Fermi-LAT Study of Gamma-ray Emission in the Direction of Supernova Remnant W49B

We present an analysis of the gamma-ray data obtained with the Large Area Telescope (LAT) onboard the Fermi Gamma-ray Space Telescope in the direction of SNR W49B (G43.3-0.2). A bright unresolved gamma-ray source detected at a significance of 38 sigma is found to coincide with SNR W49B. The energy spectrum in the 0.2-200 GeV range gradually steepens toward high energies. The luminosity is estimated to be 1.5x10^{36} (D/8 kpc)^2 erg s^-1 in this energy range. There is no indication that the gamma-ray emission comes from a pulsar. Assuming that the SNR shell is the site of gamma-ray production, the observed spectrum can be explained either by the decay of neutral pi mesons produced through the proton-proton collisions or by electron bremsstrahlung. The calculated energy density of relativistic particles responsible for the LAT flux is estimated to be remarkably large, U_{e,p}>10^4 eV cm^-3, for either gamma-ray production mechanism.Comment: 9 pages, 10 figure

Fermi-LAT Discovery of Extended Gamma-ray Emission in the Direction of Supernova Remnant W51C

The discovery of bright gamma-ray emission coincident with supernova remnant (SNR) W51C is reported using the Large Area Telescope (LAT) on board the Fermi Gamma-ray Space Telescope. W51C is a middle-aged remnant (~10^4 yr) with intense radio synchrotron emission in its shell and known to be interacting with a molecular cloud. The gamma-ray emission is spatially extended, broadly consistent with the radio and X-ray extent of SNR W51C. The energy spectrum in the 0.2-50 GeV band exhibits steepening toward high energies. The luminosity is greater than 1x10^{36} erg/s given the distance constraint of D>5.5 kpc, which makes this object one of the most luminous gamma-ray sources in our Galaxy. The observed gamma-rays can be explained reasonably by a combination of efficient acceleration of nuclear cosmic rays at supernova shocks and shock-cloud interactions. The decay of neutral pi-mesons produced in hadronic collisions provides a plausible explanation for the gamma-ray emission. The product of the average gas density and the total energy content of the accelerated protons amounts to 5x10^{51}(D/6kpc)^2 erg/cm^3. Electron density constraints from the radio and X-ray bands render it difficult to explain the LAT signal as due to inverse Compton scattering. The Fermi LAT source coincident with SNR W51C sheds new light on the origin of Galactic cosmic rays.Comment: 17 pages, 4 figures, 1 table. Accepted for ApJ Letters. Contact authors: Y. Uchiyama, S. Funk., H. Tajima, T. Tanak

Coexpression of VEGF-C and COX-2 and its association with lymphangiogenesis in human breast cancer

<p>Abstract</p> <p>Background</p> <p>Lymphangiogenesis has become a new research frontier in tumor metastasis since the discovery of reliable lymphatic markers that have allowed observation and isolation of lymphatic endothelium. Cyclooxygenase-2 (COX-2) has been reported to be involved in the critical steps in carcinogenesis. However, possible role of COX-2 in lymphangiogenesis and lymphatic metastasis is still poorly understood. In present study, we aimed to investigate the relationship between vascular endothelial growth factor-C (VEGF-C) and COX-2 in human breast cancer, and correlations with lymphangiogenesis and prognosis.</p> <p>Methods</p> <p>Tissue samples of primary tumors from 70 patients undergoing intentionally curative surgical resections for breast cancer were immunohistochemically examined for VEGF-C, COX-2, and D2-40 expressions. The association between COX-2 and VEGF-C expressions and clinicopathological parameters as well as prognosis were analysised. To demonstrate the presence of proliferating lymphatic endothelial cells, 10 random cases with high LVD counts were selected for D2-40/Ki-67 double immunostaining.</p> <p>Results</p> <p>A significant correlation was found between the expression of VEGF-C and COX-2 (<it>r </it>= 0.529, <it>P </it>< 0.001), and both elevated VEGF-C expression and elevated COX-2 expression were associated with higher lymph vessel density (LVD), lymph node metastasis and D2-40 positive lymphatic invasion (LVI) as well as worse disease free survival (DFS) and overall survival (OS) in a univariate analysis. In the double immunostain for the lymph vessel marker D2-40 and the proliferation marker Ki-67, the results confirmed Ki-67-positive nuclei in a proportion of lymph vessel endothelial cells.</p> <p>Conclusion</p> <p>There is indeed lymphangiogenesis in breast cancer, the most compelling evidence being the presence of proliferating lymphatic endothelial cells. VEGF-C and COX-2 are coexpressed and significantly associated with lymphangiogenesis and prognosis in invasive breast cancer. Suggesting COX-2 may up-regulate VEGF-C expression and thus promote lymph node metastasis via lymphangiogenesis pathway in human breast cancer.</p

Protective Unfolded Protein Response in Human Pancreatic Beta Cells Transplanted into Mice

Background: There is great interest about the possible contribution of ER stress to the apoptosis of pancreatic beta cells in the diabetic state and with islet transplantation. Methods and Findings: Expression of genes involved in ER stress were examined in beta cell enriched tissue obtained with laser capture microdissection (LCM) from frozen sections of pancreases obtained from non-diabetic subjects at surgery and from human islets transplanted into ICR-SCID mice for 4 wk. Because mice have higher glucose levels than humans, the transplanted beta cells were exposed to mild hyperglycemia and the abnormal environment of the transplant site. RNA was extracted from the LCM specimens, amplified and then subjected to microarray analysis. The transplanted beta cells showed an unfolded protein response (UPR). There was activation of many genes of the IRE-1 pathway that provide protection against the deleterious effects of ER stress, increased expression of ER chaperones and ERAD (ER-associated protein degradation) proteins. The other two arms of ER stress, PERK and ATF-6, had many down regulated genes. Downregulation of EIF2A could protect by inhibiting protein synthesis. Two genes known to contribute to apoptosis, CHOP and JNK, were downregulated. Conclusions: Human beta cells in a transplant site had UPR changes in gene expression that protect against the proapoptotic effects of unfolded proteins

Fermi Large Area Telescope Third Source Catalog

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Type 2 Diabetes Susceptibility Gene Expression in Normal or Diabetic Sorted Human Alpha and Beta Cells: Correlations with Age or BMI of Islet Donors

BACKGROUND: Genome-wide association studies have identified susceptibility genes for development of type 2 diabetes. We aimed to examine whether a subset of these (comprising FTO, IDE, KCNJ11, PPARG and TCF7L2) were transcriptionally restricted to or enriched in human beta cells by sorting islet cells into alpha and beta - specific fractions. We also aimed to correlate expression of these transcripts in both alpha and beta cell types with phenotypic traits of the islet donors and to compare diabetic and non-diabetic cells. METHODOLOGY/PRINCIPAL FINDINGS: Islet cells were sorted using a previously published method and RNA was extracted, reverse transcribed and used as the template for quantitative PCR. Sorted cells were also analysed for insulin and glucagon immunostaining and insulin secretion from the beta cells as well as insulin, glucagon and GLP-1 content. All five genes were expressed in both alpha and beta cells, with significant enrichment of KCNJ11 in the beta cells and of TCF7L2 in the alpha cells. The ratio of KCNJ11 in beta to alpha cells was negatively correlated with BMI, while KCNJ11 expression in alpha cells was negatively correlated with age but not associated with BMI. Beta cell expression of glucagon, TCF7L2 and IDE was increased in cells from islets that had spent more time in culture prior to cell sorting. In beta cells, KCNJ11, FTO and insulin were positively correlated with each other. Diabetic alpha and beta cells had decreased expression of insulin, glucagon and FTO. CONCLUSIONS/SIGNIFICANCE: This study has identified novel patterns of expression of type 2 diabetes susceptibility genes within sorted islet cells and suggested interactions of gene expression with age or BMI of the islet donors. However, expression of these genes in islets is less associated with BMI than has been found for other tissues

Essential role of microfibrillar-associated protein 4 in human cutaneous homeostasis and in its photoprotection

UVB-induced cutaneous photodamage/photoaging is characterized by qualitative and quantitative deterioration in dermal extracellular matrix (ECM) components such as collagen and elastic fibers. Disappearance of microfibrillar-associated protein 4 (MFAP-4), a possible limiting factor for cutaneous elasticity, was documented in photoaged dermis, but its function is poorly understood. To characterize its possible contribution to photoprotection, MFAP-4 expression was either augmented or inhibited in a human skin xenograft photodamage murine model and human fibroblasts. Xenografted skin with enhanced MFAP-4 expression was protected from UVB-induced photodamage/photoaging accompanied by the prevention of ECM degradation and aggravated elasticity. Additionally, remarkably increased or decreased fibrillin-1-based microfibril development was observed when fibroblasts were treated with recombinant MFAP-4 or with MFAP-4-specific siRNA, respectively. Immunoprecipitation analysis confirmed direct interaction between MFAP-4 and fibrillin-1. Taken together, our findings reveal the essential role of MFAP-4 in photoprotection and offer new therapeutic opportunities to prevent skin-associated pathologies