The interferon-stimulated gene IFITM3 restricts West Nile virus infection and pathogenesis

The interferon-induced transmembrane protein (IFITM) family of proteins inhibit infection of several different enveloped viruses in cell culture by virtue of their ability to restrict entry and fusion from late endosomes. As few studies have evaluated the importance of Ifitm3 in vivo in restricting viral pathogenesis, we investigated its significance as an antiviral gene against West Nile virus (WNV), an encephalitic flavivirus, in cells and mice. Ifitm3(−/−) mice were more vulnerable to lethal WNV infection, and this was associated with greater virus accumulation in peripheral organs and central nervous system tissues. As no difference in viral burden in the brain or spinal cord was observed after direct intracranial inoculation, Ifitm3 likely functions as an antiviral protein in nonneuronal cells. Consistent with this, Ifitm3(−/−) fibroblasts but not dendritic cells resulted in higher yields of WNV in multistep growth analyses. Moreover, transcomplementation experiments showed that Ifitm3 inhibited WNV infection independently of Ifitm1, Ifitm2, Ifitm5, and Ifitm6. Beyond a direct effect on viral infection in cells, analysis of the immune response in WNV-infected Ifitm3(−/−) mice showed decreases in the total number of B cells, CD4(+) T cells, and antigen-specific CD8(+) T cells. Finally, bone marrow chimera experiments demonstrated that Ifitm3 functioned in both radioresistant and radiosensitive cells, as higher levels of WNV were observed in the brain only when Ifitm3 was absent from both compartments. Our analyses suggest that Ifitm3 restricts WNV pathogenesis likely through multiple mechanisms, including the direct control of infection in subsets of cells. IMPORTANCE As part of the mammalian host response to viral infections, hundreds of interferon-stimulated genes (ISGs) are induced. The inhibitory activity of individual ISGs varies depending on the specific cell type and viral pathogen. Among ISGs, the genes encoding interferon-induced transmembrane protein (IFITM) have been reported to inhibit multiple families of viruses in cell culture. However, few reports have evaluated the impact of IFITM genes on viral pathogenesis in vivo. In this study, we characterized the antiviral activity of Ifitm3 against West Nile virus (WNV), an encephalitic flavivirus, using mice with a targeted gene deletion of Ifitm3. Based on extensive virological and immunological analyses, we determined that Ifitm3 protects mice from WNV-induced mortality by restricting virus accumulation in peripheral organs and, subsequently, in central nervous system tissues. Our data suggest that Ifitm3 restricts WNV pathogenesis by multiple mechanisms and functions in part by controlling infection in different cell types

Keratin 6a marks mammary bipotential progenitor cells that can give rise to a unique tumor model resembling human normal-like breast cancer.

Progenitor cells are considered an important cell of origin of human malignancies. However, there has not been any single gene that can define mammary bipotential progenitor cells, and as such it has not been possible to use genetic methods to introduce oncogenic alterations into these cells in vivo to study tumorigenesis from them. Keratin 6a is expressed in a subset of mammary luminal epithelial cells and body cells of terminal end buds. By generating transgenic mice using the Keratin 6a (K6a) gene promoter to express tumor virus A (tva), which encodes the receptor for avian leukosis virus subgroup A (ALV/A), we provide direct evidence that K6a(+) cells are bipotential progenitor cells, and the first demonstration of a non-basal location for some biopotential progenitor cells. These K6a(+) cells were readily induced to form mammary tumors by intraductal injection of RCAS (an ALV/A-derived vector) carrying the gene encoding the polyoma middle T antigen. Tumors in this K6a-tva line were papillary and resembled the normal breast-like subtype of human breast cancer. This is the first model of this subtype of human tumors and thus may be useful for preclinical testing of targeted therapy for patients with normal-like breast cancer. These observations also provide direct in vivo evidence for the hypothesis that the cell of origin affects mammary tumor phenotypes

Eddy detection inverted from Argo profiles to surface altimetry

Argo floats are widely used to characterize vertical structures of ocean eddies, yet their capability to invert sea-surface features of eddies, especially those overlooked by available altimeters, has not been explored. In this paper, we propose an “interior-to-surface” inversion algorithm to effectively expand the capacity of eddy detection by estimating altimeter-missed eddies’ surface attributes from their Argo-derived potential density anomaly profiles, given that interior property and surface signature of eddies are highly correlated. An altimeter- calibrated machine learning ensemble is employed for the inversion training based on the joint altimeter-Argo eddy data and shows promising performance with mean absolute errors of 5.4 km, 0.5 cm, and 14.3 cm2/s2 for eddy radius, amplitude, and kinetic energy. Then, the trained ensemble model is applied to independently invert the properties of eddies captured by an Argo-alone detection scheme, which yields a high spatiotemporal consistency with their altimeter-captured counterparts. In particular, a portion of Argo-alone eddies is ~25% smaller than altimeter-derived ones, indicating Argo’s unique capability of profiling weaker submesoscale eddies. Sea surface temperature and chlorophyll data are further applied to validate the reliability of eddies identified and characterized by the Argo-only algorithm. This new methodology effectively complements that of altimetry in eddy detecting and can be expanded to estimate other physical/biochemical eddy variables from a variety of in-situ observations

Novel PDE4 inhibitors derived from Chinese medicine Forsythia

Cyclic adenosine monophosphate (cAMP) is a crucial intracellular second messenger molecule that converts extracellular molecules to intracellular signal transduction pathways generating cell- and stimulus-specific effects. Importantly, specific phosphodiesterase (PDE) subtypes control the amplitude and duration of cAMP-induced physiological processes and are therefore a prominent pharmacological target currently used in a variety of fields. Here we tested the extracts from traditional Chinese medicine, Forsythia suspense seeds, which have been used for more than 2000 years to relieve respiratory symptoms. Using structural-functional analysis we found its major lignin, Forsynthin, acted as an immunosuppressant by inhibiting PDE4 in inflammatory and immune cell. Moreover, several novel, selective small molecule derivatives of Forsythin were tested in vitro and in murine models of viral and bacterial pneumonia, sepsis and cytokine-driven systemic inflammation. Thus, pharmacological targeting of PDE4 may be a promising strategy for immune-related disorders characterized by amplified host inflammatory response

Excitation Dependent Phosphorous Property and New Model of the Structured Green Luminescence in ZnO

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Relationship between climatic conditions and the relative abundance of modern C<inf>3</inf> and C<inf>4</inf> plants in three regions around the North Pacific

Using -24‰ and -14‰ as the endpoints of stable carbon isotopic composition of total organic carbon (δ13CTOC) of surface soil under pure C3 and C4 vegetation, and surface soil δ13CTOC data from eastern China, Australia and the Great Plains of North America, we estimate the relative abundance of C3/C4 plants (i. e., the ratio of C3 or C4 biomass to local primary production) in modern vegetation for each region. The relative abundance of modern C3/C4 vegetation from each region is compared to the corresponding climatic parameters (mean annual temperature and precipitation) to explore the relationship between relative C4 abundance and climate. The results indicate that temperature controls the growth of C4 plants. However, even where temperature is high enough for the growth of C4 plants, they will only dominate the landscape when precipitation declines as temperatures increase. Our results are consistent with those of other investigations of the geographic distribution of modern C4 plant species. Therefore, our results provide an important reference for interpretation of past C3/C4 relative abundance records in these three regions. © 2010 Science China Press and Springer-Verlag Berlin Heidelberg

Goldstini Can Give the Higgs a Boost

Supersymmetric collider phenomenology depends crucially on whether the lightest observable-sector supersymmetric particle (LOSP) decays, and if so, what the LOSP decay products are. For instance, in SUSY models where the gravitino is lighter than the LOSP, the LOSP decays to its superpartner and a longitudinal gravitino via supercurrent couplings. In this paper, we show that LOSP decays can be substantially modified when there are multiple sectors that break supersymmetry, where in addition to the gravitino there are light uneaten goldstini. As a particularly striking example, a bino-like LOSP can have a near 100% branching fraction to a higgs boson and an uneaten goldstino, even if the LOSP has negligible higgsino fraction. This occurs because the uneaten goldstino is unconstrained by the supercurrent, allowing additional operators to mediate LOSP decay. These operators can be enhanced in the presence of an R symmetry, leading to copious boosted higgs production in SUSY cascade decays.Comment: 30 pages, 12 figures; v2: title change, clarifications added, version to appear in JHE

Jet Substructure Without Trees

We present an alternative approach to identifying and characterizing jet substructure. An angular correlation function is introduced that can be used to extract angular and mass scales within a jet without reference to a clustering algorithm. This procedure gives rise to a number of useful jet observables. As an application, we construct a top quark tagging algorithm that is competitive with existing methods.Comment: 22 pages, 16 figures, version accepted by JHE

Identifying Boosted Objects with N-subjettiness

We introduce a new jet shape -- N-subjettiness -- designed to identify boosted hadronically-decaying objects like electroweak bosons and top quarks. Combined with a jet invariant mass cut, N-subjettiness is an effective discriminating variable for tagging boosted objects and rejecting the background of QCD jets with large invariant mass. In efficiency studies of boosted W bosons and top quarks, we find tagging efficiencies of 30% are achievable with fake rates of 1%. We also consider the discovery potential for new heavy resonances that decay to pairs of boosted objects, and find significant improvements are possible using N-subjettiness. In this way, N-subjettiness combines the advantages of jet shapes with the discriminating power seen in previous jet substructure algorithms.Comment: 26 pages, 26 figures, 2 tables; v2: references added; v3: discussion of results extende