全文获取类型
收费全文 | 5142篇 |
免费 | 586篇 |
国内免费 | 2篇 |
出版年
2021年 | 47篇 |
2018年 | 39篇 |
2017年 | 40篇 |
2016年 | 69篇 |
2015年 | 134篇 |
2014年 | 173篇 |
2013年 | 203篇 |
2012年 | 236篇 |
2011年 | 233篇 |
2010年 | 162篇 |
2009年 | 139篇 |
2008年 | 242篇 |
2007年 | 241篇 |
2006年 | 258篇 |
2005年 | 224篇 |
2004年 | 255篇 |
2003年 | 236篇 |
2002年 | 207篇 |
2001年 | 87篇 |
2000年 | 63篇 |
1999年 | 68篇 |
1998年 | 65篇 |
1997年 | 51篇 |
1996年 | 58篇 |
1995年 | 50篇 |
1994年 | 55篇 |
1993年 | 68篇 |
1992年 | 73篇 |
1991年 | 67篇 |
1990年 | 67篇 |
1989年 | 69篇 |
1988年 | 57篇 |
1987年 | 60篇 |
1986年 | 88篇 |
1985年 | 67篇 |
1984年 | 60篇 |
1983年 | 76篇 |
1982年 | 68篇 |
1981年 | 66篇 |
1980年 | 55篇 |
1979年 | 57篇 |
1978年 | 63篇 |
1977年 | 45篇 |
1976年 | 73篇 |
1975年 | 53篇 |
1974年 | 50篇 |
1973年 | 58篇 |
1972年 | 53篇 |
1971年 | 44篇 |
1969年 | 37篇 |
排序方式: 共有5730条查询结果,搜索用时 119 毫秒
991.
Xinxian Deng Di Kim Nguyen R. Scott Hansen Daniel L. Van Dyke Stanley M. Gartler Christine M. Disteche 《PLoS genetics》2009,5(12)
In mammals, dosage compensation is achieved by doubling expression of X-linked genes in both sexes, together with X inactivation in females. Up-regulation of the active X chromosome may be controlled by DNA sequence–based and/or epigenetic mechanisms that double the X output potentially in response to autosomal factor(s). To determine whether X expression is adjusted depending on ploidy, we used expression arrays to compare X-linked and autosomal gene expression in human triploid cells. While the average X:autosome expression ratio was about 1 in normal diploid cells, this ratio was lower (0.81–0.84) in triploid cells with one active X and higher (1.32–1.4) in triploid cells with two active X''s. Thus, overall X-linked gene expression in triploid cells does not strictly respond to an autosomal factor, nor is it adjusted to achieve a perfect balance. The unbalanced X:autosome expression ratios that we observed could contribute to the abnormal phenotypes associated with triploidy. Absolute autosomal expression levels per gene copy were similar in triploid versus diploid cells, indicating no apparent global effect on autosomal expression. In triploid cells with two active X''s our data support a basic doubling of X-linked gene expression. However, in triploid cells with a single active X, X-linked gene expression is adjusted upward presumably by an epigenetic mechanism that senses the ratio between the number of active X chromosomes and autosomal sets. Such a mechanism may act on a subset of genes whose expression dosage in relation to autosomal expression may be critical. Indeed, we found that there was a range of individual X-linked gene expression in relation to ploidy and that a small subset (∼7%) of genes had expression levels apparently proportional to the number of autosomal sets. 相似文献
992.
Pei Y Hancock PJ Zhang H Bartz R Cherrin C Innocent N Pomerantz CJ Seitzer J Koser ML Abrams MT Xu Y Kuklin NA Burke PA Sachs AB Sepp-Lorenzino L Barnett SF 《RNA (New York, N.Y.)》2010,16(12):2553-2563
Effective small interfering RNA (siRNA)-mediated therapeutics require the siRNA to be delivered into the cellular RNA-induced silencing complex (RISC). Quantitative information of this essential delivery step is currently inferred from the efficacy of gene silencing and siRNA uptake in the tissue. Here we report an approach to directly quantify siRNA in the RISC in rodents and monkey. This is achieved by specific immunoprecipitation of the RISC from tissue lysates and quantification of small RNAs in the immunoprecipitates by stem-loop PCR. The method, expected to be independent of delivery vehicle and target, is label-free, and the throughput is acceptable for preclinical animal studies. We characterized a lipid-formulated siRNA by integrating these approaches and obtained a quantitative perspective on siRNA tissue accumulation, RISC loading, and gene silencing. The described methodologies have utility for the study of silencing mechanism, the development of siRNA therapeutics, and clinical trial design. 相似文献
993.
994.
Background
While in principle a seemingly infinite variety of combinations of mutations could result in tumor development, in practice it appears that most human cancers fall into a relatively small number of "sub-types," each characterized a roughly equivalent sequence of mutations by which it progresses in different patients. There is currently great interest in identifying the common sub-types and applying them to the development of diagnostics or therapeutics. Phylogenetic methods have shown great promise for inferring common patterns of tumor progression, but suffer from limits of the technologies available for assaying differences between and within tumors. One approach to tumor phylogenetics uses differences between single cells within tumors, gaining valuable information about intra-tumor heterogeneity but allowing only a few markers per cell. An alternative approach uses tissue-wide measures of whole tumors to provide a detailed picture of averaged tumor state but at the cost of losing information about intra-tumor heterogeneity. 相似文献995.
Background
Identifying developmental processes regulated by Notch1 can be addressed in part by characterizing mice with graded levels of Notch1 signaling strength. Here we examine development in embryos expressing various combinations of Notch1 mutant alleles. Mice homozygous for the hypomorphic Notch1 12f allele, which removes the single O-fucose glycan in epidermal growth factor-like repeat 12 (EGF12) of the Notch1 ligand binding domain (lbd), exhibit reduced growth after weaning and defective T cell development. Mice homozygous for the inactive Notch1 lbd allele express Notch1 missing an ~20 kDa internal segment including the canonical Notch1 ligand binding domain, and die at embryonic day ~E9.5. The embryonic and vascular phenotypes of compound heterozygous Notch1 12f/lbd embryos were compared with Notch1 +/12f , Notch1 12f/12f , and Notch1 lbd/lbd embryos. Embryonic stem (ES) cells derived from these embryos were also examined in Notch signaling assays. While Notch1 signaling was stronger in Notch1 12f/lbd compound heterozygotes compared to Notch1 lbd/lbd embryos and ES cells, Notch1 signaling was even stronger in embryos carrying Notch1 12f and a null Notch1 allele. 相似文献996.
El Abdellaoui H Varaprasad CV Barawkar D Chakravarty S Maderna A Tam R Chen H Allan M Wu JZ Appleby T Yan S Zhang W Lang S Yao N Hamatake R Hong Z 《Bioorganic & medicinal chemistry letters》2006,16(21):5561-5566
The development of potent, orally bioavailable, and selective series of 5-amino-3-hydroxy-N(1-hydroxypropane-2-yl)isothiazole-4-carboxamidine inhibitors of MEK1 and MEK-2 kinase is described. Optimization of the carboxamidine and the phenoxyaniline group led to the identification of 55 which gave good potency as in vitro MEK1 inhibitors, and good oral exposure in rat. 相似文献
997.
Cbl proteins are regulators of signal transduction through many pathways and, consequently, regulate cell function and development. They are ubiquitin ligases that ubiquitinate and target many signaling molecules for degradation. The Cbl proteins themselves are regulated by an increasingly complex network of interactions that fine-tune the effects that Cbl proteins have on signaling. The negative regulation of Cbl protein function can occur via cis-acting structural elements that prevent inappropriate ubiquitin ligase activity, degradation of the Cbl proteins, inhibition without degradation owing to interaction with other signaling proteins, deubiquitination of Cbl substrates, and regulation of assembly of the endosomal ESCRT-I complex. Defects in the regulatory mechanisms that control Cbl function are implicated in the development of immunological and malignant diseases. 相似文献
998.
999.
1000.
Li C Allen A Kwagh J Doliba NM Qin W Najafi H Collins HW Matschinsky FM Stanley CA Smith TJ 《The Journal of biological chemistry》2006,281(15):10214-10221
Insulin secretion by pancreatic beta-cells is stimulated by glucose, amino acids, and other metabolic fuels. Glutamate dehydrogenase (GDH) has been shown to play a regulatory role in this process. The importance of GDH was underscored by features of hyperinsulinemia/hyperammonemia syndrome, where a dominant mutation causes the loss of inhibition by GTP and ATP. Here we report the effects of green tea polyphenols on GDH and insulin secretion. Of the four compounds tested, epigallocatechin gallate (EGCG) and epicatechin gallate were found to inhibit GDH with nanomolar ED(50) values and were therefore found to be as potent as the physiologically important inhibitor GTP. Furthermore, we have demonstrated that EGCG inhibits BCH-stimulated insulin secretion, a process that is mediated by GDH, under conditions where GDH is no longer inhibited by high energy metabolites. EGCG does not affect glucose-stimulated insulin secretion under high energy conditions where GDH is probably fully inhibited. We have further shown that these compounds act in an allosteric manner independent of their antioxidant activity and that the beta-cell stimulatory effects are directly correlated with glutamine oxidation. These results demonstrate that EGCG, much like the activator of GDH (BCH), can facilitate dissecting the complex regulation of insulin secretion by pharmacologically modulating the effects of GDH. 相似文献