全文获取类型
收费全文 | 1000篇 |
免费 | 2篇 |
国内免费 | 3篇 |
专业分类
系统科学 | 13篇 |
教育与普及 | 5篇 |
理论与方法论 | 7篇 |
现状及发展 | 224篇 |
研究方法 | 149篇 |
综合类 | 588篇 |
自然研究 | 19篇 |
出版年
2021年 | 3篇 |
2018年 | 5篇 |
2017年 | 7篇 |
2016年 | 16篇 |
2015年 | 11篇 |
2014年 | 17篇 |
2013年 | 13篇 |
2012年 | 69篇 |
2011年 | 102篇 |
2010年 | 28篇 |
2009年 | 7篇 |
2008年 | 63篇 |
2007年 | 67篇 |
2006年 | 59篇 |
2005年 | 66篇 |
2004年 | 53篇 |
2003年 | 59篇 |
2002年 | 70篇 |
2001年 | 12篇 |
2000年 | 16篇 |
1999年 | 17篇 |
1998年 | 4篇 |
1996年 | 3篇 |
1994年 | 4篇 |
1992年 | 6篇 |
1991年 | 7篇 |
1990年 | 6篇 |
1989年 | 8篇 |
1988年 | 4篇 |
1987年 | 7篇 |
1986年 | 8篇 |
1985年 | 6篇 |
1983年 | 4篇 |
1982年 | 4篇 |
1980年 | 2篇 |
1979年 | 12篇 |
1978年 | 13篇 |
1977年 | 11篇 |
1976年 | 6篇 |
1975年 | 7篇 |
1974年 | 9篇 |
1973年 | 11篇 |
1972年 | 7篇 |
1971年 | 14篇 |
1970年 | 18篇 |
1969年 | 13篇 |
1968年 | 8篇 |
1967年 | 17篇 |
1966年 | 6篇 |
1965年 | 5篇 |
排序方式: 共有1005条查询结果,搜索用时 62 毫秒
81.
Krakow D Robertson SP King LM Morgan T Sebald ET Bertolotto C Wachsmann-Hogiu S Acuna D Shapiro SS Takafuta T Aftimos S Kim CA Firth H Steiner CE Cormier-Daire V Superti-Furga A Bonafe L Graham JM Grix A Bacino CA Allanson J Bialer MG Lachman RS Rimoin DL Cohn DH 《Nature genetics》2004,36(4):405-410
The filamins are cytoplasmic proteins that regulate the structure and activity of the cytoskeleton by cross-linking actin into three-dimensional networks, linking the cell membrane to the cytoskeleton and serving as scaffolds on which intracellular signaling and protein trafficking pathways are organized (reviewed in refs. 1,2). We identified mutations in the gene encoding filamin B in four human skeletal disorders. We found homozygosity or compound heterozygosity with respect to stop-codon mutations in autosomal recessive spondylocarpotarsal syndrome (SCT, OMIM 272460) and missense mutations in individuals with autosomal dominant Larsen syndrome (OMIM 150250) and the perinatal lethal atelosteogenesis I and III phenotypes (AOI, OMIM 108720; AOIII, OMIM 108721). We found that filamin B is expressed in human growth plate chondrocytes and in the developing vertebral bodies in the mouse. These data indicate an unexpected role in vertebral segmentation, joint formation and endochondral ossification for this ubiquitously expressed cytoskeletal protein. 相似文献
82.
Davila S Furu L Gharavi AG Tian X Onoe T Qian Q Li A Cai Y Kamath PS King BF Azurmendi PJ Tahvanainen P Kääriäinen H Höckerstedt K Devuyst O Pirson Y Martin RS Lifton RP Tahvanainen E Torres VE Somlo S 《Nature genetics》2004,36(6):575-577
Mutations in PRKCSH, encoding the beta-subunit of glucosidase II, an N-linked glycan-processing enzyme in the endoplasmic reticulum (ER), cause autosomal dominant polycystic liver disease. We found that mutations in SEC63, encoding a component of the protein translocation machinery in the ER, also cause this disease. These findings are suggestive of a role for cotranslational protein-processing pathways in maintaining epithelial luminal structure and implicate noncilial ER proteins in human polycystic disease. 相似文献
83.
Saleh M Vaillancourt JP Graham RK Huyck M Srinivasula SM Alnemri ES Steinberg MH Nolan V Baldwin CT Hotchkiss RS Buchman TG Zehnbauer BA Hayden MR Farrer LA Roy S Nicholson DW 《Nature》2004,429(6987):75-79
Caspases mediate essential key proteolytic events in inflammatory cascades and the apoptotic cell death pathway. Human caspases functionally segregate into two distinct subfamilies: those involved in cytokine maturation (caspase-1, -4 and -5) and those involved in cellular apoptosis (caspase-2, -3, -6, -7, -8, -9 and -10). Although caspase-12 is phylogenetically related to the cytokine maturation caspases, in mice it has been proposed as a mediator of apoptosis induced by endoplasmic reticulum stress including amyloid-beta cytotoxicity, suggesting that it might contribute to the pathogenesis of Alzheimer's disease. Here we show that a single nucleotide polymorphism in caspase-12 in humans results in the synthesis of either a truncated protein (Csp12-S) or a full-length caspase proenzyme (Csp12-L). The read-through single nucleotide polymorphism encoding Csp12-L is confined to populations of African descent and confers hypo-responsiveness to lipopolysaccharide-stimulated cytokine production in ex vivo whole blood, but has no significant effect on apoptotic sensitivity. In a preliminary study, we find that the frequency of the Csp12-L allele is increased in African American individuals with severe sepsis. Thus, Csp12-L attenuates the inflammatory and innate immune response to endotoxins and in doing so may constitute a risk factor for developing sepsis. 相似文献
84.
85.
86.
87.
Genetic analysis of the mouse brain proteome 总被引:24,自引:0,他引:24
Klose J Nock C Herrmann M Stühler K Marcus K Blüggel M Krause E Schalkwyk LC Rastan S Brown SD Büssow K Himmelbauer H Lehrach H 《Nature genetics》2002,30(4):385-393
Proteome analysis is a fundamental step in systematic functional genomics. Here we have resolved 8,767 proteins from the mouse brain proteome by large-gel two-dimensional electrophoresis. We detected 1,324 polymorphic proteins from the European collaborative interspecific backcross. Of these, we mapped 665 proteins genetically and identified 466 proteins by mass spectrometry. Qualitatively polymorphic proteins, to 96%, reflect changes in conformation and/or mass. Quantitatively polymorphic proteins show a high frequency (73%) of allele-specific transmission in codominant heterozygotes. Variations in protein isoforms and protein quantity often mapped to chromosomal positions different from that of the structural gene, indicating that single proteins may act as polygenic traits. Genetic analysis of proteomes may detect the types of polymorphism that are most relevant in disease-association studies. 相似文献
88.
89.
The knowledge of human genetic variation that will come from the human genome sequence makes feasible a polygenic approach to disease prevention, in which it will be possible to identify individuals as susceptible by their genotype profile and to prevent disease by targeting interventions to those at risk. There is doubt, however, regarding the magnitude of these genetic effects and thus the potential to apply them to either individuals or populations. We have therefore examined the potential for prediction of risk based on common genetic variation using data from a population-based series of individuals with breast cancer. The data are compatible with a log-normal distribution of genetic risk in the population that is sufficiently wide to provide useful discrimination of high- and low-risk groups. Assuming all of the susceptibility genes could be identified, the half of the population at highest risk would account for 88% of all affected individuals. By contrast, if currently identified risk factors for breast cancer were used to stratify the population, the half of the population at highest risk would account for only 62% of all cases. These results suggest that the construction and use of genetic-risk profiles may provide significant improvements in the efficacy of population-based programs of intervention for cancers and other diseases. 相似文献
90.