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71.
Xifu Liang Gunnar Grue-Sørensen Kristoffer Månsson Per Vedsø Anke Soor Martin Stahlhut Malene Bertelsen Karen Margrethe Engell Thomas Högberg 《Bioorganic & medicinal chemistry letters》2013,23(20):5624-5629
Ingenol mebutate is the active ingredient in Picato® a new drug for the treatment of actinic keratosis. A number of derivatives related to ingenol mebutate were prepared by chemical synthesis from ingenol with the purpose of investigating the SAR and potency in assays relating to pro-inflammatory effects (induction of PMN oxidative burst and keratinocyte cytokine release), the potential of cell death induction, as well as the chemical stability. By modifications of the ingenol scaffold several prerequisites for activity were identified. The chemical stability of the compounds could be linked to an acyl migration mechanism. We were able to find analogues of ingenol mebutate with comparable in vitro properties. Some key features for potent and more stable ingenol derivatives have been identified. 相似文献
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Marusela?Oliveras-Salvá Anke?Van der Perren Nicolas?Casadei Stijn?Stroobants Silke?Nuber Rudi?D’Hooge Chris?Van den Haute Veerle?BaekelandtEmail author 《Molecular neurodegeneration》2013,8(1):44
Background
Alpha-synuclein is a key protein implicated in the pathogenesis of Parkinson's disease (PD). It is the main component of the Lewy bodies, a cardinal neuropathological feature in the disease. In addition, whole locus multiplications and point mutations in the gene coding for alpha-synuclein lead to autosomal dominant monogenic PD. Over the past decade, research on PD has impelled the development of new animal models based on alpha-synuclein. In this context, transgenic mouse lines have failed to reproduce several hallmarks of PD, especially the strong and progressive dopaminergic neurodegeneration over time that occurs in the patients. In contrast, viral vector-based models in rats and non-human primates display prominent, although highly variable, nigral dopaminergic neuron loss. However, the few studies available on viral vector-mediated overexpression of alpha-synuclein in mice report a weak neurodegenerative process and no clear Lewy body-like pathology. To address this issue, we performed a comprehensive comparative study of alpha-synuclein overexpression by means of recombinant adeno-associated viral vectors serotype 2/7 (rAAV2/7) at different doses in adult mouse substantia nigra.Results
We noted a significant and dose-dependent alpha-synucleinopathy over time upon nigral viral vector-mediated alpha-synuclein overexpression. We obtained a strong, progressive and dose-dependent loss of dopaminergic neurons in the substantia nigra, reaching a maximum of 82% after 8 weeks. This effect correlated with a reduction in tyrosine hydroxylase immunoreactivity in the striatum. Moreover, behavioural analysis revealed significant motor impairments from 12 weeks after injection on. In addition, we detected the presence of alpha-synuclein-positive aggregates in the remaining surviving neurons. When comparing wild-type to mutant A53T alpha-synuclein at the same vector dose, both induced a similar degree of cell death. These data were supported by a biochemical analysis that showed a net increase in soluble and insoluble alpha-synuclein expression over time to the same extent for both alpha-synuclein variants.Conclusions
In conclusion, our in vivo data provide evidence that strong and significant alpha-synuclein-induced neuropathology and progressive dopaminergic neurodegeneration can be achieved in mouse brain by means of rAAV2/7.74.
75.
Kim P. C. Kuypers Eef L. Theunissen Janelle H. P. van Wel Elizabeth B. de Sousa Fernandes Perna Anke Linssen Anke Sambeth Benjamin G. Schultz Johannes G. Ramaekers 《PloS one》2016,11(2)
Background
Ecstasy use has been associated with short-term and long-term memory deficits on a standard Word Learning Task (WLT). The clinical relevance of this has been debated and is currently unknown. The present study aimed at evaluating the clinical relevance of verbal memory impairment in Ecstasy users. To that end, clinical memory impairment was defined as decrement in memory performance that exceeded the cut-off value of 1.5 times the standard deviation of the average score in the healthy control sample. The primary question was whether being an Ecstasy user (E-user) was predictive of having clinically deficient memory performance compared to a healthy control group.Methods
WLT data were pooled from four experimental MDMA studies that compared memory performance during placebo and MDMA intoxication. Control data were taken from healthy volunteers with no drug use history who completed the WLT as part of a placebo-controlled clinical trial. This resulted in a sample size of 65 E-users and 65 age- and gender-matched healthy drug-naïve controls. All participants were recruited by similar means and were tested at the same testing facilities using identical standard operating procedures. Data were analyzed using linear mixed-effects models, Bayes factor, and logistic regressions.Results
Findings were that verbal memory performance of placebo-treated E-users did not differ from that of controls, and there was substantial evidence in favor of the null hypothesis. History of use was not predictive of memory impairment. During MDMA intoxication of E-users, verbal memory was impaired.Conclusion
The combination of the acute and long-term findings demonstrates that, while clinically relevant memory impairment is present during intoxication, it is absent during abstinence. This suggests that use of Ecstasy/MDMA does not lead to clinically deficient memory performance in the long term. Additionally, it has to be investigated whether the current findings apply to more complex cognitive measures in diverse ‘user categories’ using a combination of genetics, imaging techniques and neuropsychological assessments. 相似文献76.
Background
Shared Decision Making (SDM) as means to the involvement of patients in medical decision making is increasingly demanded by treatment guidelines and legislation. Also, matching of patients’ preferences to treatments has been shown to be effective regarding symptom reduction. Despite promising results for patients with substance use disorders (SUD) no systematic evaluation of the literature has been provided. The aim is therefore to give a systematic overview of the literature of patient preferences and SDM in the treatment of patients with SUD.Methods
An electronic literature search of the databases Medline, Embase, Psyndex and Clinical Trials Register was performed. Variations of the search terms substance use disorders, patient preferences and SDM were used. For data synthesis the populations, interventions and outcomes were summarized and described according to the PRISMA statement. Methodological quality of the included articles was assessed with the Mixed Methods Appraisal Tool.Results
N = 25 trials were included in this review. These were conducted between 1986 and 2014 with altogether n = 8.729 patients. Two studies found that patients with SUD preferred to be actively involved in treatment decisions. Treatment preferences were assessed in n = 18 studies, where the majority of patients preferred outpatient compared with inpatient treatment. Matching patients to preferences resulted in a reduction on substance use (n = 3 studies), but the majority of studies found no significant effect. Interventions for SDM differed across patient populations and optional therapeutic techniques.Discussion
Patients with substance use disorders should be involved in medical treatment decisions, as patients with other health conditions. A suitable approach is Shared Decision Making, emphasizing the patients’ preferences. However, due to the heterogeneity of the included studies, results should be interpreted with caution. Further research is needed regarding SDM interventions in patient populations with substance use disorders. 相似文献77.
Anna-Lena Volckmar Chung Ting Han Carolin Pütter Stefan Haas Carla I. G. Vogel Nadja Knoll Christoph Struve Maria G?bel Katharina Haas Nikolas Herrfurth Ivonne Jarick Harald Grallert Annette Schürmann Hadi Al-Hasani Johannes Hebebrand Sascha Sauer Anke Hinney 《PloS one》2016,11(2)
Introduction
Genes involved in body weight regulation that were previously investigated in genome-wide association studies (GWAS) and in animal models were target-enriched followed by massive parallel next generation sequencing.Methods
We enriched and re-sequenced continuous genomic regions comprising FTO, MC4R, TMEM18, SDCCAG8, TKNS, MSRA and TBC1D1 in a screening sample of 196 extremely obese children and adolescents with age and sex specific body mass index (BMI) ≥ 99th percentile and 176 lean adults (BMI ≤ 15th percentile). 22 variants were confirmed by Sanger sequencing. Genotyping was performed in up to 705 independent obesity trios (extremely obese child and both parents), 243 extremely obese cases and 261 lean adults.Results and Conclusion
We detected 20 different non-synonymous variants, one frame shift and one nonsense mutation in the 7 continuous genomic regions in study groups of different weight extremes. For SNP Arg695Cys (rs58983546) in TBC1D1 we detected nominal association with obesity (pTDT = 0.03 in 705 trios). Eleven of the variants were rare, thus were only detected heterozygously in up to ten individual(s) of the complete screening sample of 372 individuals. Two of them (in FTO and MSRA) were found in lean individuals, nine in extremely obese. In silico analyses of the 11 variants did not reveal functional implications for the mutations. Concordant with our hypothesis we detected a rare variant that potentially leads to loss of FTO function in a lean individual. For TBC1D1, in contrary to our hypothesis, the loss of function variant (Arg443Stop) was found in an obese individual. Functional in vitro studies are warranted. 相似文献78.
Nataliya Di Donato Ying Y. Jean A. Murat Maga Briana D. Krewson Alison B. Shupp Maria I. Avrutsky Achira Roy Sarah Collins Carissa Olds Rebecca A. Willert Agnieszka M. Czaja Rachel Johnson Jessi A. Stover Steven Gottlieb Deborah Bartholdi Anita Rauch Amy Goldstein Victoria Boyd-Kyle Kimberly A. Aldinger Ghayda M. Mirzaa Anke Nissen Karlla W. Brigatti Erik G. Puffenberger Kathleen J. Millen Kevin A. Strauss William B. Dobyns Carol M. Troy Robert N. Jinks 《American journal of human genetics》2016,99(5):1117-1129
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Manuel J. Steinbauer Richard Field John‐Arvid Grytnes Panayiotis Trigas Claudine Ah‐Peng Fabio Attorre H. John B. Birks Paulo A. V. Borges Pedro Cardoso Chang‐Hung Chou Michele De Sanctis Miguel M. de Sequeira Maria C. Duarte Rui B. Elias José María Fernández‐Palacios Rosalina Gabriel Roy E. Gereau Rosemary G. Gillespie Josef Greimler David E. V. Harter Tsurng‐Juhn Huang Severin D. H. Irl Daniel Jeanmonod Anke Jentsch Alistair S. Jump Christoph Kueffer Sandra Nogué Rüdiger Otto Jonathan Price Maria M. Romeiras Dominique Strasberg Tod Stuessy Jens‐Christian Svenning Ole R. Vetaas Carl Beierkuhnlein 《Global Ecology and Biogeography》2016,25(9):1097-1107