全文获取类型
收费全文 | 482篇 |
免费 | 19篇 |
出版年
2022年 | 4篇 |
2021年 | 8篇 |
2020年 | 5篇 |
2019年 | 10篇 |
2018年 | 9篇 |
2017年 | 11篇 |
2016年 | 4篇 |
2015年 | 14篇 |
2014年 | 21篇 |
2013年 | 29篇 |
2012年 | 33篇 |
2011年 | 37篇 |
2010年 | 21篇 |
2009年 | 13篇 |
2008年 | 26篇 |
2007年 | 20篇 |
2006年 | 17篇 |
2005年 | 36篇 |
2004年 | 9篇 |
2003年 | 25篇 |
2002年 | 14篇 |
2001年 | 9篇 |
2000年 | 8篇 |
1999年 | 11篇 |
1998年 | 6篇 |
1997年 | 9篇 |
1996年 | 9篇 |
1995年 | 4篇 |
1994年 | 9篇 |
1992年 | 2篇 |
1991年 | 4篇 |
1990年 | 12篇 |
1989年 | 6篇 |
1988年 | 3篇 |
1987年 | 2篇 |
1986年 | 8篇 |
1985年 | 5篇 |
1984年 | 5篇 |
1983年 | 2篇 |
1982年 | 3篇 |
1981年 | 4篇 |
1980年 | 2篇 |
1979年 | 1篇 |
1978年 | 1篇 |
1976年 | 2篇 |
1974年 | 2篇 |
1973年 | 1篇 |
1971年 | 1篇 |
1970年 | 1篇 |
1968年 | 1篇 |
排序方式: 共有501条查询结果,搜索用时 15 毫秒
51.
52.
Richards P Didszun C Campesan S Simpson A Horley B Young KW Glynn P Cain K Kyriacou CP Giorgini F Nicotera P 《Cell death and differentiation》2011,18(2):191-200
Huntington's disease (HD) is a fatal neurodegenerative disorder caused by expansion of a polyglutamine tract in the huntingtin protein (htt) that mediates formation of intracellular protein aggregates. In the brains of HD patients and HD transgenic mice, accumulation of protein aggregates has been causally linked to lesions in axo-dendritic and synaptic compartments. Here we show that dendritic spines - sites of synaptogenesis - are lost in the proximity of htt aggregates because of functional defects in local endosomal recycling mediated by the Rab11 protein. Impaired exit from recycling endosomes (RE) and association of endocytosed protein with intracellular structures containing htt aggregates was demonstrated in cultured hippocampal neurons cells expressing a mutant htt fragment. Dendrites in hippocampal neurons became dystrophic around enlarged amphisome-like structures positive for Rab11, LC3 and mutant htt aggregates. Furthermore, Rab11 overexpression rescues neurodegeneration and dramatically extends lifespan in a Drosophila model of HD. Our findings are consistent with the model that mutant htt aggregation increases local autophagic activity, thereby sequestering Rab11 and diverting spine-forming cargo from RE into enlarged amphisomes. This mechanism may contribute to the toxicity caused by protein misfolding found in a number of neurodegenerative diseases. 相似文献
53.
Vernillo G Piacentini MF Drake A Agnello L Fiorella P La Torre A 《Journal of strength and conditioning research / National Strength & Conditioning Association》2011,25(7):2048-2052
The aim of this case study was to describe the physiological and regulatory processes, by means of heart rate (HR) monitoring and pacing strategy, in a top-level race walker (age: 32 years; height: 1.76 m; body mass: 62 kg; training volume: 130-150 km·wk) who was focused on the attainment of the 5-km indoor race walk (RW) World Record. The HRmean was 185 ± 14.9 b·min, with an HRmean/HRmax ratio of 0.96. Almost the whole race (91.8%) was performed to an intensity ≥90% of the HRmax; lower intensity work was negligible (8.1%). The race profile was a reverse J-shaped pacing curve; in fact, the athlete completed the first 1,000 m in the fastest time, slowing during the middle 3,000 m, and increasing the speed during the final 1,000 m of the race. Despite the attempt failed (the athlete performed only the 2009 World leading performance, 18 minutes 23 seconds 47 tenths), these data suggest that a more linear strain distribution for the entire performance would be optimal instead of a fast-start strategy, which leads to a drastic decrement of the walking velocity. Moreover, this study supports the use of HR monitoring combined with the regulation of the effort to understand the physiological and regulatory processes during an indoor RW event. 相似文献
54.
Giudice EM Grandone A Cirillo G Santoro N Amato A Brienza C Savarese P Marzuillo P Perrone L 《PloS one》2011,6(11):e27933
Background and Aims
A polymorphism in adiponutrin/patatin-like phospholipase-3 gene (PNPLA3), rs738409 C->G, encoding for the I148M variant, is the strongest genetic determinant of liver fat and ALT levels in adulthood and childhood obesity. Aims of this study were i) to analyse in a large group of obese children the role of the interaction of not-genetic factors such as BMI, waist circumference (W/Hr) and insulin resistance (HOMA-IR) in exposing the association between the I148M polymorphism and ALT levels and ii) to stratify the individual risk of these children to have liver injury on the basis of this gene-environment interaction.Methods
1048 Italian obese children were investigated. Anthropometric, clinical and metabolic data were collected and the PNPLA3 I148M variant genotyped.Results
Children carrying the 148M allele showed higher ALT and AST levels (p = 0.000006 and p = 0.0002, respectively). Relationships between BMI-SDS, HOMA-IR and W/Hr with ALT were analysed in function of the different PNPLA3 genotypes. Children 148M homozygous showed a stronger correlation between ALT and W/Hr than those carrying the other genotypes (p: 0.0045) and, therefore, 148M homozygotes with high extent of abdominal fat (W/Hr above 0.62) had the highest OR (4.9, 95% C. I. 3.2–7.8, p = 0.00001) to develop pathologic ALT.Conclusions
We have i) showed for the first time that the magnitude of the association of PNPLA3 with liver enzymes is driven by the size of abdominal fat and ii) stratified the individual risk to develop liver damage on the basis of the interaction between the PNPLA3 genotype and abdominal fat. 相似文献55.
56.
57.
Much like the "microbe hypothesis" put forth over 150 years ago, the "prion hypothesis" can be definitely proven only if a prion disease is engendered in a natural host from an infectious prion produced in vitro. In this issue of Cell, come very close to accomplishing this goal by producing a prion disease in a natural host from a prion entirely generated in vitro using a PCR-like amplification system. 相似文献
58.
Bano D Young KW Guerin CJ Lefeuvre R Rothwell NJ Naldini L Rizzuto R Carafoli E Nicotera P 《Cell》2005,120(2):275-285
In brain ischemia, gating of postsynaptic glutamate receptors and other membrane channels triggers intracellular Ca2+ overload and cell death. In excitotoxic settings, the initial Ca2+ influx through glutamate receptors is followed by a second uncontrolled Ca2+ increase that leads to neuronal demise. Here we report that the major plasma membrane Ca2+ extruding system, the Na+/Ca2+ exchanger (NCX), is cleaved during brain ischemia and in neurons undergoing excitotoxicity. Inhibition of Ca2+-activated proteases (calpains) by overexpressing their endogenous inhibitor protein, calpastatin or the expression of an NCX isoform not cleaved by calpains, prevented Ca2+ overload and rescued neurons from excitotoxic death. Conversely, down-regulation of NCX by siRNA compromised neuronal Ca2+ handling, transforming the Ca2+ transient elicited by non-excitotoxic glutamate concentrations into a lethal Ca2+overload. Thus, proteolytic inactivation of NCX-driven neuronal Ca2+ extrusion is responsible for the delayed excitotoxic Ca2+ deregulation and neuronal death. 相似文献
59.
Tumor necrosis factor, cancer and anticancer therapy 总被引:9,自引:0,他引:9
Tumor necrosis factor (TNF) is being utilized as an antineoplastic agent for the treatment of patients with locally advanced solid tumors. However, its role in cancer therapy is debated. Although a large body of evidence supports TNF's antineoplastic activity, the cascade of molecular events underlying TNF-mediated tumor regression observed in vivo is still incompletely elucidated. Intriguingly, some pre-clinical findings suggest that TNF may promote cancer development and progression, which has led to propose anti-TNF therapy as a novel approach to malignancies. In the present work, we summarize the molecular biology of TNF with particular regard to its tumor-related properties, and review the experimental and clinical evidence currently available describing the complex and sometime conflicting relationship between this cytokine, cancer and antitumor therapy. Recent insights that might pave the way to further exploitation of the antineoplastic potential of TNF are also discussed. 相似文献
60.
Luigi?VezzulliEmail author Marco?Bartoli Daniele?Nizzoli Giorgio?Fanciulli Pierluigi?Viaroli Mauro?Fabiano 《Hydrobiologia》2005,550(1):211-219
The microbiological quality of wastewater in phytotreatment ponds with foliose macroalgae can be influenced by biofilm formation on thallus surface. This hypothesis was tested with an in situ experiment which was carried out in a pond with Ulva spp. receiving wastewater from a land based fish farm at Piombino (Italy). The total bacterial load (TBL) was determined in the inflowing and outflowing waters and a multifactorial design was employed to investigate the effect of different macroalgal biomass. Microbiological analysis revealed a high TBL in the water column (18.4 ± 7.4 × 108 cells ml−1). TBL of inlet water was significantly correlated with quantity and quality of particulate organic matter (POM) of inflowing water, whereas no correlation was found between TBL and POM in the outlet water. A significant decrease in the POM concentration was detected within macroalgal ponds, due to the mechanical action of thalli which favoured POM sedimentation. Nevertheless, great TBLs were found in the outlet water. These findings suggest that TBL probably depended upon macroalgae. Indeed high bacterial density was found on macroalgal thallus surface (~108 cells cm2). Furthermore, high plate counts of faecal bacteria (faecal enterococci) were determined on thallus surface (~ 40 CFU cm2) and outlet water (11 886 ± 3984 CFU 100 ml−1) supporting the evidence that macroalgae negatively affect the microbiological quality of treated water. Bacterial activities in terms of exoenzymatic rates and secondary production were two folds higher in the water within macroalgal beds, than in the open water. These preliminary results suggest that high macroalgal biomass represents a ‚hot spot’ of bacterial density and activity that may affect microbiological quality of the treated water. Bacterial control of inlet water and management of macroalgal biomass through periodic removal are essential for a more efficient treatment of wastewater in phytotreatment ponds. 相似文献