全文获取类型
收费全文 | 4585篇 |
免费 | 416篇 |
国内免费 | 1篇 |
出版年
2023年 | 21篇 |
2022年 | 47篇 |
2021年 | 83篇 |
2020年 | 58篇 |
2019年 | 66篇 |
2018年 | 66篇 |
2017年 | 64篇 |
2016年 | 133篇 |
2015年 | 214篇 |
2014年 | 233篇 |
2013年 | 318篇 |
2012年 | 422篇 |
2011年 | 369篇 |
2010年 | 250篇 |
2009年 | 242篇 |
2008年 | 300篇 |
2007年 | 311篇 |
2006年 | 303篇 |
2005年 | 291篇 |
2004年 | 270篇 |
2003年 | 253篇 |
2002年 | 278篇 |
2001年 | 44篇 |
2000年 | 28篇 |
1999年 | 48篇 |
1998年 | 73篇 |
1997年 | 39篇 |
1996年 | 32篇 |
1995年 | 36篇 |
1994年 | 23篇 |
1993年 | 25篇 |
1992年 | 17篇 |
1991年 | 7篇 |
1990年 | 4篇 |
1989年 | 3篇 |
1988年 | 4篇 |
1987年 | 2篇 |
1986年 | 2篇 |
1982年 | 2篇 |
1981年 | 1篇 |
1979年 | 1篇 |
1978年 | 1篇 |
1974年 | 4篇 |
1972年 | 3篇 |
1971年 | 5篇 |
1970年 | 1篇 |
1969年 | 2篇 |
1967年 | 1篇 |
1965年 | 1篇 |
1923年 | 1篇 |
排序方式: 共有5002条查询结果,搜索用时 15 毫秒
91.
Potential for Virus Endogenization in Humans through Testicular Germ Cell Infection: the Case of HIV
92.
Cheng-Jie Duan Arnaud Basl Marcelo Visona Liberato Joseph Gray Sergey A. Nepogodiev Robert A. Field Nathalie Juge Didier Ndeh 《The Journal of biological chemistry》2020,295(52):18625
Pectins are a major dietary nutrient source for the human gut microbiota. The prominent gut microbe Bacteroides thetaiotaomicron was recently shown to encode the founding member (BT1017) of a new family of pectin methylesterases essential for the metabolism of the complex pectin rhamnogalacturonan-II (RG-II). However, biochemical and structural knowledge of this family is lacking. Here, we showed that BT1017 is critical for the metabolism of an RG-II–derived oligosaccharide ΔBT1017oligoB generated by a BT1017 deletion mutant (ΔBT1017) during growth on carbohydrate extract from apple juice. Structural analyses of ΔBT1017oligoB using a combination of enzymatic, mass spectrometric, and NMR approaches revealed that it is a bimethylated nonaoligosaccharide (GlcA-β1,4-(2-O-Me-Xyl-α1,3)-Fuc-α1,4-(GalA-β1,3)-Rha-α1,3-Api-β1,2-(Araf-α1,3)-(GalA-α1,4)-GalA) containing components of the RG-II backbone and its side chains. We showed that the catalytic module of BT1017 adopts an α/β-hydrolase fold, consisting of a central twisted 10-stranded β-sheet sandwiched by several α-helices. This constitutes a new fold for pectin methylesterases, which are predominantly right-handed β-helical proteins. Bioinformatic analyses revealed that the family is dominated by sequences from prominent genera of the human gut microbiota, including Bacteroides and Prevotella. Our re-sults not only highlight the critical role played by this family of enzymes in pectin metabolism but also provide new insights into the molecular basis of the adaptation of B. thetaiotaomicron to the human gut. 相似文献
93.
94.
Sylvain Hanein Mathilde Garcia Lucas Fares-Taie Valérie Serre Yves De Keyzer Thierry Delaveau Isabelle Perrault Nathalie Delphin Sylvie Gerber Alain Schmitt Jean-Marc Masse Arnold Munnich Josseline Kaplan Frédéric Devaux Jean-Michel Rozet 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013
Background
Hereditary optic neuropathies (HONs) are a heterogeneous group of disorders that affect retinal ganglion cells (RGCs) and axons that form the optic nerve. Leber's Hereditary Optic Neuropathy and the autosomal dominant optic atrophy related to OPA1 mutations are the most common forms. Nonsyndromic autosomal recessive optic neuropathies are rare and their existence has been long debated. We recently identified the first gene responsible for these conditions, TMEM126A. This gene is highly expressed in retinal cellular compartments enriched in mitochondria and supposed to encode a mitochondrial transmembrane protein of unknown function.Methods
A specific polyclonal antibody targeting the TMEM126A protein has been generated. Quantitative fluorescent in situ hybridization, cellular fractionation, mitochondrial membrane association study, mitochondrial sub compartmentalization analysis by both proteolysis assays and transmission electron microscopy, and expression analysis of truncated TMEM126A constructs by immunofluorescence confocal microscopy were carried out.Results
TMEM126A mRNAs are strongly enriched in the vicinity of mitochondria and encode an inner mitochondrial membrane associated cristae protein. Moreover, the second transmembrane domain of TMEM126A is required for its mitochondrial localization.Conclusions
TMEM126A is a mitochondrial located mRNA (MLR) that may be translated in the mitochondrial surface and the protein is subsequently imported to the inner membrane. These data constitute the first step toward a better understanding of the mechanism of action of TMEM126A in RGCs and support the importance of mitochondrial dysfunction in the pathogenesis of HON.General significance
Local translation of nuclearly encoded mitochondrial mRNAs might be a mechanism for rapid onsite supply of mitochondrial membrane proteins. 相似文献95.
Amelie Croset Fabrice P. Cordelières Nathalie Berthault Cyril Buhler Jian-Sheng Sun Maria Quanz Marie Dutreix 《Nucleic acids research》2013,41(15):7344-7355
One of the major early steps of repair is the recruitment of repair proteins at the damage site, and this is coordinated by a cascade of modifications controlled by phosphatidylinositol 3-kinase-related kinases and/or poly (ADP-ribose) polymerase (PARP). We used short interfering DNA molecules mimicking double-strand breaks (called Dbait) or single-strand breaks (called Pbait) to promote DNA-dependent protein kinase (DNA-PK) and PARP activation. Dbait bound and induced both PARP and DNA-PK activities, whereas Pbait acts only on PARP. Therefore, comparative study of the two molecules allows analysis of the respective roles of the two signaling pathways: both recruit proteins involved in single-strand break repair (PARP, XRCC1 and PCNA) and prevent their recruitment at chromosomal damage. Dbait, but not Pbait, also inhibits recruitment of proteins involved in double-strand break repair (53BP1, NBS1, RAD51 and DNA-PK). By these ways, Pbait and Dbait disorganize DNA repair, thereby sensitizing cells to various treatments. Single-strand breaks repair inhibition depends on direct trapping of the main proteins on both molecules. Double-strand breaks repair inhibition may be indirect, resulting from the phosphorylation of double-strand breaks repair proteins and chromatin targets by activated DNA-PK. The DNA repair inhibition by both molecules is confirmed by their synthetic lethality with BRCA mutations. 相似文献
96.
Jonathan DeGeer Jér?me Boudeau Susanne Schmidt Fiona Bedford Nathalie Lamarche-Vane Anne Debant 《Molecular and cellular biology》2013,33(4):739-751
The chemotropic guidance cue netrin-1 mediates attraction of migrating axons during central nervous system development through the receptor Deleted in Colorectal Cancer (DCC). Downstream of netrin-1, activated Rho GTPases Rac1 and Cdc42 induce cytoskeletal rearrangements within the growth cone. The Rho guanine nucleotide exchange factor (GEF) Trio is essential for Rac1 activation downstream of netrin-1/DCC, but the molecular mechanisms governing Trio activity remain elusive. Here, we demonstrate that Trio is phosphorylated by Src family kinases in the embryonic rat cortex in response to netrin-1. In vitro, Trio was predominantly phosphorylated at Tyr2622 by the Src kinase Fyn. Though the phospho-null mutant TrioY2622F retained GEF activity toward Rac1, its expression impaired netrin-1-induced Rac1 activation and DCC-mediated neurite outgrowth in N1E-115 neuroblastoma cells. TrioY2622F impaired netrin-1-induced axonal extension in cultured cortical neurons and was unable to colocalize with DCC in growth cones, in contrast to wild-type Trio. Furthermore, depletion of Trio in cortical neurons reduced the level of cell surface DCC in growth cones, which could be restored by expression of wild-type Trio but not TrioY2622F. Together, these findings demonstrate that TrioY2622 phosphorylation is essential for the regulation of the DCC/Trio signaling complex in cortical neurons during netrin-1-mediated axon outgrowth. 相似文献
97.
Persistence of Swidden Cultivation in the Face of Globalization: A Case Study from Communities in Calakmul, Mexico 总被引:1,自引:0,他引:1
Birgit Schmook Nathalie van Vliet Claudia Radel María de Jesús Manzón-Che Susannah McCandless 《Human ecology: an interdisciplinary journal》2013,41(1):93-107
Over the last decades, political, economic and environmental pressures have encouraged changes from swidden to more intensive agricultural practices, resulting in the hypothesis that swidden cultivation systems are disappearing. In Calakmul, southeastern Mexico, communities decreased the area under milpa, the traditional maize swidden system, but a collapse did not occur. To document and explain the persistence of swidden we employ a variety of data: (1) 59 standardized household surveys from 2003 and 2010 in five villages, (2) in-depth interviews in one village, and (3) coupled human–environmental timelines in this same village. Droughts, hurricanes, and remittances were important drivers of decreases in milpa cultivation. Market crop profitability and conservation programs were also reported to affect the area under milpa. Off-farm employment and governmental transfers have tended to stabilize household economies and decrease dependency on agricultural production, but have also allowed households to maintain their milpas for subsistence and cultural reproduction. Findings in Calakmul point to the need to consider swidden as an evolving and active response to changing policy, economic, and environmental conditions. 相似文献
98.
Although a total ban on the use of TBT coatings is not expected in the short term, there is a growing need for environmentally safe antifouling systems. To assist in the rapid screening of a large number of potential antifouling substances, a method that is simple, efficient and inexpensive is required. The production of byssus threads by the blue mussel, Mytilus edulis, has often been studied for testing the antifouling efficacy of various compounds. The present study reports a new antifouling assay based on the inhibition of purified M. edulis phenoloxidase activity. The method has the advantage of being specific, reliable, sensitive and rapid. 相似文献
99.
Sabiha Abekhoukh Chris Planque Clémentine Ripoll Paulina Urbaniak Jean-Louis Paul Jean-Maurice Delabar Nathalie Janel 《Molecular neurobiology》2013,47(1):105-116
Hyperhomocysteinemia due to cystathionine beta synthase (CBS) deficiency is associated with diverse brain disease. Whereas the biological actions linking hyperhomocysteinemia to the cognitive dysfunction are not well understood, we tried to establish relationships between hyperhomocysteinemia and alterations of signaling pathways. In the brain of CBS-deficient mice, a murine model of hyperhomocysteinemia, we previously found an activation of extracellular signal-regulated kinase (ERK) pathway and an increase of Dyrk1A, a serine/threonine kinase involved in diverse functions ranging from development and growth to apoptosis. We then investigated the relationship between Dyrk1A and the signaling pathways initiated by receptor tyrosine kinases (RTK), the ERK and PI3K/Akt pathways. We found a significant increase of phospho-ERK, phospho-MEK, and phospho-Akt in the brain of CBS-deficient and Dyrk1a-overexpressing mice. This increase was abolished when CBS-deficient and Dyrk1A-transgenic mice were treated with harmine, an inhibitor of Dyrk1A kinase activity, which emphasizes the role of Dyrk1A activity on ERK and Akt activation. Sprouty 2 protein level, a negative feedback loop modulator that limits the intensity and duration of RTK activation, is decreased in the brain of CBS-deficient mice, but not in the brain of Dyrk1A transgenic mice. Furthermore, a reduced Dyrk1A and Grb2 binding on sprouty 2 and an increased interaction of Dyrk1A with Grb2 were found in the brain of Dyrk1A transgenic mice. The consequence of Dyrk1A overexpression on RTK activation seems to be a decreased interaction of sprouty 2/Grb2. These observations demonstrate ERK and Akt activation induced by Dyrk1A in the brain of hyperhomocysteinemic mice and open new perspectives to understand the basis of the cognitive defects in hyperhomocysteinemia. 相似文献
100.
David Fong Martine Bisson Gino Laberge Stephen McManus Guillaume Grenier Nathalie Faucheux Sophie Roux 《Cellular signalling》2013,25(4):717-728
BMP-9 is a potent osteogenic factor; however, its effects on osteoclasts, the bone-resorbing cells, remain unknown. To determine the effects of BMP-9 on osteoclast formation, activity and survival, we used human cord blood monocytes as osteoclast precursors that form multinucleated osteoclasts in the presence of RANKL and M-CSF in long-term cultures. BMP-9 did not affect osteoclast formation, but adding BMP-9 at the end of the culture period significantly increased bone resorption compared to untreated cultures, and reduced both the rate of apoptosis and caspase-9 activity. BMP-9 also significantly downregulated the expression of pro-apoptotic Bid, but only after RANKL and M-CSF, which are both osteoclast survival factors, had been eliminated from the culture medium. To investigate the mechanisms involved in the effects of BMP-9, we first showed that osteoclasts expressed some BMP receptors, including BMPR-IA, BMPR-IB, ALK1, and BMPR-II. We also found that BMP-9 was able to induce the phosphorylation of Smad-1/5/8 and ERK 1/2 proteins, but did not induce p38 phosphorylation. Finally, knocking down the BMPR-II receptor abrogated the BMP-9-induced ERK-signaling, as well as the increase in bone resorption. In conclusion, these results show for the first time that BMP-9 directly affects human osteoclasts, enhancing bone resorption and protecting osteoclasts against apoptosis. BMP-9 signaling in human osteoclasts involves the canonical Smad-1/5/8 pathway, and the ERK pathway. 相似文献