全文获取类型
收费全文 | 1054篇 |
免费 | 94篇 |
出版年
2023年 | 11篇 |
2022年 | 14篇 |
2021年 | 26篇 |
2020年 | 12篇 |
2019年 | 22篇 |
2018年 | 33篇 |
2017年 | 31篇 |
2016年 | 50篇 |
2015年 | 71篇 |
2014年 | 59篇 |
2013年 | 81篇 |
2012年 | 92篇 |
2011年 | 101篇 |
2010年 | 44篇 |
2009年 | 33篇 |
2008年 | 54篇 |
2007年 | 56篇 |
2006年 | 38篇 |
2005年 | 42篇 |
2004年 | 41篇 |
2003年 | 30篇 |
2002年 | 20篇 |
2001年 | 11篇 |
2000年 | 5篇 |
1998年 | 6篇 |
1997年 | 4篇 |
1996年 | 4篇 |
1995年 | 6篇 |
1994年 | 5篇 |
1993年 | 7篇 |
1992年 | 5篇 |
1991年 | 13篇 |
1990年 | 5篇 |
1989年 | 6篇 |
1988年 | 4篇 |
1987年 | 7篇 |
1986年 | 8篇 |
1985年 | 5篇 |
1984年 | 4篇 |
1983年 | 5篇 |
1982年 | 7篇 |
1981年 | 7篇 |
1980年 | 5篇 |
1979年 | 7篇 |
1977年 | 4篇 |
1976年 | 5篇 |
1975年 | 5篇 |
1970年 | 3篇 |
1969年 | 4篇 |
1968年 | 4篇 |
排序方式: 共有1148条查询结果,搜索用时 109 毫秒
91.
92.
Ratcliffe P Adam JM Baker J Bursi R Campbell R Clark JK Cottney JE Deehan M Easson AM Ecker D Edwards D Epemolu O Evans L Fields R Francis S Harradine P Jeremiah F Kiyoi T McArthur D Morrison A Passier P Pick J Schnabel PG Schulz J Steinbrede H Walker G Westwood P Wishart G de Haes JU 《Bioorganic & medicinal chemistry letters》2011,21(8):2541-2546
We report an expansion of the structure-activity relationship (SAR) of a novel series of indole-3-heterocyclic CB1 receptor agonists. Starting from the potent but poorly soluble lead, 1, a rational approach was taken in order to balance solubility, hERG activity and potency while retaining the desired long duration of action within the mouse tail flick test. This led to the discovery of compound 38 which successfully progressed into clinical development. 相似文献
93.
94.
The aim of this study was to investigate the influence of experimental conditions on levothyroxine sodium release from two
immediate-release tablet formulations which narrowly passed the standard requirements for bioequivalence studies. The in vivo study was conducted as randomised, single-dose, two-way cross-over pharmacokinetic study in 24 healthy subjects. The in vitro study was performed using various dissolution media, and obtained dissolution profiles were compared using the similarity
factor value. Drug solubility in different media was also determined. The in vivo results showed narrowly passing bioequivalence. Considering that levothyroxine sodium is classified as Class III drug according
to the Biopharmaceutics Classification System, drug bioavailability will be less sensitive to the variation in its dissolution
characteristics and it can be assumed that the differences observed in vitro in some of investigated media probably do not have significant influence on the absorption process, as long as rapid and
complete dissolution exists. The study results indicate that the current regulatory criteria for the value of similarity factor
in comparative dissolution testing, as well as request for very rapid dissolution (more than 85% of drug dissolved in 15 min),
are very restricted for immediate-release dosage forms containing highly soluble drug substance and need further investigation.
The obtained results also add to the existing debate on the appropriateness of the current bioequivalence standards for levothyroxine
sodium products. 相似文献
95.
Lige B Romano JD Bandaru VV Ehrenman K Levitskaya J Sampels V Haughey NJ Coppens I 《PLoS pathogens》2011,7(12):e1002410
Several proteins that play key roles in cholesterol synthesis, regulation, trafficking and signaling are united by sharing the phylogenetically conserved 'sterol-sensing domain' (SSD). The intracellular parasite Toxoplasma possesses at least one gene coding for a protein containing the canonical SSD. We investigated the role of this protein to provide information on lipid regulatory mechanisms in the parasite. The protein sequence predicts an uncharacterized Niemann-Pick, type C1-related protein (NPC1) with significant identity to human NPC1, and it contains many residues implicated in human NPC disease. We named this NPC1-related protein, TgNCR1. Mammalian NPC1 localizes to endo-lysosomes and promotes the movement of sterols and sphingolipids across the membranes of these organelles. Miscoding patient mutations in NPC1 cause overloading of these lipids in endo-lysosomes. TgNCR1, however, lacks endosomal targeting signals, and localizes to flattened vesicles beneath the plasma membrane of Toxoplasma. When expressed in mammalian NPC1 mutant cells and properly addressed to endo-lysosomes, TgNCR1 restores cholesterol and GM1 clearance from these organelles. To clarify the role of TgNCR1 in the parasite, we genetically disrupted NCR1; mutant parasites were viable. Quantitative lipidomic analyses on the ΔNCR1 strain reveal normal cholesterol levels but an overaccumulation of several species of cholesteryl esters, sphingomyelins and ceramides. ΔNCR1 parasites are also characterized by abundant storage lipid bodies and long membranous tubules derived from their parasitophorous vacuoles. Interestingly, these mutants can generate multiple daughters per single mother cell at high frequencies, allowing fast replication in vitro, and they are slightly more virulent in mice than the parental strain. These data suggest that the ΔNCR1 strain has lost the ability to control the intracellular levels of several lipids, which subsequently results in the stimulation of lipid storage, membrane biosynthesis and parasite division. Based on these observations, we ascribe a role for TgNCR1 in lipid homeostasis in Toxoplasma. 相似文献
96.
Martinović J Dopsaj V Kotur-Stevuljević J Dopsaj M Vujović A Stefanović A Nešić G 《Journal of strength and conditioning research / National Strength & Conditioning Association》2011,25(5):1360-1367
The objectives of this study were to determine (a) if reactive oxygen metabolites (ROMs) are a reliable parameter for monitoring oxidative stress in athletes alone or in association with other parameters of oxidative stress and depending on whether antioxidant supplements are taken or not; (b) the level of oxidative stress in athletes before the competition season; and (c) if oxidative status could be improved in volleyball athletes. Sixteen women athletes (supplemented group) received an antioxidant cocktail containing vitamin E, vitamin C, zinc gluconate, and selenium as a dietary supplement during a 6-week training period, whereas 12 of them (control group) received no dietary supplement. Blood samples were taken before and after the training period. The following parameters were measured: ROMs, superoxide anion (O2??), malondialdehyde (MDA), advanced oxidation protein products (AOPP), lipid hydroperoxide (LOOH), biological antioxidative potential (BAP), paraoxonase activity toward paraoxon (POase) and diazoxon (DZOase), superoxide dismutase(SOD), total sulfydryl group concentration (SH groups), and lipid status. Reactive oxygen metabolites were taken as the dependent variable and MDA, O2??, AOPP, and LOOH as independent variables. In the group of athletes who have received supplementation, linear regression analysis revealed that the implemented model had a lower influence on dROMs (70.4 vs. 27.9%) after the training period. The general linear model showed significant differences between parameters before and after training/supplementation (Wilks' lambda = 0.074, F = 11.76, p < 0.01). At the partial level, significant increases in ROM levels (p <0.05, 95% confidence interval [CI]: 286-337), SOD activity (CI: 113-144), and BAP (CI: 2,388-2,580) (p < 0.01) were observed. The association between ROMs and other parameters of oxidative stress was reduced in athletes who received supplements. During the precompetition training period, treatment with dietary supplements prevented the depletion of antioxidative defense in volleyball athletes. 相似文献
97.
Bartoli KM Jakovljevic J Woolford JL Saunders WS 《Molecular biology of the cell》2011,22(18):3420-3430
The kinesin-related molecular motor Eg5 plays roles in cell division, promoting spindle assembly. We show that during interphase Eg5 is associated with ribosomes and is required for optimal nascent polypeptide synthesis. When Eg5 was inhibited, ribosomes no longer bound to microtubules in vitro, ribosome transit rates slowed, and polysomes accumulated in intact cells, suggesting defects in elongation or termination during polypeptide synthesis. These results demonstrate that the molecular motor Eg5 associates with ribosomes and enhances the efficiency of translation. 相似文献
98.
Yu Z Kleifeld O Lande-Atir A Bsoul M Kleiman M Krutauz D Book A Vierstra RD Hofmann K Reis N Glickman MH Pick E 《Molecular biology of the cell》2011,22(7):911-920
Subunit composition and architectural structure of the 26S proteasome lid is strictly conserved between all eukaryotes. This eight-subunit complex bears high similarity to the eukaryotic translation initiation factor 3 and to the COP9 signalosome (CSN), which together define the proteasome CSN/COP9/initiation factor (PCI) troika. In some unicellular eukaryotes, the latter two complexes lack key subunits, encouraging questions about the conservation of their structural design. Here we demonstrate that, in Saccharomyces cerevisiae, Rpn5 plays dual roles by stabilizing proteasome and CSN structures independently. Proteasome and CSN complexes are easily dissected, with Rpn5 the only subunit in common. Together with Rpn5, we identified a total of six bona fide subunits at roughly stoichiometric ratios in isolated, affinity-purified CSN. Moreover, the copy of Rpn5 associated with the CSN is required for enzymatic hydrolysis of Rub1/Nedd8 conjugated to cullins. We propose that multitasking by a single subunit, Rpn5 in this case, allows it to function in different complexes simultaneously. These observations demonstrate that functional substitution of subunits by paralogues is feasible, implying that the canonical composition of the three PCI complexes in S. cerevisiae is more robust than hitherto appreciated. 相似文献
99.
Petrovic S Leskovac A Kotur-Stevuljevic J Joksic J Guc-Scekic M Vujic D Joksic G 《Biological chemistry》2011,392(7):625-632
Abstract Fanconi anemia (FA) is a rare cancer-prone genetic disorder characterized by progressive bone marrow failure, chromosomal instability and redox abnormalities. There is much biochemical and genetic data, which strongly suggest that FA cells experience increased oxidative stress. The present study was designed to elucidate if differences in oxidant state exist between control, idiopathic bone marrow failure (idBMF) and FA cells, and to analyze oxidant state of cells in FA heterozygous carriers as well. The results of the present study confirm an in vivo prooxidant state of FA cells and clearly indicate that FA patients can be distinguished from idBMF patients based on the oxidant state of cells. Female carriers of FA mutation also exhibited hallmarks of an in vivo prooxidant state behaving in a similar manner as FA patients. On the other hand, the oxidant state of cells in FA male carriers and idBMF families failed to show any significant difference vs. controls. We demonstrate that the altered oxidant state influences susceptibility of cells to apoptosis in both FA patients and female carriers. The results highlight the need for further research of the possible role of mitochondrial inheritance in the pathogenesis of FA. 相似文献
100.
Medugorac I Veit-Kensch CE Ramljak J Brka M Marković B Stojanović S Bytyqi H Kochoski L Kume K Grünenfelder HP Bennewitz J Förster M 《Ecology and evolution》2011,1(3):408-420
We estimated neutral diversity of 21 European cattle breeds with 105 microsatellites. Nine of them resembled unselected Balkan Buša strains with diffuse breeding barriers and the 12 others were strongly differentiated, isolated breeds. Because of the impact of neutral genetic diversity on long-term population adaptive capacity, we discuss the long-term outcome of different conservation priorities in a subdivided metapopulation of the investigated cattle breeds. The optimal contribution to a pool of total genetic diversity allocated more than 95% of long-term relevant neutral diversity to virtually unselected strains of the Balkan Buša, while the maximization of total variance preferred inbred breeds. Current artificial selection methods, such as genomic selection sped up and a recovery of underestimated traits becomes quickly impossible. We emphasize that currently neutral and even deleterious alleles might be required for future genotypes in sustainable and efficient livestock breeding and production systems of a 21st century. We provide cumulative evidences that long-term survival relies on genetic complexity and complexity relies on allelic diversity. Our results suggest that virtually unselected, nonuniform strains harbor a crucial proportion of neutral diversity and should be conserved with high global priority. As one example, we suggest a cooperative maintenance of the nondifferentiated, highly fragmented, and fast vanishing metapopulation of Balkan Buša. 相似文献