Nmnat2 protects cardiomyocytes from hypertrophy via activation of SIRT6

The discovery of sirtuins (SIRT), a family of nicotinamide adenine dinucleotide (NAD)-dependent deacetylases, has indicated that intracellular NAD level is crucial for the hypertrophic response of cardiomyocytes. Nicotinamide mononucleotide adenylyltransferase (Nmnat) is a central enzyme in NAD biosynthesis. Here we revealed that Nmnat2 protein expression and enzyme activity were down-regulated during cardiac hypertrophy. In neonatal rat cardiomyocytes, overexpression of Nmnat2 but not its catalytically inactive mutant blocked angiotensin II (Ang II)-induced cardiac hypertrophy, which was dependent on activation of SIRT6 through maintaining the intracellular NAD level. Our results suggested that modulation of Nmnat2 activity may be beneficial in cardiac hypertrophy.     

MiR-136 promotes apoptosis of glioma cells by targeting AEG-1 and Bcl-2

MicroRNAs have the capacity to coordinately repress multiple target genes and interfere with biological functions of the cell, such as proliferation and apoptosis. Here we report that miR-136 is downregulated in human glioma, and that the miRNA promotes apoptosis of glioma cells induced by chemotherapy. Two anti-apoptotic genes, AEG-1 and Bcl-2, are identified as targets of miR-136, and restoration of AEG-1 or Bcl-2 expression suppresses miR-136-enhanced apoptosis. Therefore, miR-136 might play a tumor-suppressive role in human glioma and thereby might represent a potential therapeutic strategy.     

A regulatory role for IL-10 receptor signaling in development and B cell help of T follicular helper cells in mice

IL -10 is widely accepted as a survival, proliferation, and differentiation factor for B cells. However, IL-10 deficiency accelerates disease progression as the result of autoantibody production in many autoimmune disease models. It was demonstrated that T follicular helper cells (T(FH) cells) play a key role in helping B cells that are secreting Abs. In this study, we demonstrated a regulatory role for IL-10R signaling on the development and B cell help function of T(FH) cells in vitro and in vivo. IL-1R subunit β-deficient (Il10rb(-/-)) Th cells were able to differentiate more readily into T(FH) cells, as well as secrete more IL-21 and IL-17 compared with wild-type Th cell-derived T(FH) cells. Increased IL-21 and IL-17 contributed to the enhanced B cell help functions of T(FH) cells. Further experiments demonstrated that IL-6 and IL-23 from dendritic cells in Il10rb(-/-) mice contributed to the differentiation of naive Th cells into T(FH) cells, as well as the generation of IL-21- and IL-17-producing T(FH) cells. Our results provide useful information for clarifying the immunoregulatory mechanisms associated with IL-10 deficiency in certain autoimmune disease models. This information could also be of benefit for the development of vaccines.     

Intrapulmonary administration of leukotriene B(4) augments neutrophil accumulation and responses in the lung to Klebsiella infection in CXCL1 knockout mice

In prior studies, we demonstrated that 1) CXCL1/KC is essential for NF-κB and MAPK activation and expression of CXCL2/MIP-2 and CXCL5/LPS-induced CXC chemokine in Klebsiella-infected lungs, and 2) CXCL1 derived from hematopoietic and resident cells contributes to host immunity against Klebsiella. However, the role of CXCL1 in mediating neutrophil leukotriene B(4) (LTB(4)), reactive oxygen species (ROS), and reactive nitrogen species (RNS) production is unclear, as is the contribution of these factors to host immunity. In this study, we investigated 1) the role of CXCL1 in LTB(4), NADPH oxidase, and inducible NO synthase (iNOS) expression in lungs and neutrophils, and 2) whether LTB(4) postinfection reverses innate immune defects in CXCL1(-/-) mice via regulation of NADPH oxidase and iNOS. Our results demonstrate reduced neutrophil influx, attenuated LTB(4) levels, and decreased ROS and iNOS production in the lungs of CXCL1(-/-) mice after Klebsiella pneumoniae infection. Using neutrophil depletion and repletion, we found that neutrophils are the predominant source of pulmonary LTB(4) after infection. To treat immune defects in CXCL1(-/-) mice, we intrapulmonarily administered LTB(4). Postinfection, LTB(4) treatment reversed immune defects in CXCL1(-/-) mice and improved survival, neutrophil recruitment, cytokine/chemokine expression, NF-κB/MAPK activation, and ROS/RNS production. LTB(4) also enhanced myeloperoxidase, H(2)O(2,) RNS production, and bacterial killing in K. pneumoniae-infected CXCL1(-/-) neutrophils. These novel results uncover important roles for CXCL1 in generating ROS and RNS in neutrophils and in regulating host immunity against K. pneumoniae infection. Our findings suggest that LTB(4) could be used to correct defects in neutrophil recruitment and function in individuals lacking or expressing malfunctional CXCL1.     

Crystal structure of the urokinase receptor in a ligand-free form

The urokinase receptor urokinase-type plasminogen activator receptor (uPAR) is a surface receptor capable of not only focalizing urokinase-type plasminogen activator (uPA)-mediated fibrinolysis to the pericellular micro-environment but also promoting cell migration and chemotaxis. Consistent with this multifunctional role, uPAR binds several extracellular ligands, including uPA and vitronectin. Structural studies suggest that uPAR possesses structural flexibility. It is, however, not clear whether this flexibility is an inherent property of the uPAR structure per se or whether it is induced upon ligand binding. The crystal structure of human uPAR in its ligand-free state would clarify this issue, but such information remains unfortunately elusive. We now report the crystal structures of a stabilized, human uPAR (H47C/N259C) in its ligand-free form to 2.4 Å and in complex with amino-terminal fragment (ATF) to 3.2 Å. The structure of uPAR^H47C/N259C in complex with ATF resembles the wild-type uPAR·ATF complex, demonstrating that these mutations do not perturb the uPA binding properties of uPAR. The present structure of uPAR^H47C/N259C provides the first structural definition of uPAR in its ligand-free form, which represents one of the biologically active conformations of uPAR as defined by extensive biochemical studies. The domain boundary between uPAR DI–DII domains is more flexible than the DII–DIII domain boundary. Two important structural features are highlighted by the present uPAR structure. First, the DI–DIII domain boundary may face the cell membrane. Second, loop 130–140 of uPAR plays a dynamic role during ligand loading/unloading. Together, these studies provide new insights into uPAR structure–function relationships, emphasizing the importance of the inter-domain dynamics of this modular receptor.     

A novel porcine circovirus type 2a strain, 10JS-2, with eleven-nucleotide insertions in the origin of genome replication

Here, we report a novel porcine circovirus type 2a (PCV2a) strain with 11 nucleotides (nt) inserted in the origin of genome replication (Ori). This is the first report of a PCV2a strain with nucleotide insertion in Ori. Our study will help further epidemiological studies and extend our knowledge of evolutionary characteristics of PCV2.     

Nine Complete Genome Sequences of Cutaneous Human Papillomavirus Genotypes Isolated from Healthy Skin of Individuals Living in Rural He Nan Province,China

Nine novel human papillomavirus (HPV) types were isolated from healthy skin of individuals in rural Anyang, China. All of these isolates belong to the genus Gammapapillomavirus. These data will provide us with useful information for a better understanding of PV evolution and the relationship of PV with the host.