全文获取类型
收费全文 | 6012篇 |
免费 | 567篇 |
国内免费 | 2篇 |
出版年
2022年 | 39篇 |
2021年 | 117篇 |
2020年 | 63篇 |
2019年 | 67篇 |
2018年 | 78篇 |
2017年 | 60篇 |
2016年 | 134篇 |
2015年 | 266篇 |
2014年 | 262篇 |
2013年 | 388篇 |
2012年 | 484篇 |
2011年 | 441篇 |
2010年 | 258篇 |
2009年 | 210篇 |
2008年 | 372篇 |
2007年 | 384篇 |
2006年 | 322篇 |
2005年 | 275篇 |
2004年 | 280篇 |
2003年 | 275篇 |
2002年 | 276篇 |
2001年 | 68篇 |
2000年 | 42篇 |
1999年 | 57篇 |
1998年 | 86篇 |
1997年 | 53篇 |
1996年 | 50篇 |
1995年 | 40篇 |
1994年 | 54篇 |
1993年 | 43篇 |
1992年 | 35篇 |
1991年 | 31篇 |
1990年 | 43篇 |
1989年 | 34篇 |
1988年 | 33篇 |
1986年 | 29篇 |
1985年 | 38篇 |
1984年 | 37篇 |
1983年 | 41篇 |
1982年 | 42篇 |
1981年 | 42篇 |
1980年 | 33篇 |
1978年 | 27篇 |
1977年 | 25篇 |
1976年 | 33篇 |
1975年 | 29篇 |
1974年 | 28篇 |
1973年 | 27篇 |
1972年 | 24篇 |
1969年 | 25篇 |
排序方式: 共有6581条查询结果,搜索用时 15 毫秒
231.
William S. Lagakos Xudong Guan Shiu-Ying Ho Luciana Rodriguez Sawicki Betina Corsico Sarala Kodukula Kaeko Murota Ruth E. Stark Judith Storch 《The Journal of biological chemistry》2013,288(27):19805-19815
Liver fatty acid-binding protein (LFABP; FABP1) is expressed both in liver and intestinal mucosa. Mice null for LFABP were recently shown to have altered metabolism of not only fatty acids but also monoacylglycerol, the two major products of dietary triacylglycerol hydrolysis (Lagakos, W. S., Gajda, A. M., Agellon, L., Binas, B., Choi, V., Mandap, B., Russnak, T., Zhou, Y. X., and Storch, J. (2011) Am. J. Physiol. Gastrointest. Liver Physiol. 300, G803–G814). Nevertheless, the binding and transport of monoacylglycerol (MG) by LFABP are uncertain, with conflicting reports in the literature as to whether this single chain amphiphile is in fact bound by LFABP. In the present studies, gel filtration chromatography of liver cytosol from LFABP−/− mice shows the absence of the low molecular weight peak of radiolabeled monoolein present in the fractions that contain LFABP in cytosol from wild type mice, indicating that LFABP binds sn-2 MG in vivo. Furthermore, solution-state NMR spectroscopy demonstrates two molecules of sn-2 monoolein bound in the LFABP binding pocket in positions similar to those found for oleate binding. Equilibrium binding affinities are ∼2-fold lower for MG compared with fatty acid. Finally, kinetic studies examining the transfer of a fluorescent MG analog show that the rate of transfer of MG is 7-fold faster from LFABP to phospholipid membranes than from membranes to membranes and occurs by an aqueous diffusion mechanism. These results provide strong support for monoacylglycerol as a physiological ligand for LFABP and further suggest that LFABP functions in the efficient intracellular transport of MG. 相似文献
232.
Intracellular Mycobacterium tuberculosis Exploits Host-derived Fatty Acids to Limit Metabolic Stress
Wonsik Lee Brian C. VanderVen Ruth J. Fahey David G. Russell 《The Journal of biological chemistry》2013,288(10):6788-6800
Recent data indicate that the nutrients available to Mycobacterium tuberculosis (Mtb) inside its host cell are restricted in their diversity. Fatty acids and cholesterol appear more favored; however, their degradation can result in certain metabolic stresses. Their breakdown can generate propionyl-CoA, which gives rise to potentially toxic intermediates. Detoxification of propionyl-CoA relies on the activity of the methylcitrate cycle, the methylmalonyl pathway, or incorporation of the propionyl-CoA into methyl-branched lipids in the cell wall. The current work explores carbon flux through these pathways, focusing primarily on those pathways responsible for the incorporation of propionyl-CoA into virulence-associated cell wall lipids. Exploiting both genetic and biochemical rescue, we demonstrate that these metabolic pressures are experienced by Mtb inside its host macrophage and that the bacterium accesses host fatty acid stores. The metabolism of these host lipids expands the acetyl-CoA pool and alleviates the pressure from propionyl-CoA. These data have major implications for our appreciation of central metabolism of Mtb during the course of infection. 相似文献
233.
Kazima Saira Xudong Lin Jay V. DePasse Rebecca Halpin Alan Twaddle Timothy Stockwell Brian Angus Alessandro Cozzi-Lepri Marina Delfino Vivien Dugan Dominic E. Dwyer Matthew Freiberg Andrzej Horban Marcelo Losso Ruth Lynfield Deborah N. Wentworth Edward C. Holmes Richard Davey David E. Wentworth Elodie Ghedin 《Journal of virology》2013,87(14):8064-8074
Influenza virus defective interfering (DI) particles are naturally occurring noninfectious virions typically generated during in vitro serial passages in cell culture of the virus at a high multiplicity of infection. DI particles are recognized for the role they play in inhibiting viral replication and for the impact they have on the production of infectious virions. To date, influenza virus DI particles have been reported primarily as a phenomenon of cell culture and in experimentally infected embryonated chicken eggs. They have also been isolated from a respiratory infection of chickens. Using a sequencing approach, we characterize several subgenomic viral RNAs from human nasopharyngeal specimens infected with the influenza A(H1N1)pdm09 virus. The distribution of these in vivo-derived DI-like RNAs was similar to that of in vitro DIs, with the majority of the defective RNAs generated from the PB2 (segment 1) of the polymerase complex, followed by PB1 and PA. The lengths of the in vivo-derived DI-like segments also are similar to those of known in vitro DIs, and the in vivo-derived DI-like segments share internal deletions of the same segments. The presence of identical DI-like RNAs in patients linked by direct contact is compatible with transmission between them. The functional role of DI-like RNAs in natural infections remains to be established. 相似文献
234.
David M. Poitz Friedrich Stölzel Laleh Arabanian Jens Friedrichs Denitsa Docheva Matthias Schieker Fernando A. Fierro Uwe Platzbecker Rainer Ordemann Carsten Werner Martin Bornhäuser Ruth H. Strasser Gerhard Ehninger Thomas Illmer 《Biochimica et Biophysica Acta (BBA)/Molecular Cell Research》2013,1833(12):3396-3404
235.
236.
The potential effect of sustained hypoxia on nitrogen cycling in sediment from the southern North Sea: a mesocosm experiment 总被引:1,自引:0,他引:1
The potential effect of sustained hypoxia (up to 70 days) on the production of N2 gas through denitrification and anammox, as well as sediment–water exchange of nitrite, nitrate and ammonia, oxygen consumption and penetration, were measured in mesocosms using sediment collected from the southern North Sea (north of Dogger Bank). As expected, both the penetration of oxygen into, and consumption of oxygen by, the sediment decreased by 42 and 46 %, respectively, once hypoxia was established. Importantly, the oxygen regime did not change significantly (P > 0.05) during the experiment, suggesting that organic carbon was not depleted. During the first 10 days, the exchange of NO3 ?, NO2 ? and NH4 + between the sediment and water was erratic but once a steady state was established the sediment acted as either a sink for fixed nitrogen under hypoxia or as a source in the controls. Over the course of the mesocosm experiment the rate of both anammox and denitrification increased, with anammox increasing disproportionately under hypoxia relative to the controls, whereas the rate of increase in denitrification was the same for both. Under sustained hypoxia the production of N2 gas increased by 72 % relative to the controls, with this increase in N2 production remaining constant regardless of the duration of hypoxia. Longer periods of stratification and oxygen depletion are predicted to occur more regularly in the bottom waters of shallow coastal seas as one manifestation of climate change. Under sustained hypoxia the potential for nitrogen removal by the production of N2 gas in this region of the southern North Sea was estimated to increase from 2.1 kt N 150 days?1 to 3.6 kt 150 days?1, while the efflux of dissolved inorganic nitrogen ceased altogether; both of which could down regulate the productivity of this region as a whole. 相似文献
237.
Kshitij Gupta Hyunbum Jang Kevin Harlen Anu Puri Ruth Nussinov Joel P. Schneider Robert Blumenthal 《Biophysical journal》2013
We have investigated the membrane destabilizing properties of synthetic amphiphilic cationic peptides, MAX1 and MAX35, which have the propensity to form β-hairpin structures under certain conditions, and a control non-β-hairpin-forming peptide MAX8V16E. All three peptides bind to liposomes containing a mixture of zwitterionic POPC and negatively charged POPS lipids as determined by Zeta potential measurements. Circular dichroism measurements indicated folding of MAX1 and MAX35 in the presence of the POPC/POPS liposomes, whereas no such folding was observed with MAX8V16E. There was no binding or folding of these peptides to liposomes containing only POPC. MAX1 and MAX35 induced release of contents from negatively charged liposomes, whereas MAX8V16E failed to promote solute release under identical conditions. Thus, MAX1 and MAX35 bind to, and fold at the surface of negatively charged liposomes adopting a lytic conformation. We ruled out leaky fusion as a mechanism of release by including 2 mol % PEG-PE in the liposomes, which inhibits aggregation/fusion but not folding of MAX or MAX-induced leakage. Using a concentration-dependent quenching probe (calcein), we determined that MAX-induced leakage of liposome contents was an all-or-none process. At MAX1 concentrations, which cause release of ∼50% of the liposomes that contain small (Rh <1.5 nm) markers, only ∼15% of those liposomes release a fluorescent dextran of 40 kDa. A multimeric model of the pore is presented based on these results. Atomistic molecular dynamics simulations show that barrels consisting of 10 β-hairpin MAX1 and MAX35 peptides are relatively more stable than MAX8V16E barrels in the bilayer, suggesting that barrels of this size are responsible for the peptides lytic action. 相似文献
238.
Peter W. Glunz Xiaojun Zhang Yan Zou Indawati Delucca Alexandra H. Nirschl Xuhong Cheng Carolyn A. Weigelt Daniel L. Cheney Anzhi Wei Rushith Anumula Joseph M. Luettgen Alan R. Rendina Mark Harpel Gang Luo Robert Knabb Pancras C. Wong Ruth R. Wexler E. Scott Priestley 《Bioorganic & medicinal chemistry letters》2013,23(18):5244-5248
Aminoisoquinoline and isoquinoline groups have successfully replaced the more basic P1 benzamidine group of an acylsulfonamide factor VIIa inhibitor. Inhibitory activity was optimized by the identification of additional hydrophobic and hydrophilic P′ binding interactions. The molecular details of these interactions were elucidated by X-ray crystallography and molecular modeling. We also show that decreasing the basicity of the P1 group results in improved oral bioavailability in this chemotype. 相似文献
239.
Qiaomei Fu Alissa Mittnik Philip L.F. Johnson Kirsten Bos Martina Lari Ruth Bollongino Chengkai Sun Liane Giemsch Ralf Schmitz Joachim Burger Anna Maria Ronchitelli Fabio Martini Renata G. Cremonesi Jiří Svoboda Peter Bauer David Caramelli Sergi Castellano David Reich Johannes Krause 《Current biology : CB》2013,23(7):553-559
240.
Ruth Goldschmidt Pablo M. Arce Omar M. Khdour Valérie C. Collin Sriloy Dey Jennifer Jaruvangsanti David M. Fash Sidney M. Hecht 《Bioorganic & medicinal chemistry》2013,21(4):969-978
Two new aza analogues of the neuroprotective agent idebenone have been synthesized and characterized. Their antioxidant activity, and ability to augment ATP levels have been evaluated in several different cell lines having suboptimal mitochondrial function. Both compounds were found to be good ROS scavengers, and to protect the cells from oxidative stress induced by glutathione depletion. The compounds were more effective than idebenone in neurodegenerative disease cells. These novel pyrimidinol derivatives were also shown to augment ATP levels in coenzyme Q10-deficient human lymphocytes. The more lipophilic side chains attached to the pyrimidinol redox core in these compounds resulted in less inhibition of the electron transport chain and improved antioxidant activity. 相似文献