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161.
Detelina Grozeva Keren Carss Olivera Spasic-Boskovic Michael?J. Parker Hayley Archer Helen?V. Firth Soo-Mi Park Natalie Canham Susan?E. Holder Meredith Wilson Anna Hackett Michael Field James?A.B. Floyd UKK Consortium Matthew Hurles F.?Lucy Raymond 《American journal of human genetics》2014,94(4):618-624
To identify further Mendelian causes of intellectual disability (ID), we screened a cohort of 996 individuals with ID for variants in 565 known or candidate genes by using a targeted next-generation sequencing approach. Seven loss-of-function (LoF) mutations—four nonsense (c.1195A>T [p.Lys399∗], c.1333C>T [p.Arg445∗], c.1866C>G [p.Tyr622∗], and c.3001C>T [p.Arg1001∗]) and three frameshift (c.2177_2178del [p.Thr726Asnfs∗39], c.3771dup [p.Ser1258Glufs∗65], and c.3856del [p.Ser1286Leufs∗84])—were identified in SETD5, a gene predicted to encode a methyltransferase. All mutations were compatible with de novo dominant inheritance. The affected individuals had moderate to severe ID with additional variable features of brachycephaly; a prominent high forehead with synophrys or striking full and broad eyebrows; a long, thin, and tubular nose; long, narrow upslanting palpebral fissures; and large, fleshy low-set ears. Skeletal anomalies, including significant leg-length discrepancy, were a frequent finding in two individuals. Congenital heart defects, inguinal hernia, or hypospadias were also reported. Behavioral problems, including obsessive-compulsive disorder, hand flapping with ritualized behavior, and autism, were prominent features. SETD5 lies within the critical interval for 3p25 microdeletion syndrome. The individuals with SETD5 mutations showed phenotypic similarity to those previously reported with a deletion in 3p25, and thus loss of SETD5 might be sufficient to account for many of the clinical features observed in this condition. Our findings add to the growing evidence that mutations in genes encoding methyltransferases regulating histone modification are important causes of ID. This analysis provides sufficient evidence that rare de novo LoF mutations in SETD5 are a relatively frequent (0.7%) cause of ID. 相似文献
162.
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164.
Discovery and synthesis of 6,7,8,9-tetrahydro-5H-pyrimido-[4,5-d]azepines as novel TRPV1 antagonists
Hawryluk NA Merit JE Lebsack AD Branstetter BJ Hack MD Swanson N Ao H Maher MP Bhattacharya A Wang Q Freedman JM Scott BP Wickenden AD Chaplan SR Breitenbucher JG 《Bioorganic & medicinal chemistry letters》2010,20(23):7137-7141
Utilization of a tetrahydro-pyrimdoazepine core as a bioisosteric replacement for a piperazine-urea resulted in the discovery a novel series of potent antagonists of TRPV1. The tetrahydro-pyrimdoazepines have been identified as having good in vitro and in vivo potency and acceptable physical properties. 相似文献
165.
166.
Lida E. Pimper C. Scott Baker R. Natalie P. Goodall Carlos Olavarría María I. Remis 《Conservation Genetics》2010,11(6):2157-2168
The Commerson’s dolphin, Cephalorhynchus commersonii, is found in shallow waters of the continental shelf off the eastern coast of South America between 40°S and 56°S. This species
is taken incidentally in artisanal gillnet fisheries, especially along the shallow coastline of northern Tierra del Fuego
and southern Patagonia. The biological importance of by-catch is likely to be underestimated if the boundaries of subpopulations
are not properly defined. Here, we report on the sequence variation of the mitochondrial DNA control region of the Commerson’s
dolphin from five areas defined in Tierra del Fuego, Argentina and Chile, to provide a preliminary assessment of population
structure where conservation efforts are most needed. A 466 bp fragment of the mitochondrial DNA control region was sequenced
from 196 samples of skin, teeth and bone, defining 20 haplotypes from 17 polymorphic sites. Nucleotide (π = 0.40%) and haplotype (h = 0.807) diversity were low compared to some other odontocete populations, but similar to that of other species of this genus.
Genetic differentiation evaluated through analyses of molecular variance (AMOVA) showed significant overall differences among
areas within Tierra del Fuego (Φ
ST
= 0.059, P < 0.01). An analysis of sex-specific population structure suggested that the dispersal rates of both females and males are
low, indicative of females displaying greater site fidelity. The results from mtDNA control region sequences alone revealed
significant differentiation among studied areas, which should be considered as independent management units. We recommend
that the impact of localized gillnet mortalities should be managed on a local scale in these areas of Tierra del Fuego. 相似文献
167.
Vicky P. K. H. Nguyen George Hanna Natalie Rodrigues Katerina Pizzuto Eric Yang Paul Van Slyke Harold Kim Stephen H. Chen Daniel J. Dumont 《Proteomics》2010,10(8):1658-1672
Differential protein profiling by 2‐D PAGE is generally useful in biomarker discovery, proteome analysis and routine sample preparation prior to analysis by MS. The goal of this study was to compare 2‐D PAGE‐resolved protein profile of lymphatic endothelial cells to those of venous, and arterial endothelial cells isolated from lymphatic and blood vessels of bovine mesentery (bm). Three 2‐D PAGE electrophoretograms were produced for each of the three cell types and quantitatively analyzed. Protein identification by LC‐MS/MS was performed to identify 39 proteins found to be present at statistically significantly different levels in the three cell types (p<0.05). Most of the 39 proteins have not been previously reported in EC proteomic studies of 2‐D PAGE electrophoretograms. Three proteins, HSPA1B (HSP70 family member), HSPB1 (HSP27 family member), and UBE2D3 (a member of E2 ubiquitin‐conjugating enzymes) found to be at highest levels in bm arterial endothelial cells, bm venous endothelial cells, and bm lymphatic endothelial cells, respectively, were validated by immunoblotting with appropriate antibodies. The lack of substantial overlap between our results and those of other groups' comparative studies are discussed. Functional implications of differences in levels of various proteins identified in the three cell types are also discussed. 相似文献
168.
Dunhua Zhang Alan R. Lax John M. Bland Jiujiang Yu Natalie Fedorova William C. Nierman 《Insect Science》2010,17(3):245-252
Abstract Genes encoding for glycosyl hydrolases (GH) in multiple families were recovered from an expression sequence tag library of Coptotermes formosanus, a xylophagous lower termite species. Functional analyses of these genes not only shed light on the mechanisms the insect employs to successfully use cellulosic materials as energy sources, which may serve as strategic targets for designing molecular-based bio-pesticides, but also enrich discoveries of new cellulolytic enzymes for conversion of biomass into biofuel. Our study demonstrated that cellulose could be converted to glucose by two recombinant endogenous glycosyl hydrolases (endo-β-1,4 glucanase in GH9 and β-glucosidase in GH1). While the former cleaved cellulose to cellobiose and cellotriose, the resulting simple cellodextrins were digested to glucose. Both of the Escherichia coli-expressed recombinant proteins showed properties that could be incorporated in a glucose-based ethanol production program. 相似文献
169.
Transport of protons and solutes across mitochondrial membranes is essential for many physiological processes. However, neither the proton-pumping respiratory chain complexes nor the mitochondrial secondary active solute transport proteins have been characterized electrophysiologically in their native environment. In this study, solid-supported membrane (SSM) technology was applied for electrical measurements of respiratory chain complexes CI, CII, CIII, and CIV, the F(O)F(1)-ATPase/synthase (CV), and the adenine nucleotide translocase (ANT) in inner membranes of pig heart mitochondria. Specific substrates and inhibitors were used to validate the different assays, and the corresponding K(0.5) and IC(50) values were in good agreement with previously published results obtained with other methods. In combined measurements of CI-CV, it was possible to detect oxidative phosphorylation (OXPHOS), to measure differential effects of the uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP) on the respective protein activities, and to determine the corresponding IC(50) values. Moreover, the measurements revealed a tight functional coupling of CI and CIII. Coenzyme Q (CoQ) analogues decylubiquinone (DBQ) and idebenone (Ide) stimulated the CII- and CIII-specific electrical currents but had inverse effects on CI-CIII activity. In summary, the results describe the electrophysiological and pharmacological properties of respiratory chain complexes, OXPHOS, and ANT in native mitochondrial membranes and demonstrate that SSM-based electrophysiology provides new insights into a complex molecular mechanism of the respiratory chain and the associated transport proteins. Besides, the SSM-based approach is suited for highly sensitive and specific testing of diverse respiratory chain modulators such as inhibitors, CoQ analogues, and uncoupling agents. 相似文献
170.