全文获取类型
收费全文 | 2479篇 |
免费 | 228篇 |
专业分类
2707篇 |
出版年
2023年 | 22篇 |
2022年 | 58篇 |
2021年 | 92篇 |
2020年 | 49篇 |
2019年 | 60篇 |
2018年 | 69篇 |
2017年 | 53篇 |
2016年 | 94篇 |
2015年 | 183篇 |
2014年 | 182篇 |
2013年 | 182篇 |
2012年 | 233篇 |
2011年 | 210篇 |
2010年 | 138篇 |
2009年 | 107篇 |
2008年 | 148篇 |
2007年 | 136篇 |
2006年 | 107篇 |
2005年 | 105篇 |
2004年 | 104篇 |
2003年 | 83篇 |
2002年 | 84篇 |
2001年 | 13篇 |
2000年 | 13篇 |
1999年 | 11篇 |
1998年 | 12篇 |
1997年 | 15篇 |
1996年 | 10篇 |
1995年 | 10篇 |
1994年 | 7篇 |
1993年 | 9篇 |
1992年 | 8篇 |
1991年 | 6篇 |
1990年 | 5篇 |
1989年 | 5篇 |
1988年 | 4篇 |
1986年 | 5篇 |
1984年 | 3篇 |
1983年 | 5篇 |
1982年 | 4篇 |
1981年 | 4篇 |
1980年 | 5篇 |
1978年 | 5篇 |
1977年 | 3篇 |
1976年 | 4篇 |
1972年 | 2篇 |
1971年 | 7篇 |
1969年 | 4篇 |
1955年 | 2篇 |
1948年 | 2篇 |
排序方式: 共有2707条查询结果,搜索用时 15 毫秒
991.
Caines ME Zhu H Vuckovic M Willis LM Withers SG Wakarchuk WW Strynadka NC 《The Journal of biological chemistry》2008,283(46):31279-31283
Streptococcus pneumoniae endo-alpha-N-acetylgalactosaminidase is a cell surface-anchored glycoside hydrolase from family GH101 involved in the breakdown of mucin type O-linked glycans. The 189-kDa mature enzyme specifically hydrolyzes the T-antigen disaccharide from extracellular host glycoproteins and is representative of a broadly important class of virulence factors that have remained structurally uncharacterized due to their large size and highly modular nature. Here we report a 2.9 angstroms resolution crystal structure that remarkably captures the multidomain architecture and characterizes a catalytic center unexpectedly resembling that of alpha-amylases. Our analysis presents a complete model of glycoprotein recognition and provides a basis for the structure-based design of novel Streptococcus vaccines and therapeutics. 相似文献
992.
Comini MA Rettig J Dirdjaja N Hanschmann EM Berndt C Krauth-Siegel RL 《The Journal of biological chemistry》2008,283(41):27785-27798
African trypanosomes encode three monothiol glutaredoxins (1-C-Grx). 1-C-Grx1 occurs exclusively in the mitochondrion, and 1-C-Grx2 and -3 are predicted to be mitochondrial and cytosolic proteins, respectively. All three 1-C-Grx are expressed in both the mammalian bloodstream and the insect procyclic form of Trypanosoma brucei, with the highest levels found in stationary phase and starving parasites. In the rudimentary mitochondrion of bloodstream cells, 1-C-Grx1 reaches concentrations above 200 microm/subunit. Recombinant T. brucei 1-C-Grx1 exists as a noncovalent homodimer, whereas 1-C-Grx2 and 1-C-Grx3 are monomeric proteins. In vitro, dimeric 1-C-Grx1 coordinated an H(2)O(2)-sensitive [2Fe-2S] cluster that required GSH as an additional ligand. Both bloodstream and procyclic trypanosomes were refractory to down-regulation of 1-C-Grx1 expression by RNA interference. In procyclic parasites, the 1-c-grx1 alleles could only be deleted if an ectopic copy of the gene was expressed. A 5-10-fold overexpression of 1-C-Grx1 in both parasite forms did not yield a growth phenotype under optimal culture conditions. However, exposure of these cells to the iron chelator deferoxamine or H(2)O(2), but not to iron or menadione, impaired cell growth. Treatment of wild-type bloodstream parasites with deferoxamine and H(2)O(2) caused a 2-fold down- and up-regulation of 1-C-Grx1, respectively. The results point to an essential role of the mitochondrial 1-C-Grx1 in the iron metabolism of these parasites. 相似文献
993.
Jameson N Georgelis N Fouladbash E Martens S Hannah LC Lal S 《Plant molecular biology》2008,67(3):295-304
The mass movement of gene sequences by Helitrons has significantly contributed to the lack of gene collinearity reported between different maize inbred lines. However, Helitron captured-genes reported to date represent truncated versions of their progenitor genes. In this report, we provide evidence that maize CYP72A27-Zm gene represents a cytochrome P450 monooxygenase (P450) gene recently captured by a Helitron and transposed into an Opie-2 retroposon. The four exons of the CYP72A27 gene contained within the element contain a putative open reading frame (ORF) for 428 amino acid residues. We provide evidence that Helitron captured CYP72A27-Zm is transcribed. To identify the progenitor gene and the evolutionary time of capture, we searched the plant genome database and discovered other closely related CYP72A27-Zm genes in maize and grasses. Our analysis indicates that CYP72A27-Zm represents an almost complete copy of maize CYP72A26-Zm gene captured by a Helitron about 3.1 million years ago (mya). The Helitron-captured gene then duplicated twice, approximately 1.5-1.6 mya giving rise to CYP72A36-Zm and CYP72A37-Zm. These data provide evidence that Helitrons can capture and mobilize intact genes that are transcribed and potentially encode biologically relevant proteins. 相似文献
994.
Colleen G Canning Cathie Sherrington Stephen R Lord Victor SC Fung Jacqueline CT Close Mark D Latt Kirsten Howard Natalie E Allen Sandra D O'Rourke Susan M Murray 《BMC neurology》2009,9(1):4-7
Background
People with Parkinson's disease are twice as likely to be recurrent fallers compared to other older people. As these falls have devastating consequences, there is an urgent need to identify and test innovative interventions with the potential to reduce falls in people with Parkinson's disease. The main objective of this randomised controlled trial is to determine whether fall rates can be reduced in people with Parkinson's disease using exercise targeting three potentially remediable risk factors for falls (reduced balance, reduced leg muscle strength and freezing of gait). In addition we will establish the cost effectiveness of the exercise program from the health provider's perspective.Methods/Design
230 community-dwelling participants with idiopathic Parkinson's disease will be recruited. Eligible participants will also have a history of falls or be identified as being at risk of falls on assessment. Participants will be randomly allocated to a usual-care control group or an intervention group which will undertake weight-bearing balance and strengthening exercises and use cueing strategies to address freezing of gait. The intervention group will choose between the home-based or support group-based mode of the program. Participants in both groups will receive standardized falls prevention advice. The primary outcome measure will be fall rates. Participants will record falls and medical interventions in a diary for the duration of the 6-month intervention period. Secondary measures include the Parkinson's Disease Falls Risk Score, maximal leg muscle strength, standing balance, the Short Physical Performance Battery, freezing of gait, health and well being, habitual physical activity and positive and negative affect schedule.Discussion
No adequately powered studies have investigated exercise interventions aimed at reducing falls in people with Parkinson's disease. This trial will determine the effectiveness of the exercise intervention in reducing falls and its cost effectiveness. This pragmatic program, if found to be effective, has the potential to be implemented within existing community services.Trial registration
The protocol for this study is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12608000303347). 相似文献995.
996.
Mathie NJ Franklin CE 《Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology》2006,176(8):739-747
In aquatic vertebrates that acquire oxygen aerially dive duration scales positively with body mass, i.e. larger animals can dive for longer periods, however in bimodally respiring animals the relationship between dive duration and body mass is unclear. In this study we investigated the relationships between body size, aquatic respiration, and dive duration in the bimodally respiring turtle, Elseya albagula. Under normoxic conditions, dive duration was found to be independent of body mass. The dive durations of smaller turtles were equivalent to that of larger individuals despite their relatively smaller oxygen stores and higher mass specific metabolic rates. Smaller turtles were able to increase their dive duration through the use of aquatic respiration. Smaller turtles had a relatively higher cloacal bursae surface area than larger turtles, which allowed them to extract a relatively larger amount of oxygen from the water. By removing the ability to respire aquatically (hypoxic conditions), the dive duration of the smaller turtles significantly decreased restoring the normal positive relationship between body size and dive duration that is seen in other air-breathing vertebrates. 相似文献
997.
Jonathan J. Cooper Natalie Mcall Sharon Johnson H.P.B. Davidson 《Applied animal behaviour science》2005,90(3-4):351-364
In this study, we investigated the effect of increasing the number of meals of concentrate (whilst maintaining the same daily intake) on the behaviour of stabled horses with particular reference to stereotypic activities. The study was carried out on a working equestrian yard with stables for up to 50 horses. A pilot study was used to record incidence of stereotypic behaviour and to select subjects for the main study. In this, the behaviour of 30 warm-blooded horses was recorded during their morning (08:30 h) and afternoon (16:30 h) concentrate feeds. Whilst there was a low incidence of stereotypic behaviour (5.6% of scans) in the population, they were more commonly observed in the afternoon (7.1%) than the morning observations (4.2%; P < 0.05). The higher incidence in the afternoon observation appeared to be related to the lower availability of high fibre forage during the afternoon meal. In the main study nine horses were fed their normal ration of concentrate divided between two, four or six equally sized meals. Their behaviour was compared with seven control horses, which received two meals per day throughout the trial. As the number of meals increased, the treatment horses showed a decrease in oral stereotypies (P < 0.01), but an increase in weaving (P < 0.05) and nodding (P < 0.01) prior to feeding. The control group increased weaving, nodding and oral stereotypies (all P < 0.05) as their yard-mates received more meals. Consequently there was an overall increase in incidence of stereotypy in both treatment and control horses with the increase in meal frequency. The study, therefore, suggests that dividing the stabled horses’ concentrate ration into a number of smaller meals may be an effective means of reducing oral stereotypies, but that pre-feeding stereotypies may persist and that the practise may increase the frequency of stereotypic behaviour on unfed horses in visual contact. 相似文献
998.
Raboisson P de Kock H Rosenquist A Nilsson M Salvador-Oden L Lin TI Roue N Ivanov V Wähling H Wickström K Hamelink E Edlund M Vrang L Vendeville S Van de Vreken W McGowan D Tahri A Hu L Boutton C Lenz O Delouvroy F Pille G Surleraux D Wigerinck P Samuelsson B Simmen K 《Bioorganic & medicinal chemistry letters》2008,18(17):4853-4858
SAR analysis performed with a limited set of cyclopentane-containing macrocycles led to the identification of N-[17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo [13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (TMC435350, 32c) as a potent inhibitor of HCV NS3/4A protease (Ki = 0.36 nM) and viral replication (replicon EC50 = 7.8 nM). TMC435350 also displayed low in vitro clearance and high permeability, which were confirmed by in vivo pharmacokinetic studies. TMC435350 is currently being evaluated in the clinics. 相似文献
999.
Othman RA Suh M Fischer G Azordegan N Riediger N Le K Jassal DS Moghadasian MH 《American journal of physiology. Heart and circulatory physiology》2008,294(3):H1452-H1458
Both fish and flaxseed oils are major sources of different n-3 fatty acids. Beneficial effects of fish oil on posttransplantation complications have been reported. The current study aimed to compare the effects of flaxseed and fish oils in a rat cardiac allograft model. Male Fischer and Lewis rats were used as donors and recipients, respectively, to generate a heterotopic cardiac allograft model. Animals were randomly assigned into three groups and fed a diet supplemented with 1) 5% (wt/wt) safflower oil (control, n = 7), 2) 5% (wt/wt) flaxseed oil (n = 8), or 3) 2% (wt/wt) fish oil (n = 7), and an intraperitoneal injection of cyclosporine A (CsA; 1.5 mg.kg(-1).day(-1)) over 12 wk. Body weight, blood pressure, plasma levels of lipids, CsA, select cytokines, as well as graft function and chronic rejection features were assessed. Body weight and blood CsA levels were similar among the groups. Relative to controls, both treated groups had lower systolic and diastolic blood pressure and plasma levels of macrophage chemotactic protein-1. Treatment with fish oil significantly (P < 0.05) lowered plasma levels of triglycerides, total cholesterol, and LDL-cholesterol. HDL-cholesterol concentrations were significantly higher (P < 0.05) in the flaxseed oil-treated group compared with the other two groups. Both flaxseed oil and fish oil may provide similar biochemical, hemodynamic, and inflammatory benefits after heart transplantation; however, neither of the oils was able to statistically significantly impact chronic rejection or histological evidence of apparent cyclosporine-induced nephrotoxicity in this model. 相似文献
1000.
Kim Y Ho SO Gassman NR Korlann Y Landorf EV Collart FR Weiss S 《Bioconjugate chemistry》2008,19(3):786-791
Methods for chemical modifications of proteins have been crucial for the advancement of proteomics. In particular, site-specific covalent labeling of proteins with fluorophores and other moieties has permitted the development of a multitude of assays for proteome analysis. A common approach for such a modification is solvent-accessible cysteine labeling using thiol-reactive dyes. Cysteine is very attractive for site-specific conjugation due to its relative rarity throughout the proteome and the ease of its introduction into a specific site along the protein's amino acid chain. This is achieved by site-directed mutagenesis, most often without perturbing the protein's function. Bottlenecks in this reaction, however, include the maintenance of reactive thiol groups without oxidation before the reaction, and the effective removal of unreacted molecules prior to fluorescence studies. Here, we describe an efficient, specific, and rapid procedure for cysteine labeling starting from well-reduced proteins in the solid state. The efficacy and specificity of the improved procedure are estimated using a variety of single-cysteine proteins and thiol-reactive dyes. Based on UV/vis absorbance spectra, coupling efficiencies are typically in the range 70-90%, and specificities are better than approximately 95%. The labeled proteins are evaluated using fluorescence assays, proving that the covalent modification does not alter their function. In addition to maleimide-based conjugation, this improved procedure may be used for other thiol-reactive conjugations such as haloacetyl, alkyl halide, and disulfide interchange derivatives. This facile and rapid procedure is well suited for high throughput proteome analysis. 相似文献