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排序方式: 共有320条查询结果,搜索用时 15 毫秒
1.
Srikanth Venkatraman Wanli Wu Andrew Prongay Viyyoor Girijavallabhan F. George Njoroge 《Bioorganic & medicinal chemistry letters》2009,19(1):180-183
Chronic hepatitis C infection is the leading causes for cirrhosis of the liver and hepatocellular carcinoma, leading to liver failure and liver transplantation. The etiological agent, HCV virus produces a single positive strand of RNA that is processed with the help of serine protease NS3 to produce mature virus. Inhibition of NS3 protease can be potentially used to develop effective drugs for HCV infections. Numerous efforts are now underway to develop potent inhibitors of HCV protease that contain ketoamides as serine traps. Herein we report the synthesis of a series of potent inhibitors that contain a boronic acid as a serine trap. The activity of these compounds were optimized to 200 pM. X-ray structure of compound 17 bound to NS3 protease is also discussed. 相似文献
2.
Jessica L. Teo Vanesa M. Tomatis Luke Coburn Anne K. Lagendijk Irin-Maya Schouwenaar Srikanth Budnar Thomas E. Hall Suzie Verma Robert W. McLachlan Benjamin M. Hogan Robert G. Parton Alpha S. Yap Guillermo A. Gomez 《Molecular biology of the cell》2020,31(23):2557
Epithelia can eliminate apoptotic cells by apical extrusion. This is a complex morphogenetic event where expulsion of the apoptotic cell is accompanied by rearrangement of its immediate neighbors to form a rosette. A key mechanism for extrusion is constriction of an actomyosin network that neighbor cells form at their interface with the apoptotic cell. Here we report a complementary process of cytoskeletal relaxation that occurs when cortical contractility is down-regulated at the junctions between those neighbor cells themselves. This reflects a mechanosensitive Src family kinase (SFK) signaling pathway that is activated in neighbor cells when the apoptotic cell relaxes shortly after injury. Inhibiting SFK signaling blocks both the expulsion of apoptotic cells and the rosette formation among their neighbor cells. This reveals the complex pattern of spatially distinct contraction and relaxation that must be established in the neighboring epithelium for apoptotic cells to be extruded. 相似文献
3.
Seema Bhargava Sathnur Pushpakumar Naira Metreveli Srikanth Givvimani Suresh C. Tyagi 《Molecular biology reports》2014,41(8):4889-4898
Hyperhomocysteinemia (HHcy) is associated with cognitive decline and hearing loss due to vascular dysfunction. Although we have shown that HHcy-induced increased expression of matrix metalloproteinase-9 (MMP-9) is associated with cochlear pathology in cystathionine-β-synthase heterozygous (CBS+/?) mice, it is still unclear whether MMP-9 contributes to functional deficit in cognition and hearing. Therefore, we hypothesize that HHcy-induced MMP-9 activation causes vascular, cerebral and cochlear remodeling resulting in diminished cognition and hearing. Wildtype (WT), CBS+/?, MMP-9?/? and CBS+/?/MMP-9?/? double knock-out (DKO) mice were genotyped and used. Doppler flowmetry of internal carotid artery (ICA) was performed for peak systolic velocity [PSV], pulsatility index [PI] and resistive index [RI]. Cognitive functions were assessed by Novel Object Recognition Test (NORT) and for cochlear function Auditory brainstem response (ABR) was elicited. Peak systolic velocity, pulsatility and resistive indices of ICA were decreased in CBS+/? mice, indicating reduced perfusion. ABR threshold was increased and maximum ABR amplitude and NORT indices (recognition, discrimination) were decreased in CBS+/? mice compared to WT and MMP-9?/?. All these parameters were attenuated in DKO mice suggesting a significant role of MMP-9 in HHcy-induced vascular, neural and cochlear pathophysiology. Regression analysis of PSV with ABR and cognitive parameters revealed significant correlation (0.44–0.58). For the first time, MMP-9 has been correlated directly to functional deficits of brain and cochlea, and found to have a significant role. Our data suggests a dual pathology of HHcy occurring due to a decrease in blood supply (vasculo-neural and vasculo-cochlear) and direct tissue remodeling. 相似文献
4.
Srikanth Mairpady Shambat Axana Haggar Francois Vandenesch Gerard Lina Willem J. B. van Wamel Gayathri Arakere Mattias Svensson Anna Norrby-Teglund 《PloS one》2014,9(8)
Epidemiological studies of Staphylococcus aureus have shown a relation between certain clones and the presence of specific virulence genes, but how this translates into virulence-associated functional responses is not fully elucidated. Here we addressed this issue by analyses of community-acquired S. aureus strains characterized with respect to antibiotic resistance, ST types, agr types, and virulence gene profiles. Supernatants containing exotoxins were prepared from overnight bacterial cultures, and tested in proliferation assays using human peripheral blood mononuclear cells (PBMC). The strains displayed stable phenotypic response profiles, defined by either a proliferative or cytotoxic response. Although, virtually all strains elicited superantigen-mediated proliferative responses, the strains with a cytotoxic profile induced proliferation only in cultures with the most diluted supernatants. This indicated that the superantigen-response was masked by a cytotoxic effect which was also confirmed by flow cytometry analysis. The cytotoxic supernatants contained significantly higher levels of α-toxin than did the proliferative supernatants. Addition of α-toxin to supernatants characterized as proliferative switched the response into cytotoxic profiles. In contrast, no effect of Panton Valentine Leukocidin, δ-toxin or phenol soluble modulin α-3 was noted in the proliferative assay. Furthermore, a significant association between agr type and phenotypic profile was found, where agrII and agrIII strains had predominantly a proliferative profile whereas agrI and IV strains had a predominantly cytotoxic profile. The differential response profiles associated with specific S. aureus strains with varying toxin production could possibly have an impact on disease manifestations, and as such may reflect specific pathotypes. 相似文献
5.
Nimisha Koodali Srikanth Krishnamoorthy Velayutham Dinesh Nandan Dharam Sankaralingam Shanmugam Nagarajan Muniyandi 《Molecular biology reports》2022,49(7):5963-5972
Molecular Biology Reports - Molecular studies on egg production in ducks were mostly focused on brain and ovaries as they are directly involved in egg production. Liver plays a vital role in... 相似文献
6.
Tan Van Bui Christopher Leigh Blizzard Khue Ngoc Luong Ngoc Le Van Truong Bao Quoc Tran Petr Otahal Velandai Srikanth Mark Raymond Nelson Thuy Bich Au Son Thai Ha Hai Ngoc Phung Mai Hoang Tran Michele Callisaya Seana Gall 《PloS one》2015,10(10)
IntroductionOur aims were to provide the first national estimates of physical activity (PA) for Vietnam, and to investigate issues affecting their accuracy.MethodsMeasurements were made using the Global Physical Activity Questionnaire (GPAQ) on a nationally-representative sample of 14706 participants (46.5% males, response 64.1%) aged 25−64 years selected by multi-stage stratified cluster sampling.ResultsApproximately 20% of Vietnamese people had no measureable PA during a typical week, but 72.9% (men) and 69.1% (women) met WHO recommendations for PA by adults for their age. On average, 52.0 (men) and 28.0 (women) Metabolic Equivalent Task (MET)-hours/week (largely from work activities) were reported. Work and total PA were higher in rural areas and varied by season. Less than 2% of respondents provided incomplete information, but an additional one-in-six provided unrealistically high values of PA. Those responsible for reporting errors included persons from rural areas and all those with unstable work patterns. Box-Cox transformation (with an appropriate constant added) was the most successful method of reducing the influence of large values, but energy-scaled values were most strongly associated with pathophysiological outcomes.ConclusionsAround seven-in-ten Vietnamese people aged 25–64 years met WHO recommendations for total PA, which was mainly from work activities and higher in rural areas. Nearly all respondents were able to report their activity using the GPAQ, but with some exaggerated values and seasonal variation in reporting. Data transformation provided plausible summary values, but energy-scaling fared best in association analyses. 相似文献
7.
8.
Srikanth Venkatraman Wanli Wu Neng-Yang Shih F. George Njoroge 《Bioorganic & medicinal chemistry letters》2009,19(16):4760-4763
Chronic hepatitis C infection is the primary cause for cirrhosis of the liver and hepatocellular carcinoma leading to liver failure and transplantation. The etiological agent hepatitis C virus produces a single positive strand RNA that is processed further with the help of NS3 serine protease to produce mature virus. Inhibition of this protease can potentially be used to develop drugs for HCV infections. Boceprevir is a ketoamide derived novel inhibitor of HCV NS3 protease that has been progressed to clinical trials and proven to be efficacious in humans. Herein, we report our efforts in identifying an aza-peptide derivative as a potential second generation compound, that lacks electrophilic ketoamide group and are potent in enzyme and replicon assay. 相似文献
9.
10.
The inositol 1,4,5-trisphosphate (InsP(3)) receptor is a tetrameric intracellular calcium channel. It is an integral component of the InsP(3) signaling pathway in multicellular organisms, where it regulates cellular calcium dynamics in many different contexts. In order to understand how the primary structure of the InsP(3)R affects its functional properties, the kinetics of Ca(2+)-release in vitro from single point mutants of the Drosophila InsP(3)R have been determined earlier. Among these, the Ka901 mutant in the putative selectivity-filter of the pore is of particular interest. It is non-functional in the homomeric form whereas it forms functional channels (with altered channel properties) when co-expressed with wild-type channels. Here we show that due to its changed functional properties the Ka901 mutant protein has dominant-negative effects in vivo. Cells expressing Ka901:WT channels exhibit much higher levels of cytosolic Ca(2+) upon stimulation as compared with cells over-expressing just the wild-type DmInsP(3)R, thus supporting our in vitro observations that increased Ca(2+) release is a property of heteromeric Ka901:WT channels. Furthermore, ectopic expression of the Ka901 mutant channel in aminergic cells of Drosophila alters electrophysiological properties of a flight circuit and results in defective flight behavior. 相似文献