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41.
Stéphanie Blanchard Anthony D. William Angeline C.-H. Lee Anders Poulsen Ee Ling Teo Weiping Deng Noah Tu Evelyn Tan Kay Lin Goh Wai Chung Ong Chee Pang Ng Kee Chuan Goh Zahid Bonday Eric T. Sun 《Bioorganic & medicinal chemistry letters》2010,20(8):2443-2447
A series of alkenyl indazoles were synthesized and evaluated in Aurora kinase enzyme assays. Several promising leads were optimized for selectivity towards Aurora B. Excellent binding affinity and good selectivity were achieved with optimized compounds in isolated Aurora subfamily assays. 相似文献
42.
Iain D. Hay Zahid U. Rehman Bernd H. A. Rehm 《Applied and environmental microbiology》2010,76(6):1806-1812
The ubiquitous opportunistic human pathogen Pseudomonas aeruginosa secretes a viscous extracellular polysaccharide, called alginate, as a virulence factor during chronic infection of patients with cystic fibrosis. In the present study, it was demonstrated that the outer membrane protein AlgE is required for the production of alginate in P. aeruginosa. An isogenic marker-free algE deletion mutant was constructed. This strain was incapable of producing alginate but did secrete alginate degradation products, indicating that polymerization occurs but that the alginate chain is subsequently degraded during transit through the periplasm. Alginate production was restored by introducing the algE gene. The membrane topology of the outer membrane protein AlgE was assessed by site-specific insertions of FLAG epitopes into predicted extracellular loop regions.Pseudomonas aeruginosa is an ubiquitous opportunistic human pathogen responsible for chronic infections of the lungs of patients with cystic fibrosis (CF), in whom it is the leading cause of mortality and morbidity (9). The establishment of a chronic infection in the lungs of patients with CF coincides with the switch of P. aeruginosa to a stable mucoid variant, producing copious amounts of the exopolysaccharide alginate; this is typically a poor prognostic indicator for these patients (24, 31). Alginate is a linear unbranched exopolysaccharide consisting of 1,4-linked monomers of β-d-mannuronic acid and its C-5 epimer, α-l-guluronic acid, which is known to be produced by only two bacterial genera, Pseudomonas and Azotobacter (34). The switch to a mucoid phenotype coincides with the appearance of a 54-kDa protein in the outer membrane; this protein has been identified and has been designated AlgE (13, 31).The genes encoding the alginate biosynthesis machinery are located within a 12-gene operon (algD-alg8-alg44-algK-algE-algG-algX-algL-algI-algJ-algF-algA). AlgA and AlgD, along with AlgC (not encoded in the operon), are involved in precursor synthesis (34). Alg8 is the catalytic subunit of the alginate polymerase located at the inner membrane (35). AlgG is a C-5 mannuronan epimerase (19). AlgK contains four putative Sel1-like repeats, similar to the tetratricopeptide repeat motif often found in adaptor proteins involved in the assembly of multiprotein complexes (3, 10). AlgX shows little homology to any known protein, and its role is unclear (14). Knockout mutants of AlgK, AlgG, and AlgX have nonmucoid phenotypes, although they produce short alginate fragments, due to the activity of the alginate lyase (AlgL), which degrades the nascent alginate (1, 14, 19-21, 36). AlgF, AlgI, and AlgJ are involved in acetylation of alginate, but they are not ultimately required for its production (12). The membrane-anchored protein, Alg44, is required for polymerization and has a PilZ domain for the binding of c-di-GMP, a secondary messenger essential for alginate production (16, 25, 33). The periplasmic C terminus of Alg44 shares homology with the membrane fusion proteins involved in the bridging of the periplasm in multidrug efflux pumps (11, 43). The periplasmic alginate lyase, AlgL, appears to be required for the translocation of intact alginate across the periplasm (1, 26). AlgE is an outer membrane, anion-selective channel protein through which alginate is presumably secreted (30). A protein complex or scaffold through which the alginate chain can pass and be modified and which spans the periplasm bridging the polymerase located (Alg8) at the outer membrane pore (AlgE) has been proposed (21). Indeed, it has been demonstrated that both the inner and the outer membranes are required for the in vitro polymerization of alginate (35).The requirement of AlgE for the biosynthesis of alginate in P. aeruginosa was first observed by complementation of an alginate-negative mutant derived by chemical mutagenesis with a DNA fragment containing algE (8) Secondary structure predictions suggested that AlgE forms an 18-stranded β barrel with extended extracellular loops. Several of these loops show high densities of charged amino acids, suggesting a functional role in the translocation of the anionic alginate polymer (29, 30). Preliminary analysis of AlgE crystals has been reported (48).In this study, the role of AlgE in alginate biosynthesis was investigated and the membrane topology of AlgE was assessed by site-directed insertion mutagenesis. 相似文献
43.
Dielectric heaters and sealers present the most common source of occupational exposure to excessive radio frequency (RF) fields. These systems are used industrially to heat or melt dielectric materials. Nowadays, the effects of high frequency electromagnetic (EM) fields on the health have been discussed frequently but there are few health studies done for workers around dielectric heaters and sealers. In this study, the leakage fields around dielectric heaters and sealers (27.12?MHz) were measured in MKE--Mechanical and Chemical Industry Corporation, Gazi Rocket Factory and evaluated in terms of standards. It has been observed that operators exposed to same RF fields with occupational exposure limits. Many workers have health complaints, such as elevated body temperatures in the factory. Safe distances or areas for workers should be recommended in these systems. Protective measures could be implemented to minimize these exposures. Further measurements and occupational exposure studies of RF exposed women and men are needed to demonstrate the levels of exposed Radio Frequency Radiation (RFR). Precautions should therefore be taken either to reduce the leakage fields or minimise the exposed fields. 相似文献
44.
Atrial myocytes that lack t-tubules appear to have two functionally separate sarcoplasmic Ca2+ stores: a peripheral store associated with plasmalemmal L-type calcium channels and a central store with no apparent proximity to L-type calcium channels. Here we describe a set of calcium sparks and waves that are triggered by puffing of pressurized (200-400 mmH2O) bathing solutions onto resting isolated rat atrial myocytes. Puffing of pressurized (200 mmH2O) solutions, identical to those bathing the myocytes from distances of approximately 150 microm onto the surface of a single myocyte triggered or enhanced spontaneously occurring peripheral sparks by five- to six-fold and central Ca2+ sparks by two- to three-fold, without altering the unitary spark properties. Exposure to higher pressure flows (400 mmH2O) often triggered longitudinally spreading Ca2+ waves. These results suggest that pressurized flows may directly modulate Ca2+ signaling of atrial myocytes by activating the intracellular Ca2+ release sites. 相似文献
45.
Intracellular Ca2+ oscillations, a potential pacemaking mechanism in early embryonic heart cells
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Sasse P Zhang J Cleemann L Morad M Hescheler J Fleischmann BK 《The Journal of general physiology》2007,130(2):133-144
Early (E9.5-E11.5) embryonic heart cells beat spontaneously, even though the adult pacemaking mechanisms are not yet fully established. Here we show that in isolated murine early embryonic cardiomyocytes periodic oscillations of cytosolic Ca(2+) occur and that these induce contractions. The Ca(2+) oscillations originate from the sarcoplasmic reticulum and are dependent on the IP(3) and the ryanodine receptor. The Ca(2+) oscillations activate the Na(+)-Ca(2+) exchanger, giving rise to subthreshold depolarizations of the membrane potential and/or action potentials. Although early embryonic heart cells are voltage-independent Ca(2+) oscillators, the generation of action potentials provides synchronization of the electrical and mechanical signals. Thus, Ca(2+) oscillations pace early embryonic heart cells and the ensuing activation of the Na(+)-Ca(2+) exchanger evokes small membrane depolarizations or action potentials. 相似文献
46.
47.
Khan I Marwat KB Hussain Z 《Communications in agricultural and applied biological sciences》2007,72(2):259-264
To evaluate the effect of different herbicides for controlling weeds in wheat (variety Fakhr-i-Sarhad),at higher attitude, an experiment was conducted at Agriculture Research Station, Chitral during Rabi season 2003-04, using Randomized Complete Block Design, keeping four replications. The experiment, sown in November comprised of eight treatments, viz; seven herbicides and a weedy check. Each treatment consisted of 5 rows each 30 cm apart and 5 m long thus giving a total size of 5 m x 1.5 m. The herbicides used included; terbutryn + triasulfuron at 0.16 kg, 2,4-D at 0.7 kg, fenoxaprop-P-ethyl at 0.93 kg, clodinafop at 0.05 kg, bromoxynil + MCPA at 0.49 kg, carfentrazon-ethyl at 0.02 kg and isoproturon at 1.0 kg a.i ha(-1). The data were recorded on weed kill efficiency (%), fresh weed biomass (kg ha(-1)), plant height (cm), spike length (cm), number of tillers m(-2), number of grains spike(-1), thousand grains weight (g), biological yield (kg ha(-1)), grain yield (kg ha(-1)) and harvest index (%). The data recorded on weed kill efficiency, weed biomass (kg ha1), grains yield (kg ha(-1)) and harvest index (%) were significantly affected by the different herbicidal treatments. Statistically isoproturon treatment exhibited the best performance, with maximum weed kill efficiency (48.26%) and minimum fresh weed biomass (433.3 kg ha(-1)) as compared to weedy check (6 %) and (1102 kg ha(-1)), respectively. Similarly, the spike length (8.34 cm), number of tillers (427 m(-2)), number of grains spike(-1) (38.0), thousand grains weight (39.85 g), biological yield (8475 kg ha(-1)), grain yield (2530 kg ha(-1)) and harvest index (31.3%) were the highest in isoproturon treatments as compared to weedy check having (7.64 cm), (356 m(-2)), (34.1), (37.12 g), (6858 kg), (1913 kg ha(-1)) and (27%), respectively. 相似文献
48.
Raju Dash Mir Muhammad Nasir Uddin S.M. Zahid Hosen Zahed Bin Rahim Abu Mansur Dinar Mohammad Shah Hafez Kabir Ramiz Ahmed Sultan Ashekul Islam Md Kamrul Hossain 《Bioinformation》2015,11(12):543-549
Cyclooxygenase-2 (COX-2) catalyzed synthesis of prostaglandin E2 and it associates with tumor growth, infiltration, and metastasis
in preclinical experiments. Known inhibitors against COX-2 exhibit toxicity. Therefore, it is of interest to screen natural compounds
like flavanoids against COX-2. Molecular docking using 12 known flavanoids against COX-2 by FlexX and of ArgusLab were
performed. All compounds showed a favourable binding energy of >-10 KJ/mol in FlexX and > -8 kcal/mol in ArgusLab.
However, this data requires in vitro and in vivo verification for further consideration. 相似文献
49.
The catalytic domain of epidermal growth factor receptor (EGFR) is activated by dimerization, which requires allosteric coupling between distal dimerization and catalytic sites. Although crystal structures of EGFR kinases, solved in various conformational states, have provided important insights into EGFR activation by dimerization, the atomic details of how dimerization signals are dynamically coupled to catalytic regions of the kinase core are not fully understood. In this study, we have performed unrestrained and targeted molecular dynamics simulations on the active and inactive states of EGFR, followed by principal component analysis on the simulated trajectories, to identify correlated motions in the EGFR kinase domain upon dimerization. Our analysis reveals that the conformational changes associated with the catalytic functions of the kinase core are highly correlated with motions in the juxtamembrane (JM) and C-terminal tail, two flexible structural elements that play an active role in EGFR kinase activation and dimerization. In particular, the opening and closing of the ATP binding lobe relative to the substrate binding lobe is highly correlated with motions in the JM and C-terminal tail, suggesting that ATP and substrate binding can be coordinated with dimerization through conformational changes in the JM and C-terminal tail. Our study pinpoints key residues involved in this conformational coupling, and provides new insights into the role of the JM and C-terminal tail segments in EGFR kinase functions. 相似文献
50.
The neurotransmitter dopamine is oxidized to its quinone (DA-Q), which at neutral pH undergoes intramolecular cyclization by 1,4-Michael addition, followed by oxidation to form leukochrome, then aminochrome, and finally neuromelanin. At lower pH, the amino group of DA is partially protonated, allowing the competitive intermolecular 1,4-Michael addition with nucleophiles in DNA to form the depurinating adducts, DA-6-N3Ade and DA-6-N7Gua. Catechol estrogen-3,4-quinones react by 1,4-Michael addition to form the depurinating 4-hydroxyestrone(estradiol)-1-N3Ade [4-OHE1(E2)-1-N3Ade] and 4-OHE1(E2)-1-N7Gua adducts, which are implicated in the initiation of breast and other human cancers. The effect of pH was studied by reacting tyrosinase-activated DA with DNA and measuring the formation of depurinating adducts. The most adducts were formed at pH 4, 5, and 6, and their level was nominal at pH 7 and 8. The N3Ade adduct depurinated instantaneously, but N7Gua had a half-life of 3 H. The slow loss of the N7Gua adduct is analogous to that observed in previous studies of natural and synthetic estrogens. The antioxidants N-acetylcysteine and resveratrol efficiently blocked formation of the DA-DNA adducts. Thus, slightly acidic conditions render competitive the reaction of DA-Q with DNA to form depurinating adducts. We hypothesize that formation of these adducts could lead to mutations that initiate Parkinson's disease. If so, use of N-acetylcysteine and resveratrol as dietary supplements may prevent initiation of this disease. 相似文献