New reassortant H5N6 highly pathogenic avian influenza viruses (AIVs) were isolated from apparently healthy domestic ducks in Southern China in 2014. Our results show that the viruses grew efficiently in eggs and replicated systemically in chickens. They were completely lethal in chicken (100% mortality), and the mean death time was 6 to 7 days post-inoculation. The viruses could transmit in chickens by naïve contact. BLAST analysis revealed that their HA gene was most closely related to A/wild duck/Shangdong/628/2011 (H5N1), and their NA genes were most closely related to A/swine/Guangdong/K6/2010 (H6N6). The other genes had the highest identity with A/wild duck/Fujian/1/2011(H5N1). The results of phylogenetic analysis showed that their HA genes clustered into clade 2.3.4.4 of the H5N1 viruses and all genes derived from H5 were Mix-like or H6-like viruses. Thus, the new H5N6 viruses were reassortmented of H5N1 and H6N6 virus. Therefore, the circulation of the new H5N6 AIVs may become a threat to poultry and human health.
The development of thymocytes to mature T cells in the thymus is tightly controlled by cellular selection, in which only a small fraction of thymocytes equipped with proper quality of TCRs progress to maturation. It is pivotal to protect the survival of the few T cells, which pass the selection. However, the signaling events, which safeguard the cell survival in thymus, are not totally understood. In this study, protein Ser/Thr phosphorylation in thymocytes undergoing positive selection is profiled by mass spectrometry. The results revealed large numbers of dephosphorylation changes upon T cell receptor (TCR) activation during positive selection. Subsequent substrate analysis pinpointed protein phosphatase 2A (PP2A) as the enzyme responsible for the dephosphorylation changes in developing thymocytes. PP2A catalytic subunit α (Ppp2ca) deletion in the T cell lineage in Ppp2ca flox/flox -Lck-Cre mice (PP2A cKO) displayed dysregulated dephosphorylation of apoptosis-related proteins in double-positive (DP) cells and caused substantially decreased numbers of DP CD4 + CD8 + cells. Increased levels of apoptosis in PP2A cKO DP cells were found to underlie aberrant thymocyte development. Finally, the defective thymocyte development in PP2A cKO mice could be rescued by either Bcl2 transgene expression or by p53 knockout. In summary, our work reveals an essential role of PP2A in promoting thymocyte development through the regulation of cell survival. thymocyte selection | PP2A | apoptosis T lymphocytes are the major form of adaptive immune cells that target pathogens (1, 2). T cell precursors originate in the bone marrow and then migrate to the thymus to initiate differentiation into mature T cells. In the thymus, CD4 -CD8doublenegative (DN) thymocytes (which can be subcategorized as stages DN1-DN4) acquire T cell receptor (TCR) expression through VDJ recombination and develop into CD4 + CD8 + double-positive (DP) thymocytes, which subsequently give rise to CD4 + or CD8 + single-positive (SP) T cells. Two pivotal selection processes occur, namely positive selection and negative selection, and both serve as gatekeepers in the progress of DP T cells to the SP stage. Notably, only a small percentage of DP thymocytes survive through the selection process to become mature T cells bearing TCRs with suitable reactivity. Secure survival of the T cells which do pass selection is then of pivotal importance during thymic development.It has been shown that TCRs on the DP cell surface can bind to self-peptide-major histocompatibility complex (MHC) complexes on thymic epithelial and dendritic cells, which provide signals for thymocyte survival (3-5). Up-regulation of expression of survival-related proteins is one of the known mechanisms to promote thymocyte survival in this context. Well-studied examples include the Bcl-2 family prosurvival proteins Bcl-xL, whose stage-specific enrichment promotes the survival of DP thymocytes (6). In addition to regulations at the level of gene expression, further studies revealed that posttranslational ...
New reassortant H5N8 highly pathogenic avian influenza viruses were isolated from waterfowl in Southern China. Blast analysis demonstrated that the PB2 gene in these viruses were most closely related to A/wild duck/Shangdong/628/2011 (H5N1), while their NP genes were both more closely related to A/wild duck/Shandong/1/2011 (H5N1) and A/duck/Jiangsu/k1203/2010 (H5N8). However, the HA, NA, PB1, PA, M, and NS genes had the highest identity with A/duck/Jiangsu/k1203/2010 (H5N8). Phylogenetic analysis revealed that their HA genes belonged to the same GsGd H5 clade 2.3.4.4 detected in China in 2010. Therefore, we supposed that these H5N8 viruses might be novel reassortant viruses that have a H5N8 backbone while acquiring PB2 and NP genes from H5N1 viruses. This study is useful for better understanding the genetic and antigenic evolution of H5 avian influenza viruses in Southern China.
CTLA-4 is one of the key inhibitory immune receptors and plays a critical role in maintaining immune tolerance. Both loss of CTLA-4 gene in mice and mutations in humans result in systemic autoimmune diseases with a similar phenotype. However, the precise mechanisms of CTLA-4 have not yet been entirely clarified. Structural and functional analysis of the reported autoimmune cases revealed that pathogenic CTLA-4 mutations occur frequently in ligand binding and dimerization regions. Through genetic mutation screening study, we have discovered a new CTLA-4 point mutation in a patient with recurrent autoimmune inflammation. We used steered molecular dynamics (SMD) simulation, single-molecule biophysical approaches, as well as functional assays to compare the function of this CTLA-4 mutant to the WT molecule. We demonstrated that, mechanical force induces conformational changes in CTLA-4 to enhance pre-existing contacts and activates new interactions at the CTLA-4-CD80 and CD86 binding interface. Although the mutant CTLA-4 can function to induce downstream signals, its ability in trans-endocytosis of CD80 and CD86 is impaired due to altered ligand interaction. The conclusions from this study will help us elucidate the immunoregulatory mechanisms of CTLA-4 and provide new strategies for more effective targeting of CTLA-4 in autoimmune diseases and tumors.
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