全文获取类型
收费全文 | 2215篇 |
免费 | 188篇 |
国内免费 | 3篇 |
出版年
2021年 | 26篇 |
2019年 | 22篇 |
2018年 | 15篇 |
2017年 | 26篇 |
2016年 | 34篇 |
2015年 | 56篇 |
2014年 | 65篇 |
2013年 | 100篇 |
2012年 | 113篇 |
2011年 | 125篇 |
2010年 | 70篇 |
2009年 | 63篇 |
2008年 | 88篇 |
2007年 | 107篇 |
2006年 | 79篇 |
2005年 | 88篇 |
2004年 | 103篇 |
2003年 | 89篇 |
2002年 | 95篇 |
2001年 | 24篇 |
2000年 | 22篇 |
1999年 | 39篇 |
1998年 | 39篇 |
1997年 | 26篇 |
1996年 | 20篇 |
1995年 | 19篇 |
1994年 | 20篇 |
1993年 | 24篇 |
1992年 | 28篇 |
1991年 | 26篇 |
1990年 | 20篇 |
1989年 | 23篇 |
1988年 | 23篇 |
1987年 | 16篇 |
1985年 | 21篇 |
1984年 | 26篇 |
1982年 | 35篇 |
1981年 | 27篇 |
1980年 | 31篇 |
1979年 | 16篇 |
1978年 | 26篇 |
1977年 | 19篇 |
1976年 | 26篇 |
1974年 | 24篇 |
1973年 | 21篇 |
1972年 | 17篇 |
1963年 | 14篇 |
1961年 | 17篇 |
1959年 | 15篇 |
1957年 | 16篇 |
排序方式: 共有2406条查询结果,搜索用时 15 毫秒
181.
Amandine Scandolera Fanja Rabenoelina Carine Chaintreuil Anthony Rusciani Pascal Maurice Sébastien Blaise Béatrice Romier-Crouzet Hassan El Btaouri Laurent Martiny Laurent Debelle Laurent Duca 《PloS one》2015,10(6)
Degradation of elastin leads to the production of elastin-derived peptides (EDP), which exhibit several biological effects, such as cell proliferation or protease secretion. Binding of EDP on the elastin receptor complex (ERC) triggers lactosylceramide (LacCer) production and ERK1/2 activation following ERC Neu-1 subunit activation. The ability for ERC to transduce signals is lost during aging, but the mechanism involved is still unknown. In this study, we characterized an in vitro model of aging by subculturing human dermal fibroblasts. This model was used to understand the loss of EDP biological activities during aging. Our results show that ERC uncoupling does not rely on Neu-1 or PPCA mRNA or protein level changes. Furthermore, we observe that the membrane targeting of these subunits is not affected with aging. However, we evidence that Neu-1 activity and LacCer production are altered. Basal Neu-1 catalytic activity is strongly increased in aged cells. Consequently, EDP fail to promote Neu-1 catalytic activity and LacCer production in these cells. In conclusion, we propose, for the first time, an explanation for ERC uncoupling based on the age-related alterations of Neu-1 activity and LacCer production that may explain the loss of EDP-mediated effects occurring during aging. 相似文献
182.
183.
184.
185.
186.
Merel Huisman Robert M. Staruch Michelle Ladouceur-Wodzak Maurice A. van den Bosch Dennis K. Burns Avneesh Chhabra Rajiv Chopra 《PloS one》2015,10(12)
Purpose
Ultrasound (US)-guided high intensity focused ultrasound (HIFU) has been proposed for noninvasive treatment of neuropathic pain and has been investigated in in-vivo studies. However, ultrasound has important limitations regarding treatment guidance and temperature monitoring. Magnetic resonance (MR)-imaging guidance may overcome these limitations and MR-guided HIFU (MR-HIFU) has been used successfully for other clinical indications. The primary purpose of this study was to evaluate the feasibility of utilizing 3D MR neurography to identify and guide ablation of peripheral nerves using a clinical MR-HIFU system.Methods
Volumetric MR-HIFU was used to induce lesions in the peripheral nerves of the lower limbs in three pigs. Diffusion-prep MR neurography and T1-weighted images were utilized to identify the target, plan treatment and immediate post-treatment evaluation. For each treatment, one 8 or 12 mm diameter treatment cell was used (sonication duration 20 s and 36 s, power 160–300 W). Peripheral nerves were extracted < 3 hours after treatment. Ablation dimensions were calculated from thermal maps, post-contrast MRI and macroscopy. Histological analysis included standard H&E staining, Masson’s trichrome and toluidine blue staining.Results
All targeted peripheral nerves were identifiable on MR neurography and T1-weighted images and could be accurately ablated with a single exposure of focused ultrasound, with peak temperatures of 60.3 to 85.7°C. The lesion dimensions as measured on MR neurography were similar to the lesion dimensions as measured on CE-T1, thermal dose maps, and macroscopy. Histology indicated major hyperacute peripheral nerve damage, mostly confined to the location targeted for ablation.Conclusion
Our preliminary results indicate that targeted peripheral nerve ablation is feasible with MR-HIFU. Diffusion-prep 3D MR neurography has potential for guiding therapy procedures where either nerve targeting or avoidance is desired, and may also have potential for post-treatment verification of thermal lesions without contrast injection. 相似文献187.
Mark O. Kitchen Richard T. Bryan Kim E. Haworth Richard D. Emes Christopher Luscombe Lyndon Gommersall K. K. Cheng Maurice P. Zeegers Nicholas D. James Adam J. Devall Anthony A. Fryer William E. Farrell 《PloS one》2015,10(9)
Introduction
Inappropriate DNA methylation is frequently associated with human tumour development, and in specific cases, is associated with clinical outcomes. Previous reports of DNA methylation in low/intermediate grade non-muscle invasive bladder cancer (NMIBC) have suggested that specific patterns of DNA methylation may have a role as diagnostic or prognostic biomarkers. In view of the aggressive and clinically unpredictable nature of high-grade (HG) NMIBC, and the current shortage of the preferred treatment option (Bacillus:Calmette-Guerin), novel methylation analyses may similarly reveal biomarkers of disease outcome that could risk-stratify patients and guide clinical management at initial diagnosis.Methods
Promoter-associated CpG island methylation was determined in primary tumour tissue of 36 initial presentation high-grade NMIBCs, 12 low/intermediate-grade NMIBCs and 3 normal bladder controls. The genes HOXA9, ISL1, NKX6-2, SPAG6, ZIC1 and ZNF154 were selected for investigation on the basis of previous reports and/or prognostic utility in low/intermediate-grade NMIBC. Methylation was determined by Pyrosequencing of sodium-bisulphite converted DNA, and then correlated with gene expression using RT-qPCR. Methylation was additionally correlated with tumour behaviour, including tumour recurrence and progression to muscle invasive bladder cancer or metastases.Results
The ISL1 genes’ promoter-associated island was more frequently methylated in recurrent and progressive high-grade tumours than their non-recurrent counterparts (60.0% vs. 18.2%, p = 0.008). ISL1 and HOXA9 showed significantly higher mean methylation in recurrent and progressive tumours compared to non-recurrent tumours (43.3% vs. 20.9%, p = 0.016 and 34.5% vs 17.6%, p = 0.017, respectively). Concurrent ISL1/HOXA9 methylation in HG-NMIBC reliably predicted tumour recurrence and progression within one year (Positive Predictive Value 91.7%), and was associated with disease-specific mortality (DSM).Conclusions
In this study we report methylation differences and similarities between clinical sub-types of high-grade NMIBC. We report the potential ability of methylation biomarkers, at initial diagnosis, to predict tumour recurrence and progression within one year of diagnosis. We found that specific biomarkers reliably predict disease outcome and therefore may help guide patient treatment despite the unpredictable clinical course and heterogeneity of high-grade NMIBC. Further investigation is required, including validation in a larger patient cohort, to confirm the clinical utility of methylation biomarkers in high-grade NMIBC. 相似文献188.
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
189.
190.
Maurice O. Ouko Adrian Sambade Katrin Brandner Annette Niehl Eduardo Peña Abdul Ahad Manfred Heinlein Peter Nick 《The Plant journal : for cell and molecular biology》2010,62(5):829-839
A panel of seven SR1 tobacco mutants (ATER1 to ATER7) derived via T‐DNA activation tagging and screening for resistance to a microtubule assembly inhibitor, ethyl phenyl carbamate, were used to study the role of microtubules during infection and spread of tobacco mosaic virus (TMV). In one of these lines, ATER2, α‐tubulin is shifted from the tyrosinylated into the detyrosinated form, and the microtubule plus‐end marker GFP–EB1 moves significantly slower when expressed in the background of the ATER2 mutant as compared with the SR1 wild type. The efficiency of cell‐to‐cell movement of TMV encoding GFP‐tagged movement protein (MP‐GFP) is reduced in ATER2 accompanied by a reduced association of MP‐GFP with plasmodesmata. This mutant is also more tolerant to viral infection as compared with the SR1 wild type, implying that reduced microtubule dynamics confer a comparative advantage in face of TMV infection. 相似文献