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991.
Snake venoms are cocktails comprising combinations of different proteins, peptides, enzymes and toxins. Snake toxins have
diverse characteristics having different molecular configuration, structure and mode of action. Many toxins derived from snake
venom have distinct pharmacological activities. Venom from Bungarus fasciatus (commonly known as banded krait) is a species of
elapid snake found on the South East Asia and Indian sub-continent, mainly contains neurotoxins. Beta bungartotoxin is the major
fraction of Bungarus venom and particularly act pre-synaptically by obstructing neurotransmitter release. This toxin in other
snake species functionally forms a heterodimer containing two different subunits (A and B). Dimerization of these two chains is a
pre-requisite for the proper functionality of this protein. However, B. fasciatus bungartotoxin contains only B chain and their
structural orientation in yet to be resolved. Therefore, it is of interest to describe the predicted structure model of the toxin for
functional insights. In this work we analyzed the neurotoxic nature, their alignments, secondary and three dimensional structures,
functions, active sites and stability with the help of different bioinformatical tools. A comprehensive analysis of the predicted model
provides approaching to the functional interpretation of its molecular action. 相似文献
992.
Christine M. Freeman Valerie R. Stolberg Sean Crudgington Fernando J. Martinez MeiLan K. Han Stephen W. Chensue Douglas A. Arenberg Catherine A. Meldrum Lisa McCloskey Jeffrey L. Curtis 《PloS one》2014,9(7)
CD56+ natural killer (NK) and CD56+ T cells, from sputum or bronchoalveolar lavage of subjects with chronic obstructive pulmonary disease (COPD) are more cytotoxic to highly susceptible NK targets than those from control subjects. Whether the same is true in lung parenchyma, and if NK activity actually contributes to emphysema progression are unknown. To address these questions, we performed two types of experiments on lung tissue from clinically-indicated resections (n = 60). First, we used flow cytometry on fresh single-cell suspension to measure expression of cell-surface molecules (CD56, CD16, CD8, NKG2D and NKp44) on lung lymphocytes and of the 6D4 epitope common to MICA and MICB on lung epithelial (CD326+) cells. Second, we sequentially isolated CD56+, CD8+ and CD4+ lung lymphocytes, co-cultured each with autologous lung target cells, then determined apoptosis of individual target cells using Annexin-V and 7-AAD staining. Lung NK cells (CD56+ CD3−) and CD56+ T cells (CD56+ CD3+) were present in a range of frequencies that did not differ significantly between smokers without COPD and subjects with COPD. Lung NK cells had a predominantly “cytotoxic” CD56+ CD16+ phenotype; their co-expression of CD8 was common, but the percentage expressing CD8 fell as FEV1 % predicted decreased. Greater expression by autologous lung epithelial cells of the NKG2D ligands, MICA/MICB, but not expression by lung CD56+ cells of the activating receptor NKG2D, correlated inversely with FEV1 % predicted. Lung CD56+ lymphocytes, but not CD4+ or CD8+ conventional lung T cells, rapidly killed autologous lung cells without additional stimulation. Such natural cytotoxicity was increased in subjects with severe COPD and was unexplained in multiple regression analysis by age or cancer as indication for surgery. These data show that as spirometry worsens in COPD, CD56+ lung lymphocytes exhibit spontaneous cytotoxicity of autologous structural lung cells, supporting their potential role in emphysema progression.
Trial Registration
ClinicalTrials.gov NCT00281229相似文献993.
994.
Dalby MJ Gadegaard N Riehle MO Wilkinson CD Curtis AS 《The international journal of biochemistry & cell biology》2004,36(10):2005-2015
In order for cells to react to topography, they must be able to sense shape. When considering nano-topography, these shapes are much smaller than the cell, but still strong responses to nano-topography have been seen. Filopodia, or microspikes, presented by cells at their leading edges are thought to be involved in gathering of special information. In order to investigate this, and to develop an understanding of what size of feature can be sensed by cells, morphological observation (electron and fluorescent microscopy) of fibroblasts reacting to nano-pits with 35, 75 and 120 nm diameters has been used in this study. The nano-pits are especially interesting because unlike many of the nanofeatures cited in the literature, they have no height for the cells to react to. The results showed that cell filopodia, and retraction fibres, interacted with all pit sizes, although direct interaction was hard to image on the 35 nm pits. This suggests that cells are extremely sensitive to their nanoevironment and that should be taken in to consideration when designing next-generation tissue engineering materials. We suggest that this may occur through nanocontact guidance as filopodia are moved over the pits. 相似文献
995.
Sepsis upregulates the gene expression of multiple ubiquitin ligases in skeletal muscle 总被引:8,自引:0,他引:8
Wray CJ Mammen JM Hershko DD Hasselgren PO 《The international journal of biochemistry & cell biology》2003,35(5):698-705
Muscle wasting during sepsis reflects increased expression and activity of the ubiquitin-proteasome proteolytic pathway and is at least in part mediated by glucocorticoids. The ubiquitination of proteins destined to be degraded by the proteasome is regulated by multiple enzymes, including ubiquitin ligases. We tested the hypothesis that sepsis upregulates the gene expression of the newly described ubiquitin ligases, MuRF1 and atrogin-1/MAFbx. Sepsis was induced in rats by cecal ligation and puncture. Control rats were sham-operated. In some experiments, rats were treated with the glucocorticoid receptor antagonist RU 38486 before induction of sepsis. At various time points after induction of sepsis, mRNA levels for MuRF1 and atrogin-1/MAFbx were determined in extensor digitorum longus muscles by real-time PCR. Sepsis resulted in a 10-16-fold increase in gene expression of the ubiquitin ligases studied here. These changes were much greater than those observed previously for another ubiquitin ligase, E3alpha, in muscle during sepsis. Treatment of rats with RU 38486 prevented the sepsis-induced increase in mRNA levels for MuRF1 and atrogin-1/MAFbx, suggesting that glucocorticoids participate in the upregulation of these genes in muscle during sepsis. The present results lend further support to the concept that the ubiquitin-proteasome pathway plays an important role in sepsis-induced muscle proteolysis and suggest that multiple ubiquitin ligases may participate in the development of muscle wasting during sepsis. 相似文献
996.
JJ Sohn AJ Schetter HG Yfantis LA Ridnour I Horikawa MA Khan AI Robles SP Hussain A Goto ED Bowman LJ Hofseth J Bartkova J Bartek GN Wogan DA Wink CC Harris 《PloS one》2012,7(9):e44156
Background
Cellular senescence can be a functional barrier to carcinogenesis. We hypothesized that inflammation modulates carcinogenesis through senescence and DNA damage response (DDR). We examined the association between senescence and DDR with macrophage levels in inflammatory bowel disease (IBD). In vitro experiments tested the ability of macrophages to induce senescence in primary cells. Inflammation modulating microRNAs were identified in senescence colon tissue for further investigation.Methodology/Principal Findings
Quantitative immunohistochemistry identified protein expression by colon cell type. Increased cellular senescence (HP1γ; P = 0.01) or DDR (γH2A.X; P = 0.031, phospho-Chk2, P = 0.014) was associated with high macrophage infiltration in UC. Co-culture with macrophages (ANA-1) induced senescence in >80% of primary cells (fibroblasts MRC5, WI38), illustrating that macrophages induce senescence. Interestingly, macrophage-induced senescence was partly dependent on nitric oxide synthase, and clinically relevant NO• levels alone induced senescence. NO• induced DDR in vitro, as detected by immunofluorescence. In contrast to UC, we noted in Crohn’s disease (CD) that senescence (HP1γ; P<0.001) and DDR (γH2A.X; P<0.05, phospho-Chk2; P<0.001) were higher, and macrophages were not associated with senescence. We hypothesize that nitric oxide may modulate senescence in CD; epithelial cells of CD had higher levels of NOS2 expression than in UC (P = 0.001). Microarrays and quantitative-PCR identified miR-21 expression associated with macrophage infiltration and NOS2 expression.Conclusions
Senescence was observed in IBD with senescence-associated β-galactosidase and HP1γ. Macrophages were associated with senescence and DDR in UC, and in vitro experiments with primary human cells showed that macrophages induce senescence, partly through NO•, and that NO• can induce DDR associated with senescence. Future experiments will investigate the role of NO• and miR-21 in senescence. This is the first study to implicate macrophages and nitrosative stress in a direct effect on senescence and DDR, which is relevant to many diseases of inflammation, cancer, and aging. 相似文献997.
998.
Hou Y Liu GE Bickhart DM Matukumalli LK Li C Song J Gasbarre LC Van Tassell CP Sonstegard TS 《Functional & integrative genomics》2012,12(1):81-92
Genomic structural variation is an important and abundant source of genetic and phenotypic variation. We previously reported
an initial analysis of copy number variations (CNVs) in Angus cattle selected for resistance or susceptibility to gastrointestinal
nematodes. In this study, we performed a large-scale analysis of CNVs using SNP genotyping data from 472 animals of the same
population. We detected 811 candidate CNV regions, which represent 141.8 Mb (~4.7%) of the genome. To investigate the functional
impacts of CNVs, we created 2 groups of 100 individual animals with extremely low or high estimated breeding values of eggs
per gram of feces and referred to these groups as parasite resistant (PR) or parasite susceptible (PS), respectively. We identified
297 (~51 Mb) and 282 (~48 Mb) CNV regions from PR and PS groups, respectively. Approximately 60% of the CNV regions were specific
to the PS group or PR group of animals. Selected PR- or PS-specific CNVs were further experimentally validated by quantitative
PCR. A total of 297 PR CNV regions overlapped with 437 Ensembl genes enriched in immunity and defense, like WC1 gene which uniquely expresses on gamma/delta T cells in cattle. Network analyses indicated that the PR-specific genes were
predominantly involved in gastrointestinal disease, immunological disease, inflammatory response, cell-to-cell signaling and
interaction, lymphoid tissue development, and cell death. By contrast, the 282 PS CNV regions contained 473 Ensembl genes
which are overrepresented in environmental interactions. Network analyses indicated that the PS-specific genes were particularly
enriched for inflammatory response, immune cell trafficking, metabolic disease, cell cycle, and cellular organization and
movement. 相似文献
999.
Sette A Sidney J Southwood S Moore C Berry J Dow C Bradley K Hoof I Lewis MG Hildebrand WH McMurtrey CP Wilson NA Watkins DI Mothé BR 《Immunogenetics》2012,64(6):421-434
The SIV-infected rhesus macaque (Macaca mulatta) is the most established model of AIDS disease systems, providing insight into pathogenesis and a model system for testing novel vaccines. The understanding of cellular immune responses based on the identification and study of Major Histocompatibility Complex (MHC) molecules, including their MHC:peptide-binding motif, provides valuable information to decipher outcomes of infection and vaccine efficacy. Detailed characterization of Mamu-B*039:01, a common allele expressed in Chinese rhesus macaques, revealed a unique MHC:peptide-binding preference consisting of glycine at the second position. Peptides containing a glycine at the second position were shown to be antigenic from animals positive for Mamu-B*039:01. A similar motif was previously described for the D(d) mouse MHC allele, but for none of the human HLA molecules for which a motif is known. Further investigation showed that one additional macaque allele, present in Indian rhesus macaques, Mamu-B*052:01, shares this same motif. These "G2" alleles were associated with the presence of specific residues in their B pocket. This pocket structure was found in 6% of macaque sequences but none of 950 human HLA class I alleles. Evolutionary studies using the "G2" alleles points to common ancestry for the macaque sequences, while convergent evolution is suggested when murine and macaque sequences are considered. This is the first detailed characterization of the pocket residues yielding this specific motif in nonhuman primates and mice, revealing a new supertype motif not present in humans. 相似文献
1000.
Composition of the adult digestive tract bacterial microbiome based on seven mouth surfaces, tonsils, throat and stool samples 总被引:1,自引:0,他引:1
Segata N Haake SK Mannon P Lemon KP Waldron L Gevers D Huttenhower C Izard J 《Genome biology》2012,13(6):R42-18