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排序方式: 共有10000条查询结果,搜索用时 15 毫秒
911.
Bis JC DeCarli C Smith AV van der Lijn F Crivello F Fornage M Debette S Shulman JM Schmidt H Srikanth V Schuur M Yu L Choi SH Sigurdsson S Verhaaren BF DeStefano AL Lambert JC Jack CR Struchalin M Stankovich J Ibrahim-Verbaas CA Fleischman D Zijdenbos A den Heijer T Mazoyer B Coker LH Enzinger C Danoy P Amin N Arfanakis K van Buchem MA de Bruijn RF Beiser A Dufouil C Huang J Cavalieri M Thomson R Niessen WJ Chibnik LB Gislason GK Hofman A Pikula A Amouyel P Freeman KB Phan TG Oostra BA Stein JL 《Nature genetics》2012,44(5):545-551
Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of <4.0 × 10(-7). In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 × 10(-11)) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 × 10(-11)). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 × 10(-7)) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 × 10(-7)); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794). The SNP in ASTN2 also showed suggestive association with decline in cognition in a largely independent sample (n = 1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8) and neuronal migration (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4), indicating new genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia. 相似文献
912.
Enucleated oocytes have the distinctive ability to reprogram somatic nuclei back to totipotency. Here, we investigate genome-scale DNA methylation patterns after nuclear transfer and compare them to the dynamics at fertilization. We identify specific targets for DNA demethylation after nuclear transfer, such as germline-associated promoters, as well as unique limitations that include certain repetitive element classes. 相似文献
913.
914.
Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm 总被引:2,自引:0,他引:2
ME Lindsay D Schepers NA Bolar JJ Doyle E Gallo J Fert-Bober MJ Kempers EK Fishman Y Chen L Myers D Bjeda G Oswald AF Elias HP Levy BM Anderlid MH Yang EM Bongers J Timmermans AC Braverman N Canham GR Mortier HG Brunner PH Byers J Van Eyk L Van Laer HC Dietz BL Loeys 《Nature genetics》2012,44(8):922-927
Loeys-Dietz syndrome (LDS) associates with a tissue signature for high transforming growth factor (TGF)-β signaling but is often caused by heterozygous mutations in genes encoding positive effectors of TGF-β signaling, including either subunit of the TGF-β receptor or SMAD3, thereby engendering controversy regarding the mechanism of disease. Here, we report heterozygous mutations or deletions in the gene encoding the TGF-β2 ligand for a phenotype within the LDS spectrum and show upregulation of TGF-β signaling in aortic tissue from affected individuals. Furthermore, haploinsufficient Tgfb2(+/-) mice have aortic root aneurysm and biochemical evidence of increased canonical and noncanonical TGF-β signaling. Mice that harbor both a mutant Marfan syndrome (MFS) allele (Fbn1(C1039G/+)) and Tgfb2 haploinsufficiency show increased TGF-β signaling and phenotypic worsening in association with normalization of TGF-β2 expression and high expression of TGF-β1. Taken together, these data support the hypothesis that compensatory autocrine and/or paracrine events contribute to the pathogenesis of TGF-β-mediated vasculopathies. 相似文献
915.
Zhang Z Lee JC Lin L Olivas V Au V LaFramboise T Abdel-Rahman M Wang X Levine AD Rho JK Choi YJ Choi CM Kim SW Jang SJ Park YS Kim WS Lee DH Lee JS Miller VA Arcila M Ladanyi M Moonsamy P Sawyers C Boggon TJ Ma PC Costa C Taron M Rosell R Halmos B Bivona TG 《Nature genetics》2012,44(8):852-860
Human non-small cell lung cancers (NSCLCs) with activating mutations in EGFR frequently respond to treatment with EGFR-targeted tyrosine kinase inhibitors (TKIs), such as erlotinib, but responses are not durable, as tumors acquire resistance. Secondary mutations in EGFR (such as T790M) or upregulation of the MET kinase are found in over 50% of resistant tumors. Here, we report increased activation of AXL and evidence for epithelial-to-mesenchymal transition (EMT) in multiple in vitro and in vivo EGFR-mutant lung cancer models with acquired resistance to erlotinib in the absence of the EGFR p.Thr790Met alteration or MET activation. Genetic or pharmacological inhibition of AXL restored sensitivity to erlotinib in these tumor models. Increased expression of AXL and, in some cases, of its ligand GAS6 was found in EGFR-mutant lung cancers obtained from individuals with acquired resistance to TKIs. These data identify AXL as a promising therapeutic target whose inhibition could prevent or overcome acquired resistance to EGFR TKIs in individuals with EGFR-mutant lung cancer. 相似文献
916.
RK Koenekoop H Wang J Majewski X Wang I Lopez H Ren Y Chen Y Li GA Fishman M Genead J Schwartzentruber N Solanki EI Traboulsi J Cheng CV Logan M McKibbin BE Hayward DA Parry CA Johnson M Nageeb;Finding of Rare Disease Genes 《Nature genetics》2012,44(9):1035-1039
Leber congenital amaurosis (LCA) is a blinding retinal disease that presents within the first year after birth. Using exome sequencing, we identified mutations in the nicotinamide adenine dinucleotide (NAD) synthase gene NMNAT1 encoding nicotinamide mononucleotide adenylyltransferase 1 in eight families with LCA, including the family in which LCA was originally linked to the LCA9 locus. Notably, all individuals with NMNAT1 mutations also have macular colobomas, which are severe degenerative entities of the central retina (fovea) devoid of tissue and photoreceptors. Functional assays of the proteins encoded by the mutant alleles identified in our study showed that the mutations reduce the enzymatic activity of NMNAT1 in NAD biosynthesis and affect protein folding. Of note, recent characterization of the slow Wallerian degeneration (Wld(s)) mouse model, in which prolonged axonal survival after injury is observed, identified NMNAT1 as a neuroprotective protein when ectopically expressed. Our findings identify a new disease mechanism underlying LCA and provide the first link between endogenous NMNAT1 dysfunction and a human nervous system disorder. 相似文献
917.
918.
919.
Elia J Glessner JT Wang K Takahashi N Shtir CJ Hadley D Sleiman PM Zhang H Kim CE Robison R Lyon GJ Flory JH Bradfield JP Imielinski M Hou C Frackelton EC Chiavacci RM Sakurai T Rabin C Middleton FA Thomas KA Garris M Mentch F Freitag CM Steinhausen HC Todorov AA Reif A Rothenberger A Franke B Mick EO Roeyers H Buitelaar J Lesch KP Banaschewski T Ebstein RP Mulas F Oades RD Sergeant J Sonuga-Barke E Renner TJ Romanos M Romanos J Warnke A Walitza S Meyer J Pálmason H Seitz C Loo SK Smalley SL 《Nature genetics》2012,44(1):78-84
Attention deficit hyperactivity disorder (ADHD) is a common, heritable neuropsychiatric disorder of unknown etiology. We performed a whole-genome copy number variation (CNV) study on 1,013 cases with ADHD and 4,105 healthy children of European ancestry using 550,000 SNPs. We evaluated statistically significant findings in multiple independent cohorts, with a total of 2,493 cases with ADHD and 9,222 controls of European ancestry, using matched platforms. CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 × 10(-9)). We saw GRM5 (encoding glutamate receptor, metabotropic 5) deletions in ten cases and one control (P = 1.36 × 10(-6)). We saw GRM7 deletions in six cases, and we saw GRM8 deletions in eight cases and no controls. GRM1 was duplicated in eight cases. We experimentally validated the observed variants using quantitative RT-PCR. A gene network analysis showed that genes interacting with the genes in the GRM family are enriched for CNVs in ~10% of the cases (P = 4.38 × 10(-10)) after correction for occurrence in the controls. We identified rare recurrent CNVs affecting glutamatergic neurotransmission genes that were overrepresented in multiple ADHD cohorts. 相似文献
920.