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111.
112.
A central problem associated with the design of enzyme inhibitors in general, and serine protease inhibitors in particular, is the identification of templates capable of binding to the active site of an enzyme in a predictable and substrate-like fashion, orienting appended recognition elements in a correct spatial relationship so that favorable binding interactions with multiple sites are achieved. Described herein for the first time is the design of noncovalent inhibitors of human leukocyte elastase that employs a functionalized 4-imidazolidinone scaffold. 相似文献
113.
Mizoribine monophosphate (MZP) is the active metabolite of the immunosuppressive agent mizoribine and a potent inhibitor of IMP dehydrogenase (IMPDH). This enzyme catalyzes the oxidation of IMP to XMP with the concomitant reduction of NAD via a covalent intermediate at Cys319 (E-XMP). Surprisingly, mutational analysis indicates that MZP is a transition state analogue although its structure does not resemble that of the expected transition state. Here we report the X-ray crystal structure of the E.MZP complex at 2.0 A resolution that reveals a transition state-like structure and solves the mechanistic puzzle of the IMPDH reaction. The protein assumes a new conformation where a flap folds into the NAD site and MZP, Cys319, and a water molecule are arranged in a geometry resembling the transition state. The water appears to be activated by interactions with a conserved Arg418-Tyr419 dyad. Mutagenesis experiments confirm that this new closed conformation is required for the hydrolysis of E-XMP, but not for the reduction of NAD. The closed conformation provides a structural explanation for the differences in drug selectivity and catalytic efficiency of IMPDH isozymes. 相似文献
114.
115.
Crystal structure at 2.8 A of an FcRn/heterodimeric Fc complex: mechanism of pH-dependent binding 总被引:1,自引:0,他引:1
The neonatal Fc receptor (FcRn) transports immunoglobulin G (IgG) across epithelia, binding IgG in acidic vesicles (pH < or = 6.5) and releasing IgG in the blood at pH 7.4. Well-ordered FcRn/Fc crystals are prevented by the formation of "oligomeric ribbons" of FcRn dimers bridged by Fc homodimers, thus we crystallized a 1:1 complex between rat FcRn and a heterodimeric Fc containing only one FcRn binding site. The 2.8 A complex structure demonstrates that FcRn uses its alpha2 and beta2-microglobulin domains and carbohydrate to interact with the Fc C(gamma)2-C(gamma)3 interface. The structure reveals conformational changes in Fc and three titratable salt bridges that confer pH-dependent binding, and can be used to guide rational design of therapeutic IgGs with longer serum half-lives. 相似文献
116.
Polymerase chain reactions with degenerate V gene segment primers were used to isolate the putative T-cell receptor alpha-chain gene (TCRA) from Japanese pufferfish (Takifugu rubripes). The putative TCRA chain cDNA is composed of an N-terminus leader peptide followed by the variable region and the constant region. The variable portion of the TCRA gene is encoded by V and J gene segments separated in the germline. As in mammals, the V-J junction sequences are GC rich and highly diversified. Amino acid residues that are required to maintain the function and structural integrity of the TCRA polypeptide, including the conserved Trp-Tyr-Lys and Tyr-Tyr-Cys motifs in the V gene segments, the Lys-Leu-X-Phe-Gly-X-Gly-Thr-X-Leu motif in the J gene segment, the three cysteine residues in the constant region and the charged residues in the transmembrane region are all preserved in the pufferfish. These conserved features suggest that the TCRA gene families in fish and mammals have evolved from a common ancestor. 相似文献
117.
Sensitive characterization of microbial ubiquinones from biofilms by electrospray/mass spectrometry 总被引:1,自引:0,他引:1
Utilizing high-performance liquid chromatography/electrospray/tandem mass spectrometric analysis of the neutral lipid extract of microbial cells and biofilm communities, respiratory ubiquinone (UQ) (1-methyl-2-isoprenyl-3,4-dimethoxyparabenzoquinone) isoprenologues can be separated isocratically in minutes and assayed with a limit of quantification (LOQ) of 9 p.p.b. (11.1 fmol UQ9 µL−1 ). This corresponds to about 1.29 × 107 cells of Pseudomonas putida . Highest sensitivity is achieved using flow-injection analysis with multiple reaction monitoring wherein ammoniated molecular ions of specific isoprenologues pass through quadrupole one, are collisionally dissociated in quadrupole two and identified from the product ion fragment at m/z 197.1 in quadrupole three. This assay has a repeatability of between 6% and 10% over three orders of magnitude ( r 2 = 0.996). Quinone profiling based on dominant isoprenologue patterns provides taxonomic insights. Detection of prominent UQ isoprenologues indicates presence of microeukaryotes and α Proteobacteria with UQ10 , obligatory aerobic Gram-negative bacteria with UQ4-14, facultative Gram-negative (and some γ Proteobacteria growing in microniches with oxygen or to a much lesser extent nitrate as a terminal electron acceptor with UQ8, and other γ Proteobacteria with UQ9 . High sensitivity is essential as the phospholipid fatty acid (PLFA) to UQ molar ratios are 130 or greater. Previous studies have established that recovery of sediment communities with high PLFA/UQ ratios corresponded to areas of aerobic metabolism, an important consideration in bioremediation or nuclide mobilization. 相似文献
118.
The environmental saphrophyte Burkholderia pseudomallei is the causative agent of melioidosis, a systemic, potentially life-threatening condition endemic to many parts of south-east Asia and northern Australia. We have used the soil nematode Caenorhabditis elegans as a model host to characterize the mechanisms by which this bacterium mounts a successful infection. We find that C. elegans is susceptible to a broad range of Burkholderia species, and that the virulence mechanisms used by this pathogen to kill nematodes may be similar to those used to infect mammals. We also find that the specific dynamics of the C. elegans-B. pseudomallei host-pathogen interaction can be highly influenced by environmental factors, and that nematode killing results at least in part from the presence of a diffusible toxin. Finally, by screening for bacterial mutants attenuated in their ability to kill C. elegans, we genetically identify several new potential virulence factors in B. pseudomallei. The use of C. elegans as a model host should greatly facilitate future investigations into how B. pseudomallei can interact with host organisms. 相似文献
119.
Ecosystem function for water retention and forest ecosystem conservation in a watershed of the Yangtze River 总被引:1,自引:0,他引:1
The ecosystem function for water retention in a watershed of the Yangtze River was discussed in this study. The watershed was divided into 90 types of vegetation–soil–slope complex. A GIS-embodied spatial database was used to explore the relationships between the capacity of water retention by a complex and its types of vegetation, soil and slope. Furthermore, the capacity of water retention of every complex was estimated statistically by using estimation models. The spatial distribution of various capacity of water retention in the watershed was demarcated on a map based on the attributions and the locations of complexes. In addition, we evaluated integrally the situation of water retention in the watershed based on the estimation for the complexes from which it was distinctly recognized that the serious situation mainly results from the poor capacity of water retention of vegetation. The variation-location effect describes the phenomenon in which an identical variation of a factor may produce different effects on overall situation, when this variation occurs in a different spatial location. According to the variation-location effect on the expansion of forestland, a strategy 'spatial pattern-based forestland extension was proposed to conserve forest ecosystem and improve the situation of water retention in the watershed. 相似文献
120.
Computer-integrated finite element modeling of human middle ear 总被引:5,自引:0,他引:5
The objective of this study was to produce an improved finite element (FE) model of the human middle ear and to compare the
model with human data. We began with a systematic and accurate geometric modeling technique for reconstructing the middle
ear from serial sections of a freshly frozen temporal bone. A geometric model of a human middle ear was constructed in a computer-aided
design (CAD) environment with particular attention to geometry and microanatomy. Using the geometric model, a working FE model
of the human middle ear was created using previously published material properties of middle ear components. This working
FE model was finalized by a cross-calibration technique, comparing its predicted stapes footplate displacements with laser
Doppler interferometry measurements from fresh temporal bones. The final FE model was shown to be reasonable in predicting
the ossicular mechanics of the human middle ear.
Received: 18 February 2002 / Accepted: 6 June 2002
The preparation of temporal bone histological sections of Robert K. Dyer, Jr., MD is gratefully recognized. The Whitaker
Foundation supported this work (Research Grant RG-98-0305). 相似文献