全文获取类型
收费全文 | 368篇 |
免费 | 44篇 |
出版年
2023年 | 1篇 |
2022年 | 1篇 |
2021年 | 4篇 |
2020年 | 4篇 |
2019年 | 6篇 |
2018年 | 5篇 |
2017年 | 10篇 |
2016年 | 15篇 |
2015年 | 21篇 |
2014年 | 19篇 |
2013年 | 25篇 |
2012年 | 30篇 |
2011年 | 19篇 |
2010年 | 26篇 |
2009年 | 14篇 |
2008年 | 21篇 |
2007年 | 35篇 |
2006年 | 24篇 |
2005年 | 17篇 |
2004年 | 17篇 |
2003年 | 10篇 |
2002年 | 1篇 |
2001年 | 12篇 |
2000年 | 15篇 |
1999年 | 9篇 |
1998年 | 5篇 |
1997年 | 5篇 |
1996年 | 2篇 |
1995年 | 2篇 |
1994年 | 3篇 |
1993年 | 4篇 |
1992年 | 3篇 |
1991年 | 2篇 |
1990年 | 1篇 |
1988年 | 3篇 |
1987年 | 4篇 |
1986年 | 1篇 |
1985年 | 4篇 |
1984年 | 1篇 |
1981年 | 1篇 |
1980年 | 2篇 |
1977年 | 1篇 |
1975年 | 2篇 |
1972年 | 2篇 |
1966年 | 1篇 |
1965年 | 2篇 |
排序方式: 共有412条查询结果,搜索用时 609 毫秒
41.
Ill-Raga G Palomer E Wozniak MA Ramos-Fernández E Bosch-Morató M Tajes M Guix FX Galán JJ Clarimón J Antúnez C Real LM Boada M Itzhaki RF Fandos C Muñoz FJ 《PloS one》2011,6(6):e21456
BACE1 is a key enzyme involved in the production of amyloid ß-peptide (Aß) in Alzheimer''s disease (AD) brains. Normally, its expression is constitutively inhibited due to the presence of the 5′untranslated region (5′UTR) in the BACE1 promoter. BACE1 expression is activated by phosphorylation of the eukaryotic initiation factor (eIF)2-alpha, which reverses the inhibitory effect exerted by BACE1 5′UTR. There are four kinases associated with different types of stress that could phosphorylate eIF2-alpha. Here we focus on the double-stranded (ds) RNA-activated protein kinase (PKR). PKR is activated during viral infection, including that of herpes simplex virus type 1 (HSV1), a virus suggested to be implicated in the development of AD, acting when present in brains of carriers of the type 4 allele of the apolipoprotein E gene. HSV1 is a dsDNA virus but it has genes on both strands of the genome, and from these genes complementary RNA molecules are transcribed. These could activate BACE1 expression by the PKR pathway. Here we demonstrate in HSV1-infected neuroblastoma cells, and in peripheral nervous tissue from HSV1-infected mice, that HSV1 activates PKR. Cloning BACE1 5′UTR upstream of a luciferase (luc) gene confirmed its inhibitory effect, which can be prevented by salubrinal, an inhibitor of the eIF2-alpha phosphatase PP1c. Treatment with the dsRNA analog poly (I∶C) mimicked the stimulatory effect exerted by salubrinal over BACE1 translation in the 5′UTR-luc construct and increased Aß production in HEK-APPsw cells. Summarizing, our data suggest that PKR activated in brain by HSV1 could play an important role in the development of AD. 相似文献
42.
Background
To determine the prevalence and associated factors with chronic kidney disease (CKD) in a cohort of HIV-positive individuals with undetectable viral load on HAART.Methods
From March, 2009 to September 2009, 213 individuals between 18-70 years, period on HAART ≥12 months, viral load < 50 copies/mm3, and CD4 ≥ 200 cells/mm3, were consecutively enrolled at the outpatient clinic of Hospital de Clínicas, Porto Alegre, Brazil. Exclusion criteria were obesity, malnourishment, amputee, paraplegic, previous history of renal disease, pregnancy and hepatic insufficiency. Renal function was determined by estimated glomerular filtration rate (eGFR) assessed by the modification of diet in renal disease. CKD was defined as an eGFR less or equal than 60 ml/min/1.73 m2, for a period of at least 3 months. Poisson regression was used to determine factors associated with CKD.Results
CKD was diagnosed in 8.4% of the population, and after adjustment, the risk factors were hypertension (RR = 3.88, 95%CI, 1.84 - 8.16), time on HAART (RR = 1.15, 95%CI,1.03–1.27) and tenofovir exposure (RR = 2.25, 95%CI, 1.04–4.95). Higher weight (RR = ,0.88 95%CI, 0.82–0.96) was associated to normal function.Conclusions
CKD was a common finding in this cohort of patients and was related to hypertension, time on HAART and tenofovir exposure. We suggest a more frequent monitoring of renal function, especially for those with risk factors to early identify renal impairment. 相似文献43.
Stable resistance to methotrexate has been well characterized after prolonged treatment of the HT-29 colon cancer cell line, but the mechanism of cell survival at the early stages of the drug resistance process still remains unclear. Here, we demonstrate that human cancer cells in vitro are sensitive to methotrexate only above a critical cell culture density, which specifically coincides with their ability to deplete the extracellular nucleosides from a fully supplemented culture medium. At lower cell densities, extracellular nucleosides remain intact and allow salvage nucleotide synthesis that renders cells insensitive to the drug. Consistently, medium conditioned by cells seeded at standard cell densities sensitizes low cell density cultures. Extracellular nucleosides are the determinants of sensitivity because the latter effect can be mimicked with the use of inhibitors of nucleoside cellular import and reversed by supplying exogenous thymidine and hypoxanthine. Interestingly, treatment at a sensitizing cell density does not preclude the survival of less than 1% of the cells--which have no intrinsic resistance--owing to the inability of the dying cell population to condition the culture medium; this population thus survives indefinitely to continuous treatment by keeping adapted to a low cell number. This cell density-dependent adaptive process accounts for the initial steps of in vitro resistance to methotrexate (MTX) and provides a novel mechanistic insight into the cell population dynamics of cell survival and cell death during drug treatment. 相似文献
44.
45.
46.
El Amrani FB Perelló L Real JA González-Alvarez M Alzuet G Borrás J García-Granda S Montejo-Bernardo J 《Journal of inorganic biochemistry》2006,100(7):1208-1218
A flavonol iron(III) complex, [Fe(flavonolato)(2)Cl(MeOH)], has been prepared. The compound has been characterized by X-ray crystallography, spectroscopy, magnetism and electronic paramagnetic resonance (EPR) at X- and Q-band. The geometrical environment around the metal is best described as rhombic distorted octahedral. This distortion has also been inferred from the magnetic measurements and from the EPR spectra at different temperatures, E/D(rhombicity parameter) approximately 0.06. The DNA cleavage activity of the iron(III) complex with and without ascorbate/hydrogen peroxide is reported. Mechanisms of the oxidative cleavage have been proposed when DNA strand scission is performed both with and without ascorbate/hydrogen peroxide activation. 相似文献
47.
Monnerat R Martins E Queiroz P Ordúz S Jaramillo G Benintende G Cozzi J Real MD Martinez-Ramirez A Rausell C Cerón J Ibarra JE Del Rincon-Castro MC Espinoza AM Meza-Basso L Cabrera L Sánchez J Soberon M Bravo A 《Applied and environmental microbiology》2006,72(11):7029-7035
Bacillus thuringiensis strains isolated from Latin American soil samples that showed toxicity against three Spodoptera frugiperda populations from different geographical areas (Mexico, Colombia, and Brazil) were characterized on the basis of their insecticidal activity, crystal morphology, sodium dodecyl sulfate-polyacrylamide gel electrophoresis of parasporal crystals, plasmid profiles, and cry gene content. We found that the different S. frugiperda populations display different susceptibilities to the selected B. thuringiensis strains and also to pure preparations of Cry1B, Cry1C, and Cry1D toxins. Binding assays performed with pure toxin demonstrated that the differences in the toxin binding capacities of these insect populations correlated with the observed differences in susceptibility to the three Cry toxins analyzed. Finally, the genetic variability of the three insect populations was analyzed by random amplification of polymorphic DNA-PCR, which showed significant genetic diversity among the three S. frugiperda populations analyzed. The data presented here show that the genetic variability of S. frugiperda populations should be carefully considered in the development of insect pest control strategies, including the deployment of genetically modified maize in different geographical regions. 相似文献
48.
49.
The lower Mokelumne River (LMR), located in the California Central Valley, supports a population of natural-origin Oncorhynchus mykiss. In addition, the Mokelumne River Fish Hatchery (Hatchery) contributes hatchery produced O. mykiss to the system annually. We conducted a 3 year acoustic tagging study to evaluate the migratory characteristics of LMR hatchery
and natural-origin O. mykiss to the Pacific Ocean. Specifically, we analyzed downstream movement and migration rates, routes, and success of acoustically
tagged O. mykiss of hatchery and natural origin under variable release locations in non-tidal and tidal habitats. Results from our study suggest
there are significant differences in the proportion of hatchery and natural O. mykiss that demonstrate downstream movement. Fish origin, size, and release location all had a significant effect on whether an
individual demonstrated downstream movement. Mokelumne origin O. mykiss that initiated downstream movement utilized numerous migration routes throughout the Delta during their migration towards
the Pacific Ocean. We identified four primary migration pathways from the lower Mokelumne River through the Sacramento-San
Joaquin Delta while the Delta Cross Channel was closed. However, several other pathways were utilized. Origin had a significant
effect on O. mykiss success in reaching key points in the Delta and through the Estuary. Fish size had a significant effect on whether an individual
reached the marine environment. Of the 467 O. mykiss tagged, 34 successfully reached the Pacific Ocean (Golden Gate Bridge), and of these, 33 were hatchery-origin and 1 was natural-origin.
A higher proportion of hatchery-origin fish (10% of tagged) migrated to the ocean compared to natural-origin fish (<1%). Our
study provides valuable information on the differences between hatchery and natural-origin O. mykiss migration characteristics as well as unique insight into the migratory behavior of little studied non-Sacramento River origin
salmonids. 相似文献
50.