Direct Binding of a Hepatitis C Virus Inhibitor to the Viral Capsid Protein

Over 130 million people are infected chronically with hepatitis C virus (HCV), which, together with HBV, is the leading cause of liver disease. Novel small molecule inhibitors of Hepatitis C virus (HCV) are needed to complement or replace current treatments based on pegylated interferon and ribavirin, which are only partially successful and plagued with side-effects. Assembly of the virion is initiated by the oligomerization of core, the capsid protein, followed by the interaction with NS5A and other HCV proteins. By screening for inhibitors of core dimerization, we previously discovered peptides and drug-like compounds that disrupt interactions between core and other HCV proteins, NS3 and NS5A, and block HCV production. Here we report that a biotinylated derivative of SL209, a prototype small molecule inhibitor of core dimerization (IC50 of 2.80 µM) that inhibits HCV production with an EC50 of 3.20 µM, is capable of penetrating HCV-infected cells and tracking with core. Interaction between the inhibitors, core and other viral proteins was demonstrated by SL209–mediated affinity-isolation of HCV proteins from lysates of infected cells, or of the corresponding recombinant HCV proteins. SL209-like inhibitors of HCV core may form the basis of novel treatments of Hepatitis C in combination with other target-specific HCV drugs such as inhibitors of the NS3 protease, the NS5B polymerase, or the NS5A regulatory protein. More generally, our work supports the hypothesis that inhibitors of viral capsid formation might constitute a new class of potent antiviral agents, as was recently also shown for HIV capsid inhibitors

Stratification and productivity in the in the Western Tethys (NW Algeria) during early Toarcian

17 pagesInternational audienceProfound environmental changes punctuated the Early Jurassic period, as recorded by marked carbon and oxygen isotope anomalies and major biotic crises. The response of low-latitude regions of Northern Gondwana to such intense changes is not documented as well as that of other Tethys areas. We present new calcareous nannofossil assemblages from three sections located in NW Algeria, in the Sahara and Tlemcen Basins, respectively. New stable carbon and nitrogen isotope data are provided from the Tlemcen Basin to reconstruct local environmental conditions in the wider context of a Toarcian greenhouse climate. We first established a solid chemo- and biostratigraphic framework by integrating stable carbon isotope data and calcareous nannofossil events. Calcareous nannofossil assemblages show common trends in the two basins, such as the occurrence in high proportions of the deep-dweller species Mitrolithus jansae, likely indicating stratification of the water column with a deep nutricline. This taxon dominated the assemblage during the negative carbon isotope excursion (CIE) interval, often used to delineate the base of the Toarcian anoxic event (T-OAE). Such a nannofossil record is unique in the Western Tethys domain, as M. jansae is known to drastically decrease in abundance during the T-OAE until its disappearance in the aftermath of the event. The NW Algeria nannofossil record indicates prolonged thermal stratification of water-masses, finally triggering hyper-oligotrophy and low productivity in shallow waters during the Toarcian CIE. Such peculiar conditions are likely related to the combined effects of a warm and arid climate dominating along the northern Gondwana margin and the presence of a strong clockwise gyre over the epicontinental shelf, which brought warm equatorial waters from the Tethys Ocean to the NW Algeria shelf

Restricted Oxygen‐Deficient Basins on the Northern European Epicontinental Shelf Across the Toarcian Carbon Isotope Excursion Interval

The worldwide recognition of the Toarcian carbon isotope excursion (T‐CIE) in organic‐rich sedimentary rocks has been linked to an oceanic anoxic event (OAE) which implies the world's deep oceans were anoxic ∼183 Ma. The majority of independent redox observations used to build this argument were mainly obtained from T‐CIE organic‐rich sediments deposited on northern European epicontinental shelf. However, increasing evidence has shown that this shelf had limited connection with the open ocean, making it unsuitable for reconstructing the T‐CIE ocean redox structure. To unveil such controversy, we present integrated δ15Nbulk and δ15Nker from Dotternhausen profile, Germany, combined with literature data from other T‐CIE profiles. Both δ15Nbulk and δ15Nker values are predominantly between +0.3 and +2.5‰. These positive near‐zero δ15N values imply enhanced N2 fixation by cyanobacteria using molybdenum (Mo)‐based nitrogenase to compensate bioavailable N loss following quantitative denitrification and/or anammox in a strongly redox‐stratified marine setting. Such N isotope composition contradicts the typical sedimentary δ15N values (>3‰) induced by partial water‐column denitrification and/or anammox in modern‐ocean oxygen minimum zones. We rather propose the existence of local oxygen‐deficient basins on northern European epicontinental shelf where dissolved N underwent extensive denitrification and/or anammox causing bioavailable N deficiency. Mo‐based diazotrophy thus played a critical role in discriminating N isotope compositions among multiple hydrographically restricted T‐CIE marginal basins. Restricted oxygen‐depleted environments on the northern European epicontinental shelf unlikely represent the open‐ocean redox landscape. The existence of the global OAE thus needs comprehensive redox investigations on Tethys and/or Panthalassa deep‐sea T‐CIE successions to validate.Key Points: Molybdenum‐based nitrogen fixation was prevalent in the northern European epicontinental shelf during the Toarcian carbon isotope excursion. Quantitative denitrification and/or anammox caused nitrogen famine in strongly redox‐stratified environments during the early Toarcian. Oxygen‐deficient basins on the northern European epicontinental shelf across the Toarcian carbon isotope excursion.China Scholarship Council (CSC) http://dx.doi.org/10.13039/501100004543German Research Foundatio

Irradiation tests of double-sided silicon strip detectors with a special guard ring structure

The results of the first irradiation tests of newly designed silicon microstrip detectors performed with 21 MeV protons at the Max-Planck-Institut in Heidelberg are presented. The detectors were developed and produced by the semiconductor laboratory of the Max-Planck-Institut in Munich. Novel guard ring structures allow operation of the detectors at voltages exceeding 300 V. (orig.)11 refs.SIGLEAvailable from TIB Hannover: RR 2916(95-29) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman