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91.
Simulations of beta-hairpin folding confined to spherical pores using distributed computing 总被引:1,自引:0,他引:1 下载免费PDF全文
Klimov DK Newfield D Thirumalai D 《Proceedings of the National Academy of Sciences of the United States of America》2002,99(12):8019-8024
We report the thermodynamics and kinetics of an off-lattice Go model beta-hairpin from Ig-binding protein confined to an inert spherical pore. Confinement enhances the stability of the hairpin due to the decrease in the entropy of the unfolded state. Compared with their values in the bulk, the rates of hairpin formation increase in the spherical pore. Surprisingly, the dependence of the rates on the pore radius, R(s), is nonmonotonic. The rates reach a maximum at R(s)/R(g,N)(b) approximately equal to 1.5, where R(g,N)(b) is the radius of gyration of the folded beta-hairpin in the bulk. The denatured state ensemble of the encapsulated beta-hairpin is highly structured even at substantially elevated temperatures. Remarkably, a profound effect of confinement is evident even when the beta-hairpin occupies less than a 10th of the sphere volume. Our calculations show that the emergence of substantial structure in the denatured state of proteins in inert pores is a consequence of confinement. In contrast, the structure of the bulk denatured state ensemble depends dramatically on the extent of denaturation. 相似文献
92.
Hyeon C Thirumalai D 《Proceedings of the National Academy of Sciences of the United States of America》2005,102(19):6789-6794
Mechanical unfolding trajectories, generated by applying constant force in optical-tweezer experiments, show that RNA hairpins and the P5abc subdomain of the group I intron unfold reversibly. We use coarse-grained Go-like models for RNA hairpins to explore forced unfolding over a broad range of temperatures. A number of predictions that are amenable to experimental tests are made. At the critical force, the hairpin jumps between folded and unfolded conformations without populating any discernible intermediates. The phase diagram in the force-temperature (f, T) plane shows that the hairpin unfolds by an all-or-none process. The cooperativity of the unfolding transition increases dramatically at low temperatures. Free energy of stability, obtained from time averages of mechanical unfolding trajectories, coincides with ensemble averages, which establishes ergodicity. The hopping time between the native basin of attraction (NBA) and the unfolded basin increases dramatically along the phase boundary. Thermal unfolding is stochastic, whereas mechanical unfolding occurs in "quantized steps" with great variations in the step lengths. Refolding times, upon force quench, from stretched states to the NBA are at least an order of magnitude greater than folding times by temperature quench. Upon force quench from stretched states, the NBA is reached in at least three stages. In the initial stages, the mean end-to-end distance decreases nearly continuously, and there is a sudden transition to the NBA only in the last stage. Because of the generality of the results, we propose that similar behavior should be observed in force quench refolding of proteins. 相似文献
93.
Caging helps proteins fold 总被引:4,自引:0,他引:4
94.
95.
J D Honeycutt D Thirumalai 《Proceedings of the National Academy of Sciences of the United States of America》1990,87(9):3526-3529
The possibility that several metastable minima exist in which the folded forms of a polypeptide chain have similar structural characteristics but different energies is suggested. The validity of this hypothesis is illustrated with the aid of simulation methods on a model protein that folds into a beta-barrel structure. Some implications of this hypothesis such as the existence of multiple pathways with intermediates for protein folding are discussed. 相似文献
96.
97.
Hua L Zhou R Thirumalai D Berne BJ 《Proceedings of the National Academy of Sciences of the United States of America》2008,105(44):16928-16933
The mechanism of denaturation of proteins by urea is explored by using all-atom microseconds molecular dynamics simulations of hen lysozyme generated on BlueGene/L. Accumulation of urea around lysozyme shows that water molecules are expelled from the first hydration shell of the protein. We observe a 2-stage penetration of the protein, with urea penetrating the hydrophobic core before water, forming a “dry globule.” The direct dispersion interaction between urea and the protein backbone and side chains is stronger than for water, which gives rise to the intrusion of urea into the protein interior and to urea's preferential binding to all regions of the protein. This is augmented by preferential hydrogen bond formation between the urea carbonyl and the backbone amides that contributes to the breaking of intrabackbone hydrogen bonds. Our study supports the “direct interaction mechanism” whereby urea has a stronger dispersion interaction with protein than water. 相似文献
98.
Life-threatening complications of HIV infection 总被引:1,自引:0,他引:1
Few modern diseases have experienced as rapid and dramatic change in prognosis and treatment as HIV infection. The introduction of active antiretroviral therapy (ART) and effective prophylaxis of opportunistic infections ushered in a new era in the treatment of HIV infection and changed dramatically the natural history of this disease. The rates of admission to the intensive care unit (ICU) and intensive care mortality in patients with HIV infection have shifted repeatedly during the AIDS epidemic, influenced by attitudes of patients and providers toward utility of care. In the ART era, patients with HIV infection admitted to the ICU fall into 3 general categories: those with AIDS-related opportunistic infections, those who are experiencing complications related to ART, and those with medical problems unrelated to HIV infection. In this article, the authors provide a review of the most common life-threatening complications in patients with HIV infection. 相似文献
99.
ObjectiveTo assess the oxidative stress and antioxidant defense system in the skeletal muscle of male albino rats subjected to strenuous exercise programme.MethodsWistar strain albino rats were subjected to exhaustive swimming exercise programme daily for a period of five days. The thiobarbituric acid reactive substances (TBARS), conjugated dienes, superoxide dismutase, catalase, glutathione peroxidase and glutathione-S-transferase were measured in the gastrocnemius muscle of the exercised animals.ResultsThe elevated levels of TBARS and conjugated dienes indicated the oxidative stress in the gastrocemius muscle of the exercised animals. The depleted activity levels of superoxide dismutase, catalase, glutathione peroxidase and glutathione-S-transferase in the exercise animals indicated the increased oxidative stress and decreased antioxidative defense system in the muscle.ConclusionsThe study suggests that prolonged strenuous exercise programme can induce oxidative stress and therefore an optimal level of exercise schedule should be advocated to obtain the maximum benefit of exercise programme. 相似文献
100.
Mie A Rizig Andrew McQuillin Vinay Puri Khalid Choudhury Susmita Datta Srinivasa Thirumalai Jacob Lawrence Digby Quested Jonathan Pimm Nicholas Bass Graham Lamb Helen Moorey Allison Badacsonyi Katie Kelly Jenny Morgan Bhaskar Punukollu Gomathinayagam Kandasami David Curtis Hugh Gurling 《American journal of medical genetics. Part B, Neuropsychiatric genetics》2006,(3):296-300
The chromosome 1q23.3 region, which includes the RGS4 gene has been implicated in genetic susceptibility to schizophrenia by two linkage studies with lod scores of 6.35 and 3.20 and with positive lod between 2.00 and 3.00 scores in several other studies. Reduced post mortem RGS4 gene expression in the brain of schizophrenics was reported as well as positive allelic association between markers at the RGS4 gene locus and schizophrenia. We have attempted to replicate the finding of allelic association with schizophrenia in a UK based sample of 450 subjects with schizophrenia and 450 supernormal controls. We genotyped the same SNP marker alleles investigated in the earlier studies and also a di-nucleotide (GT)14 repeat microsatellite marker, which was 7 kb distal to RGS4. In the new UK sample there was no evidence for allelic or haplotypic association between RGS4 markers and schizophrenia. This might reflect genetic heterogeneity between the population samples, genotyping or other methodological problems. The finding weakens the evidence that mutations or variation in the RGS4 gene have an effect on schizophrenia susceptibility. 相似文献