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991.
Akash Srinivasan Felyx K Wong Dimitrios Karponis 《Journal of musculoskeletal & neuronal interactions》2020,20(4):600
Calcitonin regulates blood calcium levels and possesses certain clinically useful anti-fracture properties. Specifically, it reduces vertebral fractures in postmenopausal osteoporotic women significantly compared to a placebo. Nevertheless, the use of calcitonin has declined over the years and salmon calcitonin is no longer the first-line treatment for many of its indications. Commercial calcitonin only exists in intranasal or injectable preparations, which are less preferable for patients. Efficacy of a potential oral formulation has been under investigation but achieving adequate bioavailability remains a conundrum and the latest phase III trials have not shown promising evidence justifying its use. Associations with cancer have also derailed this treatment option. Furthermore, the rise of bisphosphonates and, more recently, monoclonal antibodies (such as denosumab), has revolutionised the treatment of osteoporotic fractures. Therefore, we are posed with an interesting question: is calcitonin a treatment of the past? This review aims to explore the reasons behind this paradigm shift and outline the potential role of calcitonin in the management of fractures and other conditions in the years to come. 相似文献
992.
993.
Antonie van Leeuwenhoek - Three Gram-stain-negative, aerobic, circular, convex, red-colored and rod-shaped bacterial strains, designated BT439T, BT662T and BT683T were obtained from soil collected... 相似文献
994.
995.
Sanjiv Kumar Bhanwar Lal Puniya Shahila Parween Pradip Nahar Srinivasan Ramachandran 《PloS one》2013,8(7)
Pathogenic bacteria interacting with eukaryotic host express adhesins on their surface. These adhesins aid in bacterial attachment to the host cell receptors during colonization. A few adhesins such as Heparin binding hemagglutinin adhesin (HBHA), Apa, Malate Synthase of M. tuberculosis have been identified using specific experimental interaction models based on the biological knowledge of the pathogen. In the present work, we carried out computational screening for adhesins of M. tuberculosis. We used an integrated computational approach using SPAAN for predicting adhesins, PSORTb, SubLoc and LocTree for extracellular localization, and BLAST for verifying non-similarity to human proteins. These steps are among the first of reverse vaccinology. Multiple claims and attacks from different algorithms were processed through argumentative approach. Additional filtration criteria included selection for proteins with low molecular weights and absence of literature reports. We examined binding potential of the selected proteins using an image based ELISA. The protein Rv2599 (membrane protein) binds to human fibronectin, laminin and collagen. Rv3717 (N-acetylmuramoyl-L-alanine amidase) and Rv0309 (L,D-transpeptidase) bind to fibronectin and laminin. We report Rv2599 (membrane protein), Rv0309 and Rv3717 as novel adhesins of M. tuberculosis H37Rv. Our results expand the number of known adhesins of M. tuberculosis and suggest their regulated expression in different stages. 相似文献
996.
Venkata Pulla Rao Vendra Garima Agarwal Sushil Chandani Venu Talla Narayanaswamy Srinivasan Dorairajan Balasubramanian 《PloS one》2013,8(8)
Background
We highlight an unrecognized physiological role for the Greek key motif, an evolutionarily conserved super-secondary structural topology of the βγ-crystallins. These proteins constitute the bulk of the human eye lens, packed at very high concentrations in a compact, globular, short-range order, generating transparency. Congenital cataract (affecting 400,000 newborns yearly worldwide), associated with 54 mutations in βγ-crystallins, occurs in two major phenotypes nuclear cataract, which blocks the central visual axis, hampering the development of the growing eye and demanding earliest intervention, and the milder peripheral progressive cataract where surgery can wait. In order to understand this phenotypic dichotomy at the molecular level, we have studied the structural and aggregation features of representative mutations.Methods
Wild type and several representative mutant proteins were cloned, expressed and purified and their secondary and tertiary structural details, as well as structural stability, were compared in solution, using spectroscopy. Their tendencies to aggregate in vitro and in cellulo were also compared. In addition, we analyzed their structural differences by molecular modeling in silico.Results
Based on their properties, mutants are seen to fall into two classes. Mutants A36P, L45PL54P, R140X, and G165fs display lowered solubility and structural stability, expose several buried residues to the surface, aggregate in vitro and in cellulo, and disturb/distort the Greek key motif. And they are associated with nuclear cataract. In contrast, mutants P24T and R77S, associated with peripheral cataract, behave quite similar to the wild type molecule, and do not affect the Greek key topology.Conclusion
When a mutation distorts even one of the four Greek key motifs, the protein readily self-aggregates and precipitates, consistent with the phenotype of nuclear cataract, while mutations not affecting the motif display ‘native state aggregation’, leading to peripheral cataract, thus offering a protein structural rationale for the cataract phenotypic dichotomy “distort motif, lose central vision”. 相似文献997.
The ability to produce submicron particles of monoclonal antibodies of different sizes and shapes would enhance their application to pulmonary delivery. Although non-ionic surfactants are widely used as stabilizers in protein formulations, we hypothesized that non-ionic surfactants will affect the shape and size of submicron IgG particles manufactured through precipitation. Submicron particles of IgG1 were produced by a precipitation process which explores the fact that proteins have minimum solubility but maximum precipitation at the isoelectric point. Non-ionic surfactants were used for size and shape control, and as stabilizing agents. Aerosol performance of the antibody nanoparticles was assessed using Andersen Cascade Impactor. Spinhaler® and Handihaler® were used as model DPI devices. SEM micrographs revealed that the shape of the submicron particles was altered by varying the type of surfactant added to the precipitating medium. Particle size as measured by dynamic light scattering was also varied based on the type and concentration of the surfactant. The surfactants were able to stabilize the IgG during the precipitation process. Polyhedral, sponge-like, and spherical nanoparticles demonstrated improved aerosolization properties compared to irregularly shaped (>20 μm) unprocessed particles. Stable antibody submicron particles of different shapes and sizes were prepared. Careful control of the shape of such particles is critical to ensuring optimized lung delivery by dry powder inhalation. 相似文献
998.
Anilkumar R. Kore Annamalai Senthilvelan Balasubramanian Srinivasan Muthian Shanmugasundaram 《Nucleosides, nucleotides & nucleic acids》2013,32(8):411-420
A new, straightforward, reliable, and convenient protection-free one-pot method for the synthesis of 2′-deoxynucleoside-5′-tetraphosphate and ribonucleoside-5′-tetraphosphate is reported. The present synthetic strategy involves the monophosphorylation of a nucleoside followed by reaction with tris-(tri-n-butylammonium) triphosphate and subsequent hydrolysis of the putative cyclic tetrametaphosphate intermediate to provide nucleoside-5′-tetraphosphate in moderate yield with high purity. A plausible mechanism is proposed to account for the formation of product. 相似文献
999.
David Oyen Rainer Wechselberger Vasundara Srinivasan Jan Steyaert John N. Barlow 《Biochimica et Biophysica Acta - Proteins and Proteomics》2013,1834(10):2147-2157
Although allosteric effector antibodies are used widely as modulators of receptors and enzymes, experimental analysis of their mechanism remains highly challenging. Here, we investigate the molecular mechanisms of allosteric and non-allosteric effector antibodies in an experimentally tractable system, consisting of single-domain antibodies (nanobodies) that target the model enzyme dihydrofolate reductase (DHFR) from Escherichia coli. A panel of thirty-five nanobodies was isolated using several strategies to increase nanobody diversity. The nanobodies exhibit a variety of effector properties, including partial inhibition, strong inhibition and stimulation of DHFR activity. Despite these diverse effector properties, chemical shift perturbation NMR epitope mapping identified only two epitope regions: epitope α is a new allosteric site that is over 10 Å from the active site, while epitope β is located in the region of the Met20 loop. The structural basis for DHFR allosteric inhibition or activation upon nanobody binding to the α epitope was examined by solving the crystal structures of DHFR in complex with Nb113 (an allosteric inhibitor) and Nb179 (an allosteric activator). The structures suggest roles for conformational constraint and altered protein dynamics, but not epitope distortion, in the observed allosteric effects. The crystal structure of a β epitope region binder (ca1698) in complex with DHFR is also reported. Although CDR3 of ca1698 occupies the substrate binding site, ca1698 displays linear mixed inhibition kinetics instead of simple competitive inhibition kinetics. Two mechanisms are proposed to account for this apparent anomaly. Evidence for structural convergence of ca1698 and Nb216 during affinity maturation is also presented. 相似文献
1000.
Arivazhagan Arimappamagan Kumaravel Somasundaram Kandavel Thennarasu Sreekanthreddy Peddagangannagari Harish Srinivasan Bangalore C. Shailaja Cini Samuel Irene Rosita Pia Patric Sudhanshu Shukla Balaram Thota Krishnarao Venkatesh Prasanna Paritosh Pandey Anandh Balasubramaniam Vani Santosh Bangalore Ashwathnarayanara Chandramouli Alangar Sathyaranjandas Hegde Paturu Kondaiah Manchanahalli R. Sathyanarayana Rao 《PloS one》2013,8(4)