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The cellular protein P58IPK regulates influenza virus mRNA translation and replication through a PKR-mediated mechanism 总被引:1,自引:0,他引:1 下载免费PDF全文
Goodman AG Smith JA Balachandran S Perwitasari O Proll SC Thomas MJ Korth MJ Barber GN Schiff LA Katze MG 《Journal of virology》2007,81(5):2221-2230
We previously hypothesized that efficient translation of influenza virus mRNA requires the recruitment of P58(IPK), the cellular inhibitor of PKR, an interferon-induced kinase that targets the eukaryotic translation initiation factor eIF2alpha. P58(IPK) also inhibits PERK, an eIF2alpha kinase that is localized in the endoplasmic reticulum (ER) and induced during ER stress. The ability of P58(IPK) to interact with and inhibit multiple eIF2alpha kinases suggests it is a critical regulator of both cellular and viral mRNA translation. In this study, we sought to definitively define the role of P58(IPK) during viral infection of mammalian cells. Using mouse embryo fibroblasts from P58(IPK-/-) mice, we demonstrated that the absence of P58(IPK) led to an increase in eIF2alpha phosphorylation and decreased influenza virus mRNA translation. The absence of P58(IPK) also resulted in decreased vesicular stomatitis virus replication but enhanced reovirus yields. In cells lacking the P58(IPK) target, PKR, the trends were reversed-eIF2alpha phosphorylation was decreased, and influenza virus mRNA translation was increased. Although P58(IPK) also inhibits PERK, the presence or absence of this kinase had little effect on influenza virus mRNA translation, despite reduced levels of eIF2alpha phosphorylation in cells lacking PERK. Finally, we showed that influenza virus protein synthesis and viral mRNA levels decrease in cells that express a constitutively active, nonphosphorylatable eIF2alpha. Taken together, our results support a model in which P58(IPK) regulates influenza virus mRNA translation and infection through a PKR-mediated mechanism which is independent of PERK. 相似文献
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Laura A. Lewis Krzysztof Polanski Marta de Torres-Zabala Siddharth Jayaraman Laura Bowden Jonathan Moore Christopher A. Penfold Dafyd J. Jenkins Claire Hill Laura Baxter Satish Kulasekaran William Truman George Littlejohn Justyna Prusinska Andrew Mead Jens Steinbrenner Richard Hickman David Rand David L. Wild Sascha Ott Vicky Buchanan-Wollaston Nick Smirnoff Jim Beynon Katherine Denby Murray Grant 《The Plant cell》2015,27(11):3038-3064
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Angelo H. All Payam Gharibani Siddharth Gupta Faith A. Bazley Nikta Pashai Bin-Kuan Chou Sandeep Shah Linda M. Resar Linzhao Cheng John D. Gearhart Candace L. Kerr 《PloS one》2015,10(1)
Induced pluripotent stem (iPS) cells are at the forefront of research in regenerative medicine and are envisaged as a source for personalized tissue repair and cell replacement therapy. Here, we demonstrate for the first time that oligodendrocyte progenitors (OPs) can be derived from iPS cells generated using either an episomal, non-integrating plasmid approach or standard integrating retroviruses that survive and differentiate into mature oligodendrocytes after early transplantation into the injured spinal cord. The efficiency of OP differentiation in all 3 lines tested ranged from 40% to 60% of total cells, comparable to those derived from human embryonic stem cells. iPS cell lines derived using episomal vectors or retroviruses generated a similar number of early neural progenitors and glial progenitors while the episomal plasmid-derived iPS line generated more OPs expressing late markers O1 and RIP. Moreover, we discovered that iPS-derived OPs (iPS-OPs) engrafted 24 hours following a moderate contusive spinal cord injury (SCI) in rats survived for approximately two months and that more than 70% of the transplanted cells differentiated into mature oligodendrocytes that expressed myelin associated proteins. Transplanted OPs resulted in a significant increase in the number of myelinated axons in animals that received a transplantation 24 h after injury. In addition, nearly a 5-fold reduction in cavity size and reduced glial scarring was seen in iPS-treated groups compared to the control group, which was injected with heat-killed iPS-OPs. Although further investigation is needed to understand the mechanisms involved, these results provide evidence that patient-specific, iPS-derived OPs can survive for three months and improve behavioral assessment (BBB) after acute transplantation into SCI. This is significant as determining the time in which stem cells are injected after SCI may influence their survival and differentiation capacity. 相似文献
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Armon Sharei Radiana Trifonova Siddharth Jhunjhunwala George C. Hartoularos Alexandra T. Eyerman Abigail Lytton-Jean Mathieu Angin Siddhartha Sharma Roberta Poceviciute Shirley Mao Megan Heimann Sophia Liu Tanya Talkar Omar F. Khan Marylyn Addo Ulrich H. von Andrian Daniel G. Anderson Robert Langer Judy Lieberman Klavs F. Jensen 《PloS one》2015,10(4)
Intracellular delivery of biomolecules, such as proteins and siRNAs, into primary immune cells, especially resting lymphocytes, is a challenge. Here we describe the design and testing of microfluidic intracellular delivery systems that cause temporary membrane disruption by rapid mechanical deformation of human and mouse immune cells. Dextran, antibody and siRNA delivery performance is measured in multiple immune cell types and the approach’s potential to engineer cell function is demonstrated in HIV infection studies. 相似文献
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Progressive multiple alignment using sequence triplet optimizations and three-residue exchange costs
Konagurthu AS Whisstock J Stuckey PJ 《Journal of bioinformatics and computational biology》2004,2(4):719-745
In this paper we demonstrate a practical approach to construct progressive multiple alignments using sequence triplet optimizations rather than a conventional pairwise approach. Using the sequence triplet alignments progressively provides a scope for the synthesis of a three-residue exchange amino acid substitution matrix. We develop such a 20 x 20 x 20 matrix for the first time and demonstrate how its use in optimal sequence triplet alignments increases the sensitivity of building multiple alignments. Various comparisons were made between alignments generated using the progressive triplet methods and the conventional progressive pairwise procedure. The assessment of these data reveal that, in general, the triplet based approaches generate more accurate sequence alignments than the traditional pairwise based procedures, especially between more divergent sets of sequences. 相似文献
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Shweta Lawania Navneet Singh Digambar Behera Siddharth Sharma 《Biochemical genetics》2018,56(4):375-396
The present study investigated the role of Xeroderma pigmentosum group A (XPA) polymorphism (A23G and G709A) with lung cancer risk and its association with overall survival in North Indians. 370 cases and 370 controls were investigated to evaluate association between XPA polymorphism (A23G and G709A) with lung cancer risk using logistic regression analysis. A follow-up study was also conducted for 291 lung cancer cases illustrating correlation between overall survival in lung cancer patients and XPA variants. GG genotype showed an increased lung cancer risk (p = 0.0007) for A23G polymorphism whereas G709A polymorphism was associated with significant protective effect in heterozygous (AG) subjects (p = 0.001). When stratified according to smoking status an increased risk for lung cancer was observed for GG genotype in A23G polymorphism (p = 0.0002). A poor survival in females carrying variant genotype (GG) was observed (p = 0.001; MST = 4.16 months) for A23G polymorphism. Adenocarcinoma patients with heterozygous genotype showed an increased hazard ratio (p = 0.02) for A23G polymorphism. G709A was associated with a reduced hazard ratio marking a better survival among mutant females (HR 0.17; p = 0.05; MST = 18.63 months). It can be concluded that A23G polymorphism might contribute to increased lung cancer risk in North Indian population emphasizing on poor survival among females. G709A polymorphism might result in protective effect in lung cancer subjects. The present study had a low sample size but it could act as reference for the large sample studies in future. 相似文献
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Paul?R. Kasher Katherine?E. Schertz Megan Thomas Adam Jackson Silvia Annunziata María?J. Ballesta-Martinez Philippe?M. Campeau Peter?E. Clayton Jennifer?L. Eaton Tiziana Granata Encarna Guillén-Navarro Cristina Hernando Caroline?E. Laverriere Agne Liedén Olaya Villa-Marcos Meriel McEntagart Ann Nordgren Chiara Pantaleoni Céline Pebrel-Richard Catherine Sarret Francesca?L. Sciacca Ronnie Wright Bronwyn Kerr Eric Glasgow Siddharth Banka 《American journal of human genetics》2016,98(2):363-372