Inhibition of furin-mediated cleavage activation of HIV-1 glycoprotein gp160.

The envelope glycoprotein of human immunodeficiency virus (HIV) initiates infection by mediating fusion of the viral envelope with the cell membrane. Fusion activity requires proteolytic cleavage of the gp160 protein into gp120 and gp41 at a site containing several arginine and lysine residues. Activation at basic cleavage sites is observed with many membrane proteins of cellular and viral origin. We have recently found that the enzyme activating the haemagglutinin of fowl plague virus (FPV), an avian influenza virus, is furin. Furin, a subtilisin-like eukaryotic endoprotease, has a substrate specificity for the consensus amino-acid sequence Arg-X-Lys/Arg-Arg at the cleavage site. We show here that the glycoprotein of HIV-1, which has the same protease recognition motif as the FPV haemagglutinin, is also activated by furin.     

Human immunodeficiency viruses: SIV infection in wild gorillas

Chimpanzees (Pan troglodytes troglodytes) from west central Africa are recognized as the reservoir of simian immunodeficiency viruses (SIVcpzPtt) that have crossed at least twice to humans: this resulted in the AIDS pandemic (from human immunodeficiency virus HIV-1 group M) in one instance and infection of just a few individuals in Cameroon (by HIV-1 group N) in another. A third HIV-1 lineage (group O) from west central Africa also falls within the SIVcpzPtt radiation, but the primate reservoir of this virus has not been identified. Here we report the discovery of HIV-1 group O-like viruses in wild gorillas.     

Molecular regulation of CRAC channels and their role in lymphocyte function

Calcium (Ca²⁺) influx is required for the activation and function of all cells in the immune system. It is mediated mainly by store-operated Ca²⁺ entry (SOCE) through Ca²⁺ release-activated Ca²⁺ (CRAC) channels located in the plasma membrane. CRAC channels are composed of ORAI proteins that form the channel pore and are activated by stromal interaction molecules (STIM) 1 and 2. Located in the membrane of the endoplasmic reticulum, STIM1 and STIM2 have the dual function of sensing the intraluminal Ca²⁺ concentration in the ER and to activate CRAC channels. A decrease in the ER’s Ca²⁺ concentration induces STIM multimerization and translocation into puncta close to the plasma membrane where they bind to and activate ORAI channels. Since the identification of ORAI and STIM genes as the principal mediators of CRAC channel function, substantial advances have been achieved in understanding the molecular regulation and physiological role of CRAC channels in cells of the immune system and other organs. In this review, we discuss the mechanisms that regulate CRAC channel function and SOCE, the role of recently identified proteins and mechanisms that modulate the activation of ORAI/STIM proteins and the consequences of CRAC channel dysregulation for lymphocyte function and immunity.     

Knowing and Acting in Conditions of Uncertainty: A Complexity Perspective

As practitioners working with groups and organizations, we have reflected together on what we think is happening when we find ourselves acting into situations in which the intention motivating the action as its goal is itself emerging in the very action. Along with others, we have been excited by the ideas of self-organization in the natural sciences and also theories of practice, for example, tacit and explicit knowledge, in the social sciences. Together, these promise fresh insights into the potential of organizations. However, we find ourselves diverging significantly from writers who at first sight seem to be using similar ideas, but they do so with an exclusive focus on strategic choice and intention. To illustrate what we mean, we explore the work of Nonaka and Takeuchi and how they use Polanyi's idea of the participant observer. We do this to identify contradictions we see in their approach. We also discuss the implications of an alternative understanding of participation and what this indicates about what can and cannot be managed in the creation of new knowledge.     

Systematic generation of high-resolution deletion coverage of the Drosophila melanogaster genome

In fruit fly research, chromosomal deletions are indispensable tools for mapping mutations, characterizing alleles and identifying interacting loci. Most widely used deletions were generated by irradiation or chemical mutagenesis. These methods are labor-intensive, generate random breakpoints and result in unwanted secondary mutations that can confound phenotypic analyses. Most of the existing deletions are large, have molecularly undefined endpoints and are maintained in genetically complex stocks. Furthermore, the existence of haplolethal or haplosterile loci makes the recovery of deletions of certain regions exceedingly difficult by traditional methods, resulting in gaps in coverage. Here we describe two methods that address these problems by providing for the systematic isolation of targeted deletions in the D. melanogaster genome. The first strategy used a P element-based technique to generate deletions that closely flank haploinsufficient genes and minimize undeleted regions. This deletion set has increased overall genomic coverage by 5-7%. The second strategy used FLP recombinase and the large array of FRT-bearing insertions described in the accompanying paper to generate 519 isogenic deletions with molecularly defined endpoints. This second deletion collection provides 56% genome coverage so far. The latter methodology enables the generation of small custom deletions with predictable endpoints throughout the genome and should make their isolation a simple and routine task.     

Knowledge transfer in theoretical ecology: Implications for incommensurability,voluntarism, and pluralism

Well-known epistemologies of science have implications for how best to understand knowledge transfer (KT). Yet, to date, no serious attempt has been made to explicate these particular implications. This paper infers views about KT from two popular epistemologies; what we characterize as incommensurabilitist views (after Devitt, 2001; Bird, 2002, 2008; Sankey and Hoyningen-Huene 2013) and voluntarist views (after Van Fraassen, 1984; Dupré, 2001; Chakravartty, 2015). We argue views of the former sort define the methodological, ontological, and social conditions under which research operates within ‘different worlds’ (to use Kuhn's expression), and entail that genuine KTs under those conditions should be difficult or even impossible. By contrast, more liberal voluntarist views recognize epistemological processes that allow for transfers across different sciences even under such conditions. After outlining these antithetical positions, we identify two kinds of KTs present in well-known episodes in the history of ecology—specifically, successful model transfers from chemical kinetics and thermodynamics into areas of ecological research—which reveal significant limitations of incommensurabilitist views. We conclude by discussing how the selected examples support a pluralistic voluntarism regarding KT.     

A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC

The proteins encoded by the classical HLA class I and class II genes in the major histocompatibility complex (MHC) are highly polymorphic and are essential in self versus non-self immune recognition. HLA variation is a crucial determinant of transplant rejection and susceptibility to a large number of infectious and autoimmune diseases. Yet identification of causal variants is problematic owing to linkage disequilibrium that extends across multiple HLA and non-HLA genes in the MHC. We therefore set out to characterize the linkage disequilibrium patterns between the highly polymorphic HLA genes and background variation by typing the classical HLA genes and >7,500 common SNPs and deletion-insertion polymorphisms across four population samples. The analysis provides informative tag SNPs that capture much of the common variation in the MHC region and that could be used in disease association studies, and it provides new insight into the evolutionary dynamics and ancestral origins of the HLA loci and their haplotypes.     

Morphogenetic genes C and Nu3 overlap in bacteriophage lambda

In bacteriophage lambda, genes C and Nu3, two of the four cistrons which are essential for normal prohead formation, have overlapping nucleotide sequences. These genes are translated in the same reading frame so that the Nu3 protein is identical to the COOH-terminal one-third of the C protein. This structural relationship may provide for the functional interaction of the C and Nu3 proteins through their regions of structural homology during prohead assembly. The in-phase overlapping organisation of genes may constitute a general strategy to facilitate the mutual interaction of a pair of proteins through their common structural domains.     

3′-O-Methyl-(+)-catechin glucuronide and 3′-O-methyl-(+)-catechin sulphate: new urinary metabolites of (+)-catechin in the rat and the marmoset

Summary The major urinary metabolites of (+)-catechin (cyanidanol-3) in the rat were (+)-catechin glucuronide, 3′-O-methyl-(+)-catechin glucuronide and 3′-O-methyl-(+)-catechin sulphate. The latter conjugate was the major metabolite in marmoset urine. To whom reprint requests should be addressed. Acknowledgment. The authors wish to thank Miss Rosemary Dring and Mr P.B. Wood for skilled technical assistance, Zyma S.A., Nyon, Switzerland, for financial support, and the Medical Research Council for a research studentship (to I.C.S.).