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411.
Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease 总被引:1,自引:0,他引:1
Naj AC Jun G Beecham GW Wang LS Vardarajan BN Buros J Gallins PJ Buxbaum JD Jarvik GP Crane PK Larson EB Bird TD Boeve BF Graff-Radford NR De Jager PL Evans D Schneider JA Carrasquillo MM Ertekin-Taner N Younkin SG Cruchaga C Kauwe JS Nowotny P Kramer P Hardy J Huentelman MJ Myers AJ Barmada MM Demirci FY Baldwin CT Green RC Rogaeva E St George-Hyslop P Arnold SE Barber R Beach T Bigio EH Bowen JD Boxer A Burke JR Cairns NJ Carlson CS Carney RM Carroll SL Chui HC Clark DG Corneveaux J Cotman CW 《Nature genetics》2011,43(5):436-441
The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility. 相似文献
412.
Genome-wide association study of leaf architecture in the maize nested association mapping population 总被引:13,自引:0,他引:13
Tian F Bradbury PJ Brown PJ Hung H Sun Q Flint-Garcia S Rocheford TR McMullen MD Holland JB Buckler ES 《Nature genetics》2011,43(2):159-162
US maize yield has increased eight-fold in the past 80 years, with half of the gain attributed to selection by breeders. During this time, changes in maize leaf angle and size have altered plant architecture, allowing more efficient light capture as planting density has increased. Through a genome-wide association study (GWAS) of the maize nested association mapping panel, we determined the genetic basis of important leaf architecture traits and identified some of the key genes. Overall, we demonstrate that the genetic architecture of the leaf traits is dominated by small effects, with little epistasis, environmental interaction or pleiotropy. In particular, GWAS results show that variations at the liguleless genes have contributed to more upright leaves. These results demonstrate that the use of GWAS with specially designed mapping populations is effective in uncovering the basis of key agronomic traits. 相似文献
413.
Giardine B Borg J Higgs DR Peterson KR Philipsen S Maglott D Singleton BK Anstee DJ Basak AN Clark B Costa FC Faustino P Fedosyuk H Felice AE Francina A Galanello R Gallivan MV Georgitsi M Gibbons RJ Giordano PC Harteveld CL Hoyer JD Jarvis M Joly P Kanavakis E Kollia P Menzel S Miller W Moradkhani K Old J Papachatzopoulou A Papadakis MN Papadopoulos P Pavlovic S Perseu L Radmilovic M Riemer C Satta S Schrijver I Stojiljkovic M Thein SL Traeger-Synodinos J Tully R Wada T Waye JS Wiemann C 《Nature genetics》2011,43(4):295-301
We developed a series of interrelated locus-specific databases to store all published and unpublished genetic variation related to hemoglobinopathies and thalassemia and implemented microattribution to encourage submission of unpublished observations of genetic variation to these public repositories. A total of 1,941 unique genetic variants in 37 genes, encoding globins and other erythroid proteins, are currently documented in these databases, with reciprocal attribution of microcitations to data contributors. Our project provides the first example of implementing microattribution to incentivise submission of all known genetic variation in a defined system. It has demonstrably increased the reporting of human variants, leading to a comprehensive online resource for systematically describing human genetic variation in the globin genes and other genes contributing to hemoglobinopathies and thalassemias. The principles established here will serve as a model for other systems and for the analysis of other common and/or complex human genetic diseases. 相似文献
414.
Burdon KP Macgregor S Hewitt AW Sharma S Chidlow G Mills RA Danoy P Casson R Viswanathan AC Liu JZ Landers J Henders AK Wood J Souzeau E Crawford A Leo P Wang JJ Rochtchina E Nyholt DR Martin NG Montgomery GW Mitchell P Brown MA Mackey DA Craig JE 《Nature genetics》2011,43(6):574-578
We report a genome-wide association study for open-angle glaucoma (OAG) blindness using a discovery cohort of 590 individuals with severe visual field loss (cases) and 3,956 controls. We identified associated loci at TMCO1 (rs4656461[G] odds ratio (OR) = 1.68, P = 6.1 × 10(-10)) and CDKN2B-AS1 (rs4977756[A] OR = 1.50, P = 4.7 × 10(-9)). We replicated these associations in an independent cohort of cases with advanced OAG (rs4656461 P = 0.010; rs4977756 P = 0.042) and two additional cohorts of less severe OAG (rs4656461 combined discovery and replication P = 6.00 × 10(-14), OR = 1.51, 95% CI 1.35-1.68; rs4977756 combined P = 1.35 × 10(-14), OR = 1.39, 95% CI 1.28-1.51). We show retinal expression of genes at both loci in human ocular tissues. We also show that CDKN2A and CDKN2B are upregulated in the retina of a rat model of glaucoma. 相似文献
415.
Tanja Wilke Wilko H. Ahlrichs Olaf R.P. Bininda-Emonds 《Journal of Natural History》2019,53(7-8):413-423
The morphology of soft-bodied rotifers, including those of Synchaeta spp, can be strongly affected by preparation artefacts including contraction and deformation. The long-standing, valid species Synchaeta monopus is known exclusively from ethanol- or formaldehyde-preserved material and no live specimens of it have ever been described. Although this alone is cause for concern, we could also reproduce unique characteristics diagnostic for this species (e.g. the swollen body and the rudimental foot) by subjecting specimens of Synchaeta pectinata to the preservation conditions under which it was first described. This proxy experiment and comparisons to other Synchaeta species indicate that literature occurrences of S. monopus likely represent preserved and deformed specimens of Synchaeta cecilia or other marine species of Synchaeta, thereby highlighting the importance of thorough morphological investigations of the habitus using live specimens and of features that are unaffected by preservation (e.g. the trophi). We therefore recommend that S. monopus be listed as a species inquirenda until topotypes are examined. Furthermore, in ecological studies including rotifers, where the examination of preserved material is often unavoidable, we stress that light-microscopical images of the habitus and trophi of the specimens minimally be included to facilitate independent verification of the species assignments. 相似文献
416.
S. Lecompte M. Abou-Samra R. Boursereau L. Noel S. M. Brichard 《Cellular and molecular life sciences : CMLS》2017,74(13):2487-2501
Background
Persistent inflammation exacerbates the progression of Duchenne muscular dystrophy (DMD). The hormone, adiponectin (ApN), which is decreased in the metabolic syndrome, exhibits anti-inflammatory properties on skeletal muscle and alleviates the dystrophic phenotype of mdx mice. Here, we investigate whether ApN retains its anti-inflammatory action in myotubes obtained from DMD patients. We unravel the underlying mechanisms by studying the secretome and the early events of ApN.Methods
Primary cultures of myotubes from DMD and control patients were treated or not by ApN after an inflammatory challenge. Myokines secreted in medium were identified by cytokine antibody-arrays and ELISAs. The early events of ApN signaling were assessed by abrogating selected genes.Results
ApN retained its anti-inflammatory properties in both dystrophic and control myotubes. Profiling of secretory products revealed that ApN downregulated the secretion of two pro-inflammatory factors (TNFα and IL-17A), one soluble receptor (sTNFRII), and one chemokine (CCL28) in DMD myotubes, while upregulating IL-6 that exerts some anti-inflammatory effects. These changes were explained by pretranslational mechanisms. Earlier events of the ApN cascade involved AdipoR1, the main receptor for muscle, and the AMPK-SIRT1-PGC-1α axis leading, besides alteration of the myokine profile, to the upregulation of utrophin A (a dystrophin analog).Conclusion
ApN retains its beneficial properties in dystrophic muscles by activating the AdipoR1-AMPK-SIRT1-PGC-1α pathway, thereby inducing a shift in the secretion of downstream myokines toward a less inflammatory profile while upregulating utrophin. ApN, the early events of the cascade and downstream myokines may be therapeutic targets for the management of DMD.417.
G. M. C. Janssen P. Schwertman T. A. T. Wanga R. S. Jahangir Tafrechi P. J. A. van den Broek A. K. Raap 《Cellular and molecular life sciences : CMLS》2009,66(4):721-730
Cytoplasmic translation is under sophisticated control but how cells adapt its rate to constitutive loss of mitochondrial
oxidative phosphorylation is unknown. Here we show that translation is repressed in cells with the pathogenic A3243G mtDNA
mutation or in mtDNA-less ρ0 cells by at least two distinct pathways, one transiently targeting elongation factor eEF-2 and the other initiation factor
eIF-2α constitutively. Under conditions of exponential cell growth and mammalian target of rapamycin (mTOR) activation, eEF-2
becomes transiently phosphorylated by an AMP-activated protein kinase (AMPK)-dependent pathway, especially high in mutant
cells. Independent of AMPK and mTOR, eIF-2α is constitutively phosphorylated in mutant cells, likely a signature of endoplasmic
reticulum (ER)-stress response induced by the loss of oxidative phosphorylation. While the AMPK/eEF-2K/eEF-2 pathway appears
to function in adaptation to physiological fluctuations in ATP levels in the mutant cells, the ER stress signified by constitutive
protein synthesis inhibition through eIF-2α-mediated repression of translation initiation may have pathobiochemical consequences.
Received 29 October 2008; received after revision 11 December 2008; accepted 16 December 2008 相似文献
418.
V. Le Fourn K. Gaplovska-Kysela B. Guhl R. Santimaria C. Zuber J. Roth 《Cellular and molecular life sciences : CMLS》2009,66(8):1434-1445
Little is known about the fate of machinery proteins of the protein quality control and endoplasmic reticulum(ER)-associated
degradation (ERAD). We investigated the degradation of the ERAD component EDEM1, which directs overexpressed misfolded glycoproteins
to degradation. Endogenous EDEM1 was studied since EDEM1 overexpression not only resulted in inappropriate occurrence throughout
the ER but also caused cytotoxic effects. Proteasome inhibitors had no effect on the clearance of endogenous EDEM1 in non-starved
cells. However, EDEM1 could be detected by immunocytochemistry in autophagosomes and biochemically in LC3 immuno-purified
autophagosomes. Furthermore, influencing the lysosome-autophagy pathway by vinblastine or pepstatin A/E64d and inhibiting
autophagosome formation by 3-methyladenine or ATGs short interfering RNA knockdown stabilized EDEM1. Autophagic degradation
involved removal of cytosolic Triton X-100-insoluble deglycosylated EDEM1, but not of EDEM1-containing ER cisternae. Our studies
demonstrate that endogenous EDEM1 in cells not stressed by the expression of a transgenic misfolded protein reaches the cytosol
and is degraded by basal autophagy.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
Received 15 January 2009; received after revision 16 February 2009; accepted 17 February 2009
V. Le Fourn, K. Gaplovska-Kysela: These authors equally contributed to this work. 相似文献
419.
A. Beqqali W. van Eldik C. Mummery R. Passier 《Cellular and molecular life sciences : CMLS》2009,66(5):800-813
Studies on identification, derivation and characterization of human stem cells in the last decade have led to high expectations
in the field of regenerative medicine. Although it is clear that for successful stem cell-based therapy several obstacles
have to be overcome, other opportunities lay ahead for the use of human stem cells. A more immediate application would be
the development of human models for cell-type specific differentiation and disease in vitro. Cardiomyocytes can be generated from stem cells, which have been shown to follow similar molecular events of cardiac development
in vivo. Furthermore, several monogenic cardiovascular diseases have been described, for which in vitro models in stem cells could be generated. Here, we will discuss the potential of human embryonic stem cells, cardiac stem
cells and the recently described induced pluripotent stem cells as models for cardiac differentiation and disease.
Received 07 August 2008; received after revision 26 September 2008; accepted 03 October 2008 相似文献
420.
R. P. Massengo-Tiassé J. E. Cronan 《Cellular and molecular life sciences : CMLS》2009,66(9):1507-1517
The enoyl-acyl carrier protein reductase (ENR) is the last enzyme in the fatty acid elongation cycle. Unlike most enzymes
in this essential pathway, ENR displays an unusual diversity among organisms. The growing interest in ENRs is mainly due to
the fact that a variety of both synthetic and natural antibacterial compounds are shown to specifically target their activity.
The primary anti-tuberculosis drug, isoniazid, and the broadly used antibacterial compound, triclosan, both target this enzyme.
In this review, we discuss the diversity of ENRs, and their inhibitors in the light of current research progress.
Received 3 November 2008; received after revision 5 December 2008; accepted 8 December 2008 相似文献