2,031 research outputs found

    Comparison of finite difference and boundary integral solutions to three-dimensional spontaneous rupture

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    The spontaneously propagating shear crack on a frictional interface has proven to be a useful idealization of a natural earthquake. The corresponding boundary value problems are nonlinear and usually require computationally intensive numerical methods for their solution. Assessing the convergence and accuracy of the numerical methods is challenging, as we lack appropriate analytical solutions for comparison. As a complement to other methods of assessment, we compare solutions obtained by two independent numerical methods, a finite difference method and a boundary integral (BI) method. The finite difference implementation, called DFM, uses a traction-at-split-node formulation of the fault discontinuity. The BI implementation employs spectral representation of the stress transfer functional. The three-dimensional (3-D) test problem involves spontaneous rupture spreading on a planar interface governed by linear slip-weakening friction that essentially defines a cohesive law. To get a priori understanding of the spatial resolution that would be required in this and similar problems, we review and combine some simple estimates of the cohesive zone sizes which correspond quite well to the sizes observed in simulations. We have assessed agreement between the methods in terms of the RMS differences in rupture time, final slip, and peak slip rate and related these to median and minimum measures of the cohesive zone resolution observed in the numerical solutions. The BI and DFM methods give virtually indistinguishable solutions to the 3-D spontaneous rupture test problem when their grid spacing Ī”x is small enough so that the solutions adequately resolve the cohesive zone, with at least three points for BI and at least five node points for DFM. Furthermore, grid-dependent differences in the results, for each of the two methods taken separately, decay as a power law in Ī”x, with the same convergence rate for each method, the calculations apparently converging to a common, grid interval invariant solution. This result provides strong evidence for the accuracy of both methods. In addition, the specific solution presented here, by virtue of being demonstrably grid-independent and consistent between two very different numerical methods, may prove useful for testing new numerical methods for spontaneous rupture problems

    A protein-based set of reference markers for liver tissues and hepatocellular carcinoma

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    Background: During the last decade, investigations have focused on revealing genes or proteins that are involved in HCC carcinogenesis using either genetic or proteomic techniques. However, these studies are overshadowed by a lack of good internal reference standards. The need to identify "housekeeping" markers, whose expression is stable in various experimental and clinical conditions, is therefore of the utmost clinical relevance in quantitative studies. This is the first study employed 2-DE analysis to screen for potential reference markers and aims to correlate the abundance of these proteins with their level of transcript expression. Methods: A Chinese cohort of 224 liver tissues samples (105 cancerous, 103 non-tumourous cirrhotic, and 16 normal) was profiled using 2-DE analysis. Expression of the potential reference markers was confirmed by western blot, immunohistochemistry and real-time quantitative PCR. geNorm algorithm was employed for gene stability measure of the identified reference markers. Results: The expression levels of three protein markers beta-actin (ACTB), heat shock protein 60 (HSP60), and protein disulphide isomerase (PDI) were found to be stable using p-values (p > 0.99) as a ranking tool in all 224 human liver tissues examined by 2-DE analysis. Of high importance, ACTB and HSP 60 were successfully validated at both protein and mRNA levels in human hepatic tissues by western blot, immunohistochemistry and real-time quantitative PCR. In addition, no significant correlation of these markers with any clinicopathological features of HCC and cirrhosis was found. Gene stability measure of these two markers with other conventionally applied housekeeping genes was assessed by the geNorm algorithm, which ranked ACTB and HSP60 as the most stable genes among this cohort of clinical samples. Conclusion: Our findings identified 2 reference markers that exhibited stable expression across human liver tissues with different conditions thus should be regarded as reliable reference moieties for normalisation of gene and protein expression in clinical research employing human hepatic tissues. Ā© 2009 Sun et al; licensee BioMed Central Ltd.published_or_final_versio

    2,2ā€²-(Decane-1,10-diĀ­yl)dibenzĀ­imidĀ­azoĀ­lium dichloride trihydrate

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    The organic cation in the title compound, C24H32N4 2+Ā·2Clāˆ’Ā·3H2O, is situated on an inversion centre. The cations, anions and water molĀ­ecules are linked via Nā€”Hā‹ÆO, Nā€”Hā‹ÆCl, Oā€”Hā‹ÆO and Oā€”Hā‹ÆCl hydrogen bonds and Cā€”Hā‹ÆĻ€ interactions, forming a three-dimensional framework

    Tissue inhibitor of metalloproteinase-1 (TIMP-1) regulates mesenchymal stem cells through let-7f microRNA and Wnt/Ī²-catenin signaling

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    Tissue inhibitor of metalloproteinases 1 (TIMP-1) is a matrix metalloproteinase (MMP)-independent regulator of growth and apoptosis in various cell types. The receptors and signaling pathways that are involved in the growth factor activities of TIMP-1, however, remain controversial. RNA interference of TIMP-1 has revealed that endogenous TIMP-1 suppresses the proliferation, metabolic activity, and osteogenic differentiation capacity of human mesenchymal stem cells (hMSCs). The knockdown of TIMP-1 in hMSCs activated the Wnt/Ī²-catenin signaling pathway as indicated by the increased stability and nuclear localization of Ī²-catenin in TIMP-1ā€“deficient hMSCs. Moreover, TIMP-1 knockdown cells exhibited enhanced Ī²-catenin transcriptional activity, determined by Wnt/Ī²-catenin target gene expression analysis and a luciferase-based Ī²-cateninā€“ activated reporter assay. An analysis of a mutant form of TIMP-1 that cannot inhibit MMP indicated that the effect of TIMP-1 on Ī²-catenin signaling is MMP independent. Furthermore, the binding of CD63 to TIMP-1 on the surface of hMSCs is essential for the TIMP-1ā€“mediated effects on Wnt/Ī²-catenin signaling. An array analysis of microRNAs (miRNAs) and transfection studies with specific miRNA inhibitors and mimics showed that let-7f miRNA is crucial for the regulation of Ī²-catenin activity and osteogenic differentiation by TIMP-1. Let-7f was up-regulated in TIMP-1ā€“depleted hMSCs and demonstrably reduced axin 2, an antagonist of Ī²-catenin stability. Our results demonstrate that TIMP-1 is a direct regulator of hMSC functions and reveal a regulatory network in which let-7f modulates Wnt/Ī²-catenin activity

    Artemisinin resistance in Plasmodium falciparum malaria.

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    BACKGROUND: Artemisinin-based combination therapies are the recommended first-line treatments of falciparum malaria in all countries with endemic disease. There are recent concerns that the efficacy of such therapies has declined on the Thai-Cambodian border, historically a site of emerging antimalarial-drug resistance. METHODS: In two open-label, randomized trials, we compared the efficacies of two treatments for uncomplicated falciparum malaria in Pailin, western Cambodia, and Wang Pha, northwestern Thailand: oral artesunate given at a dose of 2 mg per kilogram of body weight per day, for 7 days, and artesunate given at a dose of 4 mg per kilogram per day, for 3 days, followed by mefloquine at two doses totaling 25 mg per kilogram. We assessed in vitro and in vivo Plasmodium falciparum susceptibility, artesunate pharmacokinetics, and molecular markers of resistance. RESULTS: We studied 40 patients in each of the two locations. The overall median parasite clearance times were 84 hours (interquartile range, 60 to 96) in Pailin and 48 hours (interquartile range, 36 to 66) in Wang Pha (P<0.001). Recrudescence confirmed by means of polymerase-chain-reaction assay occurred in 6 of 20 patients (30%) receiving artesunate monotherapy and 1 of 20 (5%) receiving artesunate-mefloquine therapy in Pailin, as compared with 2 of 20 (10%) and 1 of 20 (5%), respectively, in Wang Pha (P=0.31). These markedly different parasitologic responses were not explained by differences in age, artesunate or dihydroartemisinin pharmacokinetics, results of isotopic in vitro sensitivity tests, or putative molecular correlates of P. falciparum drug resistance (mutations or amplifications of the gene encoding a multidrug resistance protein [PfMDR1] or mutations in the gene encoding sarco-endoplasmic reticulum calcium ATPase6 [PfSERCA]). Adverse events were mild and did not differ significantly between the two treatment groups. CONCLUSIONS: P. falciparum has reduced in vivo susceptibility to artesunate in western Cambodia as compared with northwestern Thailand. Resistance is characterized by slow parasite clearance in vivo without corresponding reductions on conventional in vitro susceptibility testing. Containment measures are urgently needed. (ClinicalTrials.gov number, NCT00493363, and Current Controlled Trials number, ISRCTN64835265.

    Exploring impacts of project leadersā€™ written expressions in virtual and fluid projects: The role of personality and emotion

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    This paper aims to tackle challenges of managing projects in highly virtual and fluid contexts, characterized by diversity, dispersion, digital dependence, unstable membership, and dynamic coordination and configuration. We investigate project leadersā€™ personality and emotion expressed in written expression and examine their impacts on collaboration outcomes. IBM Watson Personality Insights and Tone Analyzer were adopted to assess the leaderā€™s personality and emotion. A computation model to classify collaboration patterns into taskwork-related and teamwork-related communication is under development. We report preliminary findings based on 417 weekly meetings between October 2018 and February 2020 in 8 open-source software teams around WordPress. The research results have the potential to inform researchers and practitioners about what personality profiles and emotions should be considered to foster collaboration in virtual and fluid projects. It is possible to extend the boundary condition of the traits school of leadership for project management in the new context

    Modulation of antigen-specific T-cells as immune therapy for chronic infectious diseases and cancer

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    Copyright: Ā© 2014 Li, Symonds, Miao, Sanderson and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.This article has been made available through the Brunel Open Access Publishing Fund.T-cell responses are induced by antigen presenting cells (APC) and signals from the microenvironment. Antigen persistence and inflammatory microenvironments in chronic infections and cancer can induce a tolerant state in T-cells resulting in hyporesponsiveness, loss of effector function, and weak biochemical signaling patterns in response to antigen stimulation. Although the mechanisms of T-cell tolerance induced in chronic infection and cancer may differ from those involved in tolerance to self-antigen, the impaired proliferation and production of IL-2 in response to antigen stimulation are hallmarks of all tolerant T cells. In this review, we will summarize the evidence that the immune responses change from non-self to ā€œselfā€-like in chronic infection and cancer, and will provide an overview of strategies for re-balancing the immune response of antigen-specific T cells in chronic infection and cancer without affecting the homeostasis of the immune system.Arthritis Research UK and Medical Research Council UK

    Phosphorylation-dependent assembly and coordination of the DNA damage checkpoint apparatus by Rad4TopBP1

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    The BRCT-domain protein Rad4(TopBP1) facilitates activation of the DNA damage checkpoint in Schizosaccharomyces pombe by physically coupling the Rad9-Rad1-Hus1 clamp, the Rad3(ATR) -Rad26(ATRIP) kinase complex, and the Crb2(53BP1) mediator. We have now determined crystal structures of the BRCT repeats of Rad4(TopBP1), revealing a distinctive domain architecture, and characterized their phosphorylation-dependent interactions with Rad9 and Crb2(53BP1). We identify a cluster of phosphorylation sites in the N-terminal region of Crb2(53BP1) that mediate interaction with Rad4(TopBP1) and reveal a hierarchical phosphorylation mechanism in which phosphorylation of Crb2(53BP1) residues Thr215 and Thr235 promotes phosphorylation of the noncanonical Thr187 site by scaffolding cyclin-dependent kinase (CDK) recruitment. Finally, we show that the simultaneous interaction of a single Rad4(TopBP1) molecule with both Thr187 phosphorylation sites in a Crb2(53BP1) dimer is essential for establishing the DNA damage checkpoint
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