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

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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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

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

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

Topological Schr\"odinger cats: Non-local quantum superpositions of topological defects

Topological defects (such as monopoles, vortex lines, or domain walls) mark locations where disparate choices of a broken symmetry vacuum elsewhere in the system lead to irreconcilable differences. They are energetically costly (the energy density in their core reaches that of the prior symmetric vacuum) but topologically stable (the whole manifold would have to be rearranged to get rid of the defect). We show how, in a paradigmatic model of a quantum phase transition, a topological defect can be put in a non-local superposition, so that - in a region large compared to the size of its core - the order parameter of the system is "undecided" by being in a quantum superposition of conflicting choices of the broken symmetry. We demonstrate how to exhibit such a "Schr\"odinger kink" by devising a version of a double-slit experiment suitable for topological defects. Coherence detectable in such experiments will be suppressed as a consequence of interaction with the environment. We analyze environment-induced decoherence and discuss its role in symmetry breaking.Comment: 7 pages, 4 figure

Search for the Elusive Higgs Boson Using Jet Structure at LHC

We consider the production of a light non-standard model Higgs boson of order 100~\GEV with an associated $W$ boson at CERN Large Hadron Collider. We focus on an interesting scenario that, the Higgs boson decays predominately into two light scalars $\chi$ with mass of few GeV which sequently decay into four gluons, i.e. $h\to 2\chi \to 4g$. Since $\chi$ is much lighter than the Higgs boson, it will be highly boosted and its decay products, the two gluons, will move close to each other, resulting in a single jet for $\chi$ decay in the detector. By using electromagnetic calorimeter-based and jet substructure analyses, we show in two cases of different $\chi$ masses that it is quite promising to extract the signal of Higgs boson out of large QCD background.Comment: 20 pages, 7 figure

Serum microRNA array analysis identifies miR-140-3p, miR-33b-3p and miR-671-3p as potential osteoarthritis biomarkers involved in metabolic processes.

Background: MicroRNAs (miRNAs) in circulation have emerged as promising biomarkers. In this study, we aimed to identify a circulating miRNA signature for osteoarthritis (OA) patients and in combination with bioinformatics analysis to evaluate the utility of selected differentially expressed miRNAs in the serum as potential OA biomarkers. Methods: Serum samples were collected from 12 primary OA patients, and 12 healthy individuals were screened using the Agilent Human miRNA Microarray platform interrogating 2549 miRNAs. Receiver Operating Characteristic (ROC) curves were constructed to evaluate the diagnostic performance of the deregulated miRNAs. Expression levels of selected miRNAs were validated by quantitative real-time PCR (qRT-PCR) in all serum and in articular cartilage samples from OA patients (n = 12) and healthy individuals (n = 7). Bioinformatics analysis was used to investigate the involved pathways and target genes for the above miRNAs. Results: We identified 279 differentially expressed miRNAs in the serum of OA patients compared to controls. Two hundred and five miRNAs (73.5%) were upregulated and 74 (26.5%) downregulated. ROC analysis revealed that 77 miRNAs had area under the curve (AUC) > 0.8 and p < 0.05. Bioinformatics analysis in the 77 miRNAs revealed that their target genes were involved in multiple signaling pathways associated with OA, among which FoxO, mTOR, Wnt, pI3K/akt, TGF-β signaling pathways, ECM-receptor interaction, and fatty acid biosynthesis. qRT-PCR validation in seven selected out of the 77 miRNAs revealed 3 significantly downregulated miRNAs (hsa-miR-33b-3p, hsa-miR-671-3p, and hsa-miR-140-3p) in the serum of OA patients, which were in silico predicted to be enriched in pathways involved in metabolic processes. Target-gene analysis of hsa-miR-140-3p, hsa-miR-33b-3p, and hsa-miR-671-3p revealed that InsR and IGFR1 were common targets of all three miRNAs, highlighting their involvement in regulation of metabolic processes that contribute to OA pathology. Hsa-miR-140-3p and hsa-miR-671-3p expression levels were consistently downregulated in articular cartilage of OA patients compared to healthy individuals. Conclusions: A serum miRNA signature was established for the first time using high density resolution miR-arrays in OA patients. We identified a three-miRNA signature, hsa-miR-140-3p, hsa-miR-671-3p, and hsa-miR-33b-3p, in the serum of OA patients, predicted to regulate metabolic processes, which could serve as a potential biomarker for the evaluation of OA risk and progression.Peer reviewedFinal Published versio