Immune-Mediated Inflammation May Contribute to the Pathogenesis of Cardiovascular Disease in Mucopolysaccharidosis Type I.

BackgroundCardiovascular disease, a progressive manifestation of α-L-iduronidase deficiency or mucopolysaccharidosis type I, continues in patients both untreated and treated with hematopoietic stem cell transplantation or intravenous enzyme replacement. Few studies have examined the effects of α-L-iduronidase deficiency and subsequent glycosaminoglycan storage upon arterial gene expression to understand the pathogenesis of cardiovascular disease.MethodsGene expression in carotid artery, ascending, and descending aortas from four non-tolerized, non-enzyme treated 19 month-old mucopolysaccharidosis type I dogs was compared with expression in corresponding vascular segments from three normal, age-matched dogs. Data were analyzed using R and whole genome network correlation analysis, a bias-free method of categorizing expression level and significance into discrete modules. Genes were further categorized based on module-trait relationships. Expression of clusterin, a protein implicated in other etiologies of cardiovascular disease, was assessed in canine and murine mucopolysaccharidosis type I aortas via Western blot and in situ immunohistochemistry.ResultsGene families with more than two-fold, significant increased expression involved lysosomal function, proteasome function, and immune regulation. Significantly downregulated genes were related to cellular adhesion, cytoskeletal elements, and calcium regulation. Clusterin gene overexpression (9-fold) and protein overexpression (1.3 to 1.62-fold) was confirmed and located specifically in arterial plaques of mucopolysaccharidosis-affected dogs and mice.ConclusionsOverexpression of lysosomal and proteasomal-related genes are expected responses to cellular stress induced by lysosomal storage in mucopolysaccharidosis type I. Upregulation of immunity-related genes implicates the potential involvement of glycosaminoglycan-induced inflammation in the pathogenesis of mucopolysaccharidosis-related arterial disease, for which clusterin represents a potential biomarker

Disease causing mutations in inverted formin 2 regulate its binding to G-actin, F-actin capping protein (CapZ α-1) and profilin 2

Focal segmental glomerulosclerosis (FSGS) is a devastating form of nephrotic syndrome which ultimately leads to end stage renal failure (ESRF). Mutations in inverted formin 2 (INF2), a member of the formin family of actin-regulating proteins, have recently been associated with a familial cause of nephrotic syndrome characterized by FSGS. INF2 is a unique formin that can both polymerize and depolymerize actin filaments. How mutations in INF2 lead to disease is unknown. In the present study, we show that three mutations associated with FSGS, E184K, S186P and R218Q, reduce INF2 auto-inhibition and increase association with monomeric actin. Furthermore using a combination of GFP–INF2 expression in human podocytes and GFP-Trap purification coupled with MS we demonstrate that INF2 interacts with profilin 2 and the F-actin capping protein, CapZ α-1. These interactions are increased by the presence of the disease causing mutations. Since both these proteins are involved in the dynamic turnover and restructuring of the actin cytoskeleton these changes strengthen the evidence that aberrant regulation of actin dynamics underlies the pathogenesis of disease

Large-eddy simulation of spectral coherence in a wind turbine wake

This work is mainly dedicated to the study of the characteristics of spectral coherence of turbulence fluctuations in wind turbine wakes. A computational fluid dynamics (CFD) code has been implemented using a large-eddy simulation (LES) approach, which is thought to be conceptually more suitable for studying the turbulence evolution in a wind turbine wake. Comparisons with experimental data from the Nørrekær Enge II Windfarm, in Denmark, and with an analytical model proposed by Panofsky and Dutton have been performed, and the results are found to be in reasonable agreement with both

The effects of ownership structure, sub-optimal cash holdings and investment inefficiency on dividend policy: evidence from Indonesia

We investigate how a firm's decision to hold excessive cash or to overinvest could influence its dividend payout policy in Indonesia. Additionally, we examine the association between corporate ownership structure and cash dividends. Using a data set of Indonesian listed firms for the period from 1995 to 2014, we find that excessive cash holding (overinvestment) positively (negatively) affects a firm's likelihood of paying dividends. Also, we find that family, foreign, state and institutional ownership have significantly negative links with dividends, which suggests the signals of expropriation of firms' wealth by major shareholders. These findings strongly support the expropriation hypothesis that commonly applies to firms with higher level of concentration or to firms in a weak legal environment by which the rights of minority interests are put at risk by large shareholders

The Darker Side of High Performance Work Systems: Examining Employee Psychological Outcomes and Counterproductive Work Behavior.

The purpose of this paper is to analyze the impact of the employee perception about high performance work systems (HPWS) on employee psychological outcomes and further their impact on counterproductive work behavior. After reviewing the literature on rhetoric versus reality of HPWS, the potential “dark side” of HPWS authors suggested that HPWS, aimed at creating a competitive advantage for organizations, do so at the expense of workers, thus resulting in negative consequences for individual employees. This paper analyzes these relationships using a total sample of 287 from firms operating in Pakistan. Findings revealed that employee perception about HPWS are positively associated with employee psychological outcomes (anxiety, job burnout, role overload) which further results in a negative behavior of the employees at workplace. One of the main limitations of this paper is the cross-sectional design of the empirical research and the fact that data were collected from managerial staff only. Findings may guide managers’ efforts in the development of learning programs which foster both individual and organizational performance. Finally, the paper provided empirical evidence of the proposed relationships in Pakistan

Areca nut chewing and dependency syndrome: Is the dependence comparable to smoking? a cross sectional study

<p>Abstract</p> <p>Background</p> <p>Areca nut is the seed of fruit oriental palm known as <it>Areca catechu</it>. Many adverse effects of nut chewing have been well documented in the medical literature. As these nuts are mixed with some other substances like tobacco and flavouring agents, it has been hypothesized that it might also cause some dependency symptoms among its users. Therefore, the objective of this study was to investigate dependency syndrome among areca nut users with and without tobacco additives and compare it with dependency associated with cigarette smoking among the male Pakistani population.</p> <p>Methods</p> <p>This was an observational cross sectional study carried out on healthy individuals, who were users of any one of the three products (areca nut only, areca nut with tobacco additives, cigarette smokers). Participants were selected by convenience sampling of people coming to hospital to seek a free oral check up. Information was collected about the socio-demographic profile, pattern of use and symptoms of dependency using the DSM-IV criteria for substance dependence. We carried out multiple logistic regressions to investigate association between socio-demographic profile, pattern of substance use and dependency syndrome.</p> <p>Results</p> <p>We carried out final analysis on 851 individuals, of which 36.8% (n = 314) were areca nut users, 28.4% (n = 242) were the chewers of areca with tobacco additives and 34.7% (n = 295) were regular cigarette smokers. Multivariate analyses showed that individuals using areca nut with tobacco additives were significantly more likely to have dependency syndrome (OR = 2.17, 95% CI 1.39-3.40) while cigarette smokers were eight times more likely to have dependency syndrome as compared to areca nut only users.</p> <p>Conclusions</p> <p>Areca nut use with and without tobacco additives was significantly associated with dependency syndrome. In comparison to exclusive areca nut users, the smokers were eight times more likely to develop dependence while areca nut users with tobacco additives were also significantly more likely to suffer from the dependence.</p