全文获取类型
收费全文 | 5695篇 |
免费 | 350篇 |
国内免费 | 1篇 |
出版年
2024年 | 4篇 |
2023年 | 29篇 |
2022年 | 70篇 |
2021年 | 128篇 |
2020年 | 90篇 |
2019年 | 132篇 |
2018年 | 164篇 |
2017年 | 136篇 |
2016年 | 181篇 |
2015年 | 306篇 |
2014年 | 311篇 |
2013年 | 426篇 |
2012年 | 505篇 |
2011年 | 456篇 |
2010年 | 310篇 |
2009年 | 295篇 |
2008年 | 382篇 |
2007年 | 361篇 |
2006年 | 322篇 |
2005年 | 284篇 |
2004年 | 265篇 |
2003年 | 231篇 |
2002年 | 218篇 |
2001年 | 58篇 |
2000年 | 32篇 |
1999年 | 55篇 |
1998年 | 46篇 |
1997年 | 28篇 |
1996年 | 31篇 |
1995年 | 24篇 |
1994年 | 25篇 |
1993年 | 16篇 |
1992年 | 11篇 |
1991年 | 10篇 |
1990年 | 8篇 |
1989年 | 11篇 |
1988年 | 9篇 |
1987年 | 6篇 |
1986年 | 5篇 |
1985年 | 8篇 |
1984年 | 11篇 |
1983年 | 8篇 |
1982年 | 9篇 |
1981年 | 6篇 |
1980年 | 3篇 |
1979年 | 6篇 |
1976年 | 3篇 |
1975年 | 3篇 |
1974年 | 4篇 |
1965年 | 1篇 |
排序方式: 共有6046条查询结果,搜索用时 160 毫秒
991.
992.
Guerra S López-Fernández LA García MA Zaballos A Esteban M 《The Journal of biological chemistry》2006,281(27):18734-18745
993.
994.
Oliveira MA Guimarães BG Cussiol JR Medrano FJ Gozzo FC Netto LE 《Journal of molecular biology》2006,359(2):433-445
Organic hydroperoxide resistance proteins (Ohr) belong to a family of proteins that possess thiol-dependent peroxidase activity endowed by reactive cysteine residues able to reduce peroxides. The crystal structure of Ohr from Xylella fastidiosa in complex with polyethylene glycol, providing insights into enzyme-substrate interactions is described herein. In addition, crystallographic studies, molecular modeling and biochemical assays also indicated that peroxides derived from long chain fatty acids could be the biological substrates of Ohr. Because different oxidation states of the reactive cysteine were present in the Ohr structures from X. fastidiosa, Pseudomonas aeruginosa and Deinococcus radiodurans it was possible to envisage a set of snapshots along the coordinate of the enzyme-catalyzed reaction. The redox intermediates of X. fastidiosa Ohr observed in the crystals were further characterized in solution by electrospray ionization mass spectrometry and by biochemical approaches. In this study, the formation of an intramolecular disulfide bond and oxidative inactivation through the formation of a sulfonic acid derivative was unequivocally demonstrated for the first time. Because Ohr proteins are exclusively present in bacteria, they may represent promising targets for therapeutical drugs. In this regard, the structural and functional analyses of Ohr presented here might be very useful. 相似文献
995.
Huang Z Liu S Zhang L Salem M Greig GM Chan CC Natsumeda Y Noguchi K 《Life sciences》2006,78(23):2663-2668
Ibudilast ophthalmic solution exhibited an improved clinical efficacy over cromoglycate in the treatment of allergic conjunctivitis. To further characterize its principal mode of action, the phosphodiesterase (PDE) inhibitory profile of ibudilast has been examined using human recombinant enzymes. Ibudilast, but not the other commonly used anti-allergic ophthalmic solutions including cromoglycate, ketotifen, tranilast and levocabastine, potently inhibits purified human PDE4A, 4B, 4C and 4D with IC50 values at 54, 65, 239 and 166 nM, respectively. Ibudilast effectively blocks lipopolysaccharide (LPS)-induced tumor necrosis factor (TNFalpha, IC50 = 6.2 microM) and N-formyl-Met-Leu-Phe (fMLP)-induced leukotriene (LT) B4 biosynthesis (IC50 = 2.5 microM) in human whole blood, which are 3 and 6-fold more potent than cilomilast, respectively. The attenuated inflammatory and allergic responses from the potent and preferential PDE4 inhibition of ibudilast may have contributed significantly to its beneficial pharmacological responses and distinguishes ibudilast from the other ophthalmic solutions in the treatment of ocular allergy. 相似文献
996.
Paulo Marcos da Matta Guedes Fredy R. S. Gutierrez Flavia L. Maia Cristiane M. Milanezi Grace K. Silva Wander R. Pavanelli Jo?o S. Silva 《PLoS neglected tropical diseases》2010,4(2)
Background
Chagas disease is a neglected disease caused by the intracellular parasite Trypanosoma cruzi. Around 30% of the infected patients develop chronic cardiomyopathy or megasyndromes, which are high-cost morbid conditions. Immune response against myocardial self-antigens and exacerbated Th1 cytokine production has been associated with the pathogenesis of the disease. As IL-17 is involved in the pathogenesis of several autoimmune, inflammatory and infectious diseases, we investigated its role during the infection with T. cruzi.Methodology/Principal Findings
First, we detected significant amounts of CD4, CD8 and NK cells producing IL-17 after incubating live parasites with spleen cells from normal BALB/c mice. IL-17 is also produced in vivo by CD4+, CD8+ and NK cells from BALB/c mice on the early acute phase of infection. Treatment of infected mice with anti-mouse IL-17 mAb resulted in increased myocarditis, premature mortality, and decreased parasite load in the heart. IL-17 neutralization resulted in increased production of IL-12, IFN-γ and TNF-α and enhanced specific type 1 chemokine and chemokine receptors expression. Moreover, the results showed that IL-17 regulates T-bet, RORγt and STAT-3 expression in the heart, showing that IL-17 controls the differentiation of Th1 cells in infected mice.Conclusion/Significance
These results show that IL-17 controls the resistance to T. cruzi infection in mice regulating the Th1 cells differentiation, cytokine and chemokine production and control parasite-induced myocarditis, regulating the influx of inflammatory cells to the heart tissue. Correlations between the levels of IL-17, the extent of myocardial destruction, and the evolution of cardiac disease could identify a clinical marker of disease progression and may help in the design of alternative therapies for the control of chronic morbidity of chagasic patients. 相似文献997.
Marcos A. Rossi Herbert B. Tanowitz Lygia M. Malvestio Mara R. Celes Erica C. Campos Valdecir Blefari Cibele M. Prado 《PLoS neglected tropical diseases》2010,4(8)
This review focuses on the short and bewildered history of Brazilian scientist Carlos Chagas''s discovery and subsequent developments, the anatomopathological features of chronic Chagas cardiomyopathy (CCC), an overview on the controversies surrounding theories concerning its pathogenesis, and studies that support the microvascular hypothesis to further explain the pathological features and clinical course of CCC. It is our belief that knowledge of this particular and remarkable cardiomyopathy will shed light not only on the microvascular involvement of its pathogenesis, but also on the pathogenetic processes of other cardiomyopathies, which will hopefully provide a better understanding of the various changes that may lead to an end-stage heart disease with similar features. This review is written to celebrate the 100th anniversary of the discovery of Chagas disease. 相似文献
998.
Maria G. Guzman Thomas Jaenisch Roger Gaczkowski Vo Thi Ty Hang Shamala Devi Sekaran Axel Kroeger Susana Vazquez Didye Ruiz Eric Martinez Juan C. Mercado Angel Balmaseda Eva Harris Efren Dimano Prisca Susan A. Leano Sutee Yoksan Elci Villegas Herminia Benduzu Iris Villalobos Jeremy Farrar Cameron P. Simmons 《PLoS neglected tropical diseases》2010,4(8)
Background
Early diagnosis of dengue can assist patient triage and management and prevent unnecessary treatments and interventions. Commercially available assays that detect the dengue virus protein NS1 in the plasma/serum of patients offers the possibility of early and rapid diagnosis.Methodology/Principal Findings
The sensitivity and specificity of the Pan-E Dengue Early ELISA and the Platelia™ Dengue NS1 Ag assays were compared against a reference diagnosis in 1385 patients in 6 countries in Asia and the Americas. Platelia was more sensitive (66%) than Pan-E (52%) in confirmed dengue cases. Sensitivity varied by geographic region, with both assays generally being more sensitive in patients from SE Asia than the Americas. Both kits were more sensitive for specimens collected within the first few days of illness onset relative to later time points. Pan-E and Platelia were both 100% specific in febrile patients without evidence of acute dengue. In patients with other confirmed diagnoses and healthy blood donors, Platelia was more specific (100%) than Pan-E (90%). For Platelia, when either the NS1 test or the IgM test on the acute sample was positive, the sensitivity versus the reference result was 82% in samples collected in the first four days of fever. NS1 sensitivity was not associated to disease severity (DF or DHF) in the Platelia test, whereas a trend for higher sensitivity in DHF cases was seen in the Pan-E test (however combined with lower overall sensitivity).Conclusions/Significance
Collectively, this multi-country study suggests that the best performing NS1 assay (Platelia) had moderate sensitivity (median 64%, range 34–76%) and high specificity (100%) for the diagnosis of dengue. The poor sensitivity of the evaluated assays in some geographical regions suggests further assessments are needed. The combination of NS1 and IgM detection in samples collected in the first few days of fever increased the overall dengue diagnostic sensitivity. 相似文献999.
Antonio Verdejo‐García Manuel Pérez‐Expósito Jacqueline Schmidt‐Río‐Valle Maria J. Fernández‐Serrano Francisco Cruz Miguel Pérez‐García Gemma López‐Belmonte Miguel Martín‐Matillas Jose A. Martín‐Lagos Ascension Marcos Cristina Campoy 《Obesity (Silver Spring, Md.)》2010,18(8):1572-1578
Increasing evidence underscores overlapping neurobiological pathways to addiction and obesity. In both conditions, reward processing of preferred stimuli is enhanced, whereas the executive control system that would normally regulate reward‐driven responses is altered. This abnormal interaction can be greater in adolescence, a period characterized by relative immaturity of executive control systems coupled with the relative maturity of reward processing systems. The aim of this study is to explore neuropsychological performance of adolescents with excess weight (n = 27, BMI range 24–51 kg/m2) vs. normal‐weight adolescents (n = 34, BMI range 17–24 kg/m2) on a comprehensive battery of executive functioning tests, including measures of working memory (letter‐number sequencing), reasoning (similarities), planning (zoo map), response inhibition (five‐digit test (FDT)–interference and Stroop), flexibility (FDT–switching and trail‐making test (TMT)), self‐regulation (revised‐strategy application test (R‐SAT)), and decision‐making (Iowa gambling task (IGT)). We also aimed to explore personality traits of impulsivity and sensitivity to reward. Independent sample t‐ and Z Kolmogorov–Smirnov tests showed significant differences between groups on indexes of inhibition, flexibility, and decision‐making (excess‐weight participants performed poorer than controls), but not on tests of working memory, planning, and reasoning, nor on personality measures. Moreover, regression models showed a significant association between BMI and flexibility performance. These results are indicative of selective alterations of particular components of executive functions in overweight adolescents. 相似文献
1000.
Nakahira M Macedo JN Seraphim TV Cavalcante N Souza TA Damalio JC Reyes LF Assmann EM Alborghetti MR Garratt RC Araujo AP Zanchin NI Barbosa JA Kobarg J 《PloS one》2010,5(11):e13799