The Role of the Deubiquitylase MYSM1 During Alphavirus Infection Amer Nubgan The members of the genus Alphavirus are positive-sense RNA viruses and it is one of two within the family Togaviridae. Most alphaviruses are predominantly transmitted to susceptible vertebrates by a mosquito vector. Alphavirus disease in humans can be severely debilitating, and depending on the particular viral species, infection may result in encephalitis and possibly life threatening symptoms. Chikungunya virus (CHIKV) is the aetiological agent represents a substantial health burden to affected populations, with clinical symptoms that include severe joint and muscle pain, rashes, and fever, as well as prolonged periods of disability in some patients. In recent years, CHIKV has received significant attention from public health authorities as a consequence of the dramatic emergence infections in the Indian Ocean islands and the Caribbean as well as the recent emergence of CHIKV in the Americas. Infections have also been reported around Europe such as in Italy, France and Greece. Currently, no safe, approved or effective vaccine or treatment exists for CHIKV infection. The ubiquitin-proteasome system (UPS), the major intracellular proteolytic pathway, mediates different kinds of cellular processes, which may be targeted by viruses to aid their replication within cells. In recent years it has been well established that both the forward reaction of ubiquitination, and the reverse reaction of deubiquitination are targeted during virus infection to enhance their replication, either by targeting of cellular proteins or encoding viral homologues of key pathway proteins. The reverse reaction is undertaken by a large family of enzymes termed deubiquitylases or DUBs, and many of these have been shown to play a crucial role, not only in virus replication but also in the regulation of the immune system and vesicle trafficking. The DUBs are attractive drug targets and have increasingly been implicated in cellular processes germane to malignancy which makes the continued characterisation of the role of DUBs during virus infection a worthwhile objective. In on-going experiments in the research group a DUB siRNA pools library screen identified 12 DUBs (USP1, USP4, USP5, USP34, USP45, USP46, OTUD6A, UCHL1, JOSD2, BRCC3 and MYSM1). Depletion of these hits in HeLa cells lead to an increase in cell viability following Semiliki Forest Virus (SFV) infection (and predicted to be pro-viral) and thus could potential be candidate antiviral targets. Inroads into understanding the role of the DUB hits during the alphavirus infection, focusing initial on the BSL2 model virus SFV, and extending this to CHIKV (at BSL3). In the present study, further screening focused on the deconvolution siRNA pools for the DUB hits. Investigation of the subsequent follow up experiments with one strong candidate DUB from this list, MYSM1. Two different approaches were taken. Firstly, the effect of depletion of MYSM1 by siRNA treatment was further investigated in HeLa cells. Secondly, the analysis was extended to investigate the role of MYSM1 in fibroblasts utilising MYSM1 genetic knockout murine embryo fibroblasts. Results from this study indicate that depletion of MYSM1 in HeLa cells by siRNAs resulted in a reduction in both SFV and CHIKV replication, as assayed by measuring RNA levels and plaque formation. It was also found that MYSM1 genetic knockout in MEF cells lead to increase in both SFV and CHIKV replication. In addition, depletion of MYSM1 by siRNAs in MRC-5 cells lead to increase in SFV replication. In conclusion, MYSM1 generated interesting data, implying a role during virus infection that appeared to depend on the cell type being infected. Up to now it is unclear what the effector mechanisms are that contribute to these observations, subject to further mechanistic and functional studies, may increase the options available for targeting this vital DUB during Alphavirus infections.
APFS Mohammed, 2014
This work studies the impact of input machining parameters of Electrical Discharge Machining (EDM) on the machining process performance. Tool steel O1 was selected as the workpiece material, copper as the electrode material, and kerosene as the dielectric medium. Experimental runs have been carried out with a Design of Experiment (DOE) technique. Twenty tests are accomplished with the current range of (18 to 24 Ampere), a pulse duration range of (150 to 200 µs), and a pulse-off time range of (25 to 75 µs). Based upon the experimental study's output results, the EDM parameter's effect (voltage of power supply, discharge current, pulse duration, and pulse pause interval) on the responses of the process represented by sur
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The current study performs an explicit nonlinear finite element simulation to predict temperature distribution and consequent stresses during the friction stir welding (FSW) of AA 7075-T651 alloy. The ABAQUS® finite element software was used to model and analyze the process steps that involve plunging, dwelling, and traverse stages. Techniques such as Arbitrary Lagrangian–Eulerian (ALE) formulation, adaptive meshing, and computational feature of mass scaling were utilized to simulate sequence events during the friction stir welding process. The contact between the welding tool and workpiece was modelled through applying Coulomb’s friction model with a nonlinear friction coefficient value. Also, the model considered the effect of nonlin
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This research aims to solve a problem in the field of accounting and financial knowledge in the world today, that is, the problem of creative accounting. Especially after the global financial crisis and the collapse of many large companies in the world, people find that they use creative accounting methods to distinguish them from reality, showing the results of their activities and their financial status. This research discusses the concept of creative accounting, the most important methods used in financial statements and its relationship with external auditing, and procedures to limit accounting creativity. This study uses descriptive analysis methods after confirming its theoretical aspects in practice. Using the statistical
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Each of the countries that make up the international community and active in international and regional relations has specific elements and tools. Their roles differ according to those components and tools. There are countries that play an effective and effective international role, while others play an effective and effective regional role. The international or regional role in order to be effective and influential must be based on a set of conditions that will give it a degree of credibility and achieve the objectives of the role. The state affects the decisions of other countries because of its ability, and the ability of the state to influence is not limited to military power only, but political, economic, demographic, technical, geo
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The relationship between F2- layer critical frequencies (foF2), total sunspot number (Ri), northern hemisphere sunspot number (Rn) and southern hemisphere sunspot number (Rs) at station located in mid- latitudes on latitude near to latitude of Iraq (Rome station, lat.: 42o N and lon.: 13o E) and for 2003(the descending phase of solar cycle 23) were studied.
This research work aims to know the correlation range between them, through correlation coefficients which correlate between them, and hence, the dependence on that index for predicting F2- layer critical frequencies. When the correlation coefficients between foF2, Ri, Rn and Rs were compared for different seasons of 2003, It is found that, correlation coefficient between foF2 and
AW Ali T, Journal of the Faculty of Medicine, 2015 - Cited by 3
В статье рассматриваются понятие наглядности и ее классификация, эффективное применение принципа наглядности, возможность и преимущество использования наглядности и современные инструменты ее реализации в ираке.
Вследствие глобальных изменений во всем мире изменилась и роль иностранного языка в системе образования. Современный человек, шагающий в ногу со временем, не мыслит себя без зна
... Show MoreMetalloendo peptidase is a neutral endopeptidase that cleaves peptides at the amino side of hydrophobic residues and inactivates several peptide hormones, including atrial natriuretic factor, giucagon, enkephalin, substance p, neurotensin, oxytocin, and bradykinin. It is also a major enzyme for the degradation of beta-amyloid. This study aimed to measure enzyme activity and compare it with other biochemical changes in sera patients with diabetic nephropathy. The study included 35 pathological samples of people with diabetic nephropathy, 24 samples from males and 11 samples from females, as well as the same number of healthy people as a comparison group of 15 males, 20 females, with the ages of both groups of patients with diabetic nephropat
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