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.
The study aims to identify the impact of the round-robin strategy on the logical thinking of fourth-year middle school students in chemistry. Two groups were employed: an experimental group consisted of (30) students who were taught according to the round-robin strategy, and the control group consisted of (30) students who were taught according to the traditional method. The researcher adopted the experimental design with partial control by preparing the visual thinking test tool, which consists of (20) multiple-choice items, it was applied as a post-test on the research sample. The result showed that there was a statistically significant difference in favor of the experimental group, which was taught according to the Round Robin s
... Show MoreConclusion :
The conflict between the fundamentalist and news theory in the methodology that each of the two schools pursued with the Twelver Shi'a Imamiyyah in deriving the legal rulings from the sources of legislation, especially in the second source, which is the noble hadith and narration after the Holy Qur’an, which is the first source has gone through multiple and complex stages that led This struggle to excess, stress, exaggeration, negligence, neglect and indulgence by each of the two schools in dealing with the noble hadith and narration and in the manufacture of rules and laws and fundamentalist and juristic theories of the process of jurisprudential development of legal rulings where every school believed and proceed
... Show Moreeclaration has become today has an important and active and influential role in the recipient public life، and are concentrated advertising on the creativity component manufacture to attract his attention toward what to be announced from a variety products ، and is dominated by television commercials tempo and imagination، and display them a variety of ways catches the attention and an impressive simulates the their senses of hearing and sight ، to influence in the receiver and the public paid for purchase. Through it crystallization the subject of our research on the importance of creativity in television advertising and effective for attracting the attention of the public towards the receiver advertised products، and in
... Show MoreThe design of the interior spaces process the product of intellectual civilization expresses the prevailing thought, discoverers of principles and beliefs through the sheen reflects the present, and generating languages graphical variety caused a different revolution in design mounting structure, and because of the complex nature of the interior spaces were and we have to be a reflection of cultural reality of being a form of cultural expression and true embodiment of scientific developments prevailing for each stage where she was born, the changes occurring in human thought and then extremism and the discrepancy tastes among individuals all communities factors have caused a change in the design structure involving modernization an
... Show More
Domesticated translation has been for a long time the norm in cultural communication between nations all over the world. The texts are translated mainly into English (being the dominant language) in terms dictated principally by the requirements of the target language (English). The claim has been that fluency, readability, and immediate intelligibility can be guaranteed as far as the reader of the target language is concerned (English). The foreignness of the text (of the culture which produced it) would be not preserved. Not only this. Being the language of predominant cultures, English has become number one among languages into which texts are translated. The imbalance has been noticeable between the volumes of works translated from a
... Show MoreThis study aims to determine the extent to which Palestinian elites use digital diplomacy to confront the Israeli narrative by exploring the motives for usage, patterns, essential digital diplomatic tools, and achieved satisfactions. The study adopted a survey methodology and employed a questionnaire distributed to a sample of 110 Palestinian political and media elites.
The study arrived at several key findings, including: Palestinian elites allocate a substantial (%67) of their efforts towards employing digital diplomacy as a response to the Israeli narrative. The foremost platforms employed for this purpose are Facebook and Twitter. The primary motivation for utilizing these digital platforms is to present
(6)
(1)
Discourse is a form of communication, and It carries with it an Intellectual framework, and It is a form of expression to communicate Ideas to people through an interactive process.The interest and analysis of discourse Is one of the most important fields of linguistic studies, and It has a basis In ancient studies, and It has become one of the most Important topics of the study, and (Sayyid al-Sadr) often uses guidance In his sermons.
By extrapolating and analyzing a set of examples received, from the perspective of the deliberative approach and the theory of speech acts, and the statement of the extent to whichh (Sayyid al-Sadr) relied on linguistic elements, and the use of the rank of the speaker In issuing directives, and the
... Show More