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Risks and benefit evaluation for controlled human infection studies, where healthy volunteers are deliberately exposed to infectious agents to evaluate vaccine efficacy, should be explicit, systematic, thorough, and non-arbitrary. Decision analysis promotes these qualities using four steps: (1) determining explicit criteria and measures for evaluation, (2) identifying alternatives to the study, (3) defining the models used to estimate the measures for each alternative, and (4) running the models to produce the estimates and compare the alternatives. In this paper, we describe how decision analysis might be applied by funders and regulators, as well as by others contemplating the use of novel controlled human infection studies for vaccine development and evaluation. 相似文献
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The 231-residue capsid (CA) protein of human immunodeficiency virus type 1 (HIV-1) spontaneously self-assembles into tubes with a hexagonal lattice that is believed to mimic the surface lattice of conical capsid cores within intact virions. We report the results of solid-state nuclear magnetic resonance (NMR) measurements on HIV-1 CA tubes that provide new information regarding changes in molecular structure that accompany CA self-assembly, local dynamics within CA tubes, and possible mechanisms for the generation of lattice curvature. This information is contained in site-specific assignments of signals in two- and three-dimensional solid-state NMR spectra, conformation-dependent 15N and 13C NMR chemical shifts, detection of highly dynamic residues under solution NMR conditions, measurements of local variations in transverse spin relaxation rates of amide 1H nuclei, and quantitative measurements of site-specific 15N–15N dipole–dipole couplings. Our data show that most of the CA sequence is conformationally ordered and relatively rigid in tubular assemblies and that structures of the N-terminal domain (NTD) and the C-terminal domain (CTD) observed in solution are largely retained. However, specific segments, including the N-terminal β-hairpin, the cyclophilin A binding loop, the inter-domain linker, segments involved in intermolecular NTD–CTD interactions, and the C-terminal tail, have substantial static or dynamical disorder in tubular assemblies. Other segments, including the 310-helical segment in CTD, undergo clear conformational changes. Structural variations associated with curvature of the CA lattice appear to be localized in the inter-domain linker and intermolecular NTD–CTD interface, while structural variations within NTD hexamers, around local 3-fold symmetry axes, and in CTD–CTD dimerization interfaces are less significant. 相似文献
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《Bioorganic & medicinal chemistry》2014,22(2):711-720
Two novel scaffolds, 4-pyridylanilinothiazoles (PAT) and 3-pyridylphenylsulfonyl benzamides (PPB), previously identified as selective cytotoxins for von Hippel–Lindau-deficient Renal Carcinoma cells, were used as templates to prepare affinity chromatography reagents to aid the identification of the molecular targets of these two classes. Structure–activity data and computational models were used to predict possible points of attachment for linker chains. In the PAT class, Click coupling of long chain azides with 2- and 3-pyridylanilinothiazoleacetylenes gave triazole-linked pyridylanilinothiazoles which did not retain the VHL-dependent selectivity of parent analogues. For the PPB class, Sonagashira coupling of 4-iodo-(3-pyridylphenylsulfonyl)benzamide with a propargyl hexaethylene glycol carbamate gave an acetylene which was reduced to the corresponding alkyl 3-pyridylphenylsulfonylbenzamide. This reagent retained the VHL-dependent selectivity of the parent analogues and was successfully utilized as an affinity reagent. 相似文献
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Graciela E. Santillán Marisa J. Sandoval Yuti Chernajovsky Patricia L. Orchansky 《Molecular and cellular biochemistry》1992,110(2):181-191
A number of cell-surface proteins are anchored in plasma membranes by a glycosylated phosphatidylinositol (PI) moiety that
is covalently attached to the carboxyl-terminal amino acid of the mature protein. We have previously reported the construction
of a cDNA clone of a truncated Platelet-derived growth factor (PDGF) receptor that consists of the extracellular domain without
the transmembrane and cytoplasmic domains. In the construction of the vector, a sequence of 51 base pairs (bp) from the 3′-untranslated
region of the receptor cDNA was linked in frame with the external domain coding sequence. The truncated receptor protein with
the peptide VTSGHCHEERVDRHDGE fused to its carboxyl terminus was covalently attached to the membrane by a PI linkage and it
was released by phosphatidylinositol specific-phospholipase C (PI-PLC). When the 51 bp sequence was deleted, the external
domain receptor protein was secreted into the media. To determine whether the PI linkage of the protein was due to the 17
amino acids added, the peptide was fused to the carboxyl terminus of the secreted protein human Interferon-β (hu-IFN-β). Chinese
hamster ovary (CHO) cells transfected with the hu-IFN-β cDNA secreted the protein to theconditioned media, whereas CHO cells
transfected with the carboxyl terminus modified-hu-IFN-β cDNA did not secrete detectable levels of protein. CHO cells expressing
the carboxyl terminus modified-hu-IFN-β were treated with PI-PLC, the media and cell lysates were analyzed by SDS-PAGE after
immunoprecipitation with antibodies against hu-IFN-β. The modified protein is anchored to the plasma membrane by a PI linkage
and it is specifically released by PI-PLC, whereas a control preparation of CHO cells expressing wild type hu-IFN-β does not
show the same pattern. The 17 amino acid peptide fused to the carboxyl terminus of IFN-β directs attachment of a PI anchor
and targets the fusion protein to the plasma membrane. 相似文献
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Predictivity of an in vitro model for acute and chronic skin irritation (SkinEthic) applied to the testing of topical vehicles 总被引:2,自引:0,他引:2
A. de Brugerolle de Fraissinette V. Picarles S. Chibout M. Kolopp J. Medina P. Burtin M.E. Ebelin S. Osborne F. K. Mayer A. Spake M. Rosdy B. De Wever R.A. Ettlin A. Cordier 《Cell biology and toxicology》1999,15(2):121-135
An in vitro human reconstructed epidermis model (SkinEthic) used for screening acute and chronic skin irritation potential
was validated against in vivo data from skin tolerability studies. The irritation potential of sodium lauryl sulfate (SLS),
calcipotriol and trans-retinoic acid was investigated. The in vitro epidermis-like model consists of cultures of keratinocytes
from human foreskin on a polycarbonate filter. The modulation of cell viability, the release and gene expression of proinflammatory
cytokines, interleukins 1α and 8, and morphological changes were evaluated during 3 days as endpoints representative for an
inflammatory reaction. The cumulative irritation potential of the topical products was evaluated in a human clinical study
by visual scoring and biophysical measurement of inflammatory skin reaction after repeated 24 h applications over 3 weeks
under Finn chamber patches. All topical products that were nonirritating in the human study were noncytotoxic and did not
induce cytokine expression in the in vitro acute model (day 1 exposure). All irritating controls exhibited specific cell viability
and cytokine patterns, which were predictive of the in vivo human data. The ranking of mild to moderate skin irritation potential
was based on the lack of cytotoxicity and the presence of cytokine patterns including gene expression specific for each irritant,
using the chronic in vitro model (up to 3 days exposure).
The human reconstructed epidermis model SkinEthic was shown to be a reliable preclinical tool predicting the irritation potential
of topical products. Moreover, it is a useful model in a two-step tiered strategy for screening acute and chronic irritation
potential for the selection of vehicles for new topical drugs.
This revised version was published online in July 2006 with corrections to the Cover Date. 相似文献
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