全文获取类型
收费全文 | 10189篇 |
免费 | 25篇 |
国内免费 | 37篇 |
专业分类
系统科学 | 30篇 |
丛书文集 | 48篇 |
教育与普及 | 30篇 |
理论与方法论 | 24篇 |
现状及发展 | 3961篇 |
研究方法 | 522篇 |
综合类 | 5468篇 |
自然研究 | 168篇 |
出版年
2012年 | 151篇 |
2011年 | 325篇 |
2010年 | 60篇 |
2009年 | 54篇 |
2008年 | 168篇 |
2007年 | 208篇 |
2006年 | 192篇 |
2005年 | 214篇 |
2004年 | 210篇 |
2003年 | 190篇 |
2002年 | 205篇 |
2001年 | 429篇 |
2000年 | 437篇 |
1999年 | 294篇 |
1996年 | 52篇 |
1994年 | 269篇 |
1992年 | 252篇 |
1991年 | 201篇 |
1990年 | 230篇 |
1989年 | 192篇 |
1988年 | 185篇 |
1987年 | 190篇 |
1986年 | 201篇 |
1985年 | 264篇 |
1984年 | 201篇 |
1983年 | 163篇 |
1982年 | 135篇 |
1981年 | 140篇 |
1980年 | 144篇 |
1979年 | 325篇 |
1978年 | 263篇 |
1977年 | 215篇 |
1976年 | 191篇 |
1975年 | 195篇 |
1974年 | 206篇 |
1973年 | 176篇 |
1972年 | 206篇 |
1971年 | 245篇 |
1970年 | 303篇 |
1969年 | 229篇 |
1968年 | 226篇 |
1967年 | 194篇 |
1966年 | 223篇 |
1965年 | 149篇 |
1959年 | 75篇 |
1958年 | 123篇 |
1957年 | 81篇 |
1956年 | 58篇 |
1954年 | 62篇 |
1948年 | 57篇 |
排序方式: 共有10000条查询结果,搜索用时 203 毫秒
201.
Kalay E Yigit G Aslan Y Brown KE Pohl E Bicknell LS Kayserili H Li Y Tüysüz B Nürnberg G Kiess W Koegl M Baessmann I Buruk K Toraman B Kayipmaz S Kul S Ikbal M Turner DJ Taylor MS Aerts J Scott C Milstein K Dollfus H Wieczorek D Brunner HG Hurles M Jackson AP Rauch A Nürnberg P Karagüzel A Wollnik B 《Nature genetics》2011,43(1):23-26
Functional impairment of DNA damage response pathways leads to increased genomic instability. Here we describe the centrosomal protein CEP152 as a new regulator of genomic integrity and cellular response to DNA damage. Using homozygosity mapping and exome sequencing, we identified CEP152 mutations in Seckel syndrome and showed that impaired CEP152 function leads to accumulation of genomic defects resulting from replicative stress through enhanced activation of ATM signaling and increased H2AX phosphorylation. 相似文献
202.
Sulem P Gudbjartsson DF Walters GB Helgadottir HT Helgason A Gudjonsson SA Zanon C Besenbacher S Bjornsdottir G Magnusson OT Magnusson G Hjartarson E Saemundsdottir J Gylfason A Jonasdottir A Holm H Karason A Rafnar T Stefansson H Andreassen OA Pedersen JH Pack AI de Visser MC Kiemeney LA Geirsson AJ Eyjolfsson GI Olafsson I Kong A Masson G Jonsson H Thorsteinsdottir U Jonsdottir I Stefansson K 《Nature genetics》2011,43(11):1127-1130
We tested 16 million SNPs, identified through whole-genome sequencing of 457 Icelanders, for association with gout and serum uric acid levels. Genotypes were imputed into 41,675 chip-genotyped Icelanders and their relatives, for effective sample sizes of 968 individuals with gout and 15,506 individuals for whom serum uric acid measurements were available. We identified a low-frequency missense variant (c.1580C>G) in ALDH16A1 associated with gout (OR = 3.12, P = 1.5 × 10(-16), at-risk allele frequency = 0.019) and serum uric acid levels (effect = 0.36 s.d., P = 4.5 × 10(-21)). We confirmed the association with gout by performing Sanger sequencing on 6,017 Icelanders. The association with gout was stronger in males relative to females. We also found a second variant on chromosome 1 associated with gout (OR = 1.92, P = 0.046, at-risk allele frequency = 0.986) and serum uric acid levels (effect = 0.48 s.d., P = 4.5 × 10(-16)). This variant is close to a common variant previously associated with serum uric acid levels. This work illustrates how whole-genome sequencing data allow the detection of associations between low-frequency variants and complex traits. 相似文献
203.
204.
205.
Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease 总被引:1,自引:0,他引:1
Naj AC Jun G Beecham GW Wang LS Vardarajan BN Buros J Gallins PJ Buxbaum JD Jarvik GP Crane PK Larson EB Bird TD Boeve BF Graff-Radford NR De Jager PL Evans D Schneider JA Carrasquillo MM Ertekin-Taner N Younkin SG Cruchaga C Kauwe JS Nowotny P Kramer P Hardy J Huentelman MJ Myers AJ Barmada MM Demirci FY Baldwin CT Green RC Rogaeva E St George-Hyslop P Arnold SE Barber R Beach T Bigio EH Bowen JD Boxer A Burke JR Cairns NJ Carlson CS Carney RM Carroll SL Chui HC Clark DG Corneveaux J Cotman CW 《Nature genetics》2011,43(5):436-441
The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility. 相似文献
206.
Yun Liu Zeyao Zhu Idy H. T. Ho Yujian Shi Yuxin Xie Jianzhen Li Yong Zhang Matthew T. V. Chan Christopher H. K. Cheng 《Cellular and molecular life sciences : CMLS》2017,74(13):2503-2511
Zebrafish is an important model to study developmental biology and human diseases. However, an effective approach to achieve spatial and temporal gene knockout in zebrafish has not been well established. In this study, we have developed a new approach, namely bacterial artificial chromosome-rescue-based knockout (BACK), to achieve conditional gene knockout in zebrafish using the Cre/loxP system. We have successfully deleted the DiGeorge syndrome critical region gene 8 (dgcr8) in zebrafish germ line and demonstrated that the maternal-zygotic dgcr8 (MZdgcr8) embryos exhibit MZdicer-like phenotypes with morphological defects which could be rescued by miR-430, indicating that canonical microRNAs play critical role in early development. Our findings establish that Cre/loxP-mediated tissue-specific gene knockout could be achieved using this BACK strategy and that canonical microRNAs play important roles in early embryonic development in zebrafish. 相似文献
207.
G. M. C. Janssen P. Schwertman T. A. T. Wanga R. S. Jahangir Tafrechi P. J. A. van den Broek A. K. Raap 《Cellular and molecular life sciences : CMLS》2009,66(4):721-730
Cytoplasmic translation is under sophisticated control but how cells adapt its rate to constitutive loss of mitochondrial
oxidative phosphorylation is unknown. Here we show that translation is repressed in cells with the pathogenic A3243G mtDNA
mutation or in mtDNA-less ρ0 cells by at least two distinct pathways, one transiently targeting elongation factor eEF-2 and the other initiation factor
eIF-2α constitutively. Under conditions of exponential cell growth and mammalian target of rapamycin (mTOR) activation, eEF-2
becomes transiently phosphorylated by an AMP-activated protein kinase (AMPK)-dependent pathway, especially high in mutant
cells. Independent of AMPK and mTOR, eIF-2α is constitutively phosphorylated in mutant cells, likely a signature of endoplasmic
reticulum (ER)-stress response induced by the loss of oxidative phosphorylation. While the AMPK/eEF-2K/eEF-2 pathway appears
to function in adaptation to physiological fluctuations in ATP levels in the mutant cells, the ER stress signified by constitutive
protein synthesis inhibition through eIF-2α-mediated repression of translation initiation may have pathobiochemical consequences.
Received 29 October 2008; received after revision 11 December 2008; accepted 16 December 2008 相似文献
208.
Wolfs JL Comfurius P Bekers O Zwaal RF Balasubramanian K Schroit AJ Lindhout T Bevers EM 《Cellular and molecular life sciences : CMLS》2009,66(2):314-323
The exposure of phosphatidylserine (PS) at the cell surface plays a critical role in blood coagulation and serves as a macrophage
recognition moiety for the engulfment of apoptotic cells. Previous observations have shown that a high extracellular [K+] and selective K+ channel blockers inhibit PS exposure in platelets and erythrocytes. Here we show that the rate of PS exposure in erythrocytes
decreases by ~50% when the intracellular [K+] increases from 0 to physiological concentrations. Using resealed erythrocyte membranes, we further show that lipid scrambling
is inducible by raising the intracellular [Ca2+] and that K+ ions have a direct inhibitory effect on this process. Lipid scrambling in resealed ghosts occurs in the absence of cell shrinkage
and microvesicle formation, processes that are generally attributed to Ca2+-induced lipid scrambling in intact erythrocytes. Thus, opening of Ca2+-sensitive K+ channels causes loss of intracellular K+ that results in reduced intrinsic inhibitory effect of these ions on scramblase activity.
Received 11 September 2008; received after revision 17 October 2008; accepted 27 October 2008 相似文献
209.
V. Sala S. Bergerone S. Gatti S. Gallo A. Ponzetto C. Ponzetto T. Crepaldi 《Cellular and molecular life sciences : CMLS》2014,71(8):1439-1452
MicroRNAs (miRNAs) are natural, single-stranded, small RNA molecules which subtly control gene expression. Several studies indicate that specific miRNAs can regulate heart function both in development and disease. Despite prevention programs and new therapeutic agents, cardiovascular disease remains the main cause of death in developed countries. The elevated number of heart failure episodes is mostly due to myocardial infarction (MI). An increasing number of studies have been carried out reporting changes in miRNAs gene expression and exploring their role in MI and heart failure. In this review, we furnish a critical analysis of where the frontier of knowledge has arrived in the fields of basic and translational research on miRNAs in cardiac ischemia. We first summarize the basal information on miRNA biology and regulation, especially concentrating on the feedback loops which control cardiac-enriched miRNAs. A focus on the role of miRNAs in the pathogenesis of myocardial ischemia and in the attenuation of injury is presented. Particular attention is given to cardiomyocyte death (apoptosis and necrosis), fibrosis, neovascularization, and heart failure. Then, we address the potential of miR-diagnosis (miRNAs as disease biomarkers) and miR-drugs (miRNAs as therapeutic targets) for cardiac ischemia and heart failure. Finally, we evaluate the use of miRNAs in the emerging field of regenerative medicine. 相似文献
210.
Nikolina Vlatković Mark T. Boyd Carlos P. Rubbi 《Cellular and molecular life sciences : CMLS》2014,71(5):771-791
Nucleoli perform a crucial cell function, ribosome biogenesis, and of critical relevance to the subject of this review, they are also extremely sensitive to cellular stresses, which can cause loss of function and/or associated structural disruption. In recent years, we have learned that cells take advantage of this stress sensitivity of nucleoli, using them as stress sensors. One major protein regulated by this role of nucleoli is the tumor suppressor p53, which is activated in response to diverse cellular injuries in order to exert its onco-protective effects. Here we discuss a model of nucleolar regulation of p53, which proposes that key steps in the promotion of p53 degradation by the ubiquitin ligase MDM2 occur in nucleoli, thus providing an explanation for the observed link between nucleolar disruption and p53 stability. We review current evidence for this compartmentalization in p53 homeostasis and highlight current limitations of the model. Interestingly, a number of current chemotherapeutic agents capable of inducing a p53 response are likely to do so by targeting nucleolar functions and these compounds may serve to inform further improved therapeutic targeting of nucleoli. 相似文献