381 research outputs found

    Testing Nelder-Mead based repulsion algorithms for multiple roots of nonlinear systems via a two-level factorial design of experiments

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    This paper addresses the challenging task of computing multiple roots of a system of nonlinear equations. A repulsion algorithm that invokes the Nelder-Mead (N-M) local search method and uses a penalty-type merit function based on the error function, known as 'erf', is presented. In the N-M algorithm context, different strategies are proposed to enhance the quality of the solutions and improve the overall efficiency. The main goal of this paper is to use a two-level factorial design of experiments to analyze the statistical significance of the observed differences in selected performance criteria produced when testing different strategies in the N-M based repulsion algorithm. The main goal of this paper is to use a two-level factorial design of experiments to analyze the statistical significance of the observed differences in selected performance criteria produced when testing different strategies in the N-M based repulsion algorithm.Fundação para a Ciência e Tecnologia (FCT

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

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    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

    Do teashirt family genes specify trunk identity? Insights from the single tiptop/teashirt homolog of Tribolium castaneum

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    The Drosophila teashirt gene acts in concert with the homeotic selector (Hox) genes to specify trunk (thorax and abdomen) identity. There has been speculation that this trunk-specifying function might be very ancient, dating back to the common ancestor of insects and vertebrates. However, other evidence suggests that the role of teashirt in trunk identity is not well conserved even within the Insecta. To address this issue, we have analyzed the function of Tc-tiotsh, the lone teashirt family member in the red flour beetle, Tribolium castaneum. Although Tc-tiotsh is important for aspects of both embryonic and imaginal development including some trunk features, we find no evidence that it acts as a trunk identity gene. We discuss this finding in the context of recent insights into the evolution and function of the Drosophila teashirt family genes

    Phylogeny and Historical Biogeography of Asian Pterourus Butterflies (Lepidoptera: Papilionidae): A Case of Intercontinental Dispersal from North America to East Asia

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    The phylogenetic status of the well-known Asian butterflies often known as Agehana (a species group, often treated as a genus or a subgenus, within Papilio sensu lato) has long remained unresolved. Only two species are included, and one of them especially, Papilio maraho, is not only rare but near-threatened, being monophagous on its vulnerable hostplant, Sassafras randaiense (Lauraceae). Although the natural history and population conservation of “Agehana” has received much attention, the biogeographic origin of this group still remains enigmatic. To clarify these two questions, a total of 86 species representatives within Papilionidae were sampled, and four genes (concatenated length 3842 bp) were used to reconstruct their phylogenetic relationships and historical scenarios. Surprisingly, “Agehana” fell within the American Papilio subgenus Pterourus and not as previously suggested, phylogenetically close to the Asian Papilio subgenus Chilasa. We therefore formally synonymize Agehana with Pterourus. Dating and biogeographic analysis allow us to infer an intercontinental dispersal of an American ancestor of Asian Pterourus in the early Miocene, which was coincident with historical paleo-land bridge connections, resulting in the present “East Asia-America” disjunction distribution. We emphasize that species exchange between East Asia and America seems to be a quite frequent occurrence in butterflies during the Oligocene to Miocene climatic optima.© 2015 Wu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

    HIV-1 Tat protein directly induces mitochondrial membrane permeabilization and inactivates cytochrome c oxidase

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    The Trans-activator protein (Tat) of human immunodeficiency virus (HIV) is a pleiotropic protein involved in different aspects of AIDS pathogenesis. As a number of viral proteins Tat is suspected to disturb mitochondrial function. We prepared pure synthetic full-length Tat by native chemical ligation (NCL), and Tat peptides, to evaluate their direct effects on isolated mitochondria. Submicromolar doses of synthetic Tat cause a rapid dissipation of the mitochondrial transmembrane potential (ΔΨm) as well as cytochrome c release in mitochondria isolated from mouse liver, heart, and brain. Accordingly, Tat decreases substrate oxidation by mitochondria isolated from these tissues, with oxygen uptake being initially restored by adding cytochrome c. The anion-channel inhibitor 4,4′-diisothiocyanostilbene-2,2′-disulfonic acid (DIDS) protects isolated mitochondria against Tat-induced mitochondrial membrane permeabilization (MMP), whereas ruthenium red, a ryanodine receptor blocker, does not. Pharmacologic inhibitors of the permeability transition pore, Bax/Bak inhibitors, and recombinant Bcl-2 and Bcl-XL proteins do not reduce Tat-induced MMP. We finally observed that Tat inhibits cytochrome c oxidase (COX) activity in disrupted mitochondria isolated from liver, heart, and brain of both mouse and human samples, making it the first described viral protein to be a potential COX inhibitor

    Mortality in Western Australian seniors with chronic respiratory diseases: a cohort study

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    <p>Abstract</p> <p>Background</p> <p>Relatively few studies have examined survival by pharmacotherapy level and the effects of patient characteristics on mortality by pharmacotherapy level in older chronic respiratory disease (CRD) patients. This study aimed to investigate these issues in older (≥ 65) CRD patients in Western Australia.</p> <p>Methods</p> <p>We identified 108,312 patients ≥ 65 years with CRD during 1992-2006 using linked medical, pharmaceutical, hospital and mortality databases held by the Commonwealth and State governments. Pharmacotherapy classification levels were designed by a clinical consensus panel. Cox regression was used to investigate the study aim.</p> <p>Results</p> <p>Patients using only short acting bronchodilators experienced similar, but slightly worse survival than patients in the highest pharmacotherapy level group using high dose inhaled corticosteroids (ICS) ± long acting bronchodilators (LABs) ± oral steroids. Patients using low to medium dose ICS ± LABs experienced relatively better survival. Also, male gender was associated with all-cause mortality in all patients (HR = 1.72, 95% CI 1.65-1.80) and especially in those in the highest pharmacotherapy level group (HR = 1.97, 95%CI = 1.84-2.10). The P-value of interaction between gender and pharmacotherapy level for the effect on all-cause death was significant (0.0003).</p> <p>Conclusions</p> <p>Older patients with CRD not using ICS experienced the worst survival in this study and may benefit from an escalation in therapeutic regime. Males had a higher risk of death than females, which was more pronounced in the highest pharmacotherapy level group. Hence, primary health care should more actively direct disease management to mild-to-moderate disease patients.</p

    Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

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    We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012

    Diversification of Schistosoma japonicum in Mainland China Revealed by Mitochondrial DNA

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    Despite the existing threat of schistosomiasis in some rural areas along the Yangtze River, the genetic diversity of Schistosoma japonicum has not been investigated across its wide geographical distribution in China, and such information may provide insight into the disease epidemiology and the development of its control measures. In this study, the adult parasites, obtained through infecting mice with cercariae from snails of the genus Oncomelania collected from a wide range of localities in currently endemic areas of schistosomiasis in the middle and lower (ML) reaches of the Yangtze River, and in Sichuan and Yunnan provinces in the upper reaches of the river in southwest (SW) China, were sequenced individually for mitochondrial genes. In general, a relatively high degree of genetic variation was observed in populations in the ML reaches in terms of nucleotide and haplotype diversity, but a low level was observed in populations in the SW. The significant difference in genetic diversity as revealed by F-statistics, and the existence of no shared haplotypes, were observed between populations in the ML reaches and those in the SW, indicating the effect of geographical separation/isolation upon the schistosomes and probably the parasite-snail system in China

    Tension, Free Space, and Cell Damage in a Microfluidic Wound Healing Assay

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    We use a novel, microfluidics-based technique to deconstruct the classical wound healing scratch assay, decoupling the contribution of free space and cell damage on the migratory dynamics of an epithelial sheet. This method utilizes multiple laminar flows to selectively cleave cells enzymatically, and allows us to present a 'damage free' denudation. We therefore isolate the influence of free space on the onset of sheet migration. First, we observe denudation directly to measure the retraction in the cell sheet that occurs after cell-cell contact is broken, providing direct and quantitative evidence of strong tension within the sheet. We further probe the mechanical integrity of the sheet without denudation, instead using laminar flows to selectively inactivate actomyosin contractility. In both cases, retraction is observed over many cell diameters. We then extend this method and complement the enzymatic denudation with analogies to wounding, including gradients in signals associated with cell damage, such as reactive oxygen species, suspected to play a role in the induction of movement after wounding. These chemical factors are evaluated in combination with the enzymatic cleavage of cells, and are assessed for their influence on the collective migration of a non-abrasively denuded epithelial sheet. We conclude that free space alone is sufficient to induce movement, but this movement is predominantly limited to the leading edge, leaving cells further from the edge less able to move towards the wound. Surprisingly, when coupled with a gradient in ROS to simulate the chemical effects of abrasion however, motility was not restored, but further inhibited.Massachusetts Institute of Technology. Presidential FellowshipNational Institutes of Health (U.S.). Biotechnology Training FellowshipSingapore-MIT Alliance for Research and TechnologyMassachusetts Institute of Biotechnology Training GrantMassachusetts Institute of Technology (Open-source Funding
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