The Nef Protein of Human Immunodeficiency Virus Establishes Superinfection Immunity by a Dual Strategy to Downregulate Cell-Surface CCR5 and CD4

SummaryBackground: Viruses frequently render cells refractory to subsequent infection with the same virus. This state of superinfection immunity counteracts potentially detrimental consequences for the infected cell and facilitates high-level replication and viral spread in the host.Results: Here, we show that human immunodeficiency virus (HIV) employs its early gene product Nef to efficiently interfere with superinfection at the viral-entry step. In this context, we identify the downregulation of cell-surface CCR5, the major HIV coreceptor, as a novel and highly conserved activity of Nef. Nef targets the CCR5 coreceptor and the HIV binding receptor CD4 via distinct cellular machineries to enhance the endocytosis rate of both HIV receptor components and to accelerate their degradation. Functionally, these genetically separable actions by Nef synergized to efficiently protect cells from HIV superinfection at the level of fusion of the viral envelope with the plasma membrane.Conclusions: HIV has evolved two independent activities for Nef to downregulate the receptor complex and to facilitate its efficient replication and spread. This evasion strategy likely represents a mechanism by which the pathogenicity factor Nef elevates viral replication in vivo and thus promotes AIDS pathogenesis

POMK regulates dystroglycan function via LARGE-mediated elongation of matriglycan

Matriglycan [-GlcA-β1,3-Xyl-α1,3-]n serves as a scaffold in many tissues for extracellular matrix proteins containing laminin-G domains including laminin, agrin, and perlecan. Like-acetylglucosaminyltransferase-1 (LARGE1) synthesizes and extends matriglycan on α-dystroglycan (α-DG) during skeletal muscle differentiation and regeneration; however, the mechanisms which regulate matriglycan elongation are unknown. Here, we show that Protein O-Mannose Kinase (POMK), which phosphorylates mannose of core M3 (GalNac-β1,3-GlcNac-β1,4-Man) preceding matriglycan synthesis, is required for LARGE1-mediated generation of full-length matriglycan on α-DG (~150 kDa). In the absence of Pomk in mouse skeletal muscle, LARGE1 synthesizes a very short matriglycan resulting in a ~90 kDa α-DG which binds laminin but cannot prevent eccentric contraction-induced force loss or muscle pathology. Solution NMR spectroscopy studies demonstrate that LARGE1 directly interacts with core M3 and binds preferentially to the phosphorylated form. Collectively, our study demonstrates that phosphorylation of core M3 by POMK enables LARGE1 to elongate matriglycan on α-DG, thereby preventing muscular dystrophy

A recipe for simulating the interannual variability of the Asian summer monsoon and its relation with ENSO

Author Posting. © The Authors, 2006. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Climate Dynamics 28 (2007): 441-460, doi: 10.1007/s00382-006-0190-0.This study investigates how accurately the interannual variability over the Indian Ocean basin and the relationship between the Indian summer monsoon and the El Nino Southern Oscillation (ENSO) can be simulated by different modelling strategies. With a hierarchy of models, from an atmospherical general circulation model (AGCM) forced by observed SST, to a coupled model with the ocean component limited to the tropical Pacific and Indian Oceans, the role of heat fluxes and of interactive coupling is analyzed. Whenever sea surface temperature anomalies in the Indian basin are created by the coupled model, the inverse relationship between the ENSO index and the Indian summer monsoon rainfall is recovered, and it is preserved if the atmospherical model is forced by the SSTs created by the coupled model. If the ocean model domain is limited to the Indian Ocean, changes in the Walker circulation over the Pacific during El Nino years induce a decrease of rainfall over the Indian subcontinent. However the observed correlation between the ENSO and the Indian Ocean Zonal Mode (IOZM) is not properly modelled and the two indices are not significantly correlated, independently on season. Whenever the ocean domain extends to the Pacific, and ENSO can impact both the atmospheric circulation and the ocean subsurface in the equatorial Eastern Indian Ocean, modelled precipitation patterns associated both to ENSO and to the IOZM closely resemble the observations.The experiments described were performed as a contribution to the ENSEMBLES project funded by the European Commission’s 6th Framework Programme, contract number GOCE-CT-2003-505539

A novel aspect of the structure of the avian thymic medulla.

We provide evidence for the compartmentalization of the avian thymic medulla and identify the avian thymic dendritic cell. The thymic anlage develops from an epithelial cord of the branchial endoderm. Branches of the cord are separated by primary septae of neural crest origin. The dilation of the primary septae produces the keratin-negative area (KNA) of the thymic medulla and fills the gaps of the keratin-positive network (KPN). Morphometric analysis indicates that the KNA takes up about half of the volume of the thymic medulla, which has reticular connective tissue, like peripheral lymphoid organs. The KNA receives blood vessels and in addition to pericytes, the myoid cells of striated muscle structure occupy this area. The myoid cells are of branchial arch or prechordal plate origin providing indirect evidence for the neural crest origin of the KNA. The marginal epithelial cells of the KPN co-express keratin and vimentin intermediate filaments, which indicate their functional peculiarity. The basal lamina of the primary septum is discontinuous on the surface of the KPN providing histological evidence for the loss of the blood-thymus barrier in the medulla. In the center of the KNA, the dendritic cells lie in close association with blood vessels, whereas the B-cells accumulate along the KPN. The organization of the KPN and KNA increases the "surface" of the so-called cortico-medullary border, thereby contributing to the efficacy of central tolerance