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71.
Arun Chandramohan Srinath Krishnamurthy Andreas Larsson Paer Nordlund Anna Jansson Ganesh S. Anand 《PLoS computational biology》2016,12(6)
A key question in mapping dynamics of protein-ligand interactions is to distinguish changes at binding sites from those associated with long range conformational changes upon binding at distal sites. This assumes a greater challenge when considering the interactions of low affinity ligands (dissociation constants, KD, in the μM range or lower). Amide hydrogen deuterium Exchange mass spectrometry (HDXMS) is a robust method that can provide both structural insights and dynamics information on both high affinity and transient protein-ligand interactions. In this study, an application of HDXMS for probing the dynamics of low affinity ligands to proteins is described using the N-terminal ATPase domain of Hsp90. Comparison of Hsp90 dynamics between high affinity natural inhibitors (KD ~ nM) and fragment compounds reveal that HDXMS is highly sensitive in mapping the interactions of both high and low affinity ligands. HDXMS reports on changes that reflect both orthosteric effects and allosteric changes accompanying binding. Orthosteric sites can be identified by overlaying HDXMS onto structural information of protein-ligand complexes. Regions distal to orthosteric sites indicate long range conformational changes with implications for allostery. HDXMS, thus finds powerful utility as a high throughput method for compound library screening to identify binding sites and describe allostery with important implications for fragment-based ligand discovery (FBLD). 相似文献
72.
The direct measurement of protein kinase C (PKC) activity in isolated membranes using a selective peptide substrate 总被引:1,自引:0,他引:1
B R Chakravarthy A Bussey J F Whitfield M Sikorska R E Williams J P Durkin 《Analytical biochemistry》1991,196(1):144-150
A protein kinase C (PKC)-selective peptide substrate was used to develop a method for measuring PKC activity directly and quantitatively in isolated cell membranes without prior detergent extraction and reconstitution of the enzyme with phosphatidylserine and TPA in the presence of excess Ca2+. This simple and rapid method can reliably measure changes in membrane-associated PKC activity induced by various bioactive compounds such as hormones and growth factors. Also, this method, which measures PKC activity in its native membrane-associated state, has the advantage of being able to distinguish between active and inactive PKC associated with cell membranes. 相似文献
73.
Lactating bonnet monkeys were used as a model to understand the mechanism of ovarian quiescence during lactation. The ovary
of the bonnet monkey in the 3rd month of lactation responds well to exogenous pregnant mare serum gonadotropin stimulation
with serum estrogen values reaching maximal levels by day 3 of the gonadotropin injection. The adminstration of ovine prolactin
to such monkeys significantly inhibited the ovarian responsiveness to exogenous gonadotropin. The responsiveness of the pituitary
of the lactating monkey (in the 3rd month of lactation) to luteinizing hormone releasing hormone injection was suppressed
and supplementation with exogenous prolactin further accentuating this effect. The relative ability of chlorpromazine given
intravenously/intramuscularly/intranasally to enhance endogenous prolactin levels was assessed. During the first 5 months
of lactation when the basal prolactin levels were high, the luteinizing hormone levels were low. As the suckling stimulus
reduces and prolactin levels fall, luteinizing hormone levels increase, the first post-parturient mensus occurring by 218
± 4 days. This event was postponed by 3 months on increasing endogenous prolactin levels by administering chlorpromazine (250
μg/day by intranasal mode) over a 5 day period every month starting from the 3rd month of lactation. 相似文献
74.
Saguna Dubey Sandeep Sambaraju Sarat Chandra Cautha Vednath Arya V. S. Chakravarthy 《Biological cybernetics》2009,101(3):201-213
A crucial insight into handwriting dynamics is embodied in the idea that stable, robust handwriting movements correspond to
attractors of an oscillatory dynamical system. We present a phase dynamic model of visuomotor performance involved in copying
simple oriented lines. Our studies on human performance in copying oriented lines revealed a systematic error pattern in orientation
of drawn lines, i.e., lines at certain orientation are drawn more accurately than at other values. Furthermore, human subjects
exhibit “flips” in direction at certain characteristic orientations. It is argued that this flipping behavior has its roots
in the fact that copying process is inherently ambiguous—a line of given orientation may be drawn in two different (mutually
opposite) directions producing the same end result. The systematic error patterns seen in human copying performance is probably
a result of the attempt of our visuomotor system to cope with this ambiguity and still be able to produce accurate copying
movements. The proposed nonlinear phase-dynamic model explains the experimentally observed copying error pattern and also
the flipping behavior with remarkable accuracy. 相似文献
75.
76.
Jochen G. Schneider Zhen Yang Manu V. Chakravarthy Irfan J. Lodhi Xiaochao Wei John Turk Clay F. Semenkovich 《The Journal of biological chemistry》2010,285(30):23398-23409
Fatty acid metabolism is perturbed in atherosclerotic lesions, but whether it affects lesion formation is unknown. To determine whether fatty acid synthesis affects atherosclerosis, we inactivated fatty-acid synthase (FAS) in macrophages of apoE-deficient mice. Serum lipids, body weight, and glucose metabolism were the same in FAS knock-out in macrophages (FASKOM) and control mice, but blood pressure was lower in FASKOM animals. Atherosclerotic extent was decreased 20–40% in different aortic regions of FASKOM as compared with control mice on Western diets. Foam cell formation was diminished in FASKOM as compared with wild type macrophages due to increased apoAI-specific cholesterol efflux and decreased uptake of oxidized low density lipoprotein. Expression of the anti-atherogenic nuclear receptor liver X receptor α (LXRα; Nr1h3) and its downstream targets, including Abca1, were increased in FASKOM macrophages, whereas expression of the potentially pro-atherogenic type B scavenger receptor CD36 was decreased. Peroxisome proliferator-activated receptor α (PPARα) target gene expression was decreased in FASKOM macrophages. PPARα agonist treatment of FASKOM and wild type macrophages normalized PPARα target gene expression as well as Nr1h3 (LXRα). Atherosclerotic lesions were more extensive when apoE null mice were transplanted with LXRα-deficient/FAS-deficient bone marrow as compared with LXRα-replete/FAS-deficient marrow, consistent with anti-atherogenic effects of LXRα in the context of FAS deficiency. These results show that macrophage FAS deficiency decreases atherosclerosis through induction of LXRα and suggest that FAS, which is induced by LXRα, may generate regulatory lipids that cause feedback inhibition of LXRα in macrophages. 相似文献
77.
Satyanarayana S Shivashankar R Vashist RP Chauhan LS Chadha SS Dewan PK Wares F Sahu S Singh V Wilson NC Harries AD 《PloS one》2010,5(10):e13338
Background
Childhood tuberculosis (TB) patients under India''s Revised National TB Control Programme (RNTCP) are managed using diagnostic algorithms and directly observed treatment with intermittent thrice-weekly short-course treatment regimens for 6–8 months. The assignment into pre-treatment weight bands leads to drug doses (milligram per kilogram) that are lower than current World Health Organization (WHO) guidelines for some patients.Objectives
The main aim of our study was to describe the baseline characteristics and treatment outcomes reported under RNTCP for registered childhood (age <15 years) TB patients in Delhi. Additionally, we compared the reported programmatic treatment completion rates between children treated as per WHO recommended anti-TB drug doses with those children treated with anti-TB drug doses below that recommended in WHO guidelines.Methods
For this cross-sectional retrospective study, we reviewed programme records of all 1089 TB patients aged <15 years registered for TB treatment from January to June, 2008 in 6 randomly selected districts of Delhi. WHO disease classification and treatment outcome definitions are used by RNTCP, and these were extracted as reported in programme records.Results and Conclusions
Among 1074 patients with records available, 651 (61%) were females, 122 (11%) were <5 years of age, 1000 (93%) were new cases, and 680 (63%) had extra-pulmonary TB (EP-TB)—most commonly peripheral lymph node disease [310 (46%)]. Among 394 pulmonary TB (PTB) cases, 165 (42%) were sputum smear-positive. The overall reported treatment completion rate was 95%. Similar reported treatment completion rates were found in all subgroups assessed, including those patients whose drug dosages were lower than that currently recommended by WHO. Further studies are needed to assess the reasons for the low proportion of under-5 years of age TB case notifications, address challenges in reaching all childhood TB patients by RNTCP, the accuracy of diagnosis, and the clinical validity of reported programme defined treatment completion. 相似文献78.
79.
80.
(?)-Epicatechin (1), a naturally occuring flavonoid compound was found to have reversed the diabetogenic action of alloxan in albino rats (2). (?)-Epicatechin administration in doses of 30 mg/kg (i.p) twice daily for 4–5 days in alloxan induced (150 mg/kg, i.p.) diabetic albino rats (either sex), has brought down the high blood sugar levels to normal values. Concurrent histological studies of the pancreas of these animals showed regeneration of the beta-cell population of the islets which were earlier necrosed by alloxan. Immunoreactive insulin (IRI) studies showed that the regenerated beta-cells of the islets of pancreas are functional in nature. 相似文献