B005 Dietary-induced insulin resistance associated with dyslipidemia induces progressive cardiac dysfunction in rats as evidenced by echocardiography

BackgroundA major complication of diabetes is the development of cardiac dysfunction in absence of vascular disease. Metabolic disorders such as insulin resistance (IR) and dyslipidemia (DL) might contribute to the induction of diabetic cardiomyopathy (DCM). However, few relevant animal models are currently available for studying the time-course of DCM and evaluating experimental therapeutics. We developed a rodent model of dietary-induced IR combined or not with DL in order to investigate the impact of chronic IR and DL on in vivo myocardial function.Methods & ResultsMale Sprague-Dawley rats were fed a western-type diet (65 % fat ; 15 % fructose ; WD: n=12). DL was induced by combining the western diet with i.p. injections of a nonionic surface-active agent (P-407 ; 0.2mg/kg, 3 times/wk ; WD-P407 n=9). A chow diet was used as control (Chow: n=9). At 6, 11 and 14 wks, cardiac function was assessed by echocardiography. After 6 wks, plasma insulin was significantly increased in both WD and WD-P407 groups (P<0.05 vs. Chow). Fasting blood glucose increased in WD group while plasma lipids markedly accumulated in WD-P407-treated rats (P<0.05 and P<0.01 vs. Chow, respectively). Pulse-wave Doppler indicated impaired diastolic function at 14 wks (E/A wave ratio: WD-P407: 1.42±0.06 vs. Chow: 1.65±0.11). M-mode imaging showed no significant differences in cardiac function and geometry under basal conditions. However, fractional shortening (FS) was significantly depressed under dobutamine stress in WD group at 14 wks (FS in % of baseline: 151±9 % vs 196±7 % ; P<0.05) whereas systolic dysfunction appeared as early as 11 wks and worsened at 14 wks in WD-P407 animals (P<0.05 and P<0.01 vs. Chow, respectively). Finally, compared to Chow, myocardial lipid tissue content were significantly higher in WD and WD-P407 groups, the cardiac lipid accumulation being more pronounced in the later.ConclusionsDL exacerbated cardiac lipotoxicity and functional complications associated with IR. This experimental model of combined IR and DL closely mimics the main clinical manifestations of DCM and might therefore constitute a useful tool for the evaluation of pharmacological treatments

Medium Modifications of Hadron Properties and Partonic Processes

Chiral symmetry is one of the most fundamental symmetries in QCD. It is closely connected to hadron properties in the nuclear medium via the reduction of the quark condensate , manifesting the partial restoration of chiral symmetry. To better understand this important issue, a number of Jefferson Lab experiments over the past decade have focused on understanding properties of mesons and nucleons in the nuclear medium, often benefiting from the high polarization and luminosity of the CEBAF accelerator. In particular, a novel, accurate, polarization transfer measurement technique revealed for the first time a strong indication that the bound proton electromagnetic form factors in 4He may be modified compared to those in the vacuum. Second, the photoproduction of vector mesons on various nuclei has been measured via their decay to e+e- to study possible in-medium effects on the properties of the rho meson. In this experiment, no significant mass shift and some broadening consistent with expected collisional broadening for the rho meson has been observed, providing tight constraints on model calculations. Finally, processes involving in-medium parton propagation have been studied. The medium modifications of the quark fragmentation functions have been extracted with much higher statistical accuracy than previously possible.Comment: to appear in J. Phys.: Conf. Proc. "New Insights into the Structure of Matter: The First Decade of Science at Jefferson Lab", eds. D. Higinbotham, W. Melnitchouk, A. Thomas; added reference

A novel homozygous KCNQ3 loss-of-function variant causes non-syndromic intellectual disability and neonatal-onset pharmacodependent epilepsy

OBJECTIVE: Heterozygous variants in KCNQ2 or, more rarely, KCNQ3 genes are responsible for early-onset developmental/epileptic disorders characterized by heterogeneous clinical presentation and course, genetic transmission, and prognosis. While familial forms mostly include benign epilepsies with seizures starting in the neonatal or early-infantile period, de novo variants in KCNQ2 or KCNQ3 have been described in sporadic cases of early-onset encephalopathy (EOEE) with pharmacoresistant seizures, various age-related pathological EEG patterns, and moderate/severe developmental impairment. All pathogenic variants in KCNQ2 or KCNQ3 occur in heterozygosity. The aim of this work was to report the clinical, molecular, and functional properties of a new KCNQ3 variant found in homozygous configuration in a 9-year-old girl with pharmacodependent neonatal-onset epilepsy and non-syndromic intellectual disability. METHODS: Exome sequencing was used for genetic investigation. KCNQ3 transcript and subunit expression in fibroblasts was analyzed with quantitative real-time PCR and Western blotting or immunofluorescence, respectively. Whole-cell patch-clamp electrophysiology was used for functional characterization of mutant subunits. RESULTS: A novel single-base duplication in exon 12 of KCNQ3 (NM_004519.3:c.1599dup) was found in homozygous configuration in the proband born to consanguineous healthy parents; this frameshift variant introduced a premature termination codon (PTC), thus deleting a large part of the C-terminal region. Mutant KCNQ3 transcript and protein abundance was markedly reduced in primary fibroblasts from the proband, consistent with nonsense-mediated mRNA decay. The variant fully abolished the ability of KCNQ3 subunits to assemble into functional homomeric or heteromeric channels with KCNQ2 subunits. SIGNIFICANCE: The present results indicate that a homozygous KCNQ3 loss-of-function variant is responsible for a severe phenotype characterized by neonatal-onset pharmacodependent seizures, with developmental delay and intellectual disability. They also reveal difference in genetic and pathogenetic mechanisms between KCNQ2- and KCNQ3-related epilepsies, a crucial observation for patients affected with EOEE and/or developmental disabilities

Vaccination with DNA plasmids expressing Gn coupled to C3d or alphavirus replicons expressing Gn protects mice against rift valley fever virus

Background: Rift Valley fever (RVF) is an arthropod-borne viral zoonosis. Rift Valley fever virus (RVFV) is an important biological threat with the potential to spread to new susceptible areas. In addition, it is a potential biowarfare agent. Methodology/Principal Findings: We developed two potential vaccines, DNA plasmids and alphavirus replicons, expressing the Gn glycoprotein of RVFV alone or fused to three copies of complement protein, C3d. Each vaccine was administered to mice in an all DNA, all replicon, or a DNA prime/replicon boost strategy and both the humoral and cellular responses were assessed. DNA plasmids expressing Gn-C3d and alphavirus replicons expressing Gn elicited high titer neutralizing antibodies that were similar to titers elicited by the live-attenuated MP12 virus. Mice vaccinated with an inactivated form of MP12 did elicit high titer antibodies, but these antibodies were unable to neutralize RVFV infection. However, only vaccine strategies incorporating alphavirus replicons elicited cellular responses to Gn. Both vaccines strategies completely prevented weight loss and morbidity and protected against lethal RVFV challenge. Passive transfer of antisera from vaccinated mice into naïve mice showed that both DNA plasmids expressing Gn-C3d and alphavirus replicons expressing Gn elicited antibodies that protected mice as well as sera from mice immunized with MP12. Conclusion/Significance: These results show that both DNA plasmids expressing Gn-C3d and alphavirus replicons expressing Gn administered alone or in a DNA prime/replicon boost strategy are effective RVFV vaccines. These vaccine strategies provide safer alternatives to using live-attenuated RVFV vaccines for human use. © 2010 Bhardwaj et al

Recent results from Pb-Au collisions at 158 GeV/c per nucleon obtained with the CERES spectrometer

During the 1996 lead run time, CERES has accumulated 42 million events, corresponding to a factor of 5 more statistics than in 1995 and 2.5 million events of a special photon-run. We report on the results of the low-mass e$^+$e$^-$-pair analysis. Since the most critical item is the poor signal-to-background ratio we also discuss the understanding of this background, in absolute terms, with the help of a detailed Monte Carlo simulation. We show preliminary results of the photon analysis and summarize the results of the hadron analysis preliminarily reported on already at QM'97Comment: 10 pages, 9 figures, Proceedings of the XIV Int. Conf. on Nucleus-Nucleus Collisions,Quark Matter 99, Torino, Italy, May 10 - 15, 199

J/psi azimuthal anisotropy relative to the reaction plane in Pb-Pb collisions at 158 GeV per nucleon

The J/$\psi$ azimuthal distribution relative to the reaction plane has been measured by the NA50 experiment in Pb-Pb collisions at 158 GeV/nucleon. Various physical mechanisms related to charmonium dissociation in the medium created in the heavy ion collision are expected to introduce an anisotropy in the azimuthal distribution of the observed J/$\psi$ mesons at SPS energies. Hence, the measurement of J/$\psi$ elliptic anisotropy, quantified by the Fourier coefficient v$_2$ of the J/$\psi$ azimuthal distribution relative to the reaction plane, is an important tool to constrain theoretical models aimed at explaining the anomalous J/$\psi$ suppression observed in Pb-Pb collisions. We present the measured J/$\psi$ yields in different bins of azimuthal angle relative to the reaction plane, as well as the resulting values of the Fourier coefficient v$_{2}$ as a function of the collision centrality and of the J/$\psi$ transverse momentum. The reaction plane has been estimated from the azimuthal distribution of the neutral transverse energy detected in an electromagnetic calorimeter. The analysis has been performed on a data sample of about 100 000 events, distributed in five centrality or p$_{\rm T}$ sub-samples. The extracted v$_{2}$ values are significantly larger than zero for non-central collisions and are seen to increase with p$_{\rm T}$.Comment: proceedings of HP08 conference corrected a typo in one equatio