Syndecan 4 Is Involved in Mediating HCV Entry through Interaction with Lipoviral Particle-Associated Apolipoprotein E

Hepatitis C virus (HCV) is a major cause of liver disease worldwide and HCV infection represents a major health problem. HCV associates with host lipoproteins forming host/viral hybrid complexes termed lipoviral particles. Apolipoprotein E (apoE) is a lipoprotein component that interacts with heparan sulfate proteoglycans (HSPG) to mediate hepatic lipoprotein uptake, and may likewise mediate HCV entry. We sought to define the functional regions of apoE with an aim to identify critical apoE binding partners involved in HCV infection. Using adenoviral vectors and siRNA to modulate apoE expression we show a direct correlation of apoE expression and HCV infectivity, whereas no correlation exists with viral protein expression. Mutating the HSPG binding domain (HSPG-BD) of apoE revealed key residues that are critical for mediating HCV infection. Furthermore, a novel synthetic peptide that mimics apoE’s HSPG-BD directly and competitively inhibits HCV infection. Genetic knockdown of the HSPG proteins syndecan (SDC) 1 and 4 revealed that SDC4 principally mediates HCV entry. Our data demonstrate that HCV uses apoE-SDC4 interactions to enter hepatoma cells and establish infection. Targeting apoE-SDC interactions could be an alternative strategy for blocking HCV entry, a critical step in maintaining chronic HCV infection.     

Conversion of large heterologies in Streptococcus pneumoniae

In genetic transformation, long deletions dramatically increase the frequency of wild-type recombinants in 2-point crosses. In 3-point crosses in which the deletion was localized between 2 point mutations we demonstrated that this hyper-recombination was the result of genetic conversion extending over several scores of bases outside the deletion. As this conversion did not require an active DNA polymerase A gene, it was proposed that the mechanism of conversion involves breakage and ligation between DNA molecules. A similar hyper-recombination was observed when donor DNA carried an insertion. These results suggest that long heterologies participated in recombination so that surrounding homologous regions are almost completely paired and that these long heterologies are converted. It appears that it is a process that evolved to correct errors of replication which lead to long deletions and which are not eliminated by other systems.     

Teleonomical optimization of a fractal model of the pulmonary arterial bed

Modeling the pulmonary arterial tree (PAT) is considered here as an optimal synthesis problem. Firstly, a class of candidate models is specified: the three-dimensional symmetric dichotomous fractal trees of elastic tubes described by Womersley's equations. Secondly, the parameters are shown to be constrained by interactions of PAT with the rest of the body; these constraints are used to limit the volume of the parametric space to which attention will be directed in the synthesis step. Thirdly, a teleonomical hypothesis is proposed: a naturally selected PAT must have a minimal input impedance under conditions keeping total arterial volume and distensibility as small as possible. This hypothesis is translated in mathematical terms and the resulting cost-function minimized in the limited parametric volume. The optimal model has parameter values and an impedance spectrum corresponding satisfactorily with real data. Moreover this model gives a clear picture of the internal hemodynamic behavior of PAT as an impedance matching device.     

Enzyme polymorphisms of Ideles populations (Ahaggar, Algeria) and the Iwellemeden Kel Kummer Twaregs (Menaka, Mali).

Surveys dealing with enzyme polymorphisms have recently been conducted in the Sahara. Results from two populations are reported here: 227 inhabitants of Ideles village (Ahaggar, Algeria); 285 nomads of a genetic isolate, the Kel Kummer Twareg tribe (Menaka, Mali). The four classical molecular variants of G6PD:A+, A-, B+, B-, are found in Ideles. The frequency of the G6PD A+ Negroid variant reaches 15% in Ideles and 7.7% among the Kel Kummer. However, gene frequencies will have to be recalculated after a study of the genetic transmission through families. The PGDC gene of 6PGD is especially frequent in the Kel Kummer where 10 'Canning' phenotypes have been observed. The PGM distribution of alleles at locus 1 in Ideles is the same as in the Mediterranean populations. The pa gene of acid phosphatase, relatively frequent in Ideles, has been excluded by drift from the Kel Kummer gene pool. AK and LDH enzymes have also been studied in both samples. The abnormal Ea1 mutation of serum pseudocholinesterase exists in Ideles and in the Kel Kummer as in other populations of the Sahara; the C5 esterase component was revealed by electrophoresis in 5% of the Kel Kummer people.     

Generalization of the QST framework in hierarchically structured populations: Impacts of inbreeding and dominance

Q_ST is a differentiation parameter based on the decomposition of the genetic variance of a trait. In the case of additive inheritance and absence of selection, it is analogous to the genic differentiation measured on individual loci, F_ST. Thus, Q_ST?F_ST comparison is used to infer selection: selective divergence when Q_ST > F_ST, or convergence when Q_ST < F_ST. The definition of Q‐statistics was extended to two‐level hierarchical population structures with Hardy–Weinberg equilibrium. Here, we generalize the Q‐statistics framework to any hierarchical population structure. First, we developed the analytical definition of hierarchical Q‐statistics for populations not at Hardy–Weinberg equilibrium. We show that the Q‐statistics values obtained with the Hardy–Weinberg definition are lower than their corresponding F‐statistics when F_IS > 0 (higher when F_IS < 0). Then, we used an island model simulation approach to investigate the impact of inbreeding and dominance on the Q_ST?F_ST framework in a hierarchical population structure. We show that, while differentiation at the lower hierarchical level (Q_SR) is a monotonic function of migration, differentiation at the upper level (Q_RT) is not. In the case of additive inheritance, we show that inbreeding inflates the variance of Q_RT, which can increase the frequency of Q_RT > F_RT cases. We also show that dominance drastically reduces Q‐statistics below F‐statistics for any level of the hierarchy. Therefore, high values of Q‐statistics are good indicators of selection, but low values are not in the case of dominance.     

Structural and dynamic studies of two antigenic loops from haemagglutinin: A relaxation matrix approach

Summary We have investigated the dynamics and structural behaviour of two antigenic peptides using ¹H NMR. The two cyclic peptides mimic the antigenic site A of influenza haemagglutinin protein; they only differ in the way they were cyclized and in the size of their respective linkers. Homonuclear relaxation parameters extracted from a complete NOE matrix were interpreted in terms of local dynamics. A set of distance constraints was deduced from these parameters which allowed 3D models to be constructed using distance geometry. NOE back-calculation was used to check the validity of the final models. Strong variations of internal motion amplitude have been found in both peptides along their backbone. Motions with high amplitudes have been localized in the Gly-Pro-Gly sequence which forms a -turn in both structures.Abbreviations DSS 3-(trimethylsilyl)-1-propanesulfonic acid - D-loop aspartic acid loop - ELISA enzyme-linked immunoabsorbent assay - f.i.d free induction decay - HOHAHA homonuclear Hartmann-Hahn spectroscopy - HPLC high pressure liquid chromatography - K-loop lysine loop - NMR nuclear magnetic resonance - NOE nuclear Overhauser enhancement - NOESY nuclear Overhauser enhancement spectroscopy - r.m.s.d. root-mean-square deviation of atomic positions     

Distribution of corticotropin-releasing factor in ovine brain determined by radioimmunoassay

We have developed and used a sensitive and specific radioimmunoassay to demonstrate the presence of CRF-like immunoreactivity in extra-hypothalamic areas of ovine brain. Synthetic CRF displaced antibody bound tracer at an ED50 value of 200 pg and there was no cross-reactivity with LHRH, TRH, ACTH, beta-endorphin and several other peptides. Displacement of bound 125I-CRF by brain extracts exhibited curves parallel to synthetic CRF standards. Highest concentrations (1 ng/mg tissue) of CRF-like immunoreactivity were found in the median eminence but surprisingly, high concentrations of CRF-like immunoreactivity were found in frontal, parietal, occipital and particularly temporal areas of cerebral cortex. Much lower concentrations were found in other brain areas including the basal ganglia, limbic system and brain stem.