite the low penetrance, hypertrophy was severe in several heterozygotes. Two individuals with both mutations developed severe FHC. The velocities of actin translocation ( Vactin) by mutant and wild-type (WT) myosins were compared in the in vitro motility assay. Compared with WT/WT, Vactinwas 34% faster for WT/D906G and 21% for WT/L908V. Surprisingly Vactinfor Leu908Val/Asp906Gly and Lys207Gln/Lys207Gln mutants were similar to WT. The apparent enhancement of mechanical performance with mutant/WT myosin was not observed for mutant/mutant myosin. This suggests that Vactinmay be a poor predictor of disease penetrance or severity and that power production may be more appropriate, or that the limited availability of double mutant patients prohibits any definitive conclusions. Finally, severe FHC in heterozygous individuals can occur despite very low penetrance, suggesting these mutations alone are insufficient to cause FHC and that uncharacterized modifying mechanisms exert powerful influences.
Calpain inhibitor-1 protects the rat heart from ischemia-reperfusion injury: analysis by mechanical work and energetics
Authors: Yoshikawa Yoshiro , Hagihara Hiroji , Ohga Yoshimi , Nakajima-Takenaka Chikako , Murata Ken-ya , Taniguchi Shigeki , Takaki Miyako
Published: November 2004

We hypothesized that calpain inhibitor-1 protected left ventricular (LV) function from ischemia-reperfusion injury by inhibiting the proteolysis of α-fodrin. To test this hypothesis, we investigated the effect of calpain inhibitor-1 on LV mechanical work and energetics in the cross-circulated rat hearts that underwent 15-min global ischemia and 60-min reperfusion ( n = 9). After ischemia-reperfusion with calpain inhibitor-1, mean end-systolic pressure at midrange LV volume and systolic pressure-volume area (PVA) at midrange LV volume (total mechanical energy per beat) were hardly changed, although they were significantly ( P < 0.01) decreased after ischemia-reperfusion without calpain inhibitor-1. Mean myocardial oxygen consumption per beat (Vo2) intercepts (PVA-independent Vo2; Vo2 for the total Ca2+ handling in excitation-contraction coupling and basal metabolism) of Vo2-PVA linear relations were also unchanged after ischemia-reperfusion with calpain inhibitor-1, although they were significantly ( P < 0.01) decreased after ischemia-reperfusion without calpain inhibitor-1. There were no significant differences in O2 costs of LV PVA and contractility among the hearts in control (or normal) postischemia-reperfusion and postischemia-reperfusion with calpain inhibitor-1. Western blot analysis of α-fodrin and the immunostaining of 150-kDa products of α-fodrin confirmed that calpain inhibitor-1 almost completely protected the proteolysis of α-fodrin. Our results indicate that calpain inhibitor-1 prevents the heart from ischemia-reperfusion injury associated with the impairment of total Ca2+ handling by directly inhibiting the proteolysis of α-fodrin.
Functional proteomic analysis of a three-tier PKCε-Akt-eNOS signaling module in cardiac protection
Authors: Zhang Jun , Baines Christopher P. , Zong Chenggong , Cardwell Ernest M. , Wang Guangwu , Vondriska Thomas M. , Ping Peipei
Published: November 2004

Cardiac protective signaling networks have been shown to involve PKCε. However, the molecular mechanisms by which PKCε interacts with other members of these networks to form task-specific modules remain unknown. Among 93 different PKCε-associated proteins that have been identified, Akt and endothelial nitric oxide (NO) synthase (eNOS) are of importance because of their independent abilities to promote cell survival and prevent cell death. The simultaneous association of PKCε, Akt, and eNOS has not been examined, and, in particular, the formation of a module containing these three proteins and the role of such a module in the regulation of NO production and cardiac protection are unknown. The present study was undertaken to determine whether these molecules form a signaling module and, thereby, play a collective role in cardiac signaling. Using recombinant proteins in vitro and PKCε transgenic mouse hearts, we demonstrate the following: 1) PKCε, Akt, and eNOS interact and form signaling modules in vitro and in the mouse heart. Activation of either PKCε or Akt enhances the formation of PKCε-Akt-eNOS signaling modules. 2) PKCε directly phosphorylates and enhances activation of Akt in vitro, and PKCε activation increases phosphorylation and activation of Akt in PKCε transgenic mouse hearts. 3) PKCε directly phosphorylates eNOS in vitro, and this phosphorylation enhances eNOS activity. Activation of PKCε in vivo increased phosphorylation of eNOS at Ser1177, indicating eNOS activation. This study characterizes, for the first time, the physical, as well as functional, coupling of PKCε, Akt, and eNOS in the heart and implicates these PKCε-Akt-eNOS signaling modules as critical signaling elements during PKCε-induced cardiac protection.
Nitric oxide donors protect murine myocardium against infarction via modulation of mitochondrial permeability transition
Authors: Wang Guangwu , Liem David A. , Vondriska Thomas M. , Honda Henry M. , Korge Paavo , Pantaleon Dawn M. , Qiao Xin , Wang Yibin , Weiss James N. , Ping Peipei
Published: November 2004

Mitochondrial permeability transition (MPT) pores have recently been implicated as a potential mediator of myocardial ischemic injury. Nitric oxide (NO) donors induce a powerful late phase of cardioprotection against ischemia-reperfusion injury; however, the cellular mechanisms involved are poorly understood. The role of MPT pores as a target of cardioprotective signaling pathways activated by NO has never been explored in detail. Thus mice were administered the NO donor diethylenetriamine (DETA)/NO (4 doses of 0.1 mg/kg iv each) 24 h before 30 min of coronary artery occlusion followed by 24 h of reperfusion. Infarct size was significantly reduced in DETA/NO-treated mice (30 ± 2% of risk region in treated mice vs. 50 ± 2% in control mice; P < 0.05), which demonstrates powerful cardioprotection. To examine the role of MPT pores, mice were administered atractyloside (Atr; 25 mg/kg iv), which induces adenine nucleotide translocase-dependent MPT, 20 min before ischemia. Atr blocked the infarct-sparing effects of DETA/NO (infarct size, 58 ± 1 vs. 30 ± 2% of risk region in DETA/NO; P < 0.05), whereas Atr alone had no effect. Mitochondria isolated from DETA/NO-treated mice exhibited increased resistance to Ca2+-induced swelling by 20 μmol/l CaCl2or by the higher concentration of 200 μmol/l, which suggests that cardioprotection involves decreased propensity for MPT. Preincubation of mitochondria from control hearts with 30 nmol/l of the pore inhibitor cyclosporin A prevented swelling by 200 μmol/l CaCl2, thereby confirming that Ca2+induces mitochondrial swelling via MPT. In accordance with the effects on infarct size, administration of Atr to the mice significantly abrogated DETA/NO-induced protection against Ca2+-induced mitochondrial swelling. These phenotypic alterations were associated with an increase in the antiapoptotic protein Bcl-2, which suggests that the underlying mechanisms may involve inhibition of cell death by Bcl-2. These data suggest that a critical process during NO donor-induced cardioprotection is to prevent MPT pore opening potentially via targeting of the adenine nucleotide translocator.
Altered muscle metaboreflex control of coronary blood flow and ventricular function in heart failure
Authors: Ansorge Eric J. , Augustyniak Robert A. , Perinot Mariana L. , Hammond Robert L. , Kim Jong-Kyung , Sala-Mercado Javier A. , Rodriguez Jaime , Rossi Noreen F. , O'Leary Donal S.
Published: November 2004

We investigated the effect of muscle metaboreflex activation on left circumflex coronary blood flow (CBF), coronary vascular conductance (CVC), and regional left ventricular performance in conscious, chronically instrumented dogs during treadmill exercise before and after the induction of heart failure (HF). In control experiments, muscle metaboreflex activation during mild exercise elicited significant reflex increases in mean arterial pressure, heart rate, and cardiac output. CBF increased significantly, whereas no significant change in CVC occurred. There was no significant change in the minimal rate of myocardial shortening (−d l/d tmin) with muscle metaboreflex activation during mild exercise (15.5 ± 1.3 to 16.8 ± 2.4 mm/s, P > 0.05); however, the maximal rate of myocardial relaxation (+d l/d tmax) increased (from 26.3 ± 4.0 to 33.7 ± 5.7 mm/s, P < 0.05). Similar hemodynamic responses were observed with metaboreflex activation during moderate exercise, except there were significant changes in both −d l/d tmin and d l/d tmax. In contrast, during mild exercise with metaboreflex activation during HF, no significant increase in cardiac output occurred, despite a significant increase in heart rate, inasmuch as a significant decrease in stroke volume occurred as well. The increases in mean arterial pressure and CBF were attenuated, and a significant reduction in CVC was observed (0.74 ± 0.14 vs. 0.62 ± 0.12 ml·min−1·mmHg−1; P < 0.05). Similar results were observed during moderate exercise in HF. Muscle metaboreflex activation did not elicit significant changes in either −d l/d tmin or +d l/d tmax during mild exercise in HF. We conclude that during HF the elevated muscle metaboreflex-induced increases in sympathetic tone to the heart functionally vasoconstrict the coronary vasculature, which may limit increases in myocardial performance.
Cortisol-induced CXCR4 augmentation mobilizes T lymphocytes after acute physical stress
Authors: Okutsu Mitsuharu , Ishii Kenji , Niu Kai Jun , Nagatomi Ryoichi
Published: November 2004

The aim of this study was to elucidate the mechanism responsible for lymphopenia after exercise. Seven young healthy men volunteered for this study. Peripheral blood mononuclear cells (PBMC) were cultured with cortisol and analyzed for C-X-C motif chemokine receptor 4 (CXCR4) expression by flow cytometry. To determine the effects of exercise, subjects performed exhaustive cycling exercise. PBMC were cultured with plasma obtained before and after the cycling exercise. Alternatively, PBMC obtained before and after exercise were cultured without plasma or glucocorticoid to examine whether PBMC were primed in vivo for CXCR4 expression. We analyzed cortisol- or plasma-treated PBMC to determine their ability to migrate through membrane filters in response to stromal cell-derived factor 1α/CXCL12. Cortisol dose- and time-dependently augmented CXCR4 expression on T lymphocytes, with <6 h of treatment sufficient to augment CXCR4 on T lymphocytes. Postexercise plasma also augmented CXCR4 expression. Cortisol or postexercise plasma treatment markedly enhanced migration of T lymphocytes toward CXCL12. Augmentation of CXCR4 on T lymphocytes by cortisol or plasma was effectively blocked by the glucocorticoid receptor antagonist RU-486. Thus exercise-elicited endogenous cortisol effectively augments CXCR4 expression on T lymphocytes, which may account for lymphopenia after exercise.
Cellular and molecular mechanisms involved in branching morphogenesis of theDrosophilatracheal system
Authors: Cabernard Clemens , Neumann Marc , Affolter Markus
Published: November 2004

Recent comparative studies have shown that, in many instances, the genetic network underlying the development of distinct organ systems is similar in invertebrate and vertebrate organisms. Genetically well-characterized, simple invertebrate model systems, such as Caenorhabditis elegans and Drosophila melanogaster, can thus provide useful insight for understanding more complex organ systems in vertebrates. Here, we summarize recent progress in the genetic analysis of tracheal development in Drosophila and compare the results to studies aimed at a better understanding of lung development in mouse and man. Clearly, both striking similarities and important differences are apparent, but it might still be too early to conclude whether the former or the latter prevail.
On the terminology for describing the length-force relationship and its changes in airway smooth muscle
Authors: Bai Tony R. , Bates Jason H. T. , Brusasco Vito , Camoretti-Mercado Blanca , Chitano Pasquale , Deng Lin Hong , Dowell Maria , Fabry Ben , Ford Lincoln E. , Fredberg Jeffrey J. , Gerthoffer William T. , Gilbert Susan H. , Gunst Susan J. , Hai Chi-Ming , Halayko Andrew J. , Hirst Stuart J , James Alan L. , Janssen Luke J. , Jones Keith A. , King Greg G. , Lakser Oren J , Lambert Rodney K. , Lauzon Anne-Marie , Lutchen Kenneth R. , Maksym Geoffrey N. , Meiss Richard A. , Mijailovich Srboljub M. , Mitchell Howard W. , Mitchell Richard W. , Mitzner Wayne , Murphy Thomas M. , Paré Peter D. , Schellenberg R. Robert , Seow Chun Y. , Sieck Gary C. , Smith Paul G. , Smolensky Alex V. , Solway Julian , Stephens Newman L. , Stewart Alastair G. , Tang Dale D. , Wang Lu
Published: November 2004

The observation that the length-force relationship in airway smooth muscle can be shifted along the length axis by accommodating the muscle at different lengths has stimulated great interest. In light of the recent understanding of the dynamic nature of length-force relationship, many of our concepts regarding smooth muscle mechanical properties, including the notion that the muscle possesses a unique optimal length that correlates to maximal force generation, are likely to be incorrect. To facilitate accurate and efficient communication among scientists interested in the function of airway smooth muscle, a revised and collectively accepted nomenclature describing the adaptive and dynamic nature of the length-force relationship will be invaluable. Setting aside the issue of underlying mechanism, the purpose of this article is to define terminology that will aid investigators in describing observed phenomena. In particular, we recommend that the term “optimal length” (or any other term implying a unique length that correlates with maximal force generation) for airway smooth muscle be avoided. Instead, the in situ length or an arbitrary but clearly defined reference length should be used. We propose the usage of “length adaptation” to describe the phenomenon whereby the length-force curve of a muscle shifts along the length axis due to accommodation of the muscle at different lengths. We also discuss frequently used terms that do not have commonly accepted definitions that should be used cautiously.
Decreased contraction-stimulated glucose transport in isolated epitrochlearis muscles of pregnant rats
Authors: Sancho Raquel , Kim Junghoon , Cartee Gregory D.
Published: November 2004

Late pregnancy is characterized by insulin resistance for glucose transport in skeletal muscle. The main purpose of this study was to investigate the effect of late pregnancy on contraction-stimulated glucose transport in isolated rat skeletal muscle after in vitro electrical stimulation. Isolated epitrochlearis muscles of 19-day pregnant and aged-matched nonpregnant control rats were studied. One muscle from each rat was stimulated to contract, and the contralateral muscle served as a resting control. Tension developed during contractile activity, 3- O-methylglucose (3-MG) transport rate, and glycogen concentration were determined. Epitrochlearis muscles from other rats were used to measure insulin-stimulated 3-MG transport. There was no detectable difference between the nonpregnant and pregnant groups for contractile performance (peak tension, total tension, or fatigue). Pregnancy was not associated with significant changes in muscle glycogen concentration (resting or after contractile activity) or the contraction-stimulated decrement in glycogen concentration. For muscles from pregnant vs. nonpregnant groups, there was a 22% reduction ( P ≤ 0.05) in contraction-stimulated glucose transport, a 28% decrease ( P ≤ 0.05) in insulin-stimulated glucose transport, and unchanged basal glucose transport. In conclusion, isolated epitrochlearis muscles from pregnant vs. nonpregnant rats had a relative decrement in contraction-stimulated glucose transport that was similar to the relative decline in insulin-stimulated glucose transport. The decrement in contraction-stimulated glucose transport was not attributable to pregnancy-related changes in tension development or glycogen levels. The similar relative decline in insulin- and contraction-stimulated glucose transport raises the possibility that pregnancy impairs a distal process that is common to mechanisms whereby each stimulus activates glucose transport.
Genotypic Effect of the −565C>T Polymorphism in the ABCA1 Gene Promoter on ABCA1 Expression and Severity of Atherosclerosis
Authors: Kyriakou Theodosios , Hodgkinson Conrad , Pontefract David E. , Iyengar Srikanth , Howell W. Martin , Wong Yuk-ki , Eriksson Per , Ye Shu
Published: November 2004

Objective—

Loss-of-function mutations of the ATP-binding cassette transporter A1 (ABCA1) gene cause Tangier disease, a rare genetic disorder with accumulation of lipid-laden macrophages and increased risk of atherosclerosis. Common variants of this gene may be a genetic factor for atherosclerosis in the general population. This study was performed to test the reported association between the −565C>T polymorphism and atherosclerosis severity and to investigate whether this variant per se had an effect on promoter activity of the ABCA1 gene.

Methods and Results—

A cohort of patients with coronary atherosclerosis were genotyped for the −565C>T polymorphism. Logistic regression analyses showed that homozygotes of the −565T allele had greatest mean number of diseased coronary arteries, particular in nonsmokers. Real-time reverse-transcriptase polymerase chain reaction showed that in atherosclerotic plaques removed from patients undergoing endarteretomy, ABCA1 expression levels were lowest in those who had the T/T genotype and highest in those of the C/C genotype. Transfection and reporter assays demonstrated that in cultured macrophages, the −565T allelic promoter had a lower activity in driving gene expression than the −565C allelic promoter. Electrophoretic mobility shift assays displayed differential binding of nuclear proteins to the 2 alleles.

Conclusions—

These results indicate that the −565C>T polymorphism has an allele-specific effect on ABCA1 gene expression and provide further evidence of a genotypic effect on coronary atherosclerosis severity.
Phenotype of Heterozygotes for Low-Density Lipoprotein Receptor Mutations Identified in Different Background Populations
Authors: Tybjærg-Hansen Anne , Jensen Henrik Kjærulf , Benn Marianne , Steffensen Rolf , Jensen Gorm , Nordestgaard Børge G.
Published: November 2004

Background—

The effect of mutations on phenotype is often overestimated because of ascertainment bias. We determined the effect of background population on cholesterol phenotype associated with specific mutations in the low-density lipoprotein (LDL) receptor and the relative importance of background population and type of mutation (LDL receptor [
LDLR
] or
APOB
R3500Q) for cholesterol phenotype.

Methods and Results—

We studied 9255 individuals from the general population, 948 patients with ischemic heart disease (IHD), and 63 patients with clinical familial hypercholesterolemia (FH) for 3 common
LDL receptor
mutations. Average increase in cholesterol in
LDL receptor
heterozygotes identified in the general population or among patients with IHD or FH compared with noncarriers was 2.9 mmol/L, 4.1 mmol/L, and 4.9 mmol/L, respectively (
P
=0.02). Background population and type of mutation determined cholesterol phenotype; average increase in LDL cholesterol from carriers in the general population to carriers with clinical FH was 1.6 mmol/L (
P
=0.03). The average increase for carriers of
LDLR
mutations compared with carriers of
APOB
R3500Q was 1.2 mmol/L (
P
=0.05).

Conclusion—

The phenotype associated with a given mutation should not be determined in patients, but rather in unselected individuals in the general population.
Hyperhomocysteinemia Is Inversely Related With Left Ventricular Ejection Fraction and Predicts Cardiovascular Mortality in High-Risk Coronary Artery Disease Hypertensives
Authors: Cesari Maurizio , Zanchetta Mario , Burlina Alberto , Pedon Luigi , Maiolino Giuseppe , Sticchi Daniele , Pessina Achille C. , Rossi Gian Paolo
Published: November 2004

Objective—

The purpose of this study was to investigate the relationship of plasma homocysteine (tHcy) levels with coronary artery disease (CAD) and left ventricular ejection fraction (LVEF) in high-risk patients undergoing coronary angiography for suspected CAD.

Methods and Results—

In 936 consecutive patients, we measured LVEF, tHcy, folate levels, and quantified CAD with a modified Duke Index score. We also genotyped patients at the methylen-tetrahydrofolate-reductase 677C→T polymorphism. Hyperhomocysteinemia (HHcy) was defined as tHcy levels ≥15.46 μmol/L; total and cardiovascular mortality was assessed at follow-up that lasted 43 months (median). CAD was confirmed in 75% of patients and ruled out in the rest (non-CAD group). No relationship of HHcy with either arterial hypertension or the CAD score was found. In contrast, there was a significant inverse relationship of tHcy with LVEF in arterial hypertensive but not in normotensive patients, regardless of previous myocardial infarction. At logistic regression, HHcy was the strongest predictor (
P
=0.001) of a low (<40%) LVEF, followed by type 2 diabetes mellitus and cigarette smoking. At follow-up, HHcy significantly predicted cardiovascular mortality but only in the arterial hypertension subgroup.

Conclusions—

In arterial hypertensive but not in normotensive patients, HHcy predicts cardiovascular mortality and a low LVEF, independent of CAD and history of myocardial infarction.
Ceramide-Induced Impairment of Endothelial Function Is Prevented by CuZn Superoxide Dismutase Overexpression
Authors: Didion Sean P. , Faraci Frank M.
Published: November 2004

Objective—

Ceramide is an important intracellular second messenger that may also increase superoxide. The goal of this study was to determine whether overexpression of CuZn superoxide dismutase (SOD) protects against ceramide-induced increases in vascular superoxide and endothelial dysfunction.

Methods and Results—

Carotid arteries from CuZnSOD-transgenic (CuZnSOD-Tg) and nontransgenic littermates were examined in vitro. Immunohistochemistry confirmed that CuZnSOD protein was greater in carotid artery from CuZnSOD-Tg compared with nontransgenic mice. Ceramide (
N
-acetyl-
d
-sphingosine; 1 and 10 μmol/L) produced concentration-dependent impairment (
P
<0.05) of vasorelaxation in response to the endothelium-dependent agonist acetylcholine (ACh) in nontransgenic mice. For example, 100 μmol/L ACh relaxed arteries from nontransgenic mice by 96±4% and 52±5% in the presence of vehicle and 10 μmol/L ceramide, respectively. In contrast, ceramide (1 or 10 μmol/L) had no effect (
P
>0.05) on responses of carotid artery to ACh in CuZnSOD-Tg mice. Ceramide had no effect on nitroprusside- or papaverine-induced relaxation in CuZnSOD-Tg or nontransgenic mice. Ceramide increased superoxide in arteries from nontransgenic vessels, and this effect was prevented by polyethyleneglycol-SOD (50 U/mL) or overexpression of CuZnSOD.

Conclusions—

These results suggest that ceramide-induced increases in superoxide impair endothelium-dependent relaxation, and that select overexpression of the CuZn isoform of SOD prevents ceramide-induced oxidative stress in vessels.
Hypertension-Linked Mutation in the Adducin α-Subunit Leads to Higher AP2-μ2 Phosphorylation and Impaired Na
+
,K
+
-ATPase Trafficking in Response to GPCR Signals and Intracellular Sodium
Authors: Efendiev Riad , Krmar Rafael T. , Ogimoto Goichi , Zwiller Jean , Tripodi Grazia , Katz Adrian I. , Bianchi Giuseppe , Pedemonte Carlos H. , Bertorello Alejandro M.
Published: November 2004

α-Adducin polymorphism in humans is associated with abnormal renal sodium handling and high blood pressure. The mechanisms by which mutations in adducin affect the renal set point for sodium excretion are not known. Decreases in Na
+
,K
+
-ATPase activity attributable to endocytosis of active units in renal tubule cells by dopamine regulates sodium excretion during high-salt diet. Milan rats carrying the hypertensive adducin phenotype have a higher renal tubule Na
+
,K
+
-ATPase activity, and their Na
+
,K
+
-ATPase molecules do not undergo endocytosis in response to dopamine as do those of the normotensive strain. Dopamine fails to promote the interaction between adaptins and the Na
+
,K
+
-ATPase because of adaptin-μ2 subunit hyperphosphorylation. Expression of the hypertensive rat or human variant of adducin into normal renal epithelial cells recreates the hypertensive phenotype with higher Na
+
,K
+
-ATPase activity, μ2-subunit hyperphosphorylation, and impaired Na
+
,K
+
-ATPase endocytosis. Thus, increased renal Na
+
,K
+
-ATPase activity and altered sodium reabsorption in certain forms of hypertension could be attributed to a mutant form of adducin that impairs the dynamic regulation of renal Na
+
,K
+
-ATPase endocytosis in response to natriuretic signals.