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71.
The energy landscape of RNA is known to be extremely rugged, and hence finding low-energy structures starting from a random structure is a challenging task for any optimization algorithm. In the current work, we have investigated the ability of one Monte Carlo-based optimization algorithm, Temperature Basin Paving, to explore the energy landscape of a small RNA T-loop hairpin. In this method, the history of the simulation is used to increase the probability of states less visited in the simulation. It has been found that using both energy and end-to-end distance as the biasing parameters in the simulation, the partially folded structure of the hairpin starting from random structures could be obtained. 相似文献
72.
73.
Nicholas G. Brown Sreejesh Shanker B. V. Venkataram Prasad Timothy Palzkill 《The Journal of biological chemistry》2009,284(48):33703-33712
TEM-1 β-lactamase is the most common plasmid-encoded β-lactamase in Gram-negative bacteria and is a model class A enzyme. The active site of class A β-lactamases share several conserved residues including Ser70, Glu166, and Asn170 that coordinate a hydrolytic water involved in deacylation. Unlike Ser70 and Glu166, the functional significance of residue Asn170 is not well understood even though it forms hydrogen bonds with both Glu166 and the hydrolytic water. The goal of this study was to examine the importance of Asn170 for catalysis and substrate specificity of β-lactam antibiotic hydrolysis. The codon for position 170 was randomized to create a library containing all 20 possible amino acids. The random library was introduced into Escherichia coli, and functional clones were selected on agar plates containing ampicillin. DNA sequencing of the functional clones revealed that only asparagine (wild type) and glycine at this position are consistent with wild-type function. The determination of kinetic parameters for several substrates revealed that the N170G mutant is very efficient at hydrolyzing substrates that contain a primary amine in the antibiotic R-group that would be close to the Asn170 side chain in the acyl-intermediate. In addition, the x-ray structure of the N170G enzyme indicated that the position of an active site water important for deacylation is altered compared with the wild-type enzyme. Taken together, the results suggest the N170G TEM-1 enzyme hydrolyzes ampicillin efficiently because of substrate-assisted catalysis where the primary amine of the ampicillin R-group positions the hydrolytic water and allows for efficient deacylation. 相似文献
74.
Anu Bhardwaj Dhananjay Kumar Tewary Rakesh Kumar Vinod Kumar Arun Kumar Sinha Adarsh Shanker 《化学与生物多样性》2010,7(1):168-177
The larvicidal activity of 18 phenylpropanoids, 1 – 18 , including phenylpropenoate, phenylpropenal, phenylpropene, and their semisynthetic analogues, were evaluated against the tobacco armyworm, Spodoptera litura (Fab .), to identify promising structures with insecticidal activity. Amongst various phenylpropanoids, isosafrole, a phenylpropene, showed the best activity, with an LC50 value of 0.6 μg/leaf cm2, followed by its hydrogenated derivative dihydrosafrole (LC50=2.7 μg/leaf cm2). The overall larvicidal activity of various phenylpropene derivatives was observed in the following order: isosafrole ( 6 )>dihydrosafrole ( 16 )>safrole ( 12 )>anethole ( 4 )>methyl eugenol ( 11 )>eugenol ( 13 )>β‐asarone ( 8 )>dihydroasarone ( 18 )>dihydroanethole ( 15 ). Dihydrosafrole might be a promising compound, although presenting a lower larvicidal activity than isosafrole, because of its better stability and resistance to oxidative degradation (due to the removal of the extremely reactive olefinic bond) in comparison to isosafrole. Such structure–activity relationship studies promote the identification of lead structures from natural sources for the development of larvicidal products against S. litura and related insect pests. 相似文献
75.
76.
Transforming growth factor beta-1 (TGF-beta1), which is present in lung tissue, has been suggested to play a role in modulating vascular cell function in vivo. The action of TGF-beta1 in vivo, especially at the local site of application to connective tissue, is anabolic and leads to pulmonary fibrosis and angiogenesis, strongly indicating that TGF-beta may have practical applications in repair of tissue injury caused by burns, trauma, or surgery. In the present study, we have used cultured bovine pulmonary artery endothelial (BPAE) cells as a model system. Expression of various proteins, including SPARC (secreted protein acidic and rich in cysteines), type IV procollagen and fibronectin (FN) was examined by radiolabeling the cells with [3H]proline, immunoprecipitation with specific antibodies, and Northern blot analyses by using specific cDNA probes. Cultured cells were labeled with [3H]proline for 24 h in either the absence or in the presence of TGF-beta1 (0-20 ng/ml). Incorporation of radioactivity was observed in a concentration-dependent manner, maximal at 5 ng/ml. Northern blot hybridization demonstrated that TGF-beta1 (5 ng/ml) treatment of BPAE cells caused an increase in steady-state levels 相似文献
77.
Dooley TP Curto EV Reddy SP Davis RL Lambert G Wilborn TW 《Biochemical and biophysical research communications》2003,303(3):828-841
DNA microarrays may be used to identify potential molecular targets for drug discovery. Yet, DNA microarray experiments provide massive amounts of data. To limit the choice of potential molecular targets, it may be desirable to eliminate genes coincidentally up-regulated in tissues implicated in absorption, distribution, metabolism, and excretion (ADME) pharmacokinetics. DNA microarray experiments were performed to demonstrate a gene-exclusion approach using as an example RNA samples of neural origin, i.e., a human neuroblastoma cell line (SK-N-SH) and brain tissue, as the intended hypothetical site(s) of drug action. Biomarkers were identified using PharmArray DNA microarrays. The lists of neuroblastoma and neural biomarkers were constrained by limiting selection to the subset of genes that were not highly expressed in three transformed cell lines from liver, colon, and kidney (HepG2, Caco-2, and 786-O, respectively) that are routinely used as representatives of the ADME system during in vitro pharmacology and toxicology experiments. Principal component analysis methods with likelihood ratio-related bioinformatic tools were utilized to identify robust potential biomarker genes for the three ADME-related cell lines, neuroblastoma, and normal brain. Biomarkers of each sample were identified and selected genes were validated by qRT-PCR. Hundreds of biomarkers of the three ADME-related cell types, representing hepatocytes, kidney epithelium, and gastrointestinal tract, may now be used as a valuable database to restrict selection of biomarkers as potential molecular targets from the intended samples (e.g., neuroblastoma in this work). In addition to biomarker discovery per se, this demonstration suggests that our model method may be viable to help restrict gene lists during selection of potential molecular targets for subsequent drug discovery. 相似文献
78.
In this study we have demonstrated the occurrence of Sporotrichum pruinosum and Cladosporium oxysporum in the bronchial secretions of a patient with a presumptive diagnosis of tuberculosis. This observation coupled with the ability of both fungi to cause infection and elicit tissue responses in experimentally infected mice supported a probable etiologic relationship with the patient which could not be confirmed in the absence of histologic evidence. In vitro some antimycotics were tested against S. pruinosum and C. oxysporum by the agar dilution method. Oxiconazole with a minimum inhibitory concentration of 0.1 g/ml–1 after 72 h and amorolfine at a concentration of 0.001 g/ml–1 after 72 h were the most active ones against S. pruinosum and C. oxysporum respectively. It is suggested that the isolation of S. pruinosum and C. oxysporum from patients with bronchopulmonary disorders should be viewed with caution. Clinical and laboratory evaluation of such patients should be done critically before arriving at a firm diagnosis. 相似文献
79.
Takashi Seo Muni Shanker Srivastava 《Biometrical journal. Biometrische Zeitschrift》2000,42(8):981-993
In this paper, repeated measures with intraclass correlation model is considered when the observations are missing at random. An exact test for the equality of the mean components and simultaneous confidence intervals (Scheffé and Bonferroni inequality types) are given for linear contrasts of the mean components when the missing observations are of a monotone type. When the missing observations are not of the monotone type, the maximum likelihood estimates are obtained numerically by iterative methods given in Srivastava and Carter (1986). These estimators are then used to obtain asymptotic tests and confidence intervals for the equality of mean components and linear contrasts, respectively. An example is given to illustrate the method. 相似文献
80.
Sharma TR Madhav MS Singh BK Shanker P Jana TK Dalal V Pandit A Singh A Gaikwad K Upreti HC Singh NK 《Molecular genetics and genomics : MGG》2005,274(6):569-578
In order to understand the molecular mechanisms involved in the gene-for-gene type of pathogen resistance, high-resolution
genetic and physical mapping of resistance loci is required to facilitate map-based cloning of resistance genes. Here, we
report the molecular mapping and cloning of a dominant gene (Pi-k
h
) present in the rice line Tetep, which is associated with resistance to rice blast disease caused by Magnaporthe grisea. This gene is effective against M. grisea populations prevalent in the Northwestern Himalayan region of India. Using 178 sequence tagged microsatellite, sequence-tagged
site, expressed sequence tag and simple sequence repeat (SSR) markers to genotype a population of 208 F2 individuals, we mapped the Pi-k
h
gene between two SSR markers (TRS26 and TRS33) which are 0.7 and 0.5 cM away, respectively, and can be used in marker-assisted-selection
for blast-resistant rice cultivars. We used the markers to identify the homologous region in the genomic sequence of Oryza sativa cv. Nipponbare, and a physical map consisting of two overlapping bacterial artificial chromosome and P1 artificial chromosome
clones was assembled, spanning a region of 143,537 bp on the long arm of chromosome 11. Using bioinformatic analyses, we then
identified a candidate blast-resistance gene in the region, and cloned the homologous sequence from Tetep. The putative Pi-k
h
gene cloned from Tetep is 1.5 kbp long with a single ORF, and belongs to the nucleotide binding site-leucine rich repeat
class of disease resistance genes. Structural and expression analysis of the Pi-k
h
gene revealed that its expression is pathogen inducible. 相似文献