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561.
Freiberg G Wilkins J David C Kofron J Jia Y Hirst GC Burns DJ Warrior U 《Journal of biomolecular screening》2004,9(1):12-21
Protein tyrosine kinases play critical roles in cell signaling and are considered attractive targets for drug discovery. The authors have applied microARCS (microarrayed compound screening) technology to develop a high-throughput screen for finding inhibitors of the p56lck tyrosine kinase. Initial assay development was performed in a homogeneous time-resolved (LANCE) format in 96-well microplates and then converted into the gel-based microARCS format. The microARCS methodology is a well-less screening format in which 8640 compounds are arrayed on a microplate-sized piece of polystyene and subsequently assayed by placing reagents cast in agarose gels in contact with these compound sheets. A blotting paper soaked with adenosine triphosphate is applied on the gel to initiate the kinase reaction in the gel. Using this screening methodology, 300,000 compounds were screened in less than 40 h. Substantial reagent reduction was achieved by converting this tyrosine kinase assay from a 96-well plate assay to microARCS, resulting in significant cost savings. 相似文献
562.
Dharamjit Kherwar Kalidindi Usha S. V. Amitha Mithra Bhupinder Singh 《Journal of plant biochemistry and biotechnology.》2018,27(3):284-292
Twenty-four SSR markers were utilized to evaluate the genetic variation across thirty-six guava varieties including wild species. The SSR markers revealed a polymorphism of 95.7% and a great range of diversity among the experimental guava germplasm. Eighty-one alleles were detected, in diversity analysis, with 2–7 alleles with a mean of 3.682 alleles per loci. The SSR loci showcased an allele frequency of 0.306 (mPgCIR251) to 0.861 (mPgCIR227) at a mean value 0.561. An average polymorphic value of 0.490 across was measured for all the 36 germplasm with the range of 0.234 in mPgCIR227 to 0.706 in mPgCIR03. The genetic diversity for SSRs varied between 0.248 (mPgCIR227) and 0.747 (mPgCIR03) with an average of 0.548. Clustering of germplasm distinctly separated pink and white flesh germplasm into two major groups. First three coordinates contributed towards 32.76% of the variation measured using principle coordinate analysis. Molecular variance (AMOVA) study showed 06 and 94% genetic variation among population and individual, respectively with five sub populations. This study provides valuable information for understanding the genetic variability in guava which can be exploited to develop varieties with better fruit yield and nutritional quality. 相似文献
563.
Usha Gupta Avshesh Mishra Saurabh S. Rathore S. K. Agarwal Shantanu Pande Naveen Garg Balraj Mittal 《Molecular and cellular biochemistry》2013,372(1-2):75-82
Rheumatic heart disease (RHD) is one of the most severe consequences of rheumatic fever. It has been suggested that angiotensin I-converting enzyme (ACE) may be involved in the increased valvular fibrosis and calcification in the pathogenesis of RHD. We conducted a case–control study to look for association of ACE I/D polymorphism with RHD in Indian population. The study incorporated 300 patients (170 males and 130 females) with RHD, and 200 controls (118 males and 82 females). We also subgrouped RHD patients into mitral valve lesion (MVL) and combined valve lesion (CVL). ACE I/D polymorphism was identified using polymerase chain reaction method. We also performed a meta-analysis of three published studies and the present study (636 RHD cases and 533 controls) to evaluate the association between the ACE I/D polymorphisms and RHD risk. A significant difference in ACE ID and DD genotypes distribution between RHD cases (OR = 1.62, 95 % CI = 1.11–2.36 and OR = 2.08, 95 % CI = 1.02–4.15, respectively) and corresponding controls was observed. On comparing the ACE genotypes of MVL and CVL subgroups with controls, ID and DD genotypes were also significantly associated with CVL (FDR Pcorr = 0.009, OR = 2.19 and FDR Pcorr = 0.014, OR = 3.29, respectively). Meta-analysis also suggested association of the ACE D allele (FDR Pcorr = 0.036, OR—1.22, 95 % CI 1.02–1.45) with RHD. In conclusion, ACE ID and DD genotypes are associated with an increased risk of RHD, particularly CVL. This suggests that the ACE I/D gene polymorphism may play an important role in the pathogenesis of RHD. 相似文献
564.
Recent measurements have demonstrated unprecedented increase in atmospheric deposition of nutrients in many parts of India. To determine whether atmospheric nutrient inputs would increase phytoplankton growth and catchment dissolved organic carbon (DOC) flushing to constrain benthic algae, we analyzed NO3 ? and PO 4 ?3 in atmospheric deposits; nutrients and DOC in runoff and lake water and standing crop biomass of phytoplankton and periphyton at Jaisamand Lake of Rajasthan, India. Atmospheric deposition of NO3 ? (7.18–29.95 kg ha?1 year?1) and PO 4 ?3 (0.56–2.15 kg ha?1 year?1) showed a consistently rising trend across the year. Microbial biomass and activity in catchment increased in response to atmospheric deposition. Lake DOC and nutrients showed strong coherence with their terrestrial and atmospheric fluxes. Phytoplankton development showed significant linearity with atmospheric input of nutrients. Air-driven input appeared to have compensated the nutrient constraints to phytoplankton during drought. The N:P stoichiometry of deposition and that of lake water indicated that, although there was a seasonal switchover to N- or P-limitation, phytoplankton were mainly co-limited by N and P due probably to the synergistic effects of combined N + P enrichment in the pelagic zone of the lake. Periphyton standing crop showed inverse relationship with phytoplankton and lake DOC. The study indicated that enhanced phytoplankton development and terrestrial DOC flushing in response to atmospheric nutrient input attenuated light penetration to constrain algal periphyton. We suggests that data on these issues may be considered in developing aquatic ecosystem models to establish future links between changing air–water–land interactions and associated shifts in lake ecosystem functioning for more accurately predicting climate change drivers and designing integrated lake basin management strategies. 相似文献
565.
566.
Niraj K. Nirala Motiur Rahman Stanley M. Walls Alka Singh Lihua Julie Zhu Takeshi Bamba Eiichiro Fukusaki Sargur M. Srideshikan Greg L. Harris Y. Tony Ip Rolf Bodmer Usha R. Acharya 《PLoS genetics》2013,9(6)
The sphingolipid ceramide elicits several stress responses, however, organisms survive despite increased ceramide but how they do so is poorly understood. We demonstrate here that the AKT/FOXO pathway regulates survival in increased ceramide environment by metabolic adaptation involving changes in glycolysis and lipolysis through novel downstream targets. We show that ceramide kinase mutants accumulate ceramide and this leads to reduction in energy levels due to compromised oxidative phosphorylation. Mutants show increased activation of Akt and a consequent decrease in FOXO levels. These changes lead to enhanced glycolysis by upregulating the activity of phosphoglyceromutase, enolase, pyruvate kinase, and lactate dehydrogenase to provide energy. A second major consequence of AKT/FOXO reprogramming in the mutants is the increased mobilization of lipid from the gut through novel lipase targets, CG8093 and CG6277 for energy contribution. Ubiquitous reduction of these targets by knockdown experiments results in semi or total lethality of the mutants, demonstrating the importance of activating them. The efficiency of these adaptive mechanisms decreases with age and leads to reduction in adult life span of the mutants. In particular, mutants develop cardiac dysfunction with age, likely reflecting the high energy requirement of a well-functioning heart. The lipases also regulate physiological triacylglycerol homeostasis and are important for energy metabolism since midgut specific reduction of them in wild type flies results in increased sensitivity to starvation and accumulation of triglycerides leading to cardiac defects. The central findings of increased AKT activation, decreased FOXO level and activation of phosphoglyceromutase and pyruvate kinase are also observed in mice heterozygous for ceramide transfer protein suggesting a conserved role of this pathway in mammals. These data reveal novel glycolytic and non-autonomous lipolytic pathways in response to increased ceramide for sustenance of high energy demanding organ functions like the heart. 相似文献
567.
A total of 72 plant extracts were tested in vitro for their ability to inhibit the mycelial growth of Lasiodiplodia theobromae and Colletotrichum musae the causal agents of crown rot disease of banana. The results showed that the leaf extract of Zimmu (an interspecific hybrid of Allium cepa L. × Allium sativum L.) and tuber extract of Zehneria scabra recorded maximum inhibition of mycelial growth and spore germination of both the test pathogens. The dipping of banana fruits in Zimmu leaf extract at 25% conc. exhibited 100% inhibition of crown rot disease in cold storage (14 °C) up to 35 days and increased the shelf life to 64 days. However, at room storage (28 ± 2 °C), the same treatment exhibited 86% inhibition of crown rot disease up to 12 days. It was found that the treatment of banana fruits with Zimmu leaf extract did not alter the organoleptic properties of banana. The biochemical analysis of banana fruits treated with Zimmu leaf extract showed significant increase in phenylalanine ammonia-lyase (PAL), chitinase and β-1,3-glucanase activities and enhanced accumulation of phenolic compounds compared to other treatments. These findings suggest that the effect of Zimmu leaf extract on crown rot disease may be associated with the direct fungi toxic property against the test pathogens and elicitation of defense related compounds in banana fruits. 相似文献
568.
Longer wavelength fluorescence resonance energy transfer depsipeptide substrates for hepatitis C virus NS3 protease 总被引:2,自引:1,他引:1
Konstantinidis AK Richardson PL Kurtz KA Tripathi R Chen CM Huang P Randolph J Towne D Donnelly J Warrior U Middleton T Kati WM 《Analytical biochemistry》2007,368(2):156-167
Maturation of the hepatitis C virus (HCV) polyprotein occurs by a series of proteolytic processes catalyzed by host cell proteases and the virally encoded proteases NS2 and NS3. Although several peptidomimetic inhibitors of NS3 protease have been published, only a few small molecule inhibitors have been reported. In an effort to improve screening efficiency by minimizing the spectral interference of various test compounds, a substrate that contains the longer wavelength fluorescence resonance energy transfer (FRET) pair, TAMRA/QSY-7, was devised. For the optimized substrate T-Abu-Q, with sequence Ac-Asp-Glu-Lys(TAMRA)-Glu-Glu-Abu-Psi(COO)Ala-Ser-Lys(QSY-7)-amide, the kinetic parameters with HCV NS3 protease are K(m)=30 microM, k(cat)=0.6s(-1), and k(cat)/K(m)=20,100s(-1)M(-1). We show that this substrate is suitable for inhibitor analysis and mechanistic studies so long as the substrate concentration is low enough (0.5 microM) to avoid complications from high inner filter effects. The substrate is especially useful with ultra-high-density screening formats, such as microarrayed compound screening technology, because there is less spectral interference from the compounds being tested than with more traditional (EDANS/DABCYL) FRET protease substrates. The merits of the new substrate, as well as potential applications of this FRET pair to other protease substrates, are discussed. 相似文献
569.
Zhou W Ibe BO Raj JU 《American journal of physiology. Heart and circulatory physiology》2007,292(6):H2773-H2781
We have previously reported that platelet-activating factor (PAF) is present in very high levels in the ovine fetal lung and circulation and that PAF serves as an important physiological vasoconstrictor of the pulmonary circulation in utero. However, it is not known whether PAF stimulates pulmonary vascular smooth muscle cell (SMC) proliferation. In this study, we used ovine fetal pulmonary venous SMCs as our model system to study the effects and mechanisms of action of PAF on SMC proliferation. We found that PAF induced SMC proliferation in a dose-dependent manner. PAF also stimulated activation of both ERK and p38 but not c-Jun NH(2) terminal kinase (JNK) mitogen-activated protein (MAP) kinase pathways. PAF (10 nM) induced phosphorylation of epidermal growth factor receptor (EGFR). Specific inhibition of EGFR by AG-1478 and by the expression of a dominant-negative EGFR mutant in SMCs attenuated PAF-stimulated cell proliferation. Inhibition of heparin-binding EGF-like growth factor (HB-EGF) release by CRM-197 and inhibition of matrix metalloproteinases (MMP) by GM-6001 abolished PAF-induced MAP kinase activation and cell proliferation. Increased alkaline phosphatase (AP) activity after PAF treatment in AP-HB-EGF fusion construct-transfected SMCs indicated that PAF induced the release of HB-EGF within 1 min. Gelatin zymography data showed that PAF stimulated MMP-2 activity and MMP-9 activity within 1 min. These results suggest that PAF promotes pulmonary vascular SMC proliferation via transactivation of EGFR through MMP activation and HB-EGF, resulting in p38 and ERK activation and that EGFR transactivation is essential for the mitogenic effect of PAF in pulmonary venous SMC. 相似文献
570.
Dutta S Das S Guhathakurta S Sen B Sinha S Chatterjee A Ghosh S Ahmed S Ghosh S Usha R 《Cellular and molecular neurobiology》2007,27(8):1035-1047
Autism is a neurodevelopmental disorder with early manifestation. It is a multifactorial disorder and several susceptible
chromosomal regions for autism are identified through genome scan studies. The gene coding for glutamate receptor 6 (GluR6 or GRIK2) has been suggested as a candidate gene for autism based on its localization in the autism specific region on chromosome 6q21
and the involvement of receptor protein in cognitive functions like learning and memory. Despite its importance, so far no
studies have been carried out on possible involvement of GluR6 with autism in the Indian population. Therefore in the present study, we have performed genetic analysis of three markers
of GluR6 (SNP1: rs2227281, SNP2: rs2227283, SNP3: rs2235076) for possible association with autism through population, and family-based
(TDT and HHRR) approaches. DSM-IV criteria and CARS/ADI-R have been utilized for diagnosis. Genotyping analysis for the SNPs
has been carried out in 101 probands with autism spectrum disorder, 180 parents and 152 controls from different regions of
India. Since the minor allele frequency of SNP3 was too low, the association studies have been carried out only for SNP1 and
SNP2. Even though two earlier studies have shown association of these markers with autism, the present case–control and TDT,
as well as HHRR analyses have not demonstrated any biased transmission of alleles or haplotypes to the affected offspring.
Thus our results suggest that these markers of GluR6 are unlikely to be associated with autism in the Indian population. 相似文献