The HIV-1 Vpu viroporin inhibitor BIT225 does not affect Vpu-mediated tetherin antagonism

Among its many roles, the HIV-1 accessory protein Vpu performs a viroporin function and also antagonizes the host cell restriction factor tetherin through its transmembrane domain. BIT225 is a small molecule inhibitor that specifically targets the Vpu viroporin function, which, in macrophages, resulted in late stage inhibition of virus release and decreased infectivity of released virus, a phenotype similar to tetherin-mediated restriction. Here, we investigated whether BIT225 might mediate its antiviral function, at least in part, via inhibition of Vpu-mediated tetherin antagonism. Using T-cell lines inducible for tetherin expression, we found that BIT225 does not exert its antiviral function by inhibiting Vpu-mediated tetherin downmodulation from the cell surface, the main site of action of tetherin activity. In addition, results from a bioluminescence resonance energy transfer (BRET) assay showed that the Vpu-tetherin interaction was not affected by BIT225. Our data provide support for the concept that tetherin antagonism and viroporin function are separable on the Vpu transmembrane and that viroporin function might be cell-type dependent. Further, this work contributes to the characterization of BIT225 as an inhibitor that specifically targets the viroporin function of Vpu.     

Utilities of gossip across organizational levels

Gossip is a subject that has been studied by researchers from an array of disciplines with various foci and methods. We measured the content of language use by members of a competitive sports team across 18 months, integrating qualitative ethnographic methods with quantitative sampling and analysis. We hypothesized that the use of gossip will vary significantly depending on whether it is used for self-serving or group-serving purposes. Our results support a model of gossip derived from multilevel selection theory that expects gossip to serve group-beneficial rules when rewards are partitioned at the group level on a scale that permits mutual monitoring. We integrate our case study with earlier studies of gossip conducted by anthropologists, psychologists, and management researchers. Kevin M. Kniffin studies cooperation within and among organizations. Kniffin is presently an Honorary Fellow of the University of Wisconsin-Madison’s Department of Anthropology. Kniffin has consulted for a variety of clients, including community-development organizations, labor unions, and credit unions. David Sloan Wilson is an evolutionary biologist interested in a broad range of issues relevant to human behavior. He has authored numerous articles and books, including most recently Darwin’s Cathedral: Evolution, Religion, and the Nature of Society (University of Chicago Press, 2002). Wilson is a professor of biological sciences and anthropology and Director of Evolutionary Studies (EvoS) at SUNY-Binghamton.     

Allosteric inhibitors of Bcr-abl-dependent cell proliferation

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized at the molecular level by the expression of Bcr-abl, a 210-kDa fusion protein with deregulated tyrosine kinase activity. Encouraged by the clinical validation of Bcr-abl as the target for the treatment of CML by imatinib, we sought to identify pharmacological agents that could target this kinase by a distinct mechanism. We report the discovery of a new class of Bcr-abl inhibitors using an unbiased differential cytotoxicity screen of a combinatorial kinase-directed heterocycle library. Compounds in this class (exemplified by GNF-2) show exclusive antiproliferative activity toward Bcr-abl-transformed cells, with potencies similar to imatinib, while showing no inhibition of the kinase activity of full-length or catalytic domain of c-abl. We propose that this new class of compounds inhibits Bcr-abl kinase activity through an allosteric non-ATP competitive mechanism.     

New forearm elements discovered of holotype specimen Australovenator wintonensis from Winton, Queensland, Australia

New skeletal elements are reported of the holotype specimen Australovenator wintonensis, from the type locality, near Winton, central western Queensland. New elements include left and right humeri, right radius, right radiale, right distal carpal 1, near complete right metacarpal I, left manual phalanx II-1, left manual phalanx II-2, near complete left manual phalanx II-3 and a left manual phalanx III-3. These new elements combined with those previously described are compared against other neovenatorids.     

How was teleology eliminated in early molecular biology?

This paper approaches the issue of the status of teleological reasoning in contemporary biology through a historical examination of events of the 1930s that surrounded Niels Bohr’s efforts to introduce ‘complementarity’ into biological discussions. The paper examines responses of three theoretical physicists who engaged boundary questions between the biological and physical sciences in this period in response to Bohr—Ernst Pascual Jordan (1902–80), Erwin Schrödinger (1887–1961), and Max Delbrück (1906–81). It is claimed that none of these physicists sufficiently understood Bohr’s ‘critical’ teleological arguments, which are traced to the lineage of Kant and Harald Høffding and their respective resolutions of the Antinomy of Teleological Judgment. The positions of these four historical actors are discussed in terms of Ernst Mayr’s distinction of ‘teleological,’ ‘teleomatic,’ and ‘teleonomic’ explanations. A return to some of the views articulated by Bohr, and behind him, to Høffding and Kant, is claimed to provide a framework for reintroducing a ‘critical’ teleology into biological discussions.     

The antiapoptotic herpes simplex virus glycoprotein J localizes to multiple cellular organelles and induces reactive oxygen species formation

The Us5 gene of herpes simplex virus (HSV) encodes glycoprotein J (gJ). The only previously reported function of gJ was its ability to inhibit apoptosis. However, the mechanism by which gJ prevents apoptosis is not understood, and it is not known whether gJ mediates additional cellular effects. In this study, we evaluated the expression, localization, and cellular effects of Us5/gJ. Us5 was first expressed 4 h after infection. gJ was detectable at 6 h and was expressed in glycosylated and unglycosylated forms. Us5 was regulated as a late gene, with partial dependency on DNA replication for expression. Us5 expression was delayed in the absence of ICP22; furthermore, expression of Us5 in trans protected cells from apoptosis induced by an HSV mutant with deletion of ICP27, suggesting that the antiapoptotic effects of ICP22 and ICP27 are mediated in part through effects on gJ expression. Within HSV-infected or Us5-transfected cells, gJ was distributed widely, especially to the endoplasmic reticulum, trans-Golgi network, and early endosomes. gJ interacted with F_oF₁ ATP synthase subunit 6 by a yeast two-hybrid screen and had strong antiapoptotic effects, which were mediated by protein rather than mRNA. Antiapoptotic activity required the extracellular and transmembrane domains of gJ, but not the intracellular domain. Consistent with inhibition of F_oF₁ ATP synthase function, Us5 was required for HSV-induced reactive oxygen species (ROS) formation, and gJ was sufficient to induce ROS in Us5-transfected cells. Thus, HSV gJ is a multifunctional protein, modulating other cellular processes in addition to inhibition of apoptosis.