Expression of HIV transgene aggravates kidney injury in diabetic mice

With the widespread use of combination antiretroviral agents, the incidence of HIV-associated nephropathy has decreased. Currently, HIV-infected patients live much longer and often suffer from comorbidities such as diabetes mellitus. Recent epidemiological studies suggest that concurrent HIV infection and diabetes mellitus may have a synergistic effect on the incidence of chronic kidney disease. To address this, we determined whether HIV-1 transgene expression accelerates diabetic kidney injury using a diabetic HIV-1 transgenic (Tg26) murine model. Diabetes was initially induced with low-dose streptozotocin in both Tg26 and wild-type mice on a C57BL/6 background, which is resistant to classic HIV-associated nephropathy. Although diabetic nephropathy is minimally observed on the C57BL/6 background, diabetic Tg26 mice exhibited a significant increase in glomerular injury compared with nondiabetic Tg26 mice and diabetic wild-type mice. Validation of microarray gene expression analysis from isolated glomeruli showed a significant upregulation of proinflammatory pathways in diabetic Tg26 mice. Thus, our study found that expression of HIV-1 genes aggravates diabetic kidney disease

How close can an Inhomogeneous Universe mimic the Concordance Model?

Recently, spatially inhomogeneous cosmological models have been proposed as an alternative to the LCDM model, with the aim of reproducing the late time dynamics of the Universe without introducing a cosmological constant or dark energy. This paper investigates the possibility of distinguishing such models from the standard LCDM using background or large scale structure data. It also illustrates and emphasizes the necessity of testing the Copernican principle in order to confront the tests of general relativity with the large scale structure.Comment: 15 pages, 7 figure

Functional variants in the LRRK2 gene confer shared effects on risk for Crohn's disease and Parkinson's disease

Crohn’s disease (CD), a form of inflammatory bowel disease, has a higher prevalence in Ashkenazi Jewish than in non-Jewish European populations. To define the role of nonsynonymous mutations, we performed exome sequencing of Ashkenazi Jewish patients with CD, followed by array-based genotyping and association analysis in 2066 CD cases and 3633 healthy controls. We detected association signals in the LRRK2 gene that conferred risk for CD (N2081D variant, P = 9.5 × 10−10) or protection from CD (N551K variant, tagging R1398H-associated haplotype, P = 3.3 × 10−8). These variants affected CD age of onset, disease location, LRRK2 activity, and autophagy. Bayesian network analysis of CD patient intestinal tissue further implicated LRRK2 in CD pathogenesis. Analysis of the extended LRRK2 locus in 24,570 CD cases, patients with Parkinson’s disease (PD), and healthy controls revealed extensive pleiotropy, with shared genetic effects between CD and PD in both Ashkenazi Jewish and non-Jewish cohorts. The LRRK2 N2081D CD risk allele is located in the same kinase domain as G2019S, a mutation that is the major genetic cause of familial and sporadic PD. Like the G2019S mutation, the N2081D variant was associated with increased kinase activity, whereas neither N551K nor R1398H variants on the protective haplotype altered kinase activity. We also confirmed that R1398H, but not N551K, increased guanosine triphosphate binding and hydrolyzing enzyme (GTPase) activity, thereby deactivating LRRK2. The presence of shared LRRK2 alleles in CD and PD provides refined insight into disease mechanisms and may have major implications for the treatment of these two seemingly unrelated diseases

Alteration of Forkhead Box O (Foxo4) Acetylation Mediates Apoptosis of Podocytes in Diabetes Mellitus

The number of kidney podocytes is reduced in diabetic nephropathy. Advanced glycation end products (AGEs) accumulate in patients with diabetes and promote the apoptosis of podocyte by activating the forkhead box O4 (Foxo4) transcription factor to increase the expression of a pro-apoptosis gene, Bcl2l11. Using chromatin immunoprecipitation we demonstrate that AGE-modified bovine serum albumin (AGE-BSA) enhances Foxo4 binding to a forkhead binding element in the promoter of Bcl2lll. AGE-BSA also increases the acetylation of Foxo4. Lysine acetylation of Foxo4 is required for Foxo4 binding and transcription of Bcl2l11 in podocytes treated with AGE-BSA. The expression of a protein deacetylase that targets Foxo4 for deacetylation, sirtuin (Sirt1), is down regulated in cultured podocytes by AGE-BSA treatment and in glomeruli of diabetic patients. SIRT1 over expression in cultured murine podocytes prevents AGE-induced apoptosis. Glomeruli isolated from diabetic db/db mice have increased acetylation of Foxo4, suppressed expression of Sirt1, and increased expression of Bcl2l11 compared to non-diabetic littermates. Together, our data provide evidence that alteration of Foxo4 acetylation and down regulation of Sirt1 expression in diabetes promote podocyte apoptosis. Strategies to preserve Sirt1 expression or reduce Foxo4 acetylation could be used to prevent podocyte loss in diabetes

Dysregulated Nephrin in Diabetic Nephropathy of Type 2 Diabetes: A Cross Sectional Study

Podocyte specific proteins are dysregulated in diabetic nephropathy, though the extent of their expression loss is not identical and may be subject to different regulatory factors. Quantifying the degree of loss may help identify the most useful protein to use as an early biomarker of diabetic nephropathy.Protein expression of synaptopodin, podocin and nephrin were quantified in 15 Type 2 diabetic renal biopsies and 12 control patients. We found statistically significant downregulation of synaptopodin (P<0.0001), podocin (P = 0.0002), and nephrin (P<0.0001) in kidney biopsies of diabetic nephropathy as compared with controls. Urinary nephrin levels (nephrinuria) were then measured in 66 patients with Type 2 diabetes and 10 healthy controls by an enzyme-linked immunosorbent assay (Exocell, Philadelphia, PA). When divided into groups according to normo-, micro-, and macroalbuminuria, nephrinuria was found to be present in 100% of diabetic patients with micro- and macroalbuminuria, as well as 54% of patients with normoalbuminuria. Nephrinuria also correlated significantly with albuminuria (rho = 0.89, p<0.001), systolic blood pressure (rho = 0.32, p = 0.007), and correlated negatively with serum albumin (rho = -0.48, p<0.0001) and eGFR (rho = -0.33, p = 0.005).These data suggest that key podocyte-specific protein expressions are significantly and differentially downregulated in diabetic nephropathy. The finding that nephrinuria is observed in a majority of these normoalbuminuric patients demonstrates that it may precede microalbuminuria. If further research confirms nephrinuria to be a biomarker of pre-clinical diabetic nephropathy, it would shed light on podocyte metabolism in disease, and raise the possibility of new and earlier therapeutic targets

Modeling scanning tunneling spectra of Bi2Sr2CaCu2O8+δBi_2 Sr_2 CaCu_2 O_{8+\delta}

Recent angle-resolved photoemission and neutron scattering data have provided new ingredients for the interpretation of scanning tunneling spectra on Bi$_2$Sr$_2$CaCu$_2$O$_{8+\delta}$. We analyze the low-temperature tunneling spectra, from oxygen overdoped to underdoped samples, including details about the bilayer splitting and the neutron resonance peak. Two van Hove singularities are identified: the first is integrated in the coherence peaks, the second is heavily broadened at higher binding energy. The shape of the tunneling spectra suggests a strong coupling of the quasiparticles with a collective mode, and a comparison with photoemission shows that the scattering rate in tunneling is an order of magnitude smaller than in ARPES. Finally, the theoretical spectra calculated with an isotropic tunneling matrix element are in better agreement with the experimental data than those obtained with anisotropic matrix elements.Comment: 7 pages, with 4 figure

SNAI2/Slug promotes growth and invasion in human gliomas

<p>Abstract</p> <p>Background</p> <p>Numerous factors that contribute to malignant glioma invasion have been identified, but the upstream genes coordinating this process are poorly known.</p> <p>Methods</p> <p>To identify genes controlling glioma invasion, we used genome-wide mRNA expression profiles of primary human glioblastomas to develop an expression-based rank ordering of 30 transcription factors that have previously been implicated in the regulation of invasion and metastasis in cancer.</p> <p>Results</p> <p>Using this approach, we identified the oncogenic transcriptional repressor, <it>SNAI2</it>/Slug, among the upper tenth percentile of invasion-related transcription factors overexpressed in glioblastomas. <it>SNAI2 </it>mRNA expression correlated with histologic grade and invasive phenotype in primary human glioma specimens, and was induced by EGF receptor activation in human glioblastoma cells. Overexpression of <it>SNAI2/</it>Slug increased glioblastoma cell proliferation and invasion <it>in vitro </it>and promoted angiogenesis and glioblastoma growth <it>in vivo</it>. Importantly, knockdown of endogenous <it>SNAI2</it>/Slug in glioblastoma cells decreased invasion and increased survival in a mouse intracranial human glioblastoma transplantation model.</p> <p>Conclusion</p> <p>This genome-scale approach has thus identified <it>SNAI2</it>/Slug as a regulator of growth and invasion in human gliomas.</p