全文获取类型
收费全文 | 664篇 |
免费 | 53篇 |
国内免费 | 1篇 |
出版年
2023年 | 4篇 |
2022年 | 9篇 |
2021年 | 33篇 |
2020年 | 12篇 |
2019年 | 14篇 |
2018年 | 15篇 |
2017年 | 12篇 |
2016年 | 24篇 |
2015年 | 42篇 |
2014年 | 44篇 |
2013年 | 68篇 |
2012年 | 70篇 |
2011年 | 55篇 |
2010年 | 34篇 |
2009年 | 27篇 |
2008年 | 32篇 |
2007年 | 38篇 |
2006年 | 37篇 |
2005年 | 31篇 |
2004年 | 16篇 |
2003年 | 24篇 |
2002年 | 19篇 |
2001年 | 4篇 |
2000年 | 4篇 |
1999年 | 6篇 |
1998年 | 9篇 |
1997年 | 2篇 |
1996年 | 5篇 |
1995年 | 4篇 |
1994年 | 6篇 |
1993年 | 11篇 |
1992年 | 3篇 |
1989年 | 1篇 |
1988年 | 2篇 |
1987年 | 1篇 |
排序方式: 共有718条查询结果,搜索用时 171 毫秒
121.
Saskia Woudstra Marie-José van Tol Zoltán Bochdanovits Nic J. van der Wee Frans G. Zitman Mark A. van Buchem Esther M. Opmeer André Aleman Brenda W. Penninx Dick J. Veltman Witte J. Hoogendijk 《PloS one》2013,8(4)
Major depressive disorder (MDD) has been associated with biased memory formation for mood-congruent information, which may be related to altered monoamine levels. The piccolo (PCLO) gene, involved in monoaminergic neurotransmission, has previously been linked to depression in a genome-wide association study. Here, we investigated the role of the PCLO risk allele on functional magnetic resonance imaging (MRI) correlates of emotional memory in a sample of 89 MDD patients (64 PCLO risk allele carriers) and 29 healthy controls (18 PCLO risk allele carriers). During negative word encoding, risk allele carriers showed significant lower activity relative to non-risk allele carriers in the insula, and trend-wise in the anterior cingulate cortex and inferior frontal gyrus. Moreover, depressed risk allele carriers showed significant lower activity relative to non-risk allele carriers in the striatum, an effect which was absent in healthy controls. Finally, amygdalar response during processing new positive words vs. known words was blunted in healthy PCLO+ carriers and in MDD patients irrespective of genotype, which may indicate that signalling of salient novel information does not occur to the same extent in PCLO+ carriers and MDD patients. The PCLO risk allele may increase vulnerability for MDD by modulating local brain function with regard to responsiveness to salient stimuli (i.e. insula) and processing novel negative information. Also, depression-specific effects of PCLO on dorsal striatal activation during negative word encoding and the absence of amygdalar salience signalling for novel positive information further suggest a role of PCLO in symptom maintenance in MDD. 相似文献
122.
Christian Puta Birgit Schulz Saskia Schoeler Walter Magerl Brunhild Gabriel Holger H. W. Gabriel Wolfgang H. R. Miltner Thomas Weiss 《PloS one》2013,8(3)
Chronic low back pain (CLBP) was shown to be associated with pathophysiological changes at several levels of the sensorimotor system. Changes in sensory thresholds have been reported but complete profiles of Quantitative Sensory Testing (QST) were only rarely obtained in CLBP patients. The aim of the present study was to investigate comprehensive QST profiles in CLBP at the painful site (back) and at a site distinct from their painful region (hand) and to compare these data with similar data in healthy controls. We found increased detection thresholds in CLBP patients compared to healthy controls for all innocuous stimuli at the back and extraterritorial to the painful region at the hand. Additionally, CLBP patients showed decreased pain thresholds at both sites. Importantly, there was no interaction between the investigated site and group, i.e. thresholds were changed both at the affected body site and for the site distinct from the painful region (hand). Our results demonstrate severe, widespread changes in somatosensory sensitivity in CLBP patients. These widespread changes point to alterations at higher levels of the neuraxis or/and to a vulnerability to nociceptive plasticity in CLBP patients. 相似文献
123.
124.
Laurens F. M. Verscheijden Carlijn H. C. Litjens Jan B. Koenderink Ron H. J. Mathijssen Marcel M. Verbeek Saskia N. de Wildt Frans G. M. Russel 《PLoS computational biology》2021,17(3)
Morphine is a widely used opioid analgesic, which shows large differences in clinical response in children, even when aiming for equivalent plasma drug concentrations. Age-dependent brain disposition of morphine could contribute to this variability, as developmental increase in blood-brain barrier (BBB) P-glycoprotein (Pgp) expression has been reported. In addition, age-related pharmacodynamics might also explain the variability in effect. To assess the influence of these processes on morphine effectiveness, a multi-compartment brain physiologically based pharmacokinetic/pharmacodynamic (PB-PK/PD) model was developed in R (Version 3.6.2). Active Pgp-mediated morphine transport was measured in MDCKII-Pgp cells grown on transwell filters and translated by an in vitro-in vivo extrapolation approach, which included developmental Pgp expression. Passive BBB permeability of morphine and its active metabolite morphine-6-glucuronide (M6G) and their pharmacodynamic parameters were derived from experiments reported in literature. Model simulations after single dose morphine were compared with measured and published concentrations of morphine and M6G in plasma, brain extracellular fluid (ECF) and cerebrospinal fluid (CSF), as well as published drug responses in children (1 day– 16 years) and adults. Visual predictive checks indicated acceptable overlays between simulated and measured morphine and M6G concentration-time profiles and prediction errors were between 1 and -1. Incorporation of active Pgp-mediated BBB transport into the PB-PK/PD model resulted in a 1.3-fold reduced brain exposure in adults, indicating only a modest contribution on brain disposition. Analgesic effect-time profiles could be described reasonably well for older children and adults, but were largely underpredicted for neonates. In summary, an age-appropriate morphine PB-PK/PD model was developed for the prediction of brain pharmacokinetics and analgesic effects. In the neonatal population, pharmacodynamic characteristics, but not brain drug disposition, appear to be altered compared to adults and older children, which may explain the reported differences in analgesic effect. 相似文献
125.
Saskia Kroschwald Cheng-Ying Chiu Dagmar Heydeck Nadine Rohwer Tatjana Gehring Ulrike Seifert Anke Lux Michael Rothe Karsten-Henrich Weylandt Hartmut Kuhn 《Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids》2018,1863(8):866-880
Lipoxygenases (ALOXs) are involved in the regulation of cellular redox homeostasis. They also have been implicated in the biosynthesis of pro- and anti-inflammatory lipid mediators and play a role in the pathogenesis of inflammatory diseases, which constitute a major health challenge owing to increasing incidence and prevalence in all industrialized countries around the world. To explore the pathophysiological role of Alox15 (leukocyte-type 12-LOX) in mouse experimental colitis we tested the impact of systemic inactivation of the Alox15 gene on the extent of dextrane sulfate sodium (DSS) colitis. We found that in wildtype mice expression of the Alox15 gene was augmented during DSS-colitis while expression of other Alox genes (Alox5, Alox15b) was hardly altered. Systemic Alox15 (leukocyte-type 12-LOX) deficiency induced less severe colitis symptoms and suppressed in vivo formation of 12-hydroxyeicosatetraenoic acid (12-HETE), the major Alox15 (leukocyte-type 12-LOX) product in mice. These alterations were paralleled by reduced expression of pro-inflammatory gene products, by sustained expression of the zonula occludens protein 1 (ZO-1) and by a less impaired intestinal epithelial barrier function. These results are consistent with in vitro incubations of colon epithelial cells, in which addition of 12S-HETE compromised enantioselectively transepithelial electric resistance. Consistent with these data transgenic overexpression of human ALOX15 intensified the inflammatory symptoms. In summary, our results indicate that systemic Alox15 (leukocyte-type 12-LOX) deficiency protects mice from DSS-colitis. Since exogenous 12-HETE compromises the expression of the tight junction protein ZO-1 the protective effect has been related to a less pronounced impairment of the intestinal epithelial barrier function. 相似文献
126.
127.
Saskia Vuurens Frank Stagnitti Gerrit de Rooij Jan Boll LI Ling Marc LeBlanc Daniel lerodiaconou Vince Versace Scott Salzman 《中国科学C辑(英文版)》2005,48(Z1)
Four sites located in the north-eastern region of the United States of America have been chosen to investigate the impacts of soil heterogeneity in the transport of solutes (bromide and chloride) through the vadose zone (the zone in the soil that lies below the root zone and above the permanent saturated groundwater). A recently proposed mathematical model based on the cumulative beta distribution has been deployed to compare and contrast the regions' heterogeneity from multiple sample percolation experiments. Significant differences in patterns of solute leaching were observed even over a small spatial scale, indicating that traditional sampling methods for solute transport, for example the gravity pan or suction lysimeters, or more recent inventions such as the multiple sample percolation systems may not be effective in estimating solute fluxes in soils when a significant degree of soil heterogeneity is present. Consequently, ignoring soil heterogeneity in solute transport studies will likely result in under- or overprediction of leached fluxes and potentially lead to serious pollution of soils and/or groundwater.The cumulative beta distribution technique is found to be a versatile and simple technique of gaining valuable information regarding soil heterogeneity effects on solute transport. It is also an excellent tool for guiding future decisions of experimental designs particularly in regard to the number of samples within one site and the number of sampling locations between sites required to obtain a representative estimate of field solute or drainage flux. 相似文献
128.
129.
Generalized linear mixed models (GLMMs) have become a frequently used tool for the analysis of non-Gaussian longitudinal data. Estimation is based on maximum likelihood theory, which assumes that the underlying probability model is correctly specified. Recent research is showing that the results obtained from these models are not always robust against departures from the assumptions on which these models are based. In the present work we have used simulations with a logistic random-intercept model to study the impact of misspecifying the random-effects distribution on the type I and II errors of the tests for the mean structure in GLMMs. We found that the misspecification can either increase or decrease the power of the tests, depending on the shape of the underlying random-effects distribution, and it can considerably inflate the type I error rate. Additionally, we have found a theoretical result which states that whenever a subset of fixed-effects parameters, not included in the random-effects structure equals zero, the corresponding maximum likelihood estimator will consistently estimate zero. This implies that under certain conditions a significant effect could be considered as a reliable result, even if the random-effects distribution is misspecified. 相似文献
130.
Frequent genes in rare diseases: panel‐based next generation sequencing to disclose causal mutations in hereditary neuropathies
下载免费PDF全文
![点击此处可从《Journal of neurochemistry》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Maike F. Dohrn Nicola Glöckle Lejla Mulahasanovic Corina Heller Julia Mohr Christine Bauer Erik Riesch Andrea Becker Florian Battke Konstanze Hörtnagel Thorsten Hornemann Saranya Suriyanarayanan Markus Blankenburg Jörg B. Schulz Kristl G. Claeys Burkhard Gess Istvan Katona Andreas Ferbert Debora Vittore Alexander Grimm Stefan Wolking Ludger Schöls Holger Lerche G. Christoph Korenke Dirk Fischer Bertold Schrank Urania Kotzaeridou Gerhard Kurlemann Bianca Dräger Anja Schirmacher Peter Young Beate Schlotter‐Weigel Saskia Biskup 《Journal of neurochemistry》2017,143(5):507-522