全文获取类型
收费全文 | 17262篇 |
免费 | 26篇 |
国内免费 | 67篇 |
专业分类
系统科学 | 123篇 |
丛书文集 | 288篇 |
教育与普及 | 43篇 |
理论与方法论 | 63篇 |
现状及发展 | 7398篇 |
研究方法 | 908篇 |
综合类 | 8269篇 |
自然研究 | 263篇 |
出版年
2013年 | 112篇 |
2012年 | 298篇 |
2011年 | 566篇 |
2010年 | 104篇 |
2009年 | 99篇 |
2008年 | 316篇 |
2007年 | 360篇 |
2006年 | 376篇 |
2005年 | 376篇 |
2004年 | 376篇 |
2003年 | 323篇 |
2002年 | 320篇 |
2001年 | 609篇 |
2000年 | 571篇 |
1999年 | 388篇 |
1992年 | 325篇 |
1991年 | 264篇 |
1990年 | 279篇 |
1989年 | 253篇 |
1988年 | 235篇 |
1987年 | 280篇 |
1986年 | 291篇 |
1985年 | 319篇 |
1984年 | 280篇 |
1983年 | 222篇 |
1982年 | 182篇 |
1981年 | 195篇 |
1980年 | 249篇 |
1979年 | 566篇 |
1978年 | 432篇 |
1977年 | 425篇 |
1976年 | 314篇 |
1975年 | 349篇 |
1974年 | 515篇 |
1973年 | 437篇 |
1972年 | 428篇 |
1971年 | 519篇 |
1970年 | 688篇 |
1969年 | 484篇 |
1968年 | 399篇 |
1967年 | 487篇 |
1966年 | 398篇 |
1965年 | 282篇 |
1959年 | 162篇 |
1958年 | 268篇 |
1957年 | 207篇 |
1956年 | 180篇 |
1955年 | 144篇 |
1954年 | 150篇 |
1948年 | 126篇 |
排序方式: 共有10000条查询结果,搜索用时 328 毫秒
401.
Twigger SN Pruitt KD Fernández-Suárez XM Karolchik D Worley KC Maglott DR Brown G Weinstock G Gibbs RA Kent J Birney E Jacob HJ 《Nature genetics》2008,40(5):523-527
It has been four years since the original publication of the draft sequence of the rat genome. Five groups are now working together to assemble, annotate and release an updated version of the rat genome. As the prevailing model for physiology, complex disease and pharmacological studies, there is an acute need for the rat's genomic resources to keep pace with the rat's prominence in the laboratory. In this commentary, we describe the current status of the rat genome sequence and the plans for its impending 'upgrade'. We then cover the key online resources providing access to the rat genome, including the new SNP views at Ensembl, the RefSeq and Genes databases at the US National Center for Biotechnology Information, Genome Browser at the University of California Santa Cruz and the disease portals for cardiovascular disease and obesity at the Rat Genome Database. 相似文献
402.
喜马拉雅山中段达索普粒雪芯中夏季风和尘埃信号记录研究 总被引:8,自引:2,他引:6
通过粒雪芯δ^18O和主要离子(Ca^2+,Mg^2+,NH^+4,SO^2-4和NO^-3)的分析表明,该粒雪芯年平均积累量为0.75m水当量。粒雪芯中δ^18O和主要离子浓度的季节变化表明,达索普冰川中高精度的记录了现代夏季风和尘埃信号。夏季风期间降水中δ^18O值由“降水量效应”所控制,雪层中较低δ^18O值则代表了夏季风信号。亚洲中部干旱半干旱区的春季尘暴输入是造成粒雪芯中Ca^2+,Mg 相似文献
403.
Evolution of neoplastic cell lineages in Barrett oesophagus. 总被引:20,自引:0,他引:20
M T Barrett C A Sanchez L J Prevo D J Wong P C Galipeau T G Paulson P S Rabinovitch B J Reid 《Nature genetics》1999,22(1):106-109
It has been hypothesized that neoplastic progression develops as a consequence of an acquired genetic instability and the subsequent evolution of clonal populations with accumulated genetic errors. Accordingly, human cancers and some premalignant lesions contain multiple genetic abnormalities not present in the normal tissues from which the neoplasms arose. Barrett oesophagus (BE) is a premalignant condition which predisposes to oesophageal adenocarcinoma (EA) that can be biopsied prospectively over time because endoscopic surveillance is recommended for early detection of cancer. In addition, oesophagectomy specimens frequently contain the premalignant epithelium from which the cancer arose. Neoplastic progression in BE is associated with alterations in TP53 (also known as p53) and CDKN2A (also known as p16) and non-random losses of heterozygosity (LOH). Aneuploid or increased 4N populations occur in more than 90-95% of EAs, arise in premalignant epithelium and predict progression. We have previously shown in small numbers of patients that disruption of TP53 and CDKN2A typically occurs before aneuploidy and cancer. Here, we determine the evolutionary relationships of non-random LOH, TP53 and CDKN2A mutations, CDKN2A CpG-island methylation and ploidy during neoplastic progression. Diploid cell progenitors with somatic genetic or epigenetic abnormalities in TP53 and CDKN2A were capable of clonal expansion, spreading to large regions of oesophageal mucosa. The subsequent evolution of neoplastic progeny frequently involved bifurcations and LOH at 5q, 13q and 18q that occurred in no obligate order relative to each other, DNA-content aneuploidy or cancer. Our results indicate that clonal evolution is more complex than predicted by linear models. 相似文献
404.
Increasing evidence implies altered signaling through the neurotrophic receptor tyrosine kinase TrkB in promoting tumor formation
and metastasis. TrkB, sometimes in conjunction with its primary ligand BDNF, is often overexpressed in a variety of human
cancers, ranging from neuroblastomas to pancreatic ductal adenocarcinomas, in which it may allow tumor expansion and contribute
to resistance to anti-tumor agents. In vitro, TrkB acts as a potent suppressor of anoikis (detachment-induced apoptosis), which is associated with the acquisition of
an aggressive tumorigenic and metastatic phenotype in vivo. In view of its predicted contribution to tumorigenicity and metastasis in humans, TrkB corresponds to a potential drug target,
and preclinical models have already been established. The encouraging results of pharmacological Trk inhibitors in tumor xenograft
models suggest that TrkB inhibition may represent a promising novel anti-tumor therapeutic strategy. This hypothesis is currently
being evaluated in clinical trials. Here, we will discuss the latest developments on TrkB in these contexts as well as highlight
some critical questions that remain to be addressed for evaluating TrkB as a therapeutic target in cancer.
Received 12 October 2005; received after revision 19 December 2005; accepted 11 January 2006 相似文献
405.
In human patients, blood coagulation disorders often associate with cancer, even in its early stages. Recently, in vitro and in vivo experimental models have shown that oncogene expression, or inactivation of tumour suppressor genes, upregulate genes that
control blood coagulation. These studies suggest that activation of blood clotting, leading to peritumoral fibrin deposition,
is instrumental in cancer development. Fibrin can indeed build up a provisional matrix, supporting the invasive growth of
neoplastic tissues and blood vessels. Interference with blood coagulation can thus be considered as part of a multifaceted
therapeutic approach to cancer.
Received 30 November 2005; received after revision 7 February 2005; accepted 8 February 2006 相似文献
406.
On the basis of evidence collected from the literature, we propose a general model by which protein kinase (PK) A and the
different PKC isoforms can inversely affect cell growth. Molecular switches, which are able to direct the signal towards antiproliferative
or mitogenic pathways, are the different isoforms of Raf and PKC. Conflicting data are also reported and discussed in an attempt
to reconcile them.
Received 10 November 2005; received after revision 28 December 2005; accepted 3 January 2006 相似文献
407.
Foser S Redwanz I Ebeling M Heizmann CW Certa U 《Cellular and molecular life sciences : CMLS》2006,63(19-20):2387-2396
A hallmark of resistance to type I interferons (IFNs) is the lack of antiproliferative responses. We show here that costimulation with IFN-alpha and transforming growth factor beta-1 (TGF-beta) potentiates antiproliferative activity in a sensitive (ME15) and resistant (D10) human melanoma cell line. A DNA microarray-based search for proliferation control genes involved that are cooperatively activated by IFN-alpha and TGF-beta, yielded 28 genes. Among these are the insulin-like growth factor-binding protein 3 (IGFBP3) and the calcium-binding protein S100A2; we demonstrate, that recombinant IGFBP3 protein is a potent growth inhibitor requiring TGF-beta activity. The antiproliferative activity of S100A2 is significantly enhanced by IFN-alpha in stably transfected ME15 or D10 cell lines. We show for the first time that IFN-alpha is a potent inducer of intracellular calcium release required for activation of S100A2. Our study provides a functional link between IFN-alpha and TGF-beta signaling and extends the function of IFN signaling to calcium-sensitive processes. 相似文献
408.
Catassi A Cesario A Arzani D Menichini P Alama A Bruzzo C Imperatori A Rotolo N Granone P Russo P 《Cellular and molecular life sciences : CMLS》2006,63(19-20):2377-2386
The effects of different marine derived agents were studied in A549 cell growth. These drugs induced cell cycle arrest at the G2-M phase associated with the up-regulation of GADD45alpha-gamma and down-regulation of c-Myc. In treated cells, GADD45alpha-gamma and c-Myc were up- and down-regulated, respectively. A cascade of events leading to apoptotic mitochondrial 'intrinsic' pathway was observed in treated cells: (1) dephosphorylation of BAD serine136; (2) BAD dissociation from 14-3-3 followed by its association with BCL-XL; (3) cytochrome c release; (4) caspase-3 activation, and (5) cleavage of vimentin. Caspase(s) inhibitor prevented the formation of cleavage products and, in turn, apoptosis was inhibited through a p53-independent mechanism. Moreover, these compounds did not activate NF-kappaB. Our findings may offer new insights into the mechanisms of action of these agents in A549 cells. The better understanding of their effects might be important to fully exploit the potential of these new drugs. 相似文献
409.
Horvath A Boikos S Giatzakis C Robinson-White A Groussin L Griffin KJ Stein E Levine E Delimpasi G Hsiao HP Keil M Heyerdahl S Matyakhina L Libè R Fratticci A Kirschner LS Cramer K Gaillard RC Bertagna X Carney JA Bertherat J Bossis I Stratakis CA 《Nature genetics》2006,38(7):794-800
Phosphodiesterases (PDEs) regulate cyclic nucleotide levels. Increased cyclic AMP (cAMP) signaling has been associated with PRKAR1A or GNAS mutations and leads to adrenocortical tumors and Cushing syndrome. We investigated the genetic source of Cushing syndrome in individuals with adrenocortical hyperplasia that was not caused by known defects. We performed genome-wide SNP genotyping, including the adrenocortical tumor DNA. The region with the highest probability to harbor a susceptibility gene by loss of heterozygosity (LOH) and other analyses was 2q31-2q35. We identified mutations disrupting the expression of the PDE11A isoform-4 gene (PDE11A) in three kindreds. Tumor tissues showed 2q31-2q35 LOH, decreased protein expression and high cyclic nucleotide levels and cAMP-responsive element binding protein (CREB) phosphorylation. PDE11A codes for a dual-specificity PDE that is expressed in adrenal cortex and is partially inhibited by tadalafil and other PDE inhibitors; its germline inactivation is associated with adrenocortical hyperplasia, suggesting another means by which dysregulation of cAMP signaling causes endocrine tumors. 相似文献
410.
Consonni C Humphry ME Hartmann HA Livaja M Durner J Westphal L Vogel J Lipka V Kemmerling B Schulze-Lefert P Somerville SC Panstruga R 《Nature genetics》2006,38(6):716-720
In the fungal phylum Ascomycota, the ability to cause disease in plants and animals has been gained and lost repeatedly during phylogenesis. In monocotyledonous barley, loss-of-function mlo alleles result in effective immunity against the Ascomycete Blumeria graminis f. sp. hordei, the causal agent of powdery mildew disease. However, mlo-based disease resistance has been considered a barley-specific phenomenon to date. Here, we demonstrate a conserved requirement for MLO proteins in powdery mildew pathogenesis in the dicotyledonous plant species Arabidopsis thaliana. Epistasis analysis showed that mlo resistance in A. thaliana does not involve the signaling molecules ethylene, jasmonic acid or salicylic acid, but requires a syntaxin, glycosyl hydrolase and ABC transporter. These findings imply that a common host cell entry mechanism of powdery mildew fungi evolved once and at least 200 million years ago, suggesting that within the Erysiphales (powdery mildews) the ability to cause disease has been a stable trait throughout phylogenesis. 相似文献