全文获取类型
收费全文 | 127篇 |
免费 | 1篇 |
国内免费 | 1篇 |
专业分类
系统科学 | 3篇 |
理论与方法论 | 1篇 |
现状及发展 | 20篇 |
研究方法 | 16篇 |
综合类 | 82篇 |
自然研究 | 7篇 |
出版年
2020年 | 1篇 |
2018年 | 1篇 |
2017年 | 2篇 |
2016年 | 4篇 |
2015年 | 2篇 |
2014年 | 2篇 |
2013年 | 2篇 |
2012年 | 12篇 |
2011年 | 18篇 |
2010年 | 2篇 |
2008年 | 11篇 |
2007年 | 8篇 |
2006年 | 8篇 |
2005年 | 8篇 |
2004年 | 8篇 |
2003年 | 8篇 |
2002年 | 10篇 |
2001年 | 1篇 |
2000年 | 1篇 |
1999年 | 1篇 |
1996年 | 2篇 |
1993年 | 2篇 |
1991年 | 1篇 |
1989年 | 2篇 |
1988年 | 1篇 |
1987年 | 1篇 |
1983年 | 1篇 |
1980年 | 1篇 |
1979年 | 1篇 |
1978年 | 1篇 |
1975年 | 1篇 |
1974年 | 1篇 |
1969年 | 1篇 |
1966年 | 2篇 |
1961年 | 1篇 |
排序方式: 共有129条查询结果,搜索用时 15 毫秒
31.
Hermansky-Pudlak syndrome type 7 (HPS-7) results from mutant dysbindin,a member of the biogenesis of lysosome-related organelles complex 1 (BLOC-1) 总被引:20,自引:0,他引:20
Li W Zhang Q Oiso N Novak EK Gautam R O'Brien EP Tinsley CL Blake DJ Spritz RA Copeland NG Jenkins NA Amato D Roe BA Starcevic M Dell'Angelica EC Elliott RW Mishra V Kingsmore SF Paylor RE Swank RT 《Nature genetics》2003,35(1):84-89
Hermansky-Pudlak syndrome (HPS; MIM 203300) is a genetically heterogeneous disorder characterized by oculocutaneous albinism, prolonged bleeding and pulmonary fibrosis due to abnormal vesicle trafficking to lysosomes and related organelles, such as melanosomes and platelet dense granules. In mice, at least 16 loci are associated with HPS, including sandy (sdy; ref. 7). Here we show that the sdy mutant mouse expresses no dysbindin protein owing to a deletion in the gene Dtnbp1 (encoding dysbindin) and that mutation of the human ortholog DTNBP1 causes a novel form of HPS called HPS-7. Dysbindin is a ubiquitously expressed protein that binds to alpha- and beta-dystrobrevins, components of the dystrophin-associated protein complex (DPC) in both muscle and nonmuscle cells. We also show that dysbindin is a component of the biogenesis of lysosome-related organelles complex 1 (BLOC-1; refs. 9-11), which regulates trafficking to lysosome-related organelles and includes the proteins pallidin, muted and cappuccino, which are associated with HPS in mice. These findings show that BLOC-1 is important in producing the HPS phenotype in humans, indicate that dysbindin has a role in the biogenesis of lysosome-related organelles and identify unexpected interactions between components of DPC and BLOC-1. 相似文献
32.
33.
Bass AJ Lawrence MS Brace LE Ramos AH Drier Y Cibulskis K Sougnez C Voet D Saksena G Sivachenko A Jing R Parkin M Pugh T Verhaak RG Stransky N Boutin AT Barretina J Solit DB Vakiani E Shao W Mishina Y Warmuth M Jimenez J Chiang DY Signoretti S Kaelin WG Spardy N Hahn WC Hoshida Y Ogino S Depinho RA Chin L Garraway LA Fuchs CS Baselga J Tabernero J Gabriel S Lander ES Getz G Meyerson M 《Nature genetics》2011,43(10):964-968
Prior studies have identified recurrent oncogenic mutations in colorectal adenocarcinoma and have surveyed exons of protein-coding genes for mutations in 11 affected individuals. Here we report whole-genome sequencing from nine individuals with colorectal cancer, including primary colorectal tumors and matched adjacent non-tumor tissues, at an average of 30.7× and 31.9× coverage, respectively. We identify an average of 75 somatic rearrangements per tumor, including complex networks of translocations between pairs of chromosomes. Eleven rearrangements encode predicted in-frame fusion proteins, including a fusion of VTI1A and TCF7L2 found in 3 out of 97 colorectal cancers. Although TCF7L2 encodes TCF4, which cooperates with β-catenin in colorectal carcinogenesis, the fusion lacks the TCF4 β-catenin-binding domain. We found a colorectal carcinoma cell line harboring the fusion gene to be dependent on VTI1A-TCF7L2 for anchorage-independent growth using RNA interference-mediated knockdown. This study shows previously unidentified levels of genomic rearrangements in colorectal carcinoma that can lead to essential gene fusions and other oncogenic events. 相似文献
34.
Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn's disease 总被引:1,自引:0,他引:1
Fisher SA Tremelling M Anderson CA Gwilliam R Bumpstead S Prescott NJ Nimmo ER Massey D Berzuini C Johnson C Barrett JC Cummings FR Drummond H Lees CW Onnie CM Hanson CE Blaszczyk K Inouye M Ewels P Ravindrarajah R Keniry A Hunt S Carter M Watkins N Ouwehand W Lewis CM Cardon L;Wellcome Trust Case Control Consortium Lobo A Forbes A Sanderson J Jewell DP Mansfield JC Deloukas P Mathew CG Parkes M Satsangi J 《Nature genetics》2008,40(6):710-712
We report results of a nonsynonymous SNP scan for ulcerative colitis and identify a previously unknown susceptibility locus at ECM1. We also show that several risk loci are common to ulcerative colitis and Crohn's disease (IL23R, IL12B, HLA, NKX2-3 and MST1), whereas autophagy genes ATG16L1 and IRGM, along with NOD2 (also known as CARD15), are specific for Crohn's disease. These data provide the first detailed illustration of the genetic relationship between these common inflammatory bowel diseases. 相似文献
35.
36.
Stiffness modeling is one of the most significant issues in the design of parallel kinematic machine (PKM). This paper presents a semi-analytical approach that enables the stiffness of PKM with complex machine frame geometry to be estimated effectively. This approach can be implemented by three steps: (i) decomposition of the entire system into two sub-systems associated with the parallel mechanism and the machine frame respectively; (ii) stiffness modeling of each sub-system using the analytical approach and the finite element analysis; and (iii) generation of the stiffness model of the entire system by means of linear superposition. In the modeling process of each sub-system, the virtual work principle and overall deflection Jacobian are employed with special attention to the bending rigidity of the constrained passive limb and the interface stiffness of the machine frame. The stiffness distribution of a 5-DOF hybrid robot named TriVariant-B is investigated as an example to illustrate the effectiveness of this approach. The contributions of component rigidities to that of the system are evaluated using global indices. It shows that the results achieved by this approach have a good match to those obtained through finite element analysis and experiments. 相似文献
37.
Sieburth D Ch'ng Q Dybbs M Tavazoie M Kennedy S Wang D Dupuy D Rual JF Hill DE Vidal M Ruvkun G Kaplan JM 《Nature》2005,436(7050):510-517
Chemical synapses are complex structures that mediate rapid intercellular signalling in the nervous system. Proteomic studies suggest that several hundred proteins will be found at synaptic specializations. Here we describe a systematic screen to identify genes required for the function or development of Caenorhabditis elegans neuromuscular junctions. A total of 185 genes were identified in an RNA interference screen for decreased acetylcholine secretion; 132 of these genes had not previously been implicated in synaptic transmission. Functional profiles for these genes were determined by comparing secretion defects observed after RNA interference under a variety of conditions. Hierarchical clustering identified groups of functionally related genes, including those involved in the synaptic vesicle cycle, neuropeptide signalling and responsiveness to phorbol esters. Twenty-four genes encoded proteins that were localized to presynaptic specializations. Loss-of-function mutations in 12 genes caused defects in presynaptic structure. 相似文献
38.
Radisky DC Levy DD Littlepage LE Liu H Nelson CM Fata JE Leake D Godden EL Albertson DG Nieto MA Werb Z Bissell MJ 《Nature》2005,436(7047):123-127
39.
40.
King N Westbrook MJ Young SL Kuo A Abedin M Chapman J Fairclough S Hellsten U Isogai Y Letunic I Marr M Pincus D Putnam N Rokas A Wright KJ Zuzow R Dirks W Good M Goodstein D Lemons D Li W Lyons JB Morris A Nichols S Richter DJ Salamov A Sequencing JG Bork P Lim WA Manning G Miller WT McGinnis W Shapiro H Tjian R Grigoriev IV Rokhsar D 《Nature》2008,451(7180):783-788
Choanoflagellates are the closest known relatives of metazoans. To discover potential molecular mechanisms underlying the evolution of metazoan multicellularity, we sequenced and analysed the genome of the unicellular choanoflagellate Monosiga brevicollis. The genome contains approximately 9,200 intron-rich genes, including a number that encode cell adhesion and signalling protein domains that are otherwise restricted to metazoans. Here we show that the physical linkages among protein domains often differ between M. brevicollis and metazoans, suggesting that abundant domain shuffling followed the separation of the choanoflagellate and metazoan lineages. The completion of the M. brevicollis genome allows us to reconstruct with increasing resolution the genomic changes that accompanied the origin of metazoans. 相似文献