全文获取类型
收费全文 | 295篇 |
免费 | 1篇 |
国内免费 | 1篇 |
专业分类
系统科学 | 4篇 |
丛书文集 | 1篇 |
理论与方法论 | 1篇 |
现状及发展 | 50篇 |
研究方法 | 66篇 |
综合类 | 160篇 |
自然研究 | 15篇 |
出版年
2021年 | 1篇 |
2020年 | 2篇 |
2018年 | 2篇 |
2017年 | 2篇 |
2016年 | 4篇 |
2015年 | 9篇 |
2014年 | 3篇 |
2013年 | 5篇 |
2012年 | 43篇 |
2011年 | 46篇 |
2010年 | 15篇 |
2009年 | 3篇 |
2008年 | 24篇 |
2007年 | 19篇 |
2006年 | 29篇 |
2005年 | 16篇 |
2004年 | 32篇 |
2003年 | 17篇 |
2002年 | 11篇 |
2000年 | 1篇 |
1997年 | 1篇 |
1982年 | 1篇 |
1980年 | 4篇 |
1977年 | 1篇 |
1976年 | 1篇 |
1975年 | 1篇 |
1973年 | 1篇 |
1970年 | 1篇 |
1969年 | 2篇 |
排序方式: 共有297条查询结果,搜索用时 819 毫秒
151.
Jaclyn Nicole Le Grand Laura Gonzalez-Cano Maria Angeliki Pavlou Jens C. Schwamborn 《Cellular and molecular life sciences : CMLS》2015,72(4):773-797
Parkinson’s disease (PD) is the second most common neurodegenerative disorder, leading to a variety of motor and non-motor symptoms. Interestingly, non-motor symptoms often appear a decade or more before the first signs of motor symptoms. Some of these non-motor symptoms are remarkably similar to those observed in cases of impaired neurogenesis and several PD-related genes have been shown to play a role in embryonic or adult neurogenesis. Indeed, animal models deficient in Nurr1, Pitx3, SNCA and PINK1 display deregulated embryonic neurogenesis and LRRK2 and VPS35 have been implicated in neuronal development-related processes such as Wnt/β-catenin signaling and neurite outgrowth. Moreover, adult neurogenesis is affected in both PD patients and PD animal models and is regulated by dopamine and dopaminergic (DA) receptors, by chronic neuroinflammation, such as that observed in PD, and by differential expression of wild-type or mutant forms of PD-related genes. Indeed, an increasing number of in vivo studies demonstrate a role for SNCA and LRRK2 in adult neurogenesis and in the generation and maintenance of DA neurons. Finally, the roles of PD-related genes, SNCA, LRRK2, VPS35, Parkin, PINK1 and DJ-1 have been studied in NSCs, progenitor cells and induced pluripotent stem cells, demonstrating a role for some of these genes in stem/progenitor cell proliferation and maintenance. Together, these studies strongly suggest a link between deregulated neurogenesis and the onset and progression of PD and present strong evidence that, in addition to a neurodegenerative disorder, PD can also be regarded as a developmental disorder. 相似文献
152.
AID is required for germinal center-derived lymphomagenesis 总被引:1,自引:0,他引:1
Pasqualucci L Bhagat G Jankovic M Compagno M Smith P Muramatsu M Honjo T Morse HC Nussenzweig MC Dalla-Favera R 《Nature genetics》2008,40(1):108-112
Most human B cell non-Hodgkin's lymphomas (B-NHLs) derive from germinal centers (GCs), the structure in which B cells undergo somatic hypermutation (SHM) and class switch recombination (CSR) before being selected for high-affinity antibody production. The pathogenesis of B-NHL is associated with distinct genetic lesions, including chromosomal translocations and aberrant SHM, which arise from mistakes occurring during CSR and SHM. A direct link between these DNA remodeling events and GC lymphoma development, however, has not been demonstrated. Here we have crossed three mouse models of B cell lymphoma driven by oncogenes (Myc, Bcl6 and Myc/Bcl6; refs. 5,6) with mice lacking activation-induced cytidine deaminase (AID), the enzyme required for both CSR and SHM. We show that AID deficiency prevents Bcl6-dependent, GC-derived B-NHL, but has no impact on Myc-driven, pre-GC lymphomas. Accordingly, abrogation of AID is associated with the disappearance of CSR- and SHM-mediated structural alterations. These results show that AID is required for GC-derived lymphomagenesis, supporting the notion that errors in AID-mediated antigen-receptor gene modification processes are principal contributors to the pathogenesis of human B-NHL. 相似文献
153.
McGowan KA Li JZ Park CY Beaudry V Tabor HK Sabnis AJ Zhang W Fuchs H de Angelis MH Myers RM Attardi LD Barsh GS 《Nature genetics》2008,40(8):963-970
Mutations in genes encoding ribosomal proteins cause the Minute phenotype in Drosophila and mice, and Diamond-Blackfan syndrome in humans. Here we report two mouse dark skin (Dsk) loci caused by mutations in Rps19 (ribosomal protein S19) and Rps20 (ribosomal protein S20). We identify a common pathophysiologic program in which p53 stabilization stimulates Kit ligand expression, and, consequently, epidermal melanocytosis via a paracrine mechanism. Accumulation of p53 also causes reduced body size and erythrocyte count. These results provide a mechanistic explanation for the diverse collection of phenotypes that accompany reduced dosage of genes encoding ribosomal proteins, and have implications for understanding normal human variation and human disease. 相似文献
154.
155.
156.
New models of collaboration in genome-wide association studies: the Genetic Association Information Network 总被引:7,自引:0,他引:7
GAIN Collaborative Research Group Manolio TA Rodriguez LL Brooks L Abecasis G;Collaborative Association Study of Psoriasis Ballinger D Daly M Donnelly P Faraone SV;International Multi-Center ADHD Genetics Project Frazer K Gabriel S Gejman P;Molecular Genetics of Schizophrenia Collaboration Guttmacher A Harris EL Insel T Kelsoe JR;Bipolar Genome Study Lander E McCowin N Mailman MD Nabel E Ostell J Pugh E Sherry S 《Nature genetics》2007,39(9):1045-1051
The Genetic Association Information Network (GAIN) is a public-private partnership established to investigate the genetic basis of common diseases through a series of collaborative genome-wide association studies. GAIN has used new approaches for project selection, data deposition and distribution, collaborative analysis, publication and protection from premature intellectual property claims. These demonstrate a new commitment to shared scientific knowledge that should facilitate rapid advances in understanding the genetics of complex diseases. 相似文献
157.
Cia Ramström Hugh Chapman Tero Viitanen Emad Afrasiabi Heli Fox Johanna Kivelä Sanna Soini Laura Korhonen Dan Lindholm Michael Pasternack Kid Törnquist 《Cellular and molecular life sciences : CMLS》2010,67(1):157-169
The HERG (KCNH2) channel is a voltage-sensitive potassium channel mainly expressed in cardiac tissue, but has also been identified in other tissues like neuronal and smooth muscle tissue, and in various tumours and tumour cell lines. The function of HERG has been extensively studied, but it is still not clear what mechanisms regulate the surface expression of the channel. In the present report, using human embryonic kidney cells stably expressing HERG, we show that diacylglycerol potently inhibits the HERG current. This is mediated by a protein kinase C-evoked endocytosis of the channel protein, and is dependent on the dynein–dynamin complex. The HERG protein was found to be located only in early endosomes and not lysosomes. Thus, diacylglycerol is an important lipid participating in the regulation of HERG surface expression and function. 相似文献
158.
Yu TW Mochida GH Tischfield DJ Sgaier SK Flores-Sarnat L Sergi CM Topçu M McDonald MT Barry BJ Felie JM Sunu C Dobyns WB Folkerth RD Barkovich AJ Walsh CA 《Nature genetics》2010,42(11):1015-1020
Genes associated with human microcephaly, a condition characterized by a small brain, include critical regulators of proliferation, cell fate and DNA repair. We describe a syndrome of congenital microcephaly and diverse defects in cerebral cortical architecture. Genome-wide linkage analysis in two families identified a 7.5-Mb locus on chromosome 19q13.12 containing 148 genes. Targeted high throughput sequence analysis of linked genes in each family yielded > 4,000 DNA variants and implicated a single gene, WDR62, as harboring potentially deleterious changes. We subsequently identified additional WDR62 mutations in four other families. Magnetic resonance imaging and postmortem brain analysis supports important roles for WDR62 in the proliferation and migration of neuronal precursors. WDR62 is a WD40 repeat-containing protein expressed in neuronal precursors as well as in postmitotic neurons in the developing brain and localizes to the spindle poles of dividing cells. The diverse phenotypes of WDR62 suggest it has central roles in many aspects of cerebral cortical development. 相似文献
159.
160.
Walker LM Huber M Doores KJ Falkowska E Pejchal R Julien JP Wang SK Ramos A Chan-Hui PY Moyle M Mitcham JL Hammond PW Olsen OA Phung P Fling S Wong CH Phogat S Wrin T Simek MD;Protocol G Principal Investigators Koff WC Wilson IA Burton DR Poignard P 《Nature》2011,477(7365):466-470
Broadly neutralizing antibodies against highly variable viral pathogens are much sought after to treat or protect against global circulating viruses. Here we probed the neutralizing antibody repertoires of four human immunodeficiency virus (HIV)-infected donors with remarkably broad and potent neutralizing responses and rescued 17 new monoclonal antibodies that neutralize broadly across clades. Many of the new monoclonal antibodies are almost tenfold more potent than the recently described PG9, PG16 and VRC01 broadly neutralizing monoclonal antibodies and 100-fold more potent than the original prototype HIV broadly neutralizing monoclonal antibodies. The monoclonal antibodies largely recapitulate the neutralization breadth found in the corresponding donor serum and many recognize novel epitopes on envelope (Env) glycoprotein gp120, illuminating new targets for vaccine design. Analysis of neutralization by the full complement of anti-HIV broadly neutralizing monoclonal antibodies now available reveals that certain combinations of antibodies should offer markedly more favourable coverage of the enormous diversity of global circulating viruses than others and these combinations might be sought in active or passive immunization regimes. Overall, the isolation of multiple HIV broadly neutralizing monoclonal antibodies from several donors that, in aggregate, provide broad coverage at low concentrations is a highly positive indicator for the eventual design of an effective antibody-based HIV vaccine. 相似文献