A new gene, termed klotho, has been identified that is involved in the suppression of several ageing phenotypes. A defect in klotho gene expression in the mouse results in a syndrome that resembles human ageing, including a short lifespan, infertility, arteriosclerosis, skin atrophy, osteoporosis and emphysema. The gene encodes a membrane protein that shares sequence similarity with the beta-glucosidase enzymes. The klotho gene product may function as part of a signalling pathway that regulates ageing in vivo and morbidity in age-related diseases.

We report that disruption of CD154 in nonobese diabetic (NOD) mice abrogates the helper function of CD4+CD25- T cells without impairing the regulatory activity of CD4+CD25+ T cells. Whereas CD4+ T cells from NOD mice enhanced a diabetogenic CD8+ T cell response in monoclonal TCR-transgenic NOD mice, CD4+ T cells from NOD.CD154(-/-) mice actively suppressed it. Suppression was mediated by regulatory CD4+CD25+ T cells capable of inhibiting CD8+ T cell responses induced by peptide-pulsed dendritic cells (DCs), but not peptide/MHC monomers. It involved inhibition of DC maturation, did not occur in the presence of CD154+ T-helper cells, and could be inhibited by activation of DCs with LPS, CpG DNA, or an agonistic anti-CD40 mAb. Thus, in at least some genetic backgrounds, CD154-CD40 interactions and innate stimuli release immature DCs from suppression by CD4+CD25+ T cells.

We propose to build a large water-Cherenkov-type muon-detector array (Tibet MD array) around the 37,000 m 2 Tibet air shower array (Tibet AS array) already constructed at 4,300 m above sea level in Tibet, China. Each muon detector is a waterproof concrete pool, 6 m wide × 6 m long × 1.5 m deep in size, equipped with a 20 inch-in-diameter PMT. The Tibet MD array consists of 240 muon detectors set up 2.5 m underground. Its total effective area will be 8,640 m 2 for muon detection. The Tibet MD array will significantly improve gamma-ray sensitivity of the Tibet AS array in the 100 TeV region (10-1000 TeV) by means of gamma/hadron separation based on counting the number of muons accompanying an air shower. The Tibet AS+MD array will have the sensitivity to gamma rays in the 100 TeV region by an order of magnitude better than any other previous existing detectors in the world. Keywords Gamma ray · Cosmic ray · Muon · SNR PACS 95.55.Ka · 98.70.Sa · 95.85.Ry

Autoimmune diabetes in nonobese diabetic (NOD) mice results from destruction of pancreatic β cells by T lymphocytes. It is believed that CD8 + cytotoxic T lymphocytes (CTLs) effect the initial β-cell insult in diabetes, but the mechanisms remain unclear. Studies of NOD.lpr mice have suggested that disease initiation is a Fas-dependent process, yet perforin-deficient NOD mice rarely develop diabetes despite expressing Fas. Here, we have investigated the role of perforin and Fas in the ability of β cell-reactive CD8 + T cells bearing a T-cell receptor (8.3-TCR) that is representative of TCRs used by CD8 + CTLs propagated from the earliest insulitic lesions of NOD mice, and that targets an immunodominant peptide/H-2K d complex on β cells, to effect β-cell damage in vitro and in vivo. In vitro, 8.3-CTLs killed antigenic peptide-pulsed non-β-cell targets via both perforin and Fas, but they killed NOD β cells via Fas exclusively. Perforin-deficient 8.3-TCR-transgenic NOD mice expressing an oligoclonal or monoclonal T-cell repertoire developed diabetes even more frequently than their perforin-competent littermates. These results demonstrate that diabetogenic CD8 + CTLs representative of CTLs putatively involved in the initiation of autoimmune diabetes kill β cells in a Fas-dependent and perforin-independent manner.

No abstract

We present the large-scale sidereal anisotropy of galactic cosmic-ray intensity in the multi-TeV region observed with the Tibet-III air shower array during the period from 1999 through 2003. The sidereal daily variation of cosmic rays observed in this experiment shows an excess of relative intensity around 4 ∼ 7 hours local sidereal time, as well as a deficit around 12 hours local sidereal time. While the amplitude of the excess is not significant when averaged over all declinations, the excess in individual declinaton bands becomes larger and clearer as the viewing direction moves toward the south. The maximum phase of the excess intensity changes from ∼7 at the northern hemisphere to ∼4 hours at the equatorial region. We also show that both the amplitude and the phase of the first harmonic vector of the daily variation are remarkably independent of primary energy in the multi-TeV region. This is the first result determining

Objective

Abstract-A decline in oxygen concentration perturbs endothelial function, which promotes local thrombosis. In this study, we determined whether hypoxia in the range of that observed in pathophysiological hypoxic states stimulates plasminogen activator inhibitor-1 (PAI-1) production in bovine aortic endothelial cells. PAI-1 production, measured by ELISA, was increased by 4.7-fold (PϽ0.05 versus normoxic control, nϭ4) at 12 hours after hypoxic stimulation. Northern blot analysis showed the progressive time-dependent increase in the steady-state level of PAI-1 mRNA expression by hypoxia, which reached a 7.5-fold increase (PϽ0.05 versus control, nϭ4) at 12 hours. Deferoxamine, which has been known to bind heme protein and to reproduce the hypoxic response, induced PAI-1 production at both the mRNA and protein levels. The half-life of PAI-1 mRNA, as determined by a standard decay assay, was not affected by hypoxia, suggesting that induction of PAI-1 mRNA was regulated mainly at the transcriptional level. Transient transfection assays of the human PAI-1 promoter-luciferase construct indicates that a hypoxia-responsive region lies between Ϫ414 and Ϫ107 relative to the transcription start site, where no putative hypoxia response element is found. The hypoxia-mediated increase in PAI-1 mRNA levels was attenuated by the tyrosine kinase inhibitors genistein (50 mol/L) and herbimycin A (1 mol/L), whereas PD98059 (50 mol/L, MEK1 inhibitor), SB203580 (10 mol/L, p38 mitogen-activated protein kinase inhibitor), and calphostin C (1 mol/L, protein kinase C inhibitor) had no effect on the induction of PAI-1 expression by hypoxia and deferoxamine. Genistein but not daidzein blocked the production of hypoxia-and deferoxamine-induced PAI-1 protein. Thus, we conclude that hypoxia stimulates PAI-1 gene transcription and protein production through a signaling pathway involving genistein-sensitive tyrosine kinases in vascular endothelial cells. Key Words: hypoxia Ⅲ PAI-1 Ⅲ tyrosine kinase Ⅲ mitogen-activated protein kinase Ⅲ endothelial cells T here is growing evidence indicating that vascular endothelium plays an obligatory role in regulating fibrinolytic activity, such as vascular tone and platelet activity. 1 Endothelial dysfunction leads to the derangement of vascular endothelial anticoagulant properties and contributes to the pathophysiology of several cardiovascular disorders, including intravascular thrombosis, intimal growth, and plaque rupture. 2 Endothelial cells have been shown to produce many vasoactive substances that intervene in the fibrinolysis and coagulation processes. Of the many components regulating the balance between procoagulant and anticoagulant properties of the endothelium, pathways controlling plasminogen activator activity are particularly important. This activity is controlled primarily by plasminogen activator inhibitor-1 (PAI-1), which is synthesized by endothelial cells, 3 smooth muscle cells, 4,5 platelets, 6 monocytes, 7 and hepatocytes. 8