全文获取类型
收费全文 | 746篇 |
免费 | 116篇 |
出版年
2022年 | 5篇 |
2021年 | 6篇 |
2019年 | 6篇 |
2018年 | 13篇 |
2017年 | 9篇 |
2016年 | 15篇 |
2015年 | 17篇 |
2014年 | 26篇 |
2013年 | 25篇 |
2012年 | 32篇 |
2011年 | 49篇 |
2010年 | 40篇 |
2009年 | 26篇 |
2008年 | 34篇 |
2007年 | 40篇 |
2006年 | 33篇 |
2005年 | 40篇 |
2004年 | 28篇 |
2003年 | 40篇 |
2002年 | 20篇 |
2001年 | 30篇 |
2000年 | 22篇 |
1999年 | 23篇 |
1998年 | 7篇 |
1997年 | 11篇 |
1996年 | 13篇 |
1995年 | 6篇 |
1994年 | 11篇 |
1993年 | 7篇 |
1992年 | 15篇 |
1991年 | 18篇 |
1990年 | 20篇 |
1989年 | 20篇 |
1988年 | 9篇 |
1987年 | 13篇 |
1986年 | 9篇 |
1985年 | 10篇 |
1984年 | 9篇 |
1983年 | 5篇 |
1982年 | 6篇 |
1981年 | 12篇 |
1980年 | 6篇 |
1979年 | 5篇 |
1978年 | 11篇 |
1976年 | 7篇 |
1975年 | 6篇 |
1974年 | 4篇 |
1973年 | 9篇 |
1972年 | 7篇 |
1968年 | 3篇 |
排序方式: 共有862条查询结果,搜索用时 15 毫秒
51.
Natalia Presa Robin D. Clugston Susanne Lingrell Samuel E. Kelly Alfred H. Merrill Sayantan Jana Zamaneh Kassiri Antonio Gómez-Muñoz Dennis E. Vance Rene L. Jacobs Jelske N. van der Veen 《生物化学与生物物理学报:疾病的分子基础》2019,1865(1):14-25
Phosphatidylethanolamine N-methyltransferase (PEMT) converts phosphatidylethanolamine (PE) to phosphatidylcholine (PC), mainly in the liver. Pemt?/? mice are protected from high-fat diet (HFD)-induced obesity and insulin resistance, but develop severe non-alcoholic fatty liver disease (NAFLD) when fed a HFD, mostly due to impaired VLDL secretion. Oxidative stress is thought to be an essential factor in the progression from simple steatosis to steatohepatitis. Vitamin E is an antioxidant that has been clinically used to improve NAFLD pathology. Our aim was to determine whether supplementation of the diet with vitamin E could attenuate HFD-induced hepatic steatosis and its progression to NASH in Pemt?/? mice. Treatment with vitamin E (0.5?g/kg) for 3?weeks improved VLDL-TG secretion and normalized cholesterol metabolism, but failed to reduce hepatic TG content. Moreover, vitamin E treatment was able to reduce hepatic oxidative stress, inflammation and fibrosis. We also observed abnormal ceramide metabolism in Pemt?/? mice fed a HFD, with elevation of ceramides and other sphingolipids and higher expression of mRNAs for acid ceramidase (Asah1) and ceramide kinase (Cerk). Interestingly, vitamin E supplementation restored Asah1 and Cerk mRNA and sphingolipid levels. Together this study shows that vitamin E treatment efficiently prevented the progression from simple steatosis to steatohepatitis in mice lacking PEMT. 相似文献
52.
Timothy F. Czajka David J. Vance Simon Davis Michael J. Rudolph Nicholas J. Mantis 《The Journal of biological chemistry》2022,298(4)
During ricin intoxication in mammalian cells, ricin''s enzymatic (RTA) and binding (RTB) subunits disassociate in the endoplasmic reticulum. RTA is then translocated into the cytoplasm where, by virtue of its ability to depurinate a conserved residue within the sarcin–ricin loop (SRL) of 28S rRNA, it functions as a ribosome-inactivating protein. It has been proposed that recruitment of RTA to the SRL is facilitated by ribosomal P-stalk proteins, whose C-terminal domains interact with a cavity on RTA normally masked by RTB; however, evidence that this interaction is critical for RTA activity within cells is lacking. Here, we characterized a collection of single-domain antibodies (VHHs) whose epitopes overlap with the P-stalk binding pocket on RTA. The crystal structures of three such VHHs (V9E1, V9F9, and V9B2) in complex with RTA revealed not only occlusion of the ribosomal P-stalk binding pocket but also structural mimicry of C-terminal domain peptides by complementarity-determining region 3. In vitro assays confirmed that these VHHs block RTA–P-stalk peptide interactions and protect ribosomes from depurination. Moreover, when expressed as “intrabodies,” these VHHs rendered cells resistant to ricin intoxication. One VHH (V9F6), whose epitope was structurally determined to be immediately adjacent to the P-stalk binding pocket, was unable to neutralize ricin within cells or protect ribosomes from RTA in vitro. These findings are consistent with the recruitment of RTA to the SRL by ribosomal P-stalk proteins as a requisite event in ricin-induced ribosome inactivation. 相似文献
53.
Siyu Wang Stephanie M. Reeve Graham T. Holt Adegoke A. Ojewole Marcel S. Frenkel Pablo Gainza Santosh Keshipeddy Vance G. Fowler Dennis L. Wright Bruce R. Donald 《PLoS computational biology》2022,18(2)
Antimicrobial resistance presents a significant health care crisis. The mutation F98Y in Staphylococcus aureus dihydrofolate reductase (SaDHFR) confers resistance to the clinically important antifolate trimethoprim (TMP). Propargyl-linked antifolates (PLAs), next generation DHFR inhibitors, are much more resilient than TMP against this F98Y variant, yet this F98Y substitution still reduces efficacy of these agents. Surprisingly, differences in the enantiomeric configuration at the stereogenic center of PLAs influence the isomeric state of the NADPH cofactor. To understand the molecular basis of F98Y-mediated resistance and how PLAs’ inhibition drives NADPH isomeric states, we used protein design algorithms in the osprey protein design software suite to analyze a comprehensive suite of structural, biophysical, biochemical, and computational data. Here, we present a model showing how F98Y SaDHFR exploits a different anomeric configuration of NADPH to evade certain PLAs’ inhibition, while other PLAs remain unaffected by this resistance mechanism. 相似文献
54.
Fe and Mn are both entrained to the same chemical reaction in apparently superimposable superoxide dismutase (SOD) proteins. However, neither Fe-substituted MnSOD nor Mn-substituted FeSOD is active. We have proposed that the two SOD proteins must apply very different redox tuning to their respective metal ions and that tuning appropriate for one metal ion results in a reduction potential (E(m)) for the other metal ion that is either too low (Fe) or too high (Mn) [Vance and Miller (1998) J. Am. Chem. Soc. 120, 461-467]. We have demonstrated that this is true for Fe-substituted MnSOD from Escherichia coli and that this metal ion-protein combination retains the ability to reduce but not oxidize superoxide. We now demonstrate that the corollary is also true: Mn-substituted FeSOD [Mn(Fe)SOD] has a very high E(m). Specifically, we have measured the E(m) of E. coli MnSOD to be 290 mV vs NHE. We have generated Mn(Fe)SOD and find that Mn is bound in an environment similar to that of the native (Mn)SOD protein. However, the E(m) is greater than 960 mV vs NHE and much higher than MnSOD's E(m) of 290 mV. We propose that the different tuning stems from different hydrogen bonding between the proteins and a molecule of solvent that is coordinated to the metal ion in both cases. Because a proton is taken up by SOD upon reduction, the protein can exert very strong control over the E(m), by modulating the degree to which coordinated solvent is protonated, in both oxidation states. Thus, coordinated solvent molecules may have widespread significance as "adapters" by which proteins can control the reactivity of bound metal ions. 相似文献
55.
Sturbois-Balcerzak B Stone SJ Sreenivas A Vance JE 《The Journal of biological chemistry》2001,276(11):8205-8212
56.
57.
Symbiotic nitrogen fixation and phosphorus acquisition. Plant nutrition in a world of declining renewable resources 总被引:29,自引:0,他引:29
下载免费PDF全文
![点击此处可从《Plant physiology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Vance CP 《Plant physiology》2001,127(2):390-397
58.
59.
Adrienne D. Kinkel Melinda E. Fernyhough Deri L. Helterline Janet L. Vierck Karen S. Oberg Tyler J. Vance Gary J. Hausman Rodney A. Hill Michael V. Dodson 《Cytotechnology》2004,46(1):49-56
Bovine adipofibroblasts, 3T3-L1 cells, L-6 myogenic cells, and sheep satellite cells were allowed to proliferate for 48 h. Oil red-O (ORO) was dissolved in three different solvents isopropanol, propylene glycol and triethyl phosphate. At 48 h, the proliferative cultures were stained with the three stains. ORO stain prepared in both propylene glycol and triethyl phosphate resulted in bright red droplets appearing in all cultures, whereas ORO dissolved in isopropanol was not taken up by any of the cells. These data suggest that certain preparations of ORO may stain cells in non-adipogenic lineages as well as undifferentiated pre-adipocytes. Caution must be exercised when choosing solvents for ORO in differentiation studies using cells of the fat/adipose lineage. 相似文献
60.
The purpose of this study was to evaluate the hypothesis that spacer devices have limited effect on the in vitro fine particle
dose emitted from solution metered dose inhalers containing different proportions of HFA134a [1,1,1,2-tetrafluoroethane] propellant.
Two solution formulations (80% and 97.5% wt/wt HFA134a) were tested across the actuator alone, actuator plus Aerochamber,
and Ace holding chamber. Particle size distributions were determined using laser diffraction (LD) and cascade impaction (CI).
Multimodal particle size distributions were identified using LD. CI analyses were characterized by a major mode located at
≈0.5 μm. The fine particle dose emitted from the inhaler spacer combinations containing 97.5% HFA134a was independent of the
device setup used. Fine particle doses were influenced by spacer setup in 80% HFA134a formulations, indicating different plume
dynamics of low vapor pressure formulations. Sampling inlet deposition was approximately O when spacer devices were used with
either formulation. When spacers were not used, sampling inlet deposition was increased significantly. However, inlet deposition
with the 97.5% HFA134a formulation was significantly less than that of the 80% HFA134a formulation (≈25% of emitted dose compared
with 69% respectively). Thus, high propellant concentration formulations appear to have more robust in vitro performance.
This is particularly important given the preponderance of poor patient compliance that is associated with spacer use. High
propellant concentrations had the advantage of fine particle doses that were independent of the device setup and significantly
lowered sampling inlet deposition when no spacer was used. 相似文献