2,261 research outputs found

    Inhibition of REV-ERBs stimulates microglial amyloid-beta clearance and reduces amyloid plaque deposition in the 5XFAD mouse model of Alzheimer\u27s disease

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    A promising new therapeutic target for the treatment of Alzheimer\u27s disease (AD) is the circadian system. Although patients with AD are known to have abnormal circadian rhythms and suffer sleep disturbances, the role of the molecular clock in regulating amyloid-beta (Aβ) pathology is still poorly understood. Here, we explored how the circadian repressors REV-ERBα and β affected Aβ clearance in mouse microglia. We discovered that, at Circadian time 4 (CT4), microglia expressed higher levels of the master clock protein BMAL1 and more rapidly phagocytosed fibrillary A

    Human CD57(+ )germinal center-T cells are the major helpers for GC-B cells and induce class switch recombination

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    BACKGROUND: The function of CD57(+ )CD4(+ )T cells, constituting a major subset of germinal center T (GC-Th) cells in human lymphoid tissues, has been unclear. There have been contradictory reports regarding the B cell helping function of CD57(+ )GC-Th cells in production of immunoglobulin (Ig). Furthermore, the cytokine and co-stimulation requirement for their helper activity remains largely unknown. To clarify and gain more insight into their function in helping B cells, we systematically investigated the capacity of human tonsil CD57(+ )GC-Th cells in inducing B cell Ig synthesis. RESULTS: We demonstrated that CD57(+ )GC-Th cells are highly efficient in helping B cell production of all four subsets of Ig (IgM, IgG, IgA and IgE) compared to other T-helper cells located in germinal centers or interfollicular areas. CD57(+ )GC-Th cells were particularly more efficient than other T cells in helping GC-B cells but not naïve B cells. CD57(+ )GC-Th cells induced the expression of activation-induced cytosine deaminase (AID) and class switch recombination in developing B cells. IgG1-3 and IgA1 were the major Ig isotypes induced by CD57(+ )GC-Th cells. CD40L, but not IL-4, IL-10 and IFN-γ, was critical in CD57(+ )GC-Th cell-driven B cell production of Ig. However, IL-10, when added exogenously, significantly enhanced the helper activity of CD57(+ )GC-Th cells, while TGF-β1 completely and IFN-γ partially suppressed the CD57(+ )GC-Th cell-driven Ig production. CONCLUSIONS: CD57(+)CD4(+ )T cells in the germinal centers of human lymphoid tissues are the major T helper cell subset for GC-B cells in Ig synthesis. Their helper activity is consistent with their capacity to induce AID and class switch recombination, and can be regulated by CD40L, IL-4, IL-10 and TGF-β

    TCF/β-catenin plays an important role in HCCR-1 oncogene expression

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    <p>Abstract</p> <p>Background</p> <p>Oncogene <it>HCCR-1 </it>functions as a negative regulator of the p53 and contributes to tumorigenesis of various human tissues. However, it is unknown how <it>HCCR-1 </it>contributes to the cellular and biochemical mechanisms of human tumorigenesis.</p> <p>Results</p> <p>In this study, we showed how the expression of <it>HCCR-1 </it>is modulated. The luciferase activity assay indicated that the <it>HCCR-1 </it>5'-flanking region at positions -166 to +30 plays an important role in <it>HCCR-1 </it>promoter activity. Computational analysis of this region identified two consensus sequences for the T-cell factor (TCF) located at -26 to -4 (Tcf1) and -136 to -114 (Tcf2). Mutation at the Tcf1 site led to a dramatic decrease in promoter activity. Mobility shift assays (EMSA) revealed that nuclear proteins bind to the Tcf1 site, but not to the Tcf2 site. LiCl, Wnt signal activator by GSK-3β inhibition, significantly increased reporter activities in wild-type Tcf1-containing constructs, but were without effect in mutant Tcf1-containing constructs in HEK/293 cells. In addition, endogenous <it>HCCR-1 </it>expression was also increased by treatment with GSK-3β inhibitor, LiCl or AR-A014418 in HEK/293 and K562 cells. Finally, we also observed that the transcription factor, TCF, and its cofactor, β-catenin, bound to the Tcf1 site.</p> <p>Conclusion</p> <p>These findings suggest that the Tcf1 site on the <it>HCCR-1 </it>promoter is a major element regulating <it>HCCR-1 </it>expression and abnormal stimulation of this site may induce various human cancers.</p

    Field Theoretical Analysis of On-line Learning of Probability Distributions

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    On-line learning of probability distributions is analyzed from the field theoretical point of view. We can obtain an optimal on-line learning algorithm, since renormalization group enables us to control the number of degrees of freedom of a system according to the number of examples. We do not learn parameters of a model, but probability distributions themselves. Therefore, the algorithm requires no a priori knowledge of a model.Comment: 4 pages, 1 figure, RevTe

    Interfacial Reactions of Ozone with Surfactant Protein B in a Model Lung Surfactant System

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    Oxidative stresses from irritants such as hydrogen peroxide and ozone (O_3) can cause dysfunction of the pulmonary surfactant (PS) layer in the human lung, resulting in chronic diseases of the respiratory tract. For identification of structural changes of pulmonary surfactant protein B (SP-B) due to the heterogeneous reaction with O_3, field-induced droplet ionization (FIDI) mass spectrometry has been utilized. FIDI is a soft ionization method in which ions are extracted from the surface of microliter-volume droplets. We report structurally specific oxidative changes of SP-B_(1−25) (a shortened version of human SP-B) at the air−liquid interface. We also present studies of the interfacial oxidation of SP-B_(1−25) in a nonionizable 1-palmitoyl-2-oleoyl-sn-glycerol (POG) surfactant layer as a model PS system, where competitive oxidation of the two components is observed. Our results indicate that the heterogeneous reaction of SP-B_(1−25) at the interface is quite different from that in the solution phase. In comparison with the nearly complete homogeneous oxidation of SP-B_(1−25), only a subset of the amino acids known to react with ozone are oxidized by direct ozonolysis in the hydrophobic interfacial environment, both with and without the lipid surfactant layer. Combining these experimental observations with the results of molecular dynamics simulations provides an improved understanding of the interfacial structure and chemistry of a model lung surfactant system subjected to oxidative stress

    Morphology Transformation of Foldamer Assemblies Triggered by Single Oxygen Atom on Critical Residue Switch

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    The synthesis of morphologically well-defined peptidic materials via self-assembly is challenging but demanding for biocompatible functional materials. Moreover, switching morphology from a given shape to other predictable forms by molecular modification of the identical building block is an even more complicated subject because the self-assembly of flexible peptides is prone to diverge upon subtle structural change. To accomplish controllable morphology transformation, systematic self-assembly studies are performed using congener short β-peptide foldamers to find a minimal structural change that alters the self-assembled morphology. Introduction of oxygen-containing β-amino acid (ATFC) for subtle electronic perturbation on hydrophobic foldamer induces a previously inaccessible solid-state conformational split to generate the most susceptible modification site for morphology transformation of the foldamer assemblies. The site-dependent morphological switching power of ATFC is further demonstrated by dual substitution experiments and proven by crystallographic analyses. Stepwise morphology transformation is shown by modifying an identical foldamer scaffold. This study will guide in designing peptidic molecules from scratch to create complex and biofunctional assemblies with nonspherical shapes

    A Multi-dimensional Code for Isothermal Magnetohydrodynamic Flows in Astrophysics

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    We present a multi-dimensional numerical code to solve isothermal magnetohydrodynamic (IMHD) equations for use in modeling astrophysical flows. First, we have built a one-dimensional code which is based on an explicit finite-difference method on an Eulerian grid, called the total variation diminishing (TVD) scheme. Recipes for building the one-dimensional IMHD code, including the normalized right and left eigenvectors of the IMHD Jacobian matrix, are presented. Then, we have extended the one-dimensional code to a multi-dimensional IMHD code through a Strang-type dimensional splitting. In the multi-dimensional code, an explicit cleaning step has been included to eliminate non-zero B\nabla\cdot B at every time step. To estimate the proformance of the code, one- and two-dimensional IMHD shock tube tests, and the decay test of a two-dimensional Alfv\'{e}n wave have been done. As an example of astrophysical applications, we have simulated the nonlinear evolution of the two-dimensional Parker instability under a uniform gravity.Comment: Accepted for publication in ApJ, using aaspp4.sty, 22 text pages with 10 figure

    Quantum-dot light-emitting diodes utilizing CdSe/ZnS nanocrystals embedded in TiO(2) thin film

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    Quantum-dot (QD) light-emitting diodes (LEDs) are demonstrated on Si wafers by embedding core-shell CdSe/ZnS nanocrystals in TiO(2) thin films via plasma-enhanced metallorganic chemical vapor deposition. The n-TiO(2)/QDs/p-Si LED devices show typical p-n diode current-voltage and efficient electroluminescence characteristics, which are critically affected by the removal of QD surface ligands. The TiO(2)/QDs/Si system we presented can offer promising Si-based optoelectronic and electronic device applications utilizing numerous nanocrystals synthesized by colloidal solution chemistry.open181

    Diffusion on a heptagonal lattice

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    We study the diffusion phenomena on the negatively curved surface made up of congruent heptagons. Unlike the usual two-dimensional plane, this structure makes the boundary increase exponentially with the distance from the center, and hence the displacement of a classical random walker increases linearly in time. The diffusion of a quantum particle put on the heptagonal lattice is also studied in the framework of the tight-binding model Hamiltonian, and we again find the linear diffusion like the classical random walk. A comparison with diffusion on complex networks is also made.Comment: 5 pages, 6 figure
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