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41.
Ruhar Singh Naveen Kumar Meena Trishala Das Ravi Datta Sharma 《Journal of biomolecular structure & dynamics》2020,38(17):5027-5036
AbstractThe funnel shaped energy landscape model of the protein folding suggests that progression of folding proceeds through multiple pathways, having the multiple intermediates which leads to multidimensional free-energy surface. Herein, we applied all-atom MD simulation to conduct a comparative study on the structure of β-lactoglobulin (β-LgA) in aqueous mixture of 8?M urea and 8?M dimethyl sulfoxide (DMSO), at different temperatures. The cumulative results of multiple simulations suggest a common unfolding pathway of β-LgA, occurred through the stable and meta-stable intermediates (I), in both urea and DMSO. However, the free-energy landscape (FEL) analyses show that the structural transitions of I-states are energetically different. In urea, FEL shows distinct ensemble of intermediates, I1 and I2, separated by the energy barrier of ~3.0?kcal mol?1. Similarly, we find the population of two distinct I1 and I2 states in DMSO, however, the I1 appeared transiently around ~30–35?ns and is short-lived. But, the I2 ensemble is observed structurally compact and long-lived (~50–150?ns) as compared to unfolding in urea. Furthermore, the I1 and I2 are separated through a high energy barrier of ~6.0?kcal mol?1. Thus, our results provide the structural insights of intermediates which essentially bear the signature of a different unfolding pathway of β-LgA in urea and DMSO. Abbreviations β-LgA β-lactoglobulin DMSO dimethyl sulfoxide FEL free-energy landscape GdmCl guanidinium chloride I intermediate state MG molten globule state PME particle mesh Ewald Q fraction of native contacts RMSD root mean square deviation RMSF root mean square fluctuation Rg radius of gyration SASA solvent Accessible Surface Area scSASA the side chain SASA Trp tryptophan Communicated by Ramaswamy H. Sarma 相似文献
42.
The discovery of broadly neutralizing antibodies that can neutralize multiple strains or subtypes of a pathogen has renewed interest in the development of broadly protective vaccines. To that end, there has been an interest in designing immunofocusing strategies to direct the immune response to specific, conserved regions on antigenic proteins. Modulation of glycosylation is one such immunofocusing strategy; extensive glycosylation is often exploited by pathogens for immune evasion. Masking epitopes on protein immunogens with “self” glycans can also shield the underlying protein surface from humoral immune surveillance. We review recent advances in applying glycosylation as an immunofocusing tool. We also highlight recent interesting work in the HIV-1 field involving the identification and elicitation of broadly neutralizing antibodies that incorporate glycans into their binding epitopes. 相似文献
43.
Marcus J. G.W. Ladds Gergana Popova Andrs Pastor-Fernndez Srinivasaraghavan Kannan Ingeborg M.M. van Leeuwen Maria Hkansson Bjrn Walse Fredrik Tholander Ravi Bhatia Chandra S. Verma David P. Lane Sonia Laín 《The Journal of biological chemistry》2020,295(52):17935
The tenovins are a frequently studied class of compounds capable of inhibiting sirtuin activity, which is thought to result in increased acetylation and protection of the tumor suppressor p53 from degradation. However, as we and other laboratories have shown previously, certain tenovins are also capable of inhibiting autophagic flux, demonstrating the ability of these compounds to engage with more than one target. In this study, we present two additional mechanisms by which tenovins are able to activate p53 and kill tumor cells in culture. These mechanisms are the inhibition of a key enzyme of the de novo pyrimidine synthesis pathway, dihydroorotate dehydrogenase (DHODH), and the blockage of uridine transport into cells. These findings hold a 3-fold significance: first, we demonstrate that tenovins, and perhaps other compounds that activate p53, may activate p53 by more than one mechanism; second, that work previously conducted with certain tenovins as SirT1 inhibitors should additionally be viewed through the lens of DHODH inhibition as this is a major contributor to the mechanism of action of the most widely used tenovins; and finally, that small changes in the structure of a small molecule can lead to a dramatic change in the target profile of the molecule even when the phenotypic readout remains static. 相似文献
44.
A series of well-orchestrated events help in the chromatin condensation and the formation of chromosomes. Apart from the formation of chromosomes, maintenance of their structure is important, especially for the cell division. The structural maintenance of chromosome (SMC) proteins, the non-SMC proteins and the SMC complexes are critical for the maintenance of chromosome structure. While condensins have roles for the DNA compaction, organization, and segregation, the cohesin functions in a cyclic manner through the cell cycle, as a “cohesin cycle.” Specific mechanisms maintain the architecture of the centromere, the kinetochore and the telomeres which are in tandem with the cell cycle checkpoints. The presence of chromosomal territories and compactness differences through the length of the chromosomes might have implications on selective susceptibility of specific chromosomes for induced genotoxicity. 相似文献
45.
The Indian subcontinent shows high levels of seasonal weather variation, but the extent to which mating-related traits (mating latency, copulation duration and number of progeny produced) are being affected by such variations in Drosophila species remain poorly understood. In the present study, we analyzed the effects of seasonal change (humidity and temperature) on mating-related traits of Drosophila melanogaster by mimicking natural conditions in the laboratory. The light body color phenotype is collected in large numbers during the rainy season, while the dark phenotype is prevalent in the winter. We found that a short-term stress, in the form of reduced humidity or temperature, causes a strong climatic selection pressure, which leads to assortative mating and longer copulation duration of the dark phenotype. By contrast, the light phenotype shows higher assortative mating and longer copulation duration after short-term high humidity or high temperature stress. Higher assortative mating and increased copulation duration results in high progeny numbers which may be a cause for the high prevalence of the dark phenotype in winter and the light phenotype in the rainy season. Thus, besides plasticity, seasonal changes in mating propensity can be a potential cause of the change in the frequency of the dark and light phenotypes of D. melanogaster during different seasons. 相似文献
46.
47.
John M. Zachara Ravi K. Kukkadapu James K. Fredrickson Yuri A. Gorby Steven C. Smith 《Geomicrobiology journal》2013,30(2):179-207
Dissimilatory metal reducing bacteria (DMRB) catalyze the reduction of Fe(III) to Fe(II) in anoxic soils, sediments, and groundwater. Two-line ferrihydrite is a bioavailable Fe(III) oxide form that is exploited by DMRB as a terminal electron acceptor. A wide variety of biomineralization products result from the interaction of DMRB with 2-line ferrihydrite. Here we describe the state of knowledge on the biotransformation of synthetic 2-line ferrihydrite by laboratory cultures of DMRB using select published data and new experimental results. A facultative DMRB is emphasized ( Shewanella putrefaciens ) upon which most of this work has been performed. Key factors controlling the identity of the secondary mineral suite are evaluated including medium composition, electron donor and acceptor concentrations, ferrihydrite aging/recrystallization status, sorbed ions, and co-associated crystalline Fe(III) oxides. It is shown that crystalline ferric (goethite, hematite, lepidocrocite), ferrous (siderite, vivianite), and mixed valence (magnetite, green rust) iron solids are formed in anoxic, circumneutral DMRB incubations. Some products are well rationalized based on thermodynamic considerations, but others appear to result from kinetic pathways driven by ions that inhibit interfacial electron transfer or the precipitation of select phases. The primary factor controlling the nature of the secondary mineral suite appears to be the Fe(II) supply rate and magnitude, and its surface reaction with the residual oxide and other sorbed ions. The common observation of end-product mineral mixtures that are not at global equilibrium indicates that microenvironments surrounding respiring DMRB cells or the reaction-path trajectory (over Eh-pH space) may influence the identity of the final biomineralization suite. 相似文献
48.
Yulia Ephstein Patrick A. Singleton Weiguo Chen Lichun Wang Ravi Salgia Prasad Kanteti Steven M. Dudek Joe G. N. Garcia Jeffrey R. Jacobson 《The Journal of biological chemistry》2013,288(4):2191-2200
Vascular endothelial cell (EC) barrier integrity is critical to vessel homeostasis whereas barrier dysfunction is a key feature of inflammatory disorders and tumor angiogenesis. We previously reported that hepatocyte growth factor (HGF)-mediated increases in EC barrier integrity are signaled through a dynamic complex present in lipid rafts involving its receptor, c-Met (1). We extended these observations to confirm that S1PR1 (sphingosine 1-phosphate receptor 1) and integrin β4 (ITGB4) are essential participants in HGF-induced EC barrier enhancement. Immunoprecipitation experiments demonstrated HGF-mediated recruitment of c-Met, ITGB4 and S1PR1 to caveolin-enriched lipid rafts in human lung EC with direct interactions of c-Met with both S1PR1 and ITGB4 accompanied by c-Met-dependent S1PR1 and ITGB4 transactivation. Reduced S1PR1 expression (siRNA) attenuated both ITGB4 and Rac1 activation as well as c-Met/ITGB4 interaction and resulted in decreased transendothelial electrical resistance. Furthermore, reduced ITGB4 expression attenuated HGF-induced c-Met activation, c-Met/S1PR1 interaction, and effected decreases in S1P- and HGF-induced EC barrier enhancement. Finally, the c-Met inhibitor, XL880, suppressed HGF-induced c-Met activation as well as S1PR1 and ITGB4 transactivation. These results support a critical role for S1PR1 and ITGB4 transactivation as rate-limiting events in the transduction of HGF signals via a dynamic c-Met complex resulting in enhanced EC barrier integrity. 相似文献
49.
Shivani Ahuja Nicole Jahr Sang-Choul Im Subramanian Vivekanandan Nataliya Popovych Stéphanie V. Le Clair Rui Huang Ronald Soong Jiadi Xu Kazutoshi Yamamoto Ravi P. Nanga Angela Bridges Lucy Waskell Ayyalusamy Ramamoorthy 《The Journal of biological chemistry》2013,288(30):22080-22095
Microsomal cytochrome b5 (cytb5) is a membrane-bound protein that modulates the catalytic activity of its redox partner, cytochrome P4502B4 (cytP450). Here, we report the first structure of full-length rabbit ferric microsomal cytb5 (16 kDa), incorporated in two different membrane mimetics (detergent micelles and lipid bicelles). Differential line broadening of the cytb5 NMR resonances and site-directed mutagenesis data were used to characterize the cytb5 interaction epitope recognized by ferric microsomal cytP450 (56 kDa). Subsequently, a data-driven docking algorithm, HADDOCK (high ambiguity driven biomolecular docking), was used to generate the structure of the complex between cytP4502B4 and cytb5 using experimentally derived restraints from NMR, mutagenesis, and the double mutant cycle data obtained on the full-length proteins. Our docking and experimental results point to the formation of a dynamic electron transfer complex between the acidic convex surface of cytb5 and the concave basic proximal surface of cytP4502B4. The majority of the binding energy for the complex is provided by interactions between residues on the C-helix and β-bulge of cytP450 and residues at the end of helix α4 of cytb5. The structure of the complex allows us to propose an interprotein electron transfer pathway involving the highly conserved Arg-125 on cytP450 serving as a salt bridge between the heme propionates of cytP450 and cytb5. We have also shown that the addition of a substrate to cytP450 likely strengthens the cytb5-cytP450 interaction. This study paves the way to obtaining valuable structural, functional, and dynamic information on membrane-bound complexes. 相似文献
50.
Morten Lillemo Arun K. Joshi Ravindra Prasad Ramesh Chand Ravi P. Singh 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》2013,126(3):711-719
Spot blotch caused by Bipolaris sorokiniana is a major disease of wheat in warm and humid wheat growing regions of the world including south Asian countries such as India, Nepal and Bangladesh. The CIMMYT bread wheat line Saar which carries the leaf tip necrosis (LTN)-associated rust resistance genes Lr34 and Lr46 has exhibited a low level of spot blotch disease in field trials conducted in Asia and South America. One hundred and fourteen recombinant inbred lines (RILs) of Avocet (Susceptible) × Saar, were evaluated along with parents in two dates of sowing in India for 3 years (2007–2008 to 2009–2010) to identify quantitative trait loci (QTL) associated with spot blotch resistance, and to determine the potential association of Lr34 and Lr46 with resistance to this disease. Lr34 was found to constitute the main locus for spot blotch resistance, and explained as much as 55 % of the phenotypic variation in the mean disease data across the six environments. Based on the large effect, the spot blotch resistance at this locus has been given the gene designation Sb1. Two further, minor QTL were detected in the sub-population of RILs not containing Lr34. The first of these was located about 40 cM distal to Lr34 on 7DS, and the other corresponded to Lr46 on 1BL. A major implication for wheat breeding is that Lr34 and Lr46, which are widely used in wheat breeding to improve resistance to rust diseases and powdery mildew, also have a beneficial effect on spot blotch. 相似文献