全文获取类型
收费全文 | 25483篇 |
免费 | 52篇 |
国内免费 | 89篇 |
专业分类
系统科学 | 105篇 |
丛书文集 | 259篇 |
教育与普及 | 60篇 |
理论与方法论 | 116篇 |
现状及发展 | 10844篇 |
研究方法 | 1163篇 |
综合类 | 12601篇 |
自然研究 | 476篇 |
出版年
2013年 | 187篇 |
2012年 | 410篇 |
2011年 | 871篇 |
2010年 | 179篇 |
2008年 | 478篇 |
2007年 | 491篇 |
2006年 | 497篇 |
2005年 | 505篇 |
2004年 | 512篇 |
2003年 | 454篇 |
2002年 | 439篇 |
2001年 | 746篇 |
2000年 | 720篇 |
1999年 | 515篇 |
1992年 | 454篇 |
1991年 | 345篇 |
1990年 | 398篇 |
1989年 | 388篇 |
1988年 | 391篇 |
1987年 | 397篇 |
1986年 | 346篇 |
1985年 | 497篇 |
1984年 | 372篇 |
1983年 | 288篇 |
1982年 | 313篇 |
1981年 | 273篇 |
1980年 | 328篇 |
1979年 | 756篇 |
1978年 | 574篇 |
1977年 | 574篇 |
1976年 | 507篇 |
1975年 | 587篇 |
1974年 | 658篇 |
1973年 | 640篇 |
1972年 | 692篇 |
1971年 | 737篇 |
1970年 | 934篇 |
1969年 | 784篇 |
1968年 | 801篇 |
1967年 | 754篇 |
1966年 | 675篇 |
1965年 | 467篇 |
1964年 | 136篇 |
1959年 | 265篇 |
1958年 | 481篇 |
1957年 | 318篇 |
1956年 | 294篇 |
1955年 | 245篇 |
1954年 | 258篇 |
1948年 | 215篇 |
排序方式: 共有10000条查询结果,搜索用时 218 毫秒
41.
Edouard T Montagner A Dance M Conte F Yart A Parfait B Tauber M Salles JP Raynal P 《Cellular and molecular life sciences : CMLS》2007,64(13):1585-1590
Activating and inactivating mutations of SHP-2 are responsible, respectively, for the Noonan (NS) and the LEOPARD (LS) syndromes.
Clinically, these developmental disorders overlap greatly, resulting in the apparent paradox of similar diseases caused by
mutations that oppositely influence SHP-2 phosphatase activity. While the mechanisms remain unclear, recent functional analysis
of SHP-2, along with the identification of other genes involved in NS and in other related syndromes (neurofibromatosis-1,
Costello and cardio-facio-cutaneous syndromes), strongly suggest that Ras/MAPK represents the major signaling pathway deregulated
by SHP-2 mutants. We discuss the idea that, with the exception of LS mutations that have been shown to exert a dominant negative
effect, all disease-causing mutations involved in Ras/MAPK-mediated signaling, including SHP-2, might lead to enhanced MAPK
activation. This suggests that a narrow range of MAPK signaling is required for appropriate development. We also discuss the
possibility that LS mutations may not simply exhibit dominant negative activity.
Received 30 November 2006; received after revision 8 February 2007; accepted 13 March 2007 相似文献
42.
Crnković-Mertens I Wagener N Semzow J Gröne EF Haferkamp A Hohenfellner M Butz K Hoppe-Seyler F 《Cellular and molecular life sciences : CMLS》2007,64(9):1137-1144
Cancer cells are typically characterized by apoptosis deficiency. In order to investigate a possible role for the anti-apoptotic
livin gene in renal cell cancer (RCC), we analyzed its expression in tumor tissue samples and in RCC-derived cell lines. In addition,
we studied the contribution of livin to the apoptotic resistance of RCC cells by RNA interference (RNAi). Livin gene expression was detected in a significant portion of RCC tumor tissue specimens (13/14, 92.9%) and tumor-derived cell
lines (12/15, 80.0%). Moreover, targeted inhibition of livin by RNAi markedly sensitized RCC cells towards proapoptotic stimuli, such as UV irradiation or the chemotherapeutic drugs
etoposide, 5-fluorouracil, and vinblastine. These effects were specific for livin expressing tumor cells. We conclude that livin can contribute significantly to the apoptosis resistance of RCC cells. Targeted inhibition of livin could represent a novel therapeutic strategy to increase the sensitivity of renal cancers towards pro-apoptotic agents.
Received 30 November 2006; received after revision 22 February 2007; accepted 20 March 2007 相似文献
43.
44.
Rogaeva E Meng Y Lee JH Gu Y Kawarai T Zou F Katayama T Baldwin CT Cheng R Hasegawa H Chen F Shibata N Lunetta KL Pardossi-Piquard R Bohm C Wakutani Y Cupples LA Cuenco KT Green RC Pinessi L Rainero I Sorbi S Bruni A Duara R Friedland RP Inzelberg R Hampe W Bujo H Song YQ Andersen OM Willnow TE Graff-Radford N Petersen RC Dickson D Der SD Fraser PE Schmitt-Ulms G Younkin S Mayeux R Farrer LA St George-Hyslop P 《Nature genetics》2007,39(2):168-177
The recycling of the amyloid precursor protein (APP) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid beta peptide (Abeta) in Alzheimer disease. We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset Alzheimer disease. These variants, which occur in at least two different clusters of intronic sequences within the SORL1 gene (also known as LR11 or SORLA) may regulate tissue-specific expression of SORL1. We also show that SORL1 directs trafficking of APP into recycling pathways and that when SORL1 is underexpressed, APP is sorted into Abeta-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease. 相似文献
45.
Péterfy M Ben-Zeev O Mao HZ Weissglas-Volkov D Aouizerat BE Pullinger CR Frost PH Kane JP Malloy MJ Reue K Pajukanta P Doolittle MH 《Nature genetics》2007,39(12):1483-1487
Hypertriglyceridemia is a hallmark of many disorders, including metabolic syndrome, diabetes, atherosclerosis and obesity. A well-known cause is the deficiency of lipoprotein lipase (LPL), a key enzyme in plasma triglyceride hydrolysis. Mice carrying the combined lipase deficiency (cld) mutation show severe hypertriglyceridemia owing to a decrease in the activity of LPL and a related enzyme, hepatic lipase (HL), caused by impaired maturation of nascent LPL and hepatic lipase polypeptides in the endoplasmic reticulum (ER). Here we identify the gene containing the cld mutation as Tmem112 and rename it Lmf1 (Lipase maturation factor 1). Lmf1 encodes a transmembrane protein with an evolutionarily conserved domain of unknown function that localizes to the ER. A human subject homozygous for a deleterious mutation in LMF1 also shows combined lipase deficiency with concomitant hypertriglyceridemia and associated disorders. Thus, through its profound effect on lipase activity, LMF1 emerges as an important candidate gene in hypertriglyceridemia. 相似文献
46.
1 Results The development of the concepts of nanotechnology has given an important impact on the design of new polymer based materials which are in most cases characterized by a multiphase morphology. When at least one phase has nanometric dimension(s) the system can be considered as a nanocomposite where the interface is not only determining for the adhesion but also may play a role in some bulk properties. Indeed in nanostructured multiphase solids the interface is significant as a bulk component. The... 相似文献
47.
48.
Human cytomegalovirus UL97 open reading frame encodes a protein that phosphorylates the antiviral nucleoside analogue ganciclovir. 总被引:32,自引:0,他引:32
Human cytomegalovirus (HCMV, a betaherpes virus) is the cause of serious disease in immunologically compromised individuals, including those with acquired immunodeficiency syndrome. One of the compounds used in the chemotherapy of HCMV infections is the nucleoside analogue 9-(1,3-dihydroxy-2-propoxymethyl)-guanine (ganciclovir). The mechanism of action of this drug is dependent on the formation of the nucleoside triphosphate, which is a strong inhibitor of the viral DNA polymerase. Thymidine kinase, which is encoded by many of the herpesviruses, catalyses the initial phosphorylation of ganciclovir. But there is no evidence for the coding of this enzyme by HCMV, and DNA sequence analysis of the HCMV genome has shown that there is no open reading frame characteristic of a herpesvirus thymidine kinase. Here we present biochemical and immunological evidence that the HCMV UL97 open reading frame codes for a protein capable of phosphorylating ganciclovir. This protein seems to be responsible for the selectivity of ganciclovir and will be useful tool in the understanding and refinement of the antiviral activity of new selective anti-HCMV compounds. 相似文献
49.
50.
DNA fingerprinting transforms the art of cell authentication. 总被引:4,自引:0,他引:4
The increasing diversity of new cell cultures is seriously stretching the capabilities of traditional methods of identification. DNA fingerprinting is set to play an important role in increasing confidence in the authenticity of cultures in research and industry. 相似文献