TGF-beta 1-induced epithelial-to-mesenchymal transition and therapeutic intervention in diabetic nephropathy

Background/Aims: Epithelial-to-mesenchymal cell transformation (EMT) is the trans-differentiation of tubular epithelial cells into myofibroblasts, an event underlying progressive chronic kidney disease in diabetes, resulting in fibrosis. Mainly reported in proximal regions of the kidney, EMT is now recognized as a key contributor to the loss of renal function throughout the nephron in diabetic nephropathy (DN). Concomitant upregulation of TGF-beta in diabetes makes this pro-fibrotic cytokine an obvious candidate in the development of these fibrotic complications. This article reviews recent findings clarifying our understanding of the role of TGF-beta and associated sub-cellular proteins in EMT. Methods: To understand the pathology of EMT and the role of TGF-beta, we reviewed the literature using PubMed for English language articles that contained key words related to EMT, TGF-beta and DN. Results: EMT and phenotypic plasticity of epithelial cells throughout the nephron involves cytoskeletal reorganization and de novo acquisition of classic mesenchymal markers. Concurrent downregulation of epithelial adhesion molecules results in a loss of function and decreased cell coupling, contributing to a loss of epithelial integrity. TGF-beta 1 is pivotal in mediating these phenotypic changes. Conclusion: TGF-beta-induced EMT is a key contributor to fibrotic scar formation as seen in DN, and novel routes for future therapeutic intervention are discussed

Power domination in maximal planar graphs

Power domination in graphs emerged from the problem of monitoring an electrical system by placing as few measurement devices in the system as possible. It corresponds to a variant of domination that includes the possibility of propagation. For measurement devices placed on a set S of vertices of a graph G, the set of monitored vertices is initially the set S together with all its neighbors. Then iteratively, whenever some monitored vertex v has a single neighbor u not yet monitored, u gets monitored. A set S is said to be a power dominating set of the graph G if all vertices of G eventually are monitored. The power domination number of a graph is the minimum size of a power dominating set. In this paper, we prove that any maximal planar graph of order n $\ge$ 6 admits a power dominating set of size at most (n--2)/4

Multiple-Play Bandits in the Position-Based Model

Sequentially learning to place items in multi-position displays or lists is a task that can be cast into the multiple-play semi-bandit setting. However, a major concern in this context is when the system cannot decide whether the user feedback for each item is actually exploitable. Indeed, much of the content may have been simply ignored by the user. The present work proposes to exploit available information regarding the display position bias under the so-called Position-based click model (PBM). We first discuss how this model differs from the Cascade model and its variants considered in several recent works on multiple-play bandits. We then provide a novel regret lower bound for this model as well as computationally efficient algorithms that display good empirical and theoretical performance

Understanding higher education in further education colleges

This summary presents the main findings from research undertaken for the Department for Business, Innovation and Skills (BIS) to understand the current nature of higher education (HE) in further education colleges (FECs) in England. The study was carried out between March 2011 and March 2012 by a team from the University of Sheffield and the Institute of Education, University of London. The research involved a range of qualitative and quantitative approaches, including: a review of the relevant literature; an analysis of administrative data on provision and participation; fieldwork in case-study FECs; interviews with managers in colleges and their partner higher education institutions (HEIs); a questionnaire survey of students coupled with in-class discussion groups; and interviews with employers. An overview of the design and conduct of the study is given in Chapter 1, including its aims, sources, methods and timetable. Methods of data collection and analysis are also described in relevant chapters and appendices

SGK1 in the kidney: disrupted sodium transport in diabetes and beyond

Renal complications of diabetes can be severe; however, the mechanisms that underlie the development and progression of diabetic nephropathy are poorly understood. Recent evidence suggests that the serum and glucocorticoid induced kinase-1 (SGK1) may be key to this process. SGK1 expression and function are increased in models of diabetes and polymorphisms of the SGK1 gene are associated with type 2 diabetes mellitus. A key regulator of sodium transport within the renal epithelium of the distal nephron, SGK1 was originally isolated as a glucocorticoid-sensitive gene that regulated the epithelial sodium channel (ENaC; known also as the sodium channel, nonvoltage-gated 1, SCNN1). It is now apparent that SGK1 modulates sodium re-absorption by a number of sodium transporters/channels throughout the length of the nephron including; the Na+/H+ exchange isoform 3 (NHE3), the Na+Cl- co-transporter (NCC) and the Na+/K+-ATPase. In addition, SGK1 is regulated by a diverse range of factors including; insulin, glucose, intracellular calcium, transforming growth factor-beta1, flow rate and osmolality. This brief review examines the evidence supporting an involvement of SGK1 in diabetic nephropathy and discusses how dysregulated sodium transport may account for the development of secondary hypertension associated with the condition. Furthermore, the article examines how aberrant SGK1 expression and activity may be responsible for the cellular changes seen in the damaged nephron

Functional expression of TRPV4 channels in human collecting duct cells: implications for secondary hypertension in diabetic nephropathy

Background. The Vanilloid subfamily of transient receptor potential (TRPV) ion channels has been widely implicated in detecting osmotic and mechanical stress. In the current study, we examine the functional expression of TRPV4 channels in cell volume regulation in cells of the human collecting duct. Methods. Western blot analysis, siRNA knockdown, and microfluorimetry were used to assess the expression and function of TRPV4 in mediating Ca2+-dependent mechanical stimulation within a novel system of the human collecting duct (HCD). Results. Native and siRNA knockdown of TRPV4 protein expression was confirmed by western blot analysis. Touch was used as a cell-directed surrogate for osmotic stress. Mechanical stimulation of HCD cells evoked a transient increase in [Ca2+]i that was dependent upon thapsigargin-sensitive store release and Ca2+ influx. At 48 hrs, high glucose and mannitol (25 mM) reduced TRPV4 expression by 54% and 24%, respectively. Similar treatment doubled SGK1 expression. Touch-evoked changes were negated following TRPV4 knockdown. Conclusion. Our data confirm expression of Ca2+-dependent TRPV4 channels in HCD cells and suggest that a loss of expression in response to high glucose attenuates the ability of the collecting duct to exhibit regulatory volume decreases, an effect that may contribute to the pathology of fluid and electrolyte imbalance as observed in diabetic nephropathy