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41.
Failli AA Shumsky JS Steffan RJ Caggiano TJ Williams DK Trybulski EJ Ning X Lock Y Tanikella T Hartmann D Chan PS Park CH 《Bioorganic & medicinal chemistry letters》2006,16(4):954-959
Our efforts in seeking low molecular weight agonists of the antidiuretic peptide hormone arginine vasopressin (AVP) have led to the identification of the clinical candidate WAY-151932 (VNA-932). Further exploration of the structural requirements for agonist activity has provided another class of potent, orally active, non-peptidic vasopressin V2 receptor selective agonists exemplified by the 5,11-dihydro-pyrido[2,3-b][1,5]benzodiazepine as a candidate for further development. 相似文献
42.
Sadiq I Fanucchi F Paparelli E Alpi E Bachi A Alpi A Perata P 《Journal of plant physiology》2011,168(18):2234-2243
Rice is the staple food for more than fifty percent of the world's population, and is therefore an important crop. However, its production is hindered by several biotic and abiotic stresses. Although rice is the only crop that can germinate even in the complete absence of oxygen (i.e. anoxia), flooding (low oxygen) is one of the major causes of reduced rice production. Rice germination under anoxia is characterized by the elongation of the coleoptile, but leaf growth is hampered. In this work, a comparative proteomic approach was used to detect and identify differentially expressed proteins in the anoxic rice coleoptile compared to the aerobic coleoptile. Thirty-one spots were successfully identified by MALDI-TOF MS analysis. The majority of the identified proteins were related to stress responses and redox metabolism. The expression levels of twenty-three proteins and their respective mRNAs were analyzed in a time course experiment. 相似文献
43.
In recent years, an increasing number of small molecules and short peptides have been identified that interfere with aggregation and/or oligomerization of the Alzheimer β-amyloid peptide (Aβ). Many of them possess aromatic moieties, suggesting a dominant role for those in interacting with Aβ along various stages of the aggregation process. In this study, we attempt to elucidate whether interactions of such aromatic inhibitors with monomeric Aβ(12-28) point to a common mechanism of action by performing atomistic molecular dynamics simulations at equilibrium. Our results suggest that, independently of the presence of inhibitors, monomeric Aβ(12-28) populates a partially collapsed ensemble that is largely devoid of canonical secondary structure at 300 K and neutral pH. The small molecules have different affinities for Aβ(12-28) that can be partially rationalized by the balance of aromatic and charged moieties constituting the molecules. There are no predominant binding modes, although aggregation inhibitors preferentially interact with the N-terminal portion of the fragment (residues 13-20). Analysis of the free energy landscape of Aβ(12-28) reveals differences highlighted by altered populations of a looplike conformer in the presence of inhibitors. We conclude that intrinsic disorder of Aβ persists at the level of binding small molecules and that inhibitors can significantly alter properties of monomeric Aβ via multiple routes of differing specificity. 相似文献
44.
Martin Karplus Amedeo Caflisch Andrej Săli Eugene Shakhnovich 《Molecular Engineering》1995,5(1-3):55-70
Simulations to study protein unfolding and folding were performed. The unfolding simulations make use of molecular dynamics and treat an atomic model of barnase in aqueous solvent. The cooperative nature of the unfolding transition and the important role of water are described. The folding simulations are based on a bead model of the protein on a cubic lattice. It is shown for the 27-mer model that a large energy gap between the lowest energy (native) state and the excited states is a necessary and sufficient condition for fast folding. 相似文献
45.
Carlo Guarnieri Giovanni Melandri Ilaria Caldarera Mauro Scheda Amedeo Ligabue Sandro Guizzardi Angelo Branzi 《Cell biochemistry and function》1990,8(3):157-162
Circulating neutrophils isolated from patients 3–4 h after a myocardial infarction produced less $ {\rm O}\frac{ \cdot }{{\rm 2}} $ compared with controls, when stimulated with phorbol myrystate acetate or formyl-methionine-leucine-phenylalanine. Three days after the infraction the $ {\rm O}\frac{ \cdot }{{\rm 2}} $ generation elicited by both stimuli further decreased markedly. Seven and 15 days after infarction the $ {\rm O}\frac{ \cdot }{{\rm 2}} $ stimulated production was only slightly lower than or similar to the control values. The neutrophils of infarcted patients showed an augmented latency period before $ {\rm O}\frac{ \cdot }{{\rm 2}} $ production compared with controls in response to exogenous stimuli, particularly three days after infarction. Electron microscopy revealed that the neutrophils isolated from the infarcted patients displayed signs of cell exhaustion with few alterations of the plasma membranes when stimulated with phorbol ester. In contrast, control neutrophils displayed alterations of the plasma membranes characteristic of active neutrophils. The results of this study indicate that the circulating neutrophils appear exhausted and functionally inhibited immediately after myocardial infarction. 相似文献
46.
Slow-wave sleep in daytime and nocturnal sleep: an estimate of the time course of "Process S" 总被引:1,自引:0,他引:1
Daan et al. (1984) have proposed that sleep and wakefulness are regulated, in part, by a "Process S" that increases during wakefulness and declines during sleep. Data derived from several studies were taken to determine the time course of Process S during both wakefulness and sleep. As required by the model, slow-wave-sleep (SWS; an index of Process S) was found to increase exponentially as a function of prior wake time (equation 1) and to decline exponentially as a function of time asleep (equation 2). The equations accounted for 91% and 96% of the variance, respectively. In addition, equation 1 accurately predicted the amount the amount of SWS in the first hour of nocturnal sleep. 相似文献
47.
Two different fructokinase isoforms of Arabidopsis thaliana have been identified and characterized by non-denaturing electrophoresis followed by activity-staining. The two fructokinases, fructokinase1 (FRK1) and fructokinase2 (FRK2), showed a high specificity for fructose and did not stain when glucose or mannose were used as substrate. Fructose and ATP at high concentrations (above 5 mM) induced a substrate inhibition of the two enzymatic activities. Arabidopsis FRK1 and FRK2 were capable of employing GTP, CTP, UTP and TTP as phosphate donors, although with a significantly lower efficiency than ATP. The two fructokinase activities were also activated by K+, at around 10–20 mM, and inhibited by ADP and AMP at concentrations above 10 mM. Finally, FRK1 and FRK2 showed a different expression pattern in the plant, with FRK1 being more abundant in the roots and FRK2 in the shoots. The results demonstrate a simple technique that provides important information about fructokinase activities in the plants and which can be useful for the analysis of Arabidopsis mutants. 相似文献
48.
The effects of a single-point mutation on folding thermodynamics and kinetics are usually interpreted by focusing on the native structure and the transition state. Here, the entire conformational spaces of a 20-residue three-stranded antiparallel beta-sheet peptide (double hairpin) and of its single-point mutant W10V are sampled close to the melting temperature by equilibrium folding-unfolding molecular dynamics simulations for a total of 40 micros. The folded state as well as the most populated free energy basins in the denatured state are isolated by grouping conformations according to fast relaxation at equilibrium. Such kinetic analysis provides more detailed and useful information than a simple projection of the free energy. The W10V mutant has the same native structure as the wild type peptide, and similar folding rate and stability. In the denatured state, the N-terminal hairpin is about 20% more structured in W10V than the wild type mainly because of van der Waals interactions. Notably, the W10V mutation influences also the van der Waals energy at the transition state ensemble causing a shift in the ratio of fluxes between two different transition state regions on parallel folding pathways corresponding to nucleation at either of the two beta-hairpins. Previous experimental studies have focused on the effects of denaturant-dependent or temperature-dependent changes in the structure of the denatured state. The atomistic simulations show that a single-point mutation in the central strand of a beta-sheet peptide results in remarkable changes in the topography of the denatured state ensemble. These changes modulate the relative accessibility of parallel folding pathways because of kinetic partitioning of the denatured state. Therefore, the observed dependence of the folding process on the starting ensemble raises questions on the biological significance of in vitro folding studies under strongly denaturing conditions. 相似文献
49.
Growth and nutrient absorption of two submerged aquatic macrophytes in mesocosms, for reinsertion in a eutrophicated shallow lake 总被引:5,自引:0,他引:5
Aquatic macrophytes play a central role in preserving the ecological equilibrium of shallow lakes and in the restoration of
eutrophic lakes that have switched to phytoplankton-dominated turbid water. Massaciuccoli Lake, a shallow lake located along
the Tuscan coast in Italy, has shown a constant and progressive simplification of the submerged plant community, for anthropogenic
reasons, leading, in recent years, to turbid water. The growth and nutrient absorption capability of two macrophyte species,
Myriophyllum verticillatum L. and Elodea canadensis Michaux, in the lake was investigated, with the prospect of a future lake restoration programme centred on their replacement.
Mesocosm experiments were conducted to monitor the plant growth and nutrient (NO2−, NO3−, NH4+, Ntot, PO43−, Ptot) content in the plant dry matter and water at the beginning and at the end of the trial. Bacterial activity was analysed
in the water in order to verify the possible nutrient absorption contribution by organisms other than plants. Both M. verticillatum and E. canadensis showed satisfactory growth and nutrient reduction in the water body. Moreover, their different growth patterns suggested
that optimal replacement can be performed with their introduction in two steps, starting with M. verticillatum, which shows the best capacity to colonise the aquatic environment, due to its tendency towards lengthening. 相似文献
50.
Alemayehu A Gorfe Philippe Ferrara Amedeo Caflisch Daniel N Marti Hans Rudolf Bosshard Ilian Jelesarov 《Proteins》2002,46(1):41-60
The use of conformational ensembles provided by nuclear magnetic resonance (NMR) experiments or generated by molecular dynamics (MD) simulations has been regarded as a useful approach to account for protein motions in the context of pK(a) calculations, yet the idea has been tested occasionally. This is the first report of systematic comparison of pK(a) estimates computed from long multiple MD simulations and NMR ensembles. As model systems, a synthetic leucine zipper, the naturally occurring coiled coil GCN4, and barnase were used. A variety of conformational averaging and titration curve-averaging techniques, or combination thereof, was adopted and/or modified to investigate the effect of extensive global conformational sampling on the accuracy of pK(a) calculations. Clustering of coordinates is proposed as an approach to reduce the vast diversity of MD ensembles to a few structures representative of the average electrostatic properties of the system in solution. Remarkable improvement of the accuracy of pK(a) predictions was achieved by the use of multiple MD simulations. By using multiple trajectories the absolute error in pK(a) predictions for the model leucine zipper was reduced to as low as approximately 0.25 pK(a) units. The validity, advantages, and limitations of explicit conformational sampling by MD, compared with the use of an average structure and a high internal protein dielectric value as means to improve the accuracy of pK(a) calculations, are discussed. 相似文献