全文获取类型
收费全文 | 1459篇 |
免费 | 72篇 |
国内免费 | 2篇 |
出版年
2023年 | 2篇 |
2022年 | 6篇 |
2021年 | 18篇 |
2020年 | 5篇 |
2019年 | 5篇 |
2018年 | 14篇 |
2017年 | 11篇 |
2016年 | 22篇 |
2015年 | 58篇 |
2014年 | 68篇 |
2013年 | 82篇 |
2012年 | 89篇 |
2011年 | 115篇 |
2010年 | 69篇 |
2009年 | 68篇 |
2008年 | 94篇 |
2007年 | 106篇 |
2006年 | 105篇 |
2005年 | 96篇 |
2004年 | 95篇 |
2003年 | 84篇 |
2002年 | 95篇 |
2001年 | 13篇 |
2000年 | 16篇 |
1999年 | 20篇 |
1998年 | 26篇 |
1997年 | 17篇 |
1996年 | 18篇 |
1995年 | 20篇 |
1994年 | 8篇 |
1993年 | 11篇 |
1992年 | 8篇 |
1991年 | 10篇 |
1990年 | 4篇 |
1989年 | 10篇 |
1988年 | 7篇 |
1987年 | 4篇 |
1986年 | 2篇 |
1985年 | 4篇 |
1984年 | 6篇 |
1983年 | 3篇 |
1982年 | 4篇 |
1981年 | 2篇 |
1979年 | 1篇 |
1978年 | 3篇 |
1977年 | 2篇 |
1976年 | 3篇 |
1975年 | 1篇 |
1970年 | 1篇 |
1969年 | 1篇 |
排序方式: 共有1533条查询结果,搜索用时 31 毫秒
81.
82.
Julien Marlet Annick Ankri Jean-Luc Charuel Pascale Ghillani-Dalbin Amélie Perret Isabelle Martin-Toutain Julien Haroche Zahir Amoura Lucile Musset Makoto Miyara 《PloS one》2015,10(9)
Context
Anti-DFS70 antibodies are the most frequent antinuclear antibodies (ANA) found in healthy individuals. We assessed the clinical significance of the presence of anti-DFS70 antibodies.Methods
We defined a group of patients (n = 421) with anti-DFS70 antibodies and a group of patients (n = 63) with a history of idiopathic arterial and/or venous thrombotic disease and/or obstetric complication (i.e. ≥3 miscarriages, fetal death or premature birth with eclampsia). Anti-DFS70 antibodies prevalence was also assessed in a cohort of 300 healthy blood donors.Results
The prevalence of thrombotic disease and/or obstetric complication in the 421 patients with anti-DFS70 antibodies was 13.1% (n = 55) and the prevalence of connective tissue disease was 19% (n = 80). Among the 63 patients with a history of thrombosis and/or obstetric complications, 7 (11.1%) had anti-DFS70 antibodies and among the latter, 5 had no common thrombophilic factor. In contrast, the prevalence of anti-DFS70 antibodies was of 3.0% (9 out of 300) in healthy donors. Finally, the Activated Partial Thromboplastin Time (aPTT) ratio of patients with a history of thrombosis and anti-DFS70 antibodies was lower than the aPTT ratio of other patients, suggesting that thrombotic patients with anti-DFS70 antibodies may have a hypercoagulable state.Conclusion
We described here for the first time an immune procoagulant state involving anti-DFS70 antibodies. 相似文献83.
Alain Hendlisz Amelie Deleporte Thierry Delaunoit Rapha?l Maréchal Marc Peeters Stéphane Holbrechts Marc Van den Eynde Ghislain Houbiers Bertrand Filleul Jean-Luc Van Laethem Sarah Ceyssens Anna-Maria Barbuto Renaud Lhommel Gauthier Demolin Camilo Garcia Hazem El Mansy Lieveke Ameye Michel Moreau Thomas Guiot Marianne Paesmans Martine Piccart Patrick Flamen 《PloS one》2015,10(9)
Background
Tumoral heterogeneity is a major determinant of resistance in solid tumors. FDG-PET/CT can identify early during chemotherapy non-responsive lesions within the whole body tumor load. This prospective multicentric proof-of-concept study explores intra-individual metabolic response (mR) heterogeneity as a treatment efficacy biomarker in chemorefractory metastatic colorectal cancer (mCRC).Methods
Standardized FDG-PET/CT was performed at baseline and after the first cycle of combined sorafenib (600mg/day for 21 days, then 800mg/day) and capecitabine (1700 mg/m²/day administered D1-14 every 21 days). MR assessment was categorized according to the proportion of metabolically non-responding (non-mR) lesions (stable FDG uptake with SUVmax decrease <15%) among all measurable lesions.Results
Ninety-two patients were included. The median overall survival (OS) and progression-free survival (PFS) were 8.2 months (95% CI: 6.8–10.5) and 4.2 months (95% CI: 3.4–4.8) respectively. In the 79 assessable patients, early PET-CT showed no metabolically refractory lesion in 47%, a heterogeneous mR with at least one non-mR lesion in 32%, and a consistent non-mR or early disease progression in 21%. On exploratory analysis, patients without any non-mR lesion showed a significantly longer PFS (HR 0.34; 95% CI: 0.21–0.56, P-value <0.001) and OS (HR 0.58; 95% CI: 0.36–0.92, P-value 0.02) compared to the other patients. The proportion of non-mR lesions within the tumor load did not impact PFS/OS.Conclusion
The presence of at least one metabolically refractory lesion is associated with a poorer outcome in advanced mCRC patients treated with combined sorafenib-capecitabine. Early detection of treatment-induced mR heterogeneity may represent an important predictive efficacy biomarker in mCRC.Trial Registration
ClinicalTrials.gov NCT01290926 相似文献84.
David J. Menger Philemon Omusula Maarten Holdinga Tobias Homan Ana S. Carreira Patrice Vandendaele Jean-Luc Derycke Collins K. Mweresa Wolfgang Richard Mukabana Joop J. A. van Loon Willem Takken 《PloS one》2015,10(4)
Malaria continues to place a disease burden on millions of people throughout the tropics, especially in sub-Saharan Africa. Although efforts to control mosquito populations and reduce human-vector contact, such as long-lasting insecticidal nets and indoor residual spraying, have led to significant decreases in malaria incidence, further progress is now threatened by the widespread development of physiological and behavioural insecticide-resistance as well as changes in the composition of vector populations. A mosquito-directed push-pull system based on the simultaneous use of attractive and repellent volatiles offers a complementary tool to existing vector-control methods. In this study, the combination of a trap baited with a five-compound attractant and a strip of net-fabric impregnated with micro-encapsulated repellent and placed in the eaves of houses, was tested in a malaria-endemic village in western Kenya. Using the repellent delta-undecalactone, mosquito house entry was reduced by more than 50%, while the traps caught high numbers of outdoor flying mosquitoes. Model simulations predict that, assuming area-wide coverage, the addition of such a push-pull system to existing prevention efforts will result in up to 20-fold reductions in the entomological inoculation rate. Reductions of such magnitude are also predicted when mosquitoes exhibit a high resistance against insecticides. We conclude that a push-pull system based on non-toxic volatiles provides an important addition to existing strategies for malaria prevention. 相似文献
85.
Laurent J. Catoire Manuela Zoonens Carine van Heijenoort Fabrice Giusti Éric Guittet Jean-Luc Popot 《European biophysics journal : EBJ》2010,39(4):623-630
The atomic structure of OmpX, the smallest member of the bacterial outer membrane protein family, has been previously established
by X-ray crystallography and NMR spectroscopy. In apparent conflict with electrophysiological studies, the lumen of its transmembrane
β-barrel appears too tightly packed with amino acid side chains to let any solute flow through. In the present study, high-resolution
solution NMR spectra were obtained of OmpX kept water-soluble by either amphipol A8-35 or the detergent dihexanoylphosphatidylcholine.
Hydrogen/deuterium exchange measurements performed after prolonged equilibration show that, whatever the surfactant used,
some of the amide protons of the membrane-spanning region exchange much more readily than others, which likely reflects the
dynamics of the barrel. 相似文献
86.
Pascal Maurice Avais M Daulat Rostislav Turecek Klara Ivankova-Susankova Francesco Zamponi Maud Kamal Nathalie Clement Jean-Luc Guillaume Bernhard Bettler C��line Gal��s Philippe Delagrange Ralf Jockers 《The EMBO journal》2010,29(21):3646-3659
Functional asymmetry of G‐protein‐coupled receptor (GPCR) dimers has been reported for an increasing number of cases, but the molecular architecture of signalling units associated to these dimers remains unclear. Here, we characterized the molecular complex of the melatonin MT1 receptor, which directly and constitutively couples to Gi proteins and the regulator of G‐protein signalling (RGS) 20. The molecular organization of the ternary MT1/Gi/RGS20 complex was monitored in its basal and activated state by bioluminescence resonance energy transfer between probes inserted at multiple sites of the complex. On the basis of the reported crystal structures of Gi and the RGS domain, we propose a model wherein one Gi and one RGS20 protein bind to separate protomers of MT1 dimers in a pre‐associated complex that rearranges upon agonist activation. This model was further validated with MT1/MT2 heterodimers. Collectively, our data extend the concept of asymmetry within GPCR dimers, reinforce the notion of receptor specificity for RGS proteins and highlight the advantage of GPCRs organized as dimers in which each protomer fulfils its specific task by binding to different GPCR‐interacting proteins. 相似文献
87.
Vercheval L Bauvois C di Paolo A Borel F Ferrer JL Sauvage E Matagne A Frère JM Charlier P Galleni M Kerff F 《The Biochemical journal》2010,432(3):495-504
The activity of class D β-lactamases is dependent on Lys70 carboxylation in the active site. Structural, kinetic and affinity studies show that this post-translational modification can be affected by the presence of a poor substrate such as moxalactam but also by the V117T substitution. Val117 is a strictly conserved hydrophobic residue located in the active site. In addition, inhibition of class D β-lactamases by chloride ions is due to a competition between the side chain carboxylate of the modified Lys70 and chloride ions. Determination of the individual kinetic constants shows that the deacylation of the acyl-enzyme is the rate-limiting step for the wild-type OXA-10 β-lactamase. 相似文献
88.
Phage display establishes a link between a polypeptide and its corresponding gene. It has been much used for the isolation
of proteins binding to chosen molecular targets. A second link was designed more recently between a phage-displayed enzyme
and its reaction product. Affinity chromatography for the product then allows the isolation of catalytically active enzymes
and of their genes. Using this strategy, a polymerase with 15 mutations was selected by directed evolution of Thermus aquaticus DNA polymerase I. The kinetic characterisation reported here highlights the variant’s broad template specificity and classifies
this enzyme as a thermostable DNA-dependent and RNA-dependent DNA-polymerase. 相似文献
89.
Loïck Le Dantec Gaelle Cardinet Julio Bonet Mathieu Fouché Karima Boudehri Amparo Monfort Jean-Luc Poëssel Annick Moing Elisabeth Dirlewanger 《Tree Genetics & Genomes》2010,6(6):995-1012
The goal of the present study was to identify candidate genes (CGs) involved in fruit quality in peach that can be transferred to other Rosaceae species. Two cDNA libraries from fruit of the “Fantasia” peach cultivar, constructed at two stages of development, were used to generate a set of expressed sequence tag sequences. A total of 1,730 peach unigenes were obtained after clustering. Sequences and corresponding annotations were stored in a relational database and are available through a web interface. Fifty-nine CGs involved in fruit growth and development or fruit quality at maturity, focusing on sweetness, acidity, and phenolic compound content, were selected according to their annotation. Fifty-five primer pairs, designed from peach CG sequences and giving PCR products in peach, were tested in strawberry and 36 gave amplified products. Eight CGs were mapped in peach, 14 in strawberry, four in both species and confirmed the pattern of synteny already proposed using comparative mapping. In peach, the CGs are located in three linkage groups (3, 5, 7), and in strawberry they are distributed in all seven Fragaria linkage groups. Colocalization between some of these CGs and quantitative trait loci for fruit quality traits were identified and are awaiting confirmation in further analyses. 相似文献