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51.
Molecular mechanisms and design principles for promiscuous inhibitors to avoid drug resistance: Lessons learned from HIV‐1 protease inhibition 下载免费PDF全文
Molecular recognition is central to biology and ranges from highly selective to broadly promiscuous. The ability to modulate specificity at will is particularly important for drug development, and discovery of mechanisms contributing to binding specificity is crucial for our basic understanding of biology and for applications in health care. In this study, we used computational molecular design to create a large dataset of diverse small molecules with a range of binding specificities. We then performed structural, energetic, and statistical analysis on the dataset to study molecular mechanisms of achieving specificity goals. The work was done in the context of HIV‐1 protease inhibition and the molecular designs targeted a panel of wild‐type and drug‐resistant mutant HIV‐1 protease structures. The analysis focused on mechanisms for promiscuous binding to bind robustly even to resistance mutants. Broadly binding inhibitors tended to be smaller in size, more flexible in chemical structure, and more hydrophobic in nature compared to highly selective ones. Furthermore, structural and energetic analyses illustrated mechanisms by which flexible inhibitors achieved binding; we found ligand conformational adaptation near mutation sites and structural plasticity in targets through torsional flips of asymmetric functional groups to form alternative, compensatory packing interactions or hydrogen bonds. As no inhibitor bound to all variants, we designed small cocktails of inhibitors to do so and discovered that they often jointly covered the target set through mechanistic complementarity. Furthermore, using structural plasticity observed in experiments, and potentially in simulations, is suggested to be a viable means of designing adaptive inhibitors that are promiscuous binders. Proteins 2015; 83:351–372. © 2014 Wiley Periodicals, Inc. 相似文献
52.
Abraham Verghese Suresh Devi Thangam Senthil Kumar Radhakrishnan Nallur Kothandaraman Krishna Kumar Gopalakrishna Pommaiah Shetty 《Biocontrol Science and Technology》2018,28(10):961-969
ABSTRACTConservation biological control is an approach to enhance the efficacy of natural enemies by ensuring their availability in an agro-ecosystem on a long temporal scale. An increased survival often leads to better fecundity and improved behaviour of the natural enemies, which in turn ensures sustainable pest management. This paper, apart from being a concise review of conservation biological control, deals with selected India-specific case studies and field experiences on habitat manipulation and refugia. Results from a Bengaluru-based study during 2012–2015 on conservation biological control in an organic mango ecosystem are also presented. It also dwells briefly on conservation of insectivorous birds and touches upon conservation biocontrol with respect to entomopathogenic microorganisms and plant disease antagonists. 相似文献
53.
Two eriophyid mites,Acaphylla theae andCalacarus carinatus, have been known for some time as important pests of tea. In recent years a third eriophyid,Acaphyllisa parindiae, has also become abundant. The vertical distribution of these three species on tea is examined. 相似文献
54.
V V Radhakrishnan A Mathai S B Rao S Sehgal 《Indian journal of experimental biology》1990,28(9):812-815
Polyvalent antiserum to culture filtrate of H37 Ra M. tuberculosis was raised in rabbits. Monospecific antiserum was raised against M. tuberculosis antigen-5, prepared from the culture filtrates by immunoabsorbent affinity chromatography. On immunoelectrophoresis, antigen-5 demonstrated single precipitin arc against polyvalent and monospecific antisera. The culture filtrate antigen demonstrated multiple precipitin arcs against polyvalent antiserum and single precipitin are against monospecific antiserum. Antigen-5 could be isolated and characterized from the culture filtrate of H37 Ra M. tuberculosis. Immunoelectrophoresis could be one of the method to characterize the mycobacterial antigens prepared in the laboratory. 相似文献
55.
In order to investigate a possible interaction between free amino acids and dipeptides during their mucosal uptake in man
and monkey, perfusion studiesin vivo and uptake studiesin vitro using labelled and non-labelled dipeptides and amino acids have been carried out. In contrast to the observations of other
workers, inhibition of glycyl-glycine uptake was observed with free leucine and methioninc but not with glycine, proline,
hydroxyproline or alanine. Leucine and methionine caused inhibition of cytosol glycyl-glycine hydrolase activity, while glycine
had no effect. The dipeptide uptake and dipeptide hydrolysis by cytosol enzyme was competitively inhibited by leucine. Although
brush border glycyl-glycine hydrolase was also inhibited by leucine, the inhibition was noncompetitive. These data indicate
that a few free amino acids can interact with dipeptides during uptake. This interaction might occur either at the transport
step or at the stage of intracellular dipeptide hydrolysis.
The work reported here was carried out at Wellcome Research Unit, Christian Medical College and Hospital, Vellore 632 004. 相似文献
56.
Molecular biophysics is a broad, diverse, and dynamic field that has presented a variety of unique challenges and opportunities for training future generations of investigators. Having been or currently being intimately associated with the Molecular Biophysics Training Program at Northwestern, we present our perspectives on various issues that we have encountered over the years. We propose no cookie-cutter solutions, as there is no consensus on what constitutes the "ideal" program. However, there is uniformity in opinion on some key issues that might be useful to those interested in establishing a biophysics training program. 相似文献
57.
Pandurang?M.?Jadhav S.?Radhakrishnan Vikas?D.?GhuleEmail author Raj?K.?Pandey 《Journal of molecular modeling》2015,21(5):134
Development of new energetic salts is the key factor in replacing low performance compounds in conventional formulations of high explosives as well as propellants. Ten salts based on the nitroformate anion and various nitrogen-rich cations were designed and their geometric optimizations carried out using the density functional method. With reasonable oxygen balance (from ?36 % to 0 %), heats of formation (47–624 kJ mol?1) and high densities (1.81–1.89 g cm?3), the detonation velocity (D) and pressure (P) values of salts were calculated as 8.62–9.36 km s?1 and 33.10–40.01 GPa, respectively. Lastly, the nitroformate salts studied in this work are of prospective interest as high performance explosives. 相似文献
58.
Fibrocartilage,a tissue with macromaterial properties between dense fibrous tissue and hyaline cartilage, is not well understood in its ultrastructure and regional viscoelastic properties. Here nanoindentation with atomic force microscopy was performed on fresh fibrocartilage samples of rabbit jaw joint condyles. Each sample was divided into anteromedial, anterolateral, posteromedial, and posterolateral regions for probing and topographic imaging in 2 x 2 microm and 10 x 10 microm scan sizes. Young's moduli differed significantly among these regions in a descending gradient from the anteromedial (2.34 +/- 0.26 MPa) to the posterolateral (0.95 +/- 0.06 MPa). The Poisson ratio, defined as lateral strain over axial strain, had the same gradient distribution: highest for the anteromedial region (0.46 +/- 0.05) and lowest for the posterolateral region (0.31 +/- 0.05). The same four regions showed a descending gradient of surface roughness: highest for the anteromedial (321.6 +/- 13.8 nm) and lowest for the posterolateral (155.6 +/- 12.6 nm). Thus, the regional ultrastructural and viscoelastic properties of fibrocartilage appear to be coregulated. Based on these region-specific gradient distributions, fibrocartilage is constructed to withstand tissue-borne shear stresses, which likely propagate across its different regions. A model of shear gradient and concentric gradient is proposed to describe the region-specific capacity of fibrocartilage to sustain shear stresses in tendons, ligaments, joints, and the healing bone across species. 相似文献
59.
Liu H Radhakrishnan P Magoun L Prabu M Campellone KG Savage P He F Schiffer CA Leong JM 《Molecular microbiology》2002,45(6):1557-1573
Attachment to host cells by enterohaemorrhagic Escherichia coli (EHEC) is associated with the formation of a highly organized cytoskeletal structure containing filamentous actin, termed an attaching and effacing (AE) lesion. Intimin, an outer membrane protein of EHEC, is required for the formation of AE lesions, as is Tir, a bacterial protein that is translocated into the host cell to function as a receptor for intimin. We established a yeast two-hybrid assay for intimin-Tir interaction and, after random mutagenesis, isolated 24 point mutants in intimin, which disrupted Tir recognition in this system. Analysis of 11 point mutants revealed a correlation between recognition of recombinant Tir and the ability to trigger AE lesions. Many of the mutations fell within a 50-residue region near the C-terminus of intimin. Alanine-scanning mutagenesis of this region revealed four residues (Ser890, Thr909, Asn916 and Asn927) that are critical for Tir recognition. Mapping the sequences of EHEC intimin and Tir onto the crystal structure of the intimin-Tir complex of enteropathogenic E. coli predicts that each of these four intimin residues lies at the intimin-Tir interface and contributes to a pocket that interacts with Ile298 of EHEC Tir. Thus, this genetic approach to intimin function both identified residues critical for Tir binding and demonstrated a correlation between the ability to bind Tir and the ability to trigger actin focusing. 相似文献
60.
Coupling of fast and slow modes in the reaction pathway of the minimal hammerhead ribozyme cleavage 总被引:1,自引:0,他引:1
Radhakrishnan R 《Biophysical journal》2007,93(7):2391-2399
By employing classical molecular dynamics, correlation analysis of coupling between slow and fast dynamical modes, and free energy (umbrella) sampling using classical as well as mixed quantum mechanics molecular mechanics force fields, we uncover a possible pathway for phosphoryl transfer in the self-cleaving reaction of the minimal hammerhead ribozyme. The significance of this pathway is that it initiates from the minimal hammerhead crystal structure and describes the reaction landscape as a conformational rearrangement followed by a covalent transformation. The delineated mechanism is catalyzed by two metal (Mg(2+)) ions, proceeds via an in-line-attack by CYT 17 O2' on the scissile phosphorous (ADE 1.1 P), and is therefore consistent with the experimentally observed inversion configuration. According to the delineated mechanism, the coupling between slow modes involving the hammerhead backbone with fast modes in the cleavage site appears to be crucial for setting up the in-line nucleophilic attack. 相似文献