全文获取类型
收费全文 | 1818篇 |
免费 | 207篇 |
国内免费 | 2篇 |
出版年
2021年 | 18篇 |
2019年 | 15篇 |
2016年 | 23篇 |
2015年 | 52篇 |
2014年 | 68篇 |
2013年 | 75篇 |
2012年 | 88篇 |
2011年 | 85篇 |
2010年 | 53篇 |
2009年 | 49篇 |
2008年 | 63篇 |
2007年 | 61篇 |
2006年 | 59篇 |
2005年 | 72篇 |
2004年 | 64篇 |
2003年 | 61篇 |
2002年 | 80篇 |
2001年 | 67篇 |
2000年 | 55篇 |
1999年 | 46篇 |
1998年 | 24篇 |
1997年 | 27篇 |
1996年 | 19篇 |
1995年 | 20篇 |
1994年 | 24篇 |
1993年 | 33篇 |
1992年 | 33篇 |
1991年 | 41篇 |
1990年 | 30篇 |
1989年 | 34篇 |
1988年 | 26篇 |
1987年 | 33篇 |
1986年 | 24篇 |
1985年 | 25篇 |
1984年 | 20篇 |
1983年 | 22篇 |
1982年 | 14篇 |
1981年 | 14篇 |
1980年 | 20篇 |
1978年 | 18篇 |
1977年 | 19篇 |
1976年 | 15篇 |
1975年 | 14篇 |
1974年 | 24篇 |
1973年 | 16篇 |
1972年 | 16篇 |
1971年 | 16篇 |
1970年 | 22篇 |
1968年 | 15篇 |
1967年 | 22篇 |
排序方式: 共有2027条查询结果,搜索用时 31 毫秒
101.
Dorota Dziadkowiec Karol Kramarz Karolina Kanik Piotr Wi?niewski Antony M. Carr 《Nucleic acids research》2013,41(17):8196-8209
Previously we identified Rrp1 and Rrp2 as two proteins required for the Sfr1/Swi5-dependent branch of homologous recombination (HR) in Schizosaccharomyces pombe. Here we use a yeast two-hybrid approach to demonstrate that Rrp1 and Rrp2 can interact with each other and with Swi5, an HR mediator protein. Rrp1 and Rrp2 form co-localizing methyl methanesulphonate–induced foci in nuclei, further suggesting they function as a complex. To place the Rrp1/2 proteins more accurately within HR sub-pathways, we carried out extensive epistasis analysis between mutants defining Rrp1/2, Rad51 (recombinase), Swi5 and Rad57 (HR-mediators) plus the anti-recombinogenic helicases Srs2 and Rqh1. We confirm that Rrp1 and Rrp2 act together with Srs2 and Swi5 and independently of Rad57 and show that Rqh1 also acts independently of Rrp1/2. Mutants devoid of Srs2 are characterized by elevated recombination frequency with a concomitant increase in the percentage of conversion-type recombinants. Strains devoid of Rrp1 or Rrp2 did not show a change in HR frequency, but the number of conversion-type recombinants was increased, suggesting a possible function for Rrp1/2 with Srs2 in counteracting Rad51 activity. Our data allow us to propose a model placing Rrp1 and Rrp2 functioning together with Swi5 and Srs2 in a synthesis-dependent strand annealing HR repair pathway. 相似文献
102.
Heather S. Carr Yan Zuo Wonkyung Oh Jeffrey A. Frost 《Molecular and cellular biology》2013,33(14):2773-2786
Net1 is a RhoA guanine nucleotide exchange factor (GEF) that is overexpressed in a subset of human cancers and contributes to cancer cell motility and invasion in vitro. However, the molecular mechanism accounting for its role in cell motility and invasion has not been described. In the present work, we show that expression of both Net1 isoforms in breast cancer cells is required for efficient cell motility. Although loss of Net1 isoform expression only partially blocks RhoA activation, it inhibits lysophosphatidic acid (LPA)-stimulated migration as efficiently as knockdown of RhoA itself. However, we demonstrate that the Net1A isoform predominantly controls myosin light-chain phosphorylation and is required for trailing edge retraction during migration. Net1A interacts with focal adhesion kinase (FAK), localizes to focal adhesions, and is necessary for FAK activation and focal adhesion maturation during cell spreading. Net1A expression is also required for efficient invasion through a Matrigel matrix. Analysis of invading cells demonstrates that Net1A is required for amoeboid invasion, and loss of Net1A expression causes cells to shift to a mesenchymal phenotype characterized by high β1-integrin activity and membrane type 1 matrix metalloproteinase (MT1-MMP) expression. These results demonstrate a previously unrecognized role for the Net1A isoform in controlling FAK activation during planar cell movement and amoeboid motility during extracellular matrix (ECM) invasion. 相似文献
103.
Fluoro‐Sorafenib (Regorafenib) effects on hepatoma cells: Growth inhibition,quiescence, and recovery
Brian I. Carr Aldo Cavallini Catia Lippolis Rosalba D'Alessandro Caterina Messa Maria G. Refolo Angela Tafaro 《Journal of cellular physiology》2013,228(2):292-297
To evaluate the growth‐inhibitory properties of the potent multi‐kinase antagonist Regorafenib (Fluoro‐Sorafenib), which was synthesized as a more potent Sorafenib, a Raf inhibitor and to determine whether similar mechanisms were involved, human hepatoma cell lines were grown in the presence or absence of Regorafanib and examined for growth inhibition. Western blots were performed for Raf targets, apoptosis, and autophagy. Regorafenib inhibited growth of human Hep3B, PLC/PRF/5, and HepG2 cells in a concentration‐ and time‐dependent manner. Multiple signaling pathways were altered, including MAP kinases phospho‐ERK and phospho‐JNK and its target phospho‐c‐Jun. There was evidence for apoptosis by FACS, cleavage of caspases and increased Bax levels; as well as induction of autophagy, as judged by increased Beclin‐1 and LC3 (II) levels. Prolonged drug exposure resulted in cell quiescence. Full growth recovery occurred after drug removal, unlike with doxorubicin chemotherapy. Regorafenib is a potent inhibitor of cell growth. Cells surviving Regorafenib treatment remain viable, but quiescent and capable of regrowth following drug removal. The reversibility of tumor cell growth suppression after drug removal may have clinical implications. J. Cell. Physiol. 228: 292–297, 2013. © 2012 Wiley Periodicals, Inc. 相似文献
104.
Xiaoxiao Cheng Vaclav Veverka Anand Radhakrishnan Lorna C. Waters Frederick W. Muskett Sara H. Morgan Jiandong Huo Chao Yu Edward J. Evans Alasdair J. Leslie Meryn Griffiths Colin Stubberfield Robert Griffin Alistair J. Henry Andreas Jansson John E. Ladbury Shinji Ikemizu Mark D. Carr Simon J. Davis 《The Journal of biological chemistry》2013,288(17):11771-11785
105.
T. Mitchell Aide Matthew L. Clark H. Ricardo Grau David López‐Carr Marc A. Levy Daniel Redo Martha Bonilla‐Moheno George Riner María J. Andrade‐Núñez María Muñiz 《Biotropica》2013,45(2):262-271
Forest cover change directly affects biodiversity, the global carbon budget, and ecosystem function. Within Latin American and the Caribbean region (LAC), many studies have documented extensive deforestation, but there are also many local studies reporting forest recovery. These contrasting dynamics have been largely attributed to demographic and socio‐economic change. For example, local population change due to migration can stimulate forest recovery, while the increasing global demand for food can drive agriculture expansion. However, as no analysis has simultaneously evaluated deforestation and reforestation from the municipal to continental scale, we lack a comprehensive assessment of the spatial distribution of these processes. We overcame this limitation by producing wall‐to‐wall, annual maps of change in woody vegetation and other land‐cover classes between 2001 and 2010 for each of the 16,050 municipalities in LAC, and we used nonparametric Random Forest regression analyses to determine which environmental or population variables best explained the variation in woody vegetation change. Woody vegetation change was dominated by deforestation (?541,835 km2), particularly in the moist forest, dry forest, and savannas/shrublands biomes in South America. Extensive areas also recovered woody vegetation (+362,430 km2), particularly in regions too dry or too steep for modern agriculture. Deforestation in moist forests tended to occur in lowland areas with low population density, but woody cover change was not related to municipality‐scale population change. These results emphasize the importance of quantitating deforestation and reforestation at multiple spatial scales and linking these changes with global drivers such as the global demand for food. 相似文献
106.
Toshihide Yamasaki Duje Buric Christine Chacon Gérard Audran Diane Braguer Sylvain R.A. Marque Manon Carré Paul Brémond 《Bioorganic & medicinal chemistry》2019,27(10):1942-1951
Previously, we described alkoxyamines bearing a pyridine ring as new pro-drugs with low molecular weights and theranostic activity. Upon chemical stimulus, alkoxyamines undergo homolysis and release free radicals, which can, reportedly, enhance magnetic resonance imaging and trigger cancer cell death. In the present study, we describe the synthesis and the anti-cancer activity of sixteen novel alkoxyamines that contain an imidazole ring. Activation of the homolysis was conducted by protonation and/or methylation. These new molecules displayed cytotoxic activities towards human glioblastoma cell lines, including the U251-MG cells that are highly resistant to the conventional chemotherapeutic agent Temozolomide. We further showed that the biological activities of the alkoxyamines were not only related to their half-life times of homolysis. We lastly identified the alkoxyamine (RS/SR)-4a, with both a high antitumour activity and favourable logD7.4 and pKa values, which make it a robust candidate for blood-brain barrier penetrating therapeutics against brain neoplasia. 相似文献
107.
108.
Opel M Lando D Bonilla C Trewick SC Boukaba A Walfridsson J Cauwood J Werler PJ Carr AM Kouzarides T Murzina NV Allshire RC Ekwall K Laue ED 《PloS one》2007,2(4):e386
In order to gain a more global view of the activity of histone demethylases, we report here genome-wide studies of the fission yeast SWIRM and polyamine oxidase (PAO) domain homologues of mammalian LSD1. Consistent with previous work we find that the two S. pombe proteins, which we name Swm1 and Swm2 (after SWIRM1 and SWIRM2), associate together in a complex. However, we find that this complex specifically demethylates lysine 9 in histone H3 (H3K9) and both up- and down-regulates expression of different groups of genes. Using chromatin-immunoprecipitation, to isolate fragments of chromatin containing either H3K4me2 or H3K9me2, and DNA microarray analysis (ChIP-chip), we have studied genome-wide changes in patterns of histone methylation, and their correlation with gene expression, upon deletion of the swm1(+) gene. Using hyper-geometric probability comparisons we uncover genetic links between lysine-specific demethylases, the histone deacetylase Clr6, and the chromatin remodeller Hrp1. The data presented here demonstrate that in fission yeast the SWIRM/PAO domain proteins Swm1 and Swm2 are associated in complexes that can remove methyl groups from lysine 9 methylated histone H3. In vitro, we show that bacterially expressed Swm1 also possesses lysine 9 demethylase activity. In vivo, loss of Swm1 increases the global levels of both H3K9me2 and H3K4me2. A significant accumulation of H3K4me2 is observed at genes that are up-regulated in a swm1 deletion strain. In addition, H3K9me2 accumulates at some genes known to be direct Swm1/2 targets that are down-regulated in the swm1Delta strain. The in vivo data indicate that Swm1 acts in concert with the HDAC Clr6 and the chromatin remodeller Hrp1 to repress gene expression. In addition, our in vitro analyses suggest that the H3K9 demethylase activity requires an unidentified post-translational modification to allow it to act. Thus, our results highlight complex interactions between histone demethylase, deacetylase and chromatin remodelling activities in the regulation of gene expression. 相似文献
109.
110.