全文获取类型
收费全文 | 204篇 |
免费 | 22篇 |
出版年
2021年 | 4篇 |
2020年 | 1篇 |
2018年 | 2篇 |
2017年 | 1篇 |
2016年 | 3篇 |
2015年 | 8篇 |
2014年 | 11篇 |
2013年 | 7篇 |
2012年 | 14篇 |
2011年 | 12篇 |
2010年 | 12篇 |
2009年 | 7篇 |
2008年 | 10篇 |
2007年 | 10篇 |
2006年 | 8篇 |
2005年 | 4篇 |
2004年 | 4篇 |
2003年 | 8篇 |
2002年 | 13篇 |
2001年 | 6篇 |
2000年 | 9篇 |
1999年 | 1篇 |
1998年 | 2篇 |
1997年 | 2篇 |
1996年 | 2篇 |
1995年 | 4篇 |
1994年 | 7篇 |
1993年 | 4篇 |
1992年 | 5篇 |
1991年 | 6篇 |
1990年 | 4篇 |
1989年 | 2篇 |
1988年 | 4篇 |
1987年 | 1篇 |
1985年 | 3篇 |
1984年 | 4篇 |
1983年 | 1篇 |
1982年 | 3篇 |
1981年 | 3篇 |
1980年 | 2篇 |
1979年 | 2篇 |
1978年 | 1篇 |
1975年 | 2篇 |
1974年 | 1篇 |
1973年 | 1篇 |
1970年 | 1篇 |
1969年 | 1篇 |
1968年 | 1篇 |
1967年 | 1篇 |
1956年 | 1篇 |
排序方式: 共有226条查询结果,搜索用时 31 毫秒
81.
Arturo Sanz Sanz Yashavanthi Niranjan Henrik Hammarén Daniela Ungureanu Rob Ruijtenbeek Ivo P. Touw Olli Silvennoinen Riet Hilhorst 《Biochimica et Biophysica Acta - Proteins and Proteomics》2014,1844(10):1835-1841
JAK2 tyrosine kinase regulates many cellular functions. Its activity is controlled by the pseudokinase (JH2) domain by still poorly understood mechanisms. The V617F mutation in the pseudokinase domain activates JAK2 and causes myeloproliferative neoplasms. We conducted a detailed kinetic analysis of recombinant JAK2 tyrosine kinase domain (JH1) and wild-type and V617F tandem kinase (JH1JH2) domains using peptide microarrays to define the functions of the kinase domains. The results show that i) JAK2 follows a random Bi–Bi reaction mechanism ii) JH2 domain restrains the activity of the JH1 domain by reducing the affinity for ATP and ATP competitive inhibitors iii) V617F decreases affinity for ATP but increases catalytic activity compared to wild-type and iv) the SH2–JH2 linker region participates in controlling activity by reducing the affinity for ATP. 相似文献
82.
M. Lobeek E. Badings M. Lenssen R. Uijlings K. Koster E. van t Riet F. M. A. C. Martens 《Netherlands heart journal》2021,29(3):142
BackgroundThe best available imaging technique for the detection of prior myocardial infarction (MI) is cardiac magnetic resonance (CMR) with late gadolinium enhancement (LGE). Although the electrocardiogram (ECG) still plays a major role in the diagnosis of prior MI, the diagnostic value of the ECG remains uncertain. This study evaluates the diagnostic value of the ECG in the assessment of prior MI.MethodsIn this retrospective study, data from electronic patient files were collected of 1033 patients who had undergone CMR with LGE between January 2014 and December 2017. After the exclusion of 59 patients, the data of 974 patients were analysed. Twelve-lead ECGs were blinded and evaluated for signs of prior MI by two cardiologists separately. Disagreement in interpretation was resolved by the judgement of a third cardiologist. Outcomes of CMR with LGE were used as the gold standard.ResultsThe sensitivity of the ECG in the detection of MI was 38.0% with a 95% confidence interval (CI) of 31.6–44.8%. The specificity was 86.9% (95% CI 84.4–89.1%). The positive and negative predictive value were 43.6% (95% CI 36.4–50.9%) and 84.0% (95% CI 81.4–86.5%) respectively. In 170 ECGs (17.5%), the two cardiologists disagreed on the presence or absence of MI. Inter-rater variability was moderate (κ 0.51, 95% CI 0.45–0.58, p < 0.001).ConclusionThe ECG has a low diagnostic value in the detection of prior MI. However, if the ECG shows no signs of prior MI, the absence of MI is likely. This study confirms that a history of MI should not be based solely on an ECG. 相似文献
83.
84.
Katarina Wolf Mariska te Lindert Marina Krause Stephanie Alexander Joost te Riet Amanda L. Willis Robert M. Hoffman Carl G. Figdor Stephen J. Weiss Peter Friedl 《The Journal of cell biology》2013,201(7):1069-1084
Cell migration through 3D tissue depends on a physicochemical balance between cell deformability and physical tissue constraints. Migration rates are further governed by the capacity to degrade ECM by proteolytic enzymes, particularly matrix metalloproteinases (MMPs), and integrin- and actomyosin-mediated mechanocoupling. Yet, how these parameters cooperate when space is confined remains unclear. Using MMP-degradable collagen lattices or nondegradable substrates of varying porosity, we quantitatively identify the limits of cell migration by physical arrest. MMP-independent migration declined as linear function of pore size and with deformation of the nucleus, with arrest reached at 10% of the nuclear cross section (tumor cells, 7 µm2; T cells, 4 µm2; neutrophils, 2 µm2). Residual migration under space restriction strongly depended upon MMP-dependent ECM cleavage by enlarging matrix pore diameters, and integrin- and actomyosin-dependent force generation, which jointly propelled the nucleus. The limits of interstitial cell migration thus depend upon scaffold porosity and deformation of the nucleus, with pericellular collagenolysis and mechanocoupling as modulators. 相似文献
85.
Gerben ter Riet Paula Chesley Alan G. Gross Lara Siebeling Patrick Muggensturm Nadine Heller Martin Umbehr Daniela Vollenweider Tsung Yu Elie A. Akl Lizzy Brewster Olaf M. Dekkers Ingrid Mühlhauser Bernd Richter Sonal Singh Steven Goodman Milo A. Puhan 《PloS one》2013,8(11)
Background
Acknowledgment of all serious limitations to research evidence is important for patient care and scientific progress. Formal research on how biomedical authors acknowledge limitations is scarce.Objectives
To assess the extent to which limitations are acknowledged in biomedical publications explicitly, and implicitly by investigating the use of phrases that express uncertainty, so-called hedges; to assess the association between industry support and the extent of hedging.Design
We analyzed reporting of limitations and use of hedges in 300 biomedical publications published in 30 high and medium -ranked journals in 2007. Hedges were assessed using linguistic software that assigned weights between 1 and 5 to each expression of uncertainty.Results
Twenty-seven percent of publications (81/300) did not mention any limitations, while 73% acknowledged a median of 3 (range 1–8) limitations. Five percent mentioned a limitation in the abstract. After controlling for confounders, publications on industry-supported studies used significantly fewer hedges than publications not so supported (p = 0.028).Limitations
Detection and classification of limitations was – to some extent – subjective. The weighting scheme used by the hedging detection software has subjective elements.Conclusions
Reporting of limitations in biomedical publications is probably very incomplete. Transparent reporting of limitations may protect clinicians and guideline committees against overly confident beliefs and decisions and support scientific progress through better design, conduct or analysis of new studies. 相似文献86.
Veerle M.J. Grispen Barbara Irtelli Henk W.J. Hakvoort Riet Vooijs Tijs Bliek Wilma M. ten Bookum Jos A.C. Verkleij Henk Schat 《Environmental and Experimental Botany》2009,66(1):69-73
We expressed the AtMT2b gene under the 35 S cauliflower mosaic virus promoter in Nicotiana tabacum (Sr1), using leaf disc transformation. Arsenite tolerance and uptake, as well as arsenite-induced phytochelatin (PC) accumulation in roots were measured in transgenic lines, and compared to untransformed (‘wild type’) tobacco. Measured after 5 days of exposure, arsenite tolerance was slightly but significantly decreased in the transgenic lines compared to wild type. The highest AtMT2b expressing line exhibited a significantly decreased arsenic accumulation in roots, but an increased accumulation in shoots, while the total amount of arsenic taken up remained unchanged, suggesting that AtMT2b expression enhanced the arsenic root to shoot transport. The same transformant line also exhibited a decreased rate of phytochelatin accumulation in the roots, but the phytochelatin-SH to As molar ratio was higher than in wild type, suggesting that the lower arsenite tolerance in the transformant lines was not due to a potential shortage of cysteine for PC synthesis, imposed by expression of the transgene. 相似文献
87.
Thomas De Meyer Dominique Eeckhout Riet De Rycke Sylvie De Buck Serge Muyldermans Ann Depicker 《Plant molecular biology》2014,84(1-2):83-93
Antibodies and antibody derived fragments are excellent tools for the detection and purification of proteins. However, only few antibodies targeting Arabidopsis seed proteins are currently available. Here, we evaluate the process to make antibody libraries against crude protein extracts and more particularly to generate a VHH phage library against native Arabidopsis thaliana seed proteins. After immunising a dromedary with a crude Arabidopsis seed extract, we cloned the single-domain antigen-binding fragments from their heavy-chain only antibodies in a phage display vector and selected nanobodies (VHHs) against native Arabidopsis seed proteins. For 16 VHHs, the corresponding antigens were identified by affinity purification and MS/MS analysis. They were shown to bind the major Arabidopsis seed storage proteins albumin and globulin (14 to albumin and 2 to globulin). All 16 VHHs were suitable primary reagents for the detection of the Arabidopsis seed storage proteins by ELISA. Furthermore, several of the anti-albumin VHHs were used successfully for storage protein localisation via electron microscopy. The easy cloning, selection and production, together with the demonstrated functionality and applicability, strongly suggest that the VHH antibody format will play a more prominent role in future protein research, in particular for the study of native proteins. 相似文献
88.
van Vliet-Ostaptchouk JV van Haeften TW Landman GW Reiling E Kleefstra N Bilo HJ Klungel OH de Boer A van Diemen CC Wijmenga C Boezen HM Dekker JM van 't Riet E Nijpels G Welschen LM Zavrelova H Bruin EJ Elbers CC Bauer F Onland-Moret NC van der Schouw YT Grobbee DE Spijkerman AM van der A DL Simonis-Bik AM Eekhoff EM Diamant M Kramer MH Boomsma DI de Geus EJ Willemsen G Slagboom PE Hofker MH 't Hart LM 《PloS one》2012,7(3):e32148
Background
Genome-wide association studies in Japanese populations recently identified common variants in the KCNQ1 gene to be associated with type 2 diabetes. We examined the association of these variants within KCNQ1 with type 2 diabetes in a Dutch population, investigated their effects on insulin secretion and metabolic traits and on the risk of developing complications in type 2 diabetes patients.Methodology
The KCNQ1 variants rs151290, rs2237892, and rs2237895 were genotyped in a total of 4620 type 2 diabetes patients and 5285 healthy controls from the Netherlands. Data on macrovascular complications, nephropathy and retinopathy were available in a subset of diabetic patients. Association between genotype and insulin secretion/action was assessed in the additional sample of 335 individuals who underwent a hyperglycaemic clamp.Principal Findings
We found that all the genotyped KCNQ1 variants were significantly associated with type 2 diabetes in our Dutch population, and the association of rs151290 was the strongest (OR 1.20, 95% CI 1.07–1.35, p = 0.002). The risk C-allele of rs151290 was nominally associated with reduced first-phase glucose-stimulated insulin secretion, while the non-risk T-allele of rs2237892 was significantly correlated with increased second-phase glucose-stimulated insulin secretion (p = 0.025 and 0.0016, respectively). In addition, the risk C-allele of rs2237892 was associated with higher LDL and total cholesterol levels (p = 0.015 and 0.003, respectively). We found no evidence for an association of KCNQ1 with diabetic complications.Conclusions
Common variants in the KCNQ1 gene are associated with type 2 diabetes in a Dutch population, which can be explained at least in part by an effect on insulin secretion. Furthermore, our data suggest that KCNQ1 is also associated with lipid metabolism. 相似文献89.
G Ter Riet DA Korevaar M Leenaars PJ Sterk CJ Van Noorden LM Bouter R Lutter RP Elferink L Hooft 《PloS one》2012,7(9):e43404
Context
Publication bias jeopardizes evidence-based medicine, mainly through biased literature syntheses. Publication bias may also affect laboratory animal research, but evidence is scarce.Objectives
To assess the opinion of laboratory animal researchers on the magnitude, drivers, consequences and potential solutions for publication bias. And to explore the impact of size of the animals used, seniority of the respondent, working in a for-profit organization and type of research (fundamental, pre-clinical, or both) on those opinions.Design
Internet-based survey.Setting
All animal laboratories in The Netherlands.Participants
Laboratory animal researchers.Main Outcome Measure(s)
Median (interquartile ranges) strengths of beliefs on 5 and 10-point scales (1: totally unimportant to 5 or 10: extremely important).Results
Overall, 454 researchers participated. They considered publication bias a problem in animal research (7 (5 to 8)) and thought that about 50% (32–70) of animal experiments are published. Employees (n = 21) of for-profit organizations estimated that 10% (5 to 50) are published. Lack of statistical significance (4 (4 to 5)), technical problems (4 (3 to 4)), supervisors (4 (3 to 5)) and peer reviewers (4 (3 to 5)) were considered important reasons for non-publication (all on 5-point scales). Respondents thought that mandatory publication of study protocols and results, or the reasons why no results were obtained, may increase scientific progress but expected increased bureaucracy. These opinions did not depend on size of the animal used, seniority of the respondent or type of research.Conclusions
Non-publication of “negative” results appears to be prevalent in laboratory animal research. If statistical significance is indeed a main driver of publication, the collective literature on animal experimentation will be biased. This will impede the performance of valid literature syntheses. Effective, yet efficient systems should be explored to counteract selective reporting of laboratory animal research. 相似文献90.
S Xu A De Becker H De Raeve B Van Camp K Vanderkerken I Van Riet 《Biochemical and biophysical research communications》2012,424(3):391-397
Mesenchymal stem cells (MSCs) have currently generated numerous interests in pre-clinical and clinical applications due to their multiple lineages differentiation potential and immunomodulary effects. However, accumulating evidence indicates that MSCs, especially murine MSCs (mMSCs), can undergo spontaneous transformation after long-term in vitro culturing, which might reduce the therapeutic application possibilities of these stem cells. In the present study, we observed that in vitro expanded bone marrow (BM) derived mMSCs from the C57Bl/KaLwRij mouse strain can lose their specific stem cells markers (CD90 and CD105) and acquire CD34 expression, accompanied with an altered morphology and an impaired tri-lineages differentiation capacity. Compared to normal mMSCs, these transformed mMSCs exhibited an increased proliferation rate, an enhanced colony formation and migration ability as well as a higher sensitivity to anti-tumor drugs. Transformed mMSCs were highly tumorigenic in vivo, resulting in aggressive sarcoma formation when transplanted in non-immunocompromised mice. Furthermore, we found that Notch signaling downstream genes (hey1, hey2 and heyL) were significantly upregulated in transformed mMSCs, while Hedgehog signaling downstream genes Gli1 and Ptch1 and the Wnt signaling downstream gene beta-catenin were all decreased. Taken together, we observed that murine in vitro expanded BM-MSCs can transform into CD34 expressing cells that induce sarcoma formation in vivo. We assume that dysregulation of the Notch(+)/Hh(-)/Wnt(-) signaling pathway is associated with the malignant phenotype of the transformed mMSCs. 相似文献