全文获取类型
收费全文 | 14044篇 |
免费 | 222篇 |
国内免费 | 541篇 |
专业分类
系统科学 | 1458篇 |
丛书文集 | 419篇 |
教育与普及 | 1925篇 |
理论与方法论 | 132篇 |
现状及发展 | 687篇 |
研究方法 | 1141篇 |
综合类 | 9003篇 |
自然研究 | 42篇 |
出版年
2018年 | 44篇 |
2017年 | 63篇 |
2016年 | 63篇 |
2015年 | 71篇 |
2014年 | 146篇 |
2013年 | 84篇 |
2012年 | 652篇 |
2011年 | 813篇 |
2010年 | 243篇 |
2009年 | 103篇 |
2008年 | 644篇 |
2007年 | 868篇 |
2006年 | 964篇 |
2005年 | 1197篇 |
2004年 | 879篇 |
2003年 | 956篇 |
2002年 | 724篇 |
2001年 | 665篇 |
2000年 | 841篇 |
1999年 | 365篇 |
1998年 | 136篇 |
1997年 | 82篇 |
1996年 | 87篇 |
1995年 | 67篇 |
1994年 | 89篇 |
1993年 | 147篇 |
1992年 | 125篇 |
1991年 | 126篇 |
1990年 | 123篇 |
1989年 | 127篇 |
1988年 | 180篇 |
1987年 | 193篇 |
1986年 | 228篇 |
1985年 | 213篇 |
1984年 | 238篇 |
1983年 | 218篇 |
1982年 | 218篇 |
1981年 | 189篇 |
1980年 | 152篇 |
1979年 | 79篇 |
1970年 | 54篇 |
1964年 | 34篇 |
1959年 | 140篇 |
1958年 | 222篇 |
1957年 | 162篇 |
1956年 | 129篇 |
1955年 | 136篇 |
1954年 | 111篇 |
1948年 | 37篇 |
1946年 | 34篇 |
排序方式: 共有10000条查询结果,搜索用时 515 毫秒
911.
912.
Kapfhamer D Valladares O Sun Y Nolan PM Rux JJ Arnold SE Veasey SC Bućan M 《Nature genetics》2002,32(2):290-295
Rab3a is the most abundant Rab (ras-associated binding) protein in the brain and has a regulatory role in synaptic vesicle trafficking. Mice with a targeted loss-of-function mutation in Rab3a have defects in Ca(2+)-dependent synaptic transmission: the number of vesicles released in response to an action potential is greater than in wildtype mice, resulting in greater synaptic depression and the abolishment of CA3 mossy-fiber long term potentiation. The effect of these changes on behavior is unknown. In a screen for mouse mutants with abnormal rest-activity and sleep patterns, we identified a semidominant mutation, called earlybird, that shortens the circadian period of locomotor activity. Sequence analysis of Rab3a identified a point mutation in the conserved amino acid (Asp77Gly) within the GTP-binding domain of this protein in earlybird mutants, resulting in significantly reduced levels of Rab3a protein. Phenotypic assessment of earlybird mice and a null allele of Rab3a revealed anomalies in circadian period and sleep homeostasis, providing evidence that Rab3a-mediated synaptic transmission is involved in these behaviors. 相似文献
913.
Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme,in spinocerebellar ataxia with axonal neuropathy 总被引:14,自引:0,他引:14
914.
915.
916.
917.
Systematic screen for human disease genes in yeast 总被引:19,自引:0,他引:19
Steinmetz LM Scharfe C Deutschbauer AM Mokranjac D Herman ZS Jones T Chu AM Giaever G Prokisch H Oefner PJ Davis RW 《Nature genetics》2002,31(4):400-404
High similarity between yeast and human mitochondria allows functional genomic study of Saccharomyces cerevisiae to be used to identify human genes involved in disease. So far, 102 heritable disorders have been attributed to defects in a quarter of the known nuclear-encoded mitochondrial proteins in humans. Many mitochondrial diseases remain unexplained, however, in part because only 40-60% of the presumed 700-1,000 proteins involved in mitochondrial function and biogenesis have been identified. Here we apply a systematic functional screen using the pre-existing whole-genome pool of yeast deletion mutants to identify mitochondrial proteins. Three million measurements of strain fitness identified 466 genes whose deletions impaired mitochondrial respiration, of which 265 were new. Our approach gave higher selection than other systematic approaches, including fivefold greater selection than gene expression analysis. To apply these advantages to human disorders involving mitochondria, human orthologs were identified and linked to heritable diseases using genomic map positions. 相似文献
918.
Paxillin binds schwannomin and regulates its density-dependent localization and effect on cell morphology 总被引:22,自引:0,他引:22
Fernandez-Valle C Tang Y Ricard J Rodenas-Ruano A Taylor A Hackler E Biggerstaff J Iacovelli J 《Nature genetics》2002,31(4):354-362
Neurofibromatosis type 2 is an autosomal dominant disorder characterized by tumors, predominantly schwannomas, in the nervous system. It is caused by mutations in the gene NF2, encoding the growth regulator schwannomin (also known as merlin). Mutations occur throughout the 17-exon gene, with most resulting in protein truncation and undetectable amounts of schwannomin protein. Pathogenic mutations that result in production of defective schwannomin include in-frame deletions of exon 2 and three independent missense mutations within this same exon. Mice with conditional deletion of exon 2 in Schwann cells develop schwannomas, which confirms the crucial nature of exon 2 for growth control. Here we report that the molecular adaptor paxillin binds directly to schwannomin at residues 50-70, which are encoded by exon 2. This interaction mediates the membrane localization of schwannomin to the plasma membrane, where it associates with beta 1 integrin and erbB2. It defines a pathogenic mechanism for the development of NF2 in humans with mutations in exon 2 of NF2. 相似文献
919.
Hoffmann K Dreger CK Olins AL Olins DE Shultz LD Lucke B Karl H Kaps R Müller D Vayá A Aznar J Ware RE Sotelo Cruz N Lindner TH Herrmann H Reis A Sperling K 《Nature genetics》2002,31(4):410-414
Pelger-Hu?t anomaly (PHA; OMIM *169400) is an autosomal dominant disorder characterized by abnormal nuclear shape and chromatin organization in blood granulocytes. Affected individuals show hypolobulated neutrophil nuclei with coarse chromatin. Presumed homozygous individuals have ovoid neutrophil nuclei, as well as varying degrees of developmental delay, epilepsy and skeletal abnormalities. Homozygous offspring in an extinct rabbit lineage showed severe chondrodystrophy, developmental anomalies and increased pre- and postnatal mortality. Here we show, by carrying out a genome-wide linkage scan, that PHA is linked to chromosome 1q41-43. We identified four splice-site, two frameshift and two nonsense mutations in LBR, encoding the lamin B receptor. The lamin B receptor (LBR), a member of the sterol reductase family, is evolutionarily conserved and integral to the inner nuclear membrane; it targets heterochromatin and lamins to the nuclear membrane. Lymphoblastoid cells from heterozygous individuals affected with PHA show reduced expression of the lamin B receptor, and cells homozygous with respect to PHA contain only trace amounts of it. We found that expression of the lamin B receptor affects neutrophil nuclear shape and chromatin distribution in a dose-dependent manner. Our findings have implications for understanding nuclear envelope-heterochromatin interactions, the pathogenesis of Pelger-like conditions in leukemia, infection and toxic drug reactions, and the evolution of neutrophil nuclear shape. 相似文献
920.
Vetter DE Li C Zhao L Contarino A Liberman MC Smith GW Marchuk Y Koob GF Heinemann SF Vale W Lee KF 《Nature genetics》2002,31(4):363-369
Urocortin is a member of the corticotropin-releasing hormone peptide family and is found in many discrete brain regions. The distinct expression pattern of urocortin suggests that it influences such behaviors as feeding, anxiety and auditory processing. To better define the physiological roles of urocortin, we have generated mice carrying a null mutation of the urocortin gene. Urocortin-deficient mice have normal basal feeding behavior and stress responses, but show heightened anxiety-like behaviors in the elevated plus maze and open-field tests. In addition, hearing is impaired in the mutant mice at the level of the inner ear, suggesting that urocortin is involved in the normal development of cochlear sensory-cell function. These results provide the first example of a function for any peptidergic system in hearing. 相似文献