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51.
Protein Kinase C β-II (PKC β-II) is an important enzyme in the development of diabetic complications like cardiomyopathy, retinopathy, neuropathy, nephropathy and angiopathy. PKC β-II is activated in vascular tissues during diabetic vascular abnormalities. Thus, PKC β-II is considered as a potent drug target and the crystal structure of the kinase domain of PKC β-II (PDB id: 2I0E) was used to design inhibitors using Structure-Based Drug Design (SBDD) approach. Sixty inhibitors structurally similar to Staurosporine were retrieved from PubChem Compound database and High Throughput Virtual screening (HTVs) was carried out with PKC β-II. Based on the HTVs results and the nature of active site residues of PKC β-II, Staurosporine inhibitors were designed using SBDD. Induced Fit Docking (IFD) studies were carried out between kinase domain of PKC β-II and the designed inhibitors. These IFD complexes showed favorable docking score, glide energy, glide emodel and hydrogen bond and hydrophobic interactions with the active site of PKC β-II. Binding free energy was calculated for IFD complexes using Prime MM-GBSA method. The conformational changes induced by the inhibitor at the active site of PKC β-II were observed for the back bone Cα atoms and side-chain chi angles. PASS prediction tool was used to analyze the biological activities for the designed inhibitors. The various physicochemical properties were calculated for the compounds. One of the designed inhibitors successively satisfied all the in silico parameters among the others and seems to be a potent inhibitor against PKC β-II. 相似文献
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Lawal A Kern M Sanjeevi A Antonik S Mepani R Rittmann T Hussaini S Hofmann C Tatro L Jesmanowicz A Verber M Shaker R 《American journal of physiology. Gastrointestinal and liver physiology》2008,294(3):G787-G794
The cingulate and insular cortices are parts of the limbic system that process and modulate gastrointestinal sensory signals. We hypothesized that sensitization of these two limbic area may operate in esophageal sensitization. Thus the objective of the study was to elucidate the neurocognitive processing in the cingulate and insular cortices to mechanical stimulation of the proximal esophagus following infusion of acid or phosphate buffer solution (PBS) into the esophagus. Twenty-six studies (14 to acid and 12 to PBS infusion) were performed in 20 healthy subjects (18-35 yr) using high-resolution (2.5 x 2.5 x 2.5 mm(3) voxel size) functional MRI (fMRI). Paradigm-driven, 2-min fMRI scans were performed during randomly timed 15-s intervals of proximal esophageal barostatically controlled distentions and rest, before and after 30-min of distal esophageal acid or PBS perfusion (0.1 N HCl or 0.1 M PBS at 1 ml/min). Following distal esophageal acid infusion, at subliminal and liminal levels of proximal esophageal distentions, the number of activated voxels in both cingulate and insular cortices showed a significant increase compared with before acid infusion (P < 0.05). No statistically significant change in cortical activity was noted following PBS infusion. We conclude that 1) acid stimulation of the esophagus results in sensitization of the cingulate and insular cortices to subliminal and liminal nonpainful mechanical stimulations, and 2) these findings can have ramifications with regard to the mechanisms of some esophageal symptoms attributed to reflux disease. 相似文献
54.
A defining event in type I export of hemolysin by Escherichia coli is the substrate-triggered recruitment of the TolC channel-tunnel by an inner membrane complex. This complex comprises a traffic ATPase (HlyB) and the 478 residue adaptor protein (HlyD), which contacts TolC during recruitment. HlyD has a large periplasmic domain (amino acid residues 81-478) linked by a single transmembrane helix to a small N-terminal cytosolic domain (1-59). Export was disabled by deletion of the ca 60 amino acid residue cytosolic domain of HlyD, even though the truncated HlyD (HlyDDelta45) was, like the wild-type, able to trimerise in the cytosolic membrane, and interact with the traffic ATPase. The mutant HlyB/HlyDDelta45 inner membrane complex engaged the hemolysin substrate, but this substrate-engaged complex failed to trigger recruitment of TolC. Further analyses showed that HlyDDelta45 was specifically unable to bind the substrate. The result suggests that substrate engagement by the traffic ATPase alone is insufficient to trigger TolC recruitment, and that substrate binding to the HlyD cytosolic domain is essential. Analysis of three further N-terminal deletion variants, HlyDDelta26, HlyDDelta26-45 and HlyDDelta34-38, indicated that an extreme N-terminal amphipathic helix and a cytosolic cluster of charged residues are central to the cytosolic domain function. The cytosolic amphipathic helix was not essential for substrate engagement or TolC recruitment, but export was impaired without it. In contrast, when the charged amino acid residues were deleted, the substrate was still engaged by HlyD but engagement was unproductive, i.e. TolC recruitment was not triggered. Our results are compatible with the HlyD cytosolic domain mediating transduction of the substrate binding signal directly, presumably to the HlyD periplasmic domain, to trigger recruitment of TolC and assemble the type I export complex. 相似文献
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A robust test for linear contrast using modified maximum likelihood estimators based on symmetrically censored samples proposed by Tiku (1973, 1982a) is studied in this paper from the Bayesian point of view. The effects of asymmetric censoring on this testing procedure is investigated and a good approximation to its posterior distribution in this case is worked out. We also present an example which illustrates the method of obtaining the highest posterior density interval for the linear combination of the unknown location parameters. 相似文献
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Verma Urja Kashmira Khaire Suresh Balakrishnan Gowri Kumari Uggini 《In vitro cellular & developmental biology. Animal》2018,54(10):756-769
Chick embryonic cells can be used to develop an easy and economical in vitro model for conducting studies on the disease muscle dystrophy (MD). For this, the limb myoblasts from 11th day chick embryo were isolated and cultured. To this muscle cell culture, anti-dystroglycan antibody (IIH6) was added so as to target the α-dystroglycan and disrupt the connection between the cytoskeletal proteins and the extracellular matrix (which is a characteristic feature of MD). Cells were allowed to differentiate further and the morphometrics and mRNA expression were studied. The IIH6-treated muscle cells displayed changes in morphometry, contractibility, and also atrophy was observed when compared to the control cultures. Concomitant gene expression studies showed an upregulation in TGF-β expression, while the muscle sculpture genes MYOD1, MYF5, LAMA2 and MYOG were downregulated resembling the MD in vivo. This simple and cost-effective method can be useful in studies to further understand the disease mechanism and also in conducting initial studies on effect of novel pharmacological agents. 相似文献
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Population ecology of the giant forest hog,Hylochoerus meinertzhageni in Chebera Churchura National Park,Ethiopia
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Aemro Mekonnen Afework Bekele Mundanthra Balakrishnan 《African Journal of Ecology》2018,56(2):272-278
Population, feeding habit, distribution and activity patterns of the giant forest hog (Hylochoerus meinertzhageni) were studied in Chebera Churchura National Park (CCNP), Ethiopia, using line transect sample counts. Population estimate of the hogs was 845 individuals. Among the counted individuals, 42.4% were males and 57.6% were females. Among them, 32.8% were adults, 26.9% were subadults, and 40.3% were piglets. Large sounders of up to 20 individuals were seen during the wet season. They were seen in all habitat types in CCNP with higher abundance in the riverine vegetation. Availability of food, green vegetation cover and water were factors governing distribution of forest hogs in the study area. Grass was the major food item of the hogs (90%), mainly of Panicum sp., Acalypha psilostachya, Cissapelos rigidifolia, Psilotrichum gnaphalobryum and Abutilon ceclii. Feeding was the major activity for which 49.7% of the active daytime was used. Resting (lying down, standing and wallowing) was the next major activity, for which they spent 38.8% of the daytime, followed by other activities (11.5%). Morning and late afternoon activity peaks were more intensive during the dry season. This female‐biased giant forest hog population is expected to sustain in CCNP. 相似文献