全文获取类型
收费全文 | 9552篇 |
免费 | 864篇 |
国内免费 | 14篇 |
出版年
2023年 | 35篇 |
2022年 | 81篇 |
2021年 | 225篇 |
2020年 | 118篇 |
2019年 | 146篇 |
2018年 | 172篇 |
2017年 | 151篇 |
2016年 | 264篇 |
2015年 | 439篇 |
2014年 | 453篇 |
2013年 | 588篇 |
2012年 | 765篇 |
2011年 | 683篇 |
2010年 | 440篇 |
2009年 | 462篇 |
2008年 | 597篇 |
2007年 | 544篇 |
2006年 | 545篇 |
2005年 | 480篇 |
2004年 | 477篇 |
2003年 | 460篇 |
2002年 | 408篇 |
2001年 | 132篇 |
2000年 | 111篇 |
1999年 | 111篇 |
1998年 | 98篇 |
1997年 | 62篇 |
1996年 | 63篇 |
1995年 | 56篇 |
1994年 | 65篇 |
1993年 | 58篇 |
1992年 | 79篇 |
1991年 | 61篇 |
1990年 | 61篇 |
1989年 | 68篇 |
1988年 | 59篇 |
1987年 | 46篇 |
1986年 | 48篇 |
1985年 | 37篇 |
1984年 | 49篇 |
1983年 | 54篇 |
1982年 | 34篇 |
1981年 | 43篇 |
1980年 | 40篇 |
1979年 | 56篇 |
1977年 | 32篇 |
1976年 | 36篇 |
1975年 | 32篇 |
1974年 | 37篇 |
1973年 | 30篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
961.
Inactivation of Ku-mediated end joining suppresses mec1Delta lethality by depleting the ribonucleotide reductase inhibitor Sml1 through a pathway controlled by Tel1 kinase and the Mre11 complex
下载免费PDF全文
![点击此处可从《Molecular and cellular biology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Corda Y Lee SE Guillot S Walther A Sollier J Arbel-Eden A Haber JE Géli V 《Molecular and cellular biology》2005,25(23):10652-10664
RAD53 and MEC1 are essential Saccharomyces cerevisiae genes required for the DNA replication and DNA damage checkpoint responses. Their lethality can be suppressed by increasing the intracellular pool of deoxynucleotide triphosphates. We report that deletion of YKU70 or YKU80 suppresses mec1Delta, but not rad53Delta, lethality. We show that suppression of mec1Delta lethality is not due to Ku--associated telomeric defects but rather results from the inability of Ku- cells to efficiently repair DNA double strand breaks by nonhomologous end joining. Consistent with these results, mec1Delta lethality is also suppressed by lif1Delta, which like yku70Delta and yku80Delta, prevents nonhomologous end joining. The viability of yku70Delta mec1Delta and yku80Delta mec1Delta cells depends on the ATM-related Tel1 kinase, the Mre11-Rad50-Xrs2 complex, and the DNA damage checkpoint protein Rad9. We further report that this Mec1-independent pathway converges with the Rad53/Dun1-regulated checkpoint kinase cascade and leads to the degradation of the ribonucleotide reductase inhibitor Sml1. 相似文献
962.
Expression of constitutively stable hybrid hypoxia-inducible factor-1alpha protects cultured rat cardiomyocytes against simulated ischemia-reperfusion injury 总被引:13,自引:0,他引:13
963.
Tang V Dhirapong A Yabes AP Weiss RH 《American journal of physiology. Cell physiology》2005,289(1):C199-C206
Atherosclerosis, now considered an inflammatory process, is the leading cause of death in the Western world and is manifested by a variety of diseases in multiple organ systems. Because of its prevalence and associated morbidity, novel therapies directed at arresting this progressive process are urgently needed. The inflammatory mediator TNF-, which is known to contribute to apoptosis in vascular smooth muscle cells, has been shown to be intimately involved in the atherosclerotic process, being present at elevated levels in human atheroma as well as possibly being responsible for plaque rupture, a clinically devastating event. In light of our earlier finding that p73 is a proapoptotic protein in vascular smooth muscle cells, which are involved in plaque progression as well as rupture, we asked whether TNF- mediates apoptosis in these cells through p73. We now show that p73 is present in spindle-shaped cells within human atheroma, and p73, an isoform that is pivotal in both apoptosis and growth suppression, is induced in vascular smooth muscle cells in vitro by serum but not by PDGF-BB. In addition, TNF-, when added to these cells in the presence of serum-containing media, increases p73 expression and causes apoptosis in both rat and human vascular smooth muscle cells. Inhibition of p73 activity with a dominant inhibitory NH2-terminally deleted p73 plasmid results in markedly decreased TNF--induced apoptosis. Thus p73 is likely a mediator of the apoptotic effect of TNF- in the vasculature, such that future targeting of the p73 isoforms may ultimately prove useful in novel atherosclerosis therapies. atherosclerosis; inflammation; plaque 相似文献
964.
Regulatory elements of the melanocortin 1 receptor 总被引:1,自引:0,他引:1
965.
Expanded granular sludge bed-anaerobic filter (EGSB-AF) bioreactors were operated at 15 degrees C for the treatment of 2,4,6-trichlorophenol (TCP)-containing volatile fatty acid (VFA)-based wastewaters. The seed sludge used as inoculum for the control (no TCP) and test reactor was unexposed to chlorophenols (CPs) prior to the 425-day trial. TCP supplementation to the feed at 50 mg TCPl(-1) partially inhibited the anaerobic degradation of the VFA feed measured as COD removal efficiency. However, the withdrawal and subsequent application of stepwise increments to the TCP loading resulted in steady COD removal. Terminal restriction fragment length polymorphism analysis showed Methanosaeta-like Archaea in the control reactor over the experimental period. Different methanogenic populations were detected in the test reactor and responded to the changes in feed composition. Bacterial community analyses indicated changes in the community structure over time and suggested the presence of Campylobacter-like, Acidimicrobium-like and Heliophilum-like organisms in the samples. TCP mineralisation was by a reductive dechlorination pathway through 2,4-dichlorophenol (DCP) and 4-chlorophenol (4-CP) or 2-chlorophenol (2-CP). CP degradation rates in sludge granules from the lower chamber of the hybrid EGSB-AF reactor was in the order TCP > DCP > 4-CP > 2-CP. However, a biodegradability order of lower CPs > TCP was observed in fixed-film biomass taken from the upper reactor chamber, thus reflecting the role of this reactor section in the metabolism of residual lower CPs from the lower sludge-bed stage of operation. 相似文献
966.
Greggio E Bergantino E Carter D Ahmad R Costin GE Hearing VJ Clarimon J Singleton A Eerola J Hellström O Tienari PJ Miller DW Beilina A Bubacco L Cookson MR 《Journal of neurochemistry》2005,93(1):246-256
Tyrosinase is a key enzyme in the synthesis of melanin in skin and hair and has also been proposed to contribute to the formation of neuromelanin (NM). The presence of NM, which is biochemically similar to melanin in peripheral tissues, identifies groups of neurons susceptible in Parkinson's disease (PD). Whether tyrosinase is beneficial or detrimental to neurons is unclear; whilst the enzyme activity of tyrosinase generates dopamine-quinones and other oxidizing compounds, NM may form a sink for such radical species. In the present study, we demonstrated that tyrosinase is expressed at low levels in the human brain. We found that mRNA, protein and enzyme activity are all present but at barely detectable levels. In cell culture systems, expression of tyrosinase increases neuronal susceptibility to oxidizing conditions, including dopamine itself. We related these in vitro observations to the human disease by assessing whether there was any genetic association between the gene encoding tyrosinase and idiopathic PD. We found neither genotypic or haplotypic association with three polymorphic markers of the gene. This argues against a strong genetic association between tyrosinase and PD, although the observed contribution to cellular toxicity suggests that a biochemical association is likely. 相似文献
967.
The characteristics governing the dynamics of populations can evolve and this evolution can either be towards stability or chaos. Yet it is not obvious how or why such population characteristics can evolve through selection on individuals. In this paper we construct a mathematical model, inspired by experimental results, illustrating the dynamics of a population of competing Drosophila. We demonstrate how selection of life history characteristics and stability influence one another as a population interacts with its environment. We generalize this result and show that population stability can evolve as a consequence of selection on individuals. 相似文献
968.
To date, the majority of theoretical models describing the dynamics of infectious diseases in vivo are based on the assumption of well-mixed virus and cell populations. Because many infections take place in solid tissues, spatially structured models represent an important step forward in understanding what happens when the assumption of well-mixed populations is relaxed. Here, we explore models of virus and virus-immune dynamics where dispersal of virus and immune effector cells was constrained to occur locally. The stability properties of our spatial virus-immune dynamics models remained robust under almost all biologically plausible dispersal schemes, regardless of their complexity. The various spatial dynamics were compared to the basic non-spatial dynamics and important differences were identified: When space was assumed to be homogeneous, the dynamics generated by non-spatial and spatially structured models differed substantially at the peak of the infection. Thus, non-spatial models may lead to systematic errors in the estimates of parameters underlying acute infection dynamics. When space was assumed to be heterogeneous, spatial coupling not only changed the equilibrium properties of the uncoupled populations but also equalized the dynamics and thereby reduced the likelihood of dynamic elimination of the infection. In line with experimental and clinical observations, long-lasting oscillation periods were virtually absent. When source-sink dynamics were considered, the long-term outcome of the infection depended critically on the degree of spatial coupling. The infection collapsed when emigration from source sites became too large. Finally, we discuss the implications of spatially structured models on medical treatment of infectious diseases, and note that a huge gap exists in data accurately describing infection dynamics in solid tissues. 相似文献
969.
Hepatitis C virus internal ribosome entry site-dependent translation in Saccharomyces cerevisiae is independent of polypyrimidine tract-binding protein, poly(rC)-binding protein 2, and La protein
下载免费PDF全文
![点击此处可从《Journal of virology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Translation initiation of some viral and cellular mRNAs occurs by ribosome binding to an internal ribosome entry site (IRES). Internal initiation mediated by the hepatitis C virus (HCV) IRES in Saccharomyces cerevisiae was shown by translation of the second open reading frame in a bicistronic mRNA. Introduction of a single base change in the HCV IRES, known to abrogate internal initiation in mammalian cells, abolished translation of the second open reading frame. Internal initiation mediated by the HCV IRES was independent of the nonsense-mediated decay pathway and the cap binding protein eIF4E, indicating that translation is not a result of mRNA degradation or 5'-end-dependent initiation. Human La protein binds the HCV IRES and is required for efficient internal initiation. Disruption of the S. cerevisiae genes that encode La protein orthologs and synthesis of wild-type human La protein in yeast had no effect on HCV IRES-dependent translation. Polypyrimidine tract-binding protein (Ptb) and poly-(rC)-binding protein 2 (Pcbp2), which may be required for HCV IRES-dependent initiation in mammalian cells, are not encoded within the S. cerevisiae genome. HCV IRES-dependent translation in S. cerevisiae was independent of human Pcbp2 protein and stimulated by the presence of human Ptb protein. These findings demonstrate that the genome of S. cerevisiae encodes all proteins necessary for internal initiation of translation mediated by the HCV IRES. 相似文献
970.
Hébrard E Pinel-Galzi A Catherinot V Labesse G Brugidou C Fargette D 《Journal of virology》2005,79(7):4407-4414
Rice yellow mottle virus is classified in five major serotypes; the molecular diversity of the coat protein (CP) is well established, but the amino acids involved in the recognition by discriminant monoclonal antibodies (MAbs) remain unknown. Reconstruction of a phylogenetic tree and sequence alignment of the CP gene of a sample representative of the continental-large diversity were used to identify 10 serospecific amino acids (i.e., conserved in all isolates belonging to the same serotype and distinct in other serotypes). Positions occupied by serospecific residues were localized on the crystal structure of the CP monomer and on modeled capsomers. Structural, molecular, and serological properties of each serotype were analyzed, and subsequently, hypotheses on the potential role of amino acids in discriminating reactions with antibodies were formulated. The residues 114 and 115 (serospecific of Sr1) and 190 (serospecific of Sr2) were localized on the outer surface of the capsid and might be directly involved in the immunoreactivity with MAb D and MAb A, respectively. In contrast, residues 180 (Sr3) and 178 (Sr5) lay within the inner surface of the capsid. To understand the role of these internal positions in the recognition with the antibodies, two substitutions (T180K and G178D) were introduced in the CP of an infectious clone. These mutations modified the antigenicity with MAb G and MAb E discriminating Sr3 and Sr5, respectively, while the reaction with MAb D remained unaffected. This result suggests an indirect effect of these two internal mutations on local immunostructure while the global structure was maintained. 相似文献