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.
Abstract
In light of the great technological development and the emergence of globalization has increased global competition, where it became competitive exercise pressure on all sectors. In light of this companies mast enviorment depend on the means that keeps them on the competitive position through access to information about competitors in order to help them to draw a strategy that will achieve a competitive edge either through excellence or reduce the costs of their products and this means intelligence competitive and reverse engineering that help to gain information on competitors analyze and put of the decision-maker From this point formed the idea of research in the statement of the role of
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Abstract
The various countries seek to encourage their local investments through the various policies they follow. The most important of these is the monetary policy, which is a means and procedures taken by the monetary authority to control the supply of money and maintain its stability of its financial impact on economic activity.
The effect of monetary policy is to stimulate domestic investment through money supply that is inversely related to the interest rate and a direct relationship with domestic investment. When money supply increases, interest rates fall and local investment growth rates rise, but when the rise in money supply is high, Inflationary measure
Objective: To investigate and prove that aspirin
protects, or at least attenuates amikacin ototoxicity in
humans.
Method: This study was conducted in 60 patients that
completed all
requirements .The patients were divided into two
groups:
• Control group: receive placebo treatment.
• Drug–treated group: They receive aspirin
coated tablets (1.5gm/ day), 500mg 8 hourly.
Both groups had similar aspects regarding the gender,
age and weight. The duration of therapy was 7 days
and dosage of amikacin was 1gm/day (500mg 12
hourly).
Results: Comparison of Audiometry test in
Ear/Nose/Throat (E.N.T.) Department (Pure Tone
Audiometry) at 1000 Hertz (Hz), 2000 Hz, 4000 Hz,
and 8000 Hz showed sig
Included a research problem , pointing to deficiencies and neglect in Arabic language teaching in primary and middle school , what makes sense to form your linguistic Bell ( Listening ) is missing , especially grammar, vocabulary endings .
And stressed the importance of research that teaching students the Arabic language is the balance of the next life , and that any defect infects will demolish an important part of their structure and the fact that the theater is a form of human directcommunication , and it`s way is the word this helps students to develop some communication skills , and language the backbone of these skills ,1- The research sample was identified in all age children ( 6-12 ), which c
... Show MoreThe problem of the paper focused on the role of the learning organization in the crisis management strategy, and the extent of the actual interest in both the learning organization and the crisis management and aimed at diagnosing and analyzing that and surrounding questions. The Statistical Package for the Social Sciences (SPSS) program was used to calculate the results and the correlation coefficient between the two main variables. The methodology was descriptive and analytical. The case study was followed by a questionnaire that was distributed to a sample of 31 teachers. The paper adopted a seven-dimensional model of systemic thinking that encourages questioning, empowerment, provision of advanced technologies, and strategic lea
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This study dealt with the basics of financial inclusion in terms of concept, importance and objectives, The empowerment of women financially and bank,and then the relationship between financial inclusion and women, and determine the requirements of inclusion Financial resources for women. The analytical descriptive method was used for data, which included reviewing and analyzing information And data in economic and financial literature. The study: reached a number of conclusions, the most important of which are Financial inclusion contributes to women's financial and banking support, as there is a positive relationship between financial institutions Banking and women's access to financial and banking services, thus playing a role i
... Show MoreABSTRACT The importance and objectives of the study were an attempt to understand the methodology of disseminating radical thought and the reasons of social acceptability that make young people embrace this thought. It also sheds light on the impact of this phenomenon on the regional role of Egypt and examines the strategic means and standards that the Egyptian state focuses on in immunization and prevention of extremism.
The research aims to identify the role determined by the dimensions of marketing in the relationship represented by (trust in the relationship, commitment to the relationship, communication during the relationship) in how to contribute to the success of the industrial project management in Iraq as a case study in the General Directorate of Industrial Development. Their number is (50) workers, where the research problem centered on knowing the impact and importance of relationship marketing on the success of industrial project management. The descriptive analytical approach. Using SPSS and Amos, the researcher tested and analysed hypotheses about the relationship and the influence between the research variables through a questionnaire . Test
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Developing countries have depended since long time on the developed countries to increase the levels of development and improving rates of growth direction to the best way where taking this dependence many shapes influenced by the evolution form of international relations and this dependence shows how the great deficiencies in sources of local financing, which called developing countries to increase their reliance on external funding sources, represented in the form of grants, subsidies, loans and foreign investment, pursuing States in that the application of economic reform policies in pursuit of faster economic growth and restructure its economy and achieve economic stability. In the early eighties of the last
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