全文获取类型
收费全文 | 1044篇 |
免费 | 95篇 |
国内免费 | 1篇 |
出版年
2024年 | 2篇 |
2023年 | 5篇 |
2022年 | 6篇 |
2021年 | 21篇 |
2020年 | 8篇 |
2019年 | 14篇 |
2018年 | 16篇 |
2017年 | 23篇 |
2016年 | 43篇 |
2015年 | 64篇 |
2014年 | 78篇 |
2013年 | 79篇 |
2012年 | 93篇 |
2011年 | 82篇 |
2010年 | 60篇 |
2009年 | 46篇 |
2008年 | 64篇 |
2007年 | 60篇 |
2006年 | 65篇 |
2005年 | 40篇 |
2004年 | 40篇 |
2003年 | 44篇 |
2002年 | 41篇 |
2001年 | 11篇 |
2000年 | 13篇 |
1999年 | 11篇 |
1998年 | 10篇 |
1997年 | 12篇 |
1996年 | 10篇 |
1995年 | 11篇 |
1994年 | 10篇 |
1993年 | 9篇 |
1992年 | 12篇 |
1991年 | 6篇 |
1990年 | 3篇 |
1989年 | 4篇 |
1988年 | 2篇 |
1987年 | 7篇 |
1986年 | 3篇 |
1985年 | 3篇 |
1984年 | 2篇 |
1982年 | 1篇 |
1981年 | 2篇 |
1974年 | 1篇 |
1973年 | 1篇 |
1971年 | 2篇 |
排序方式: 共有1140条查询结果,搜索用时 15 毫秒
61.
19F Nuclear Magnetic Resonance as a Tool To Investigate Microbial Degradation of Fluorophenols to Fluorocatechols and Fluoromuconates 总被引:1,自引:0,他引:1
下载免费PDF全文
![点击此处可从《Applied microbiology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Marelle G. Boersma Tatiana Y. Dinarieva Wouter J. Middelhoven Willem J. H. van Berkel Joel Doran Jacques Vervoort Ivonne M. C. M. Rietjens 《Applied microbiology》1998,64(4):1256-1263
A method was developed to study the biodegradation and oxidative biodehalogenation of fluorinated phenols by 19F nuclear magnetic resonance (NMR). Characterization of the 19F NMR spectra of metabolite profiles of a series of fluorophenols, converted by purified phenol hydroxylase, catechol 1,2-dioxygenase, and/or by the yeast-like fungus Exophiala jeanselmei, provided possibilities for identification of the 19F NMR chemical shift values of fluorinated catechol and muconate metabolites. As an example, the 19F NMR method thus defined was used to characterize the time-dependent metabolite profiles of various halophenols in either cell extracts or in incubations with whole cells of E. jeanselmei. The results obtained for these two systems are similar, except for the level of muconates observed. Altogether, the results of the present study describe a 19F NMR method which provides an efficient tool for elucidating the metabolic pathways for conversion of fluorine-containing phenols by microorganisms, with special emphasis on possibilities for biodehalogenation and detection of the type of fluorocatechols and fluoromuconates involved. In addition, the method provides possibilities for studying metabolic pathways in vivo in whole cells. 相似文献
62.
Molecular Dissection of the Rho-associated Protein Kinase (p160ROCK)-regulated Neurite Remodeling in Neuroblastoma N1E-115 Cells 总被引:19,自引:0,他引:19
下载免费PDF全文
![点击此处可从《The Journal of cell biology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Masaya Hirose Toshimasa Ishizaki Naoki Watanabe Masayoshi Uehata Onno Kranenburg Wouter H. Moolenaar Fumio Matsumura Midori Maekawa Haruhiko Bito Shuh Narumiya 《The Journal of cell biology》1998,141(7):1625-1636
A critical role for the small GTPase Rho and one of its targets, p160ROCK (a Rho-associated coiled coil-forming protein kinase), in neurite remodeling was examined in neuroblastoma N1E-115 cells. Using wild-type and a dominant-negative form of p160ROCK and a p160ROCK-specific inhibitor, Y-27632, we show here that p160ROCK activation is necessary and sufficient for the agonist-induced neurite retraction and cell rounding. The neurite retraction was accompanied by elevated phosphorylation of myosin light chain and the disassembly of the intermediate filaments and microtubules. Y-27632 blocked both neurite retraction and the elevation of myosin light chain phosphorylation in a similar concentration-dependent manner. On the other hand, suppression of p160ROCK activity by expression of a dominant-negative form of p160ROCK induced neurites in the presence of serum by inducing the reassembly of the intermediate filaments and microtubules. The neurite outgrowth by the p160ROCK inhibition was blocked by coexpression of dominant-negative forms of Cdc42 and Rac, indicating that p160ROCK constitutively and negatively regulates neurite formation at least in part by inhibiting activation of Cdc42 and Rac. The assembly of microtubules and intermediate filaments to form extended processes by inhibitors of the Rho–ROCK pathway was also observed in Swiss 3T3 cells. These results indicate that Rho/ROCK-dependent tonic inhibition of cell process extension is exerted via activation of the actomysin-based contractility, in conjunction with a suppression of assembly of intermediate filaments and microtubules in many cell types including, but not exclusive to, neuronal cells. 相似文献
63.
Wouter?T.?GudeEmail author Mari?tte?M.?van Engen-Verheul Sabine?N.?van der Veer Hareld?M.?C.?Kemps Monique?W.?M.?Jaspers Nicolette?F.?de Keizer Niels?Peek 《Implementation science : IS》2015,11(1):160
Background
The objective of this study was to assess the effect of a web-based audit and feedback (A&F) intervention with outreach visits to support decision-making by multidisciplinary teams.Methods
We performed a multicentre cluster-randomized trial within the field of comprehensive cardiac rehabilitation (CR) in the Netherlands. Our participants were multidisciplinary teams in Dutch CR centres who were enrolled in the study between July 2012 and December 2013 and received the intervention for at least 1 year. The intervention included web-based A&F with feedback on clinical performance, facilities for goal setting and action planning, and educational outreach visits. Teams were randomized either to receive feedback that was limited to psychosocial rehabilitation (study group A) or to physical rehabilitation (study group B). The main outcome measure was the difference in performance between study groups in 11 care processes and six patient outcomes, measured at patient level. Secondary outcomes included effects on guideline concordance for the four main CR therapies.Results
Data from 18 centres (14,847 patients) were analysed, of which 12 centres (9353 patients) were assigned to group A and six (5494 patients) to group B. During the intervention, a total of 233 quality improvement goals was identified by participating teams, of which 49 (21%) were achieved during the study period. Except for a modest improvement in data completeness (4.5% improvement per year; 95% CI 0.65 to 8.36), we found no effect of our intervention on any of our primary or secondary outcome measures.Conclusions
Within a multidisciplinary setting, our web-based A&F intervention engaged teams to define local performance improvement goals but failed to support them in actually completing the improvement actions that were needed to achieve those goals. Future research should focus on improving the actionability of feedback on clinical performance and on addressing the socio-technical perspective of the implementation process.Trial registration
NTR325164.
Freek?Cox Eirikur?SaelandEmail author Matthijs?Baart Martin?Koldijk Jeroen?Tolboom Liesbeth?Dekking Wouter?Koudstaal Karin?L?vgren Bengtsson Jaap?Goudsmit Katarina?Rado?evi? 《Virology journal》2015,12(1):210
Background
Influenza virus infections are responsible for significant morbidity worldwide and therefore it remains a high priority to develop more broadly protective vaccines. Adjuvation of current seasonal influenza vaccines has the potential to achieve this goal.Methods
To assess the immune potentiating properties of Matrix-M?, mice were immunized with virosomal trivalent seasonal vaccine adjuvated with Matrix-M?. Serum samples were isolated to determine the hemagglutination inhibiting (HAI) antibody titers against vaccine homologous and heterologous strains. Furthermore, we assess whether adjuvation with Matrix-M? broadens the protective efficacy of the virosomal trivalent seasonal vaccine against vaccine homologous and heterologous influenza viruses.Results
Matrix-M? adjuvation enhanced HAI antibody titers and protection against vaccine homologous strains. Interestingly, Matrix-M? adjuvation also resulted in HAI antibody titers against heterologous influenza B strains, but not against the tested influenza A strains. Even though the protection against heterologous influenza A was induced by the adjuvated vaccine, in the absence of HAI titers the protection was accompanied by severe clinical scores and body weight loss. In contrast, in the presence of heterologous HAI titers full protection against the heterologous influenza B strain without any disease symptoms was obtained.Conclusion
The results of this study emphasize the promising potential of a Matrix-M?-adjuvated seasonal trivalent virosomal influenza vaccine. Adjuvation of trivalent virosomal vaccine does not only enhance homologous protection, but in addition induces protection against heterologous strains and thus provides overall more potent and broad protective immunity.65.
Detailed imaging and genetic analysis reveal a secondary BRAFL505H resistance mutation and extensive intrapatient heterogeneity in metastatic BRAF mutant melanoma patients treated with vemurafenib
下载免费PDF全文
![点击此处可从《Pigment cell & melanoma research》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Inge Ubink Nicolle J. M. Besselink Mark Pieterse Wouter Veldhuis Marijn van Stralen Eelco F. J. Meijer Stefan M. Willems Michael A. Hadders Thomas Kuilman Oscar Krijgsman Daniel S. Peeper Marco J. Koudijs Edwin Cuppen Emile E. Voest Martijn P. Lolkema 《Pigment cell & melanoma research》2015,28(3):318-323
Resistance to treatment is the main problem of targeted treatment for cancer. We followed ten patients during treatment with vemurafenib, by three‐dimensional imaging. In all patients, only a subset of lesions progressed. Next‐generation DNA sequencing was performed on sequential biopsies in four patients to uncover mechanisms of resistance. In two patients, we identified mutations that explained resistance to vemurafenib; one of these patients had a secondary BRAF L505H mutation. This is the first observation of a secondary BRAF mutation in a vemurafenib‐resistant patient‐derived melanoma sample, which confirms the potential importance of the BRAF L505H mutation in the development of therapy resistance. Moreover, this study hints toward an important role for tumor heterogeneity in determining the outcome of targeted treatments. 相似文献
66.
Jetske van ’t Sant Aernoud T. L. Fiolet Iris A. H. ter Horst Maarten J. Cramer Mirjam H. Mastenbroek Wouter M. van Everdingen Thomas P. Mast Pieter A. Doevendans Henneke Versteeg Mathias Meine 《PloS one》2015,10(5)
AimsResponse to cardiac resynchronization therapy (CRT) is often assessed six months after implantation. Our objective was to assess the number of patients changing from responder to non-responder between six and 14 months, so-called late non-responders, and compare them to patients who were responder both at six and 14 months, so-called stable responders. Furthermore, we assessed predictive values of six and 14-month response concerning clinical outcome.Methods105 patients eligible for CRT were enrolled. Clinical, laboratory, ECG, and echocardiographic parameters and patient-reported health status (Kansas City Cardiomyopathy Questionnaire [KCCQ]) were assessed before, and six and 14 months after implantation. Response was defined as ≥15% LVESV decrease as compared to baseline. Major adverse cardiac events (MACE) were registered until 24 months after implantation. Predictive values of six and 14-month response for MACE were examined.ResultsIn total, 75 (71%) patients were six-month responders of which 12 (16%) patients became late non-responder. At baseline, late non-responders more often had ischemic cardiomyopathy and atrial fibrillation, higher BNP and less dyssynchrony compared to stable responders. At six months, late non-responders showed significantly less LVESV decrease, and higher creatinine levels. Mean KCCQ scores of late non-responders were lower than those of stable responders at every time point, with the difference being significant at 14 months. The 14 months response was a better predictor of MACE than six months response.ConclusionsThe assessment of treatment outcomes after six months of CRT could be premature and response rates beyond might better correlate to long-term clinical outcome. 相似文献
67.
M. Nassif H. Lu T.C. Konings B.J. Bouma A. Vonk Noordegraaf B. Straver N.A. Blom S.A. Clur A.P.C.M. Backx M. Groenink S.M. Boekholdt D.R. Koolbergen M.G. Hazekamp B.J.M. Mulder R.J. de Winter 《Netherlands heart journal》2015,23(11):539-545
Cardiac platypnoea-orthodeoxia syndrome (POS) is a position-dependent condition of dyspnoea and hypoxaemia due to right-to-left shunting. It often remains unrecognised in clinical practice, possibly because of its complex underlying pathophysiology. We present four consecutive patients with POS and patent foramen ovale (PFO) who underwent a successful percutaneous PFO closure, describe the mechanism of their POS and provide a review of the literature. 相似文献
68.
Anouk A. J. Hamers Laura van Dam José M. Teixeira Duarte Mariska Vos Goran Marinkovi? Claudia M. van Tiel Sybren L. Meijer Anne-Marieke van Stalborch Stephan Huveneers Anje A. te Velde Wouter J. de Jonge Carlie J. M. de Vries 《PloS one》2015,10(8)
Nuclear receptor Nur77, also referred to as NR4A1 or TR3, plays an important role in innate and adaptive immunity. Nur77 is crucial in regulating the T helper 1/regulatory T-cell balance, is expressed in macrophages and drives M2 macrophage polarization. In this study we aimed to define the function of Nur77 in inflammatory bowel disease. In wild-type and Nur77-/- mice, colitis development was studied in dextran sodium sulphate (DSS)- and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced models. To understand the underlying mechanism, Nur77 was overexpressed in macrophages and gut epithelial cells. Nur77 protein is expressed in colon tissues from Crohn’s disease and Ulcerative colitis patients and colons from colitic mice in inflammatory cells and epithelium. In both mouse colitis models inflammation was increased in Nur77-/- mice. A higher neutrophil influx and enhanced IL-6, MCP-1 and KC production was observed in Nur77-deficient colons after DSS-treatment. TNBS-induced influx of T-cells and inflammatory monocytes into the colon was higher in Nur77-/- mice, along with increased expression of MCP-1, TNFα and IL-6, and decreased Foxp3 RNA expression, compared to wild-type mice. Overexpression of Nur77 in lipopolysaccharide activated RAW macrophages resulted in up-regulated IL-10 and downregulated TNFα, MIF-1 and MCP-1 mRNA expression through NFκB repression. Nur77 also strongly decreased expression of MCP-1, CXCL1, IL-8, MIP-1α and TNFα in gut epithelial Caco-2 cells. Nur77 overexpression suppresses the inflammatory status of both macrophages and gut epithelial cells and together with the in vivo mouse data this supports that Nur77 has a protective function in experimental colitis. These findings may have implications for development of novel targeted treatment strategies regarding inflammatory bowel disease and other inflammatory diseases. 相似文献
69.
Marsh K?nigs Wouter D. Weeda L. W. Ernest van Heurn R. Jeroen Vermeulen J. Carel Goslings Jan S. K. Luitse Bwee Tien Poll-Thé Anita Beelen Marleen van der Wees Rachèl J. J. K. Kemps Coriene E. Catsman-Berrevoets Jaap Oosterlaan 《PloS one》2015,10(12)
Background
Axonal injury after traumatic brain injury (TBI) may cause impaired sensory integration. We aim to determine the effects of childhood TBI on visual integration in relation to general neurocognitive functioning.Methods
We compared children aged 6–13 diagnosed with TBI (n = 103; M = 1.7 years post-injury) to children with traumatic control (TC) injury (n = 44). Three TBI severity groups were distinguished: mild TBI without risk factors for complicated TBI (mildRF- TBI, n = 22), mild TBI with ≥1 risk factor (mildRF+ TBI, n = 46) or moderate/severe TBI (n = 35). An experimental paradigm measured speed and accuracy of goal-directed behavior depending on: (1) visual identification; (2) visual localization; or (3) both, measuring visual integration. Group-differences on reaction time (RT) or accuracy were tracked down to task strategy, visual processing efficiency and extra-decisional processes (e.g. response execution) using diffusion model analysis. General neurocognitive functioning was measured by a Wechsler Intelligence Scale short form.Results
The TBI group had poorer accuracy of visual identification and visual integration than the TC group (Ps ≤ .03; ds ≤ -0.40). Analyses differentiating TBI severity revealed that visual identification accuracy was impaired in the moderate/severe TBI group (P = .05, d = -0.50) and that visual integration accuracy was impaired in the mildRF+ TBI group and moderate/severe TBI group (Ps < .02, ds ≤ -0.56). Diffusion model analyses tracked impaired visual integration accuracy down to lower visual integration efficiency in the mildRF+ TBI group and moderate/severe TBI group (Ps < .001, ds ≤ -0.73). Importantly, intelligence impairments observed in the TBI group (P = .009, d = -0.48) were statistically explained by visual integration efficiency (P = .002).Conclusions
Children with mildRF+ TBI or moderate/severe TBI have impaired visual integration efficiency, which may contribute to poorer general neurocognitive functioning. 相似文献70.
Yi Wu Noshir F. Dabhoiwala Jaco Hagoort Jin-Lu Shan Li-Wen Tan Bin-Ji Fang Shao-Xiang Zhang Wouter H. Lamers 《PloS one》2015,10(8)