A dynamic explanation for the origin of the western Mediterranean organic-rich layers

The eastern Mediterranean sapropels are among the most intensively investigated phenomena in the paleoceanographic record, but relatively little has been written regarding the origin of the equivalent of the sapropels in the western Mediterranean, the organic-rich layers (ORLs). ORLs are recognized as sediment layers containing enhanced total organic carbon that extend throughout the deep basins of the western Mediterranean and are associated with enhanced total barium concentration and a reduced diversity (dysoxic but not anoxic) benthic foraminiferal assemblage. Consequently, it has been suggested that ORLs represent periods of enhanced productivity coupled with reduced deep ventilation, presumably related to increased continental runoff, in close analogy to the sapropels. We demonstrate that despite their superficial similarity, the timing of the deposition of the most recent ORL in the Alboran Sea is different than that of the approximately coincident sapropel, indicating that there are important differences between their modes of formation. We go on to demonstrate, through physical arguments, that a likely explanation for the origin of the Alboran ORLs lies in the response of the western Mediterranean basin to a strong reduction in surface water density and a shoaling of the interface between intermediate and deep water during the deglacial period. Furthermore, we provide evidence that deep convection had already slowed by the time of Heinrich Event 1 and explore this event as a potential agent for preconditioning deep convection collapse. Important differences between Heinrich-like and deglacial-like influences are highlighted, giving new insights into the response of the western Mediterranean system to external forcing

Precision of the current methods to measure the alkenone proxy UK'37 and absolute alkenone abundance in sediments : results of an interlaboratory comparison study

Measurements of the UK'37 index and the absolute abundance of alkenones in marine sediments are increasingly used in paleoceanographic research as proxies of past sea surface temperature and haptophyte (mainly coccolith-bearing species) primary productivity, respectively. An important aspect of these studies is to be able to compare reliably data obtained by different laboratories from a wide variety of locations. Hence the intercomparability of data produced by the research community is essential. Here we report results from an anonymous interlaboratory comparison study involving 24 of the leading laboratories that carry out alkenone measurements worldwide. The majority of laboratories produce data that are intercomparable within the considered confidence limits. For the measurement of alkenone concentrations, however, there are systematic biases between laboratories, which might be related to the techniques employed to quantify the components. The maximum difference between any two laboratories for any two single measurements of UK'37 in sediments is estimated, with a probability of 95%, to be <2.18C. In addition, the overall within-laboratory precision for the UK'37 temperature estimates is estimated to be <1.68C (95% probability). Similarly, from the analyses of alkenone concentrations the interlaboratory reproducibility is estimated at 32%, and the repeatability is estimated at 24%. The former is compared to a theoretical estimate of reproducibility and found to be excessively high. Hence there is certainly scope and a demonstrable need to improve reproducibility and repeatability of UK'37 and especially alkenone quantification data across the community of scientists involved in alkenone research

Molecular Design, Functional Characterization and Structural Basis of a Protein Inhibitor Against the HIV-1 Pathogenicity Factor Nef

Increased spread of HIV-1 and rapid emergence of drug resistance warrants development of novel antiviral strategies. Nef, a critical viral pathogenicity factor that interacts with host cell factors but lacks enzymatic activity, is not targeted by current antiviral measures. Here we inhibit Nef function by simultaneously blocking several highly conserved protein interaction surfaces. This strategy, referred to as “wrapping Nef”, is based on structure-function analyses that led to the identification of four target sites: (i) SH3 domain interaction, (ii) interference with protein transport processes, (iii) CD4 binding and (iv) targeting to lipid membranes. Screening combinations of Nef-interacting domains, we developed a series of small Nef interacting proteins (NIs) composed of an SH3 domain optimized for binding to Nef, fused to a sequence motif of the CD4 cytoplasmic tail and combined with a prenylation signal for membrane association. NIs bind to Nef in the low nM affinity range, associate with Nef in human cells and specifically interfere with key biological activities of Nef. Structure determination of the Nef-inhibitor complex reveals the molecular basis for binding specificity. These results establish Nef-NI interfaces as promising leads for the development of potent Nef inhibitors

HIV Capsid is a Tractable Target for Small Molecule Therapeutic Intervention

Despite a high current standard of care in antiretroviral therapy for HIV, multidrug-resistant strains continue to emerge, underscoring the need for additional novel mechanism inhibitors that will offer expanded therapeutic options in the clinic. We report a new class of small molecule antiretroviral compounds that directly target HIV-1 capsid (CA) via a novel mechanism of action. The compounds exhibit potent antiviral activity against HIV-1 laboratory strains, clinical isolates, and HIV-2, and inhibit both early and late events in the viral replication cycle. We present mechanistic studies indicating that these early and late activities result from the compound affecting viral uncoating and assembly, respectively. We show that amino acid substitutions in the N-terminal domain of HIV-1 CA are sufficient to confer resistance to this class of compounds, identifying CA as the target in infected cells. A high-resolution co-crystal structure of the compound bound to HIV-1 CA reveals a novel binding pocket in the N-terminal domain of the protein. Our data demonstrate that broad-spectrum antiviral activity can be achieved by targeting this new binding site and reveal HIV CA as a tractable drug target for HIV therapy

Rationally Designed Interfacial Peptides Are Efficient In Vitro Inhibitors of HIV-1 Capsid Assembly with Antiviral Activity

Virus capsid assembly constitutes an attractive target for the development of antiviral therapies; a few experimental inhibitors of this process for HIV-1 and other viruses have been identified by screening compounds or by selection from chemical libraries. As a different, novel approach we have undertaken the rational design of peptides that could act as competitive assembly inhibitors by mimicking capsid structural elements involved in intersubunit interfaces. Several discrete interfaces involved in formation of the mature HIV-1 capsid through polymerization of the capsid protein CA were targeted. We had previously designed a peptide, CAC1, that represents CA helix 9 (a major part of the dimerization interface) and binds the CA C-terminal domain in solution. Here we have mapped the binding site of CAC1, and shown that it substantially overlaps with the CA dimerization interface. We have also rationally modified CAC1 to increase its solubility and CA-binding affinity, and designed four additional peptides that represent CA helical segments involved in other CA interfaces. We found that peptides CAC1, its derivative CAC1M, and H8 (representing CA helix 8) were able to efficiently inhibit the in vitro assembly of the mature HIV-1 capsid. Cocktails of several peptides, including CAC1 or CAC1M plus H8 or CAI (a previously discovered inhibitor of CA polymerization), or CAC1M+H8+CAI, also abolished capsid assembly, even when every peptide was used at lower, sub-inhibitory doses. To provide a preliminary proof that these designed capsid assembly inhibitors could eventually serve as lead compounds for development of anti-HIV-1 agents, they were transported into cultured cells using a cell-penetrating peptide, and tested for antiviral activity. Peptide cocktails that drastically inhibited capsid assembly in vitro were also able to efficiently inhibit HIV-1 infection ex vivo. This study validates a novel, entirely rational approach for the design of capsid assembly interfacial inhibitors that show antiviral activity

Precision of the current methods to measure the alkenone proxy U₃₇ K’ and absolute alkenone abundance in sediments: results of an interlaboratory comparison study

Measurements of the U₃₇ K’ index and the absolute abundance of alkenones in marine sediments are increasingly used in paleoceanographic research as proxies of past sea surface temperature and haptophyte (mainly coccolith-bearing species) primary productivity, respectively. An important aspect of these studies is to be able to compare reliably data obtained by different laboratories from a wide variety of locations. Hence the intercomparability of data produced by the research community is essential. Here we report results from an anonymous interlaboratory comparison study involving 24 of the leading laboratories that carry out alkenone measurements worldwide. The majority of laboratories produce data that are intercomparable within the considered confidence limits. For the measurement of alkenone concentrations, however, there are systematic biases between laboratories, which might be related to the techniques employed to quantify the components. The maximum difference between any two laboratories for any two single measurements of U₃₇ K’ in sediments is estimated, with a probability of 95%, to be <2.1°C. In addition, the overall within-laboratory precision for the U₃₇ K’ temperature estimates is estimated to be <1.6°C (95% probability). Similarly, from the analyses of alkenone concentrations the interlaboratory reproducibility is estimated at 32%, and the repeatability is estimated at 24%. The former is compared to a theoretical estimate of reproducibility and found to be excessively high. Hence there is certainly scope and a demonstrable need to improve reproducibility and repeatability of U₃₇ K’ and especially alkenone quantification data across the community of scientists involved in alkenone research

Influence de l'azote des constituants pariétaux sur la dégradabilité in sacco de l'azote des aliments

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