全文获取类型
收费全文 | 635篇 |
免费 | 47篇 |
出版年
2021年 | 7篇 |
2020年 | 4篇 |
2019年 | 5篇 |
2018年 | 7篇 |
2017年 | 9篇 |
2016年 | 14篇 |
2015年 | 21篇 |
2014年 | 29篇 |
2013年 | 33篇 |
2012年 | 42篇 |
2011年 | 29篇 |
2010年 | 26篇 |
2009年 | 19篇 |
2008年 | 27篇 |
2007年 | 31篇 |
2006年 | 26篇 |
2005年 | 48篇 |
2004年 | 21篇 |
2003年 | 28篇 |
2002年 | 26篇 |
2001年 | 16篇 |
2000年 | 14篇 |
1999年 | 12篇 |
1998年 | 11篇 |
1997年 | 15篇 |
1996年 | 7篇 |
1994年 | 7篇 |
1993年 | 8篇 |
1992年 | 10篇 |
1991年 | 11篇 |
1990年 | 6篇 |
1989年 | 7篇 |
1988年 | 3篇 |
1987年 | 9篇 |
1986年 | 7篇 |
1985年 | 9篇 |
1984年 | 4篇 |
1982年 | 3篇 |
1980年 | 6篇 |
1979年 | 6篇 |
1978年 | 6篇 |
1977年 | 5篇 |
1976年 | 5篇 |
1975年 | 4篇 |
1974年 | 5篇 |
1973年 | 3篇 |
1971年 | 3篇 |
1970年 | 8篇 |
1968年 | 4篇 |
1966年 | 3篇 |
排序方式: 共有682条查询结果,搜索用时 15 毫秒
141.
142.
Nanomedicine, or medicine using nanometric devices, has emerged in the past decade as an exhilarating domain that can help to solve a number of problems linked to unsatisfactory therapeutic responses of so-called 'old drugs'. This dissatisfaction stems from inadequate biodistribution after a drug's application, which leads to a limited therapeutic response but also to numerous side effects to healthy organs. The biodistribution of drugs encapsulated in a nanoobject that will act as a vector can be modified to tune its therapeutic efficacy. This review provides a general overview of existing colloidal nanovectors: liposomes, polymeric micelles, polymeric vesicles, polymeric nanoparticles (NPs), and dendrimers. We describe their characteristics, advantages and drawbacks, and discuss their use in the treatment of various diseases. 相似文献
143.
EV Tsimakouridze M Straume PS Podobed H Chin J LaMarre R Johnson M Antenos GM Kirby A Mackay P Huether JA Simpson M Sole G Gadal TA Martino 《Chronobiology international》2012,29(7):810-821
There is critical demand in contemporary medicine for gene expression markers in all areas of human disease, for early detection of disease, classification, prognosis, and response to therapy. The integrity of circadian gene expression underlies cardiovascular health and disease; however time-of-day profiling in heart disease has never been examined. We hypothesized that a time-of-day chronomic approach using samples collected across 24-h cycles and analyzed by microarrays and bioinformatics advances contemporary approaches, because it includes sleep-time and/or wake-time molecular responses. As proof of concept, we demonstrate the value of this approach in cardiovascular disease using a murine Transverse Aortic Constriction (TAC) model of pressure overload-induced cardiac hypertrophy in mice. First, microarrays and a novel algorithm termed DeltaGene were used to identify time-of-day differences in gene expression in cardiac hypertrophy 8 wks post-TAC. The top 300 candidates were further analyzed using knowledge-based platforms, paring the list to 20 candidates, which were then validated by real-time polymerase chain reaction (RTPCR). Next, we tested whether the time-of-day gene expression profiles could be indicative of disease progression by comparing the 1- vs. 8-wk TAC. Lastly, since protein expression is functionally relevant, we monitored time-of-day cycling for the analogous cardiac proteins. This approach is generally applicable and can lead to new understanding of disease. 相似文献
144.
Griffin SV Olivier JP Pippin JW Roberts JM Shankland SJ 《The Journal of biological chemistry》2006,281(38):28048-28057
The limited regenerative capacity of the glomerular podocyte following injury underlies the development of glomerulosclerosis and progressive renal failure in a diverse range of kidney diseases. We discovered that, in the kidney, cyclin I is uniquely expressed in the glomerular podocyte, and have constructed cyclin I knock-out mice to explore the biological function of cyclin I in these cells. Cyclin I knock-out (-/-) podocytes showed an increased susceptibility to apoptosis both in vitro and in vivo. Following induction of experimental glomerulonephritis, podocyte apoptosis was increased 4-fold in the cyclin I -/- mice, which was associated with dramatically decreased renal function. Our previous data showed that the Cdk inhibitor p21(Cip1/Waf1) protects podocytes from certain apoptotic stimuli. In cultured cyclin I -/- podocytes, the level of p21(Cip1/Waf1) was lower at base line, had a shorter half-life, and declined more rapidly in response to apoptotic stimuli than in wild-type cells. Enforced expression of p21(Cip1/Waf1) reversed the susceptibility of cyclin I -/- podocytes to apoptosis. Cyclin I protects podocytes from apoptosis, and we provide preliminary data to suggest that this is mediated by stabilization of p21(Cip1/Waf1). 相似文献
145.
Therapeutic protein transduction of mammalian cells and mice by nucleic acid-free lentiviral nanoparticles 总被引:1,自引:1,他引:0
下载免费PDF全文
![点击此处可从《Nucleic acids research》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Link N Aubel C Kelm JM Marty RR Greber D Djonov V Bourhis J Weber W Fussenegger M 《Nucleic acids research》2006,34(2):e16
The straightforward production and dose-controlled administration of protein therapeutics remain major challenges for the biopharmaceutical manufacturing and gene therapy communities. Transgenes linked to HIV-1-derived vpr and pol-based protease cleavage (PC) sequences were co-produced as chimeric fusion proteins in a lentivirus production setting, encapsidated and processed to fusion peptide-free native protein in pseudotyped lentivirions for intracellular delivery and therapeutic action in target cells. Devoid of viral genome sequences, protein-transducing nanoparticles (PTNs) enabled transient and dose-dependent delivery of therapeutic proteins at functional quantities into a variety of mammalian cells in the absence of host chromosome modifications. PTNs delivering Manihot esculenta linamarase into rodent or human, tumor cell lines and spheroids mediated hydrolysis of the innocuous natural prodrug linamarin to cyanide and resulted in efficient cell killing. Following linamarin injection into nude mice, linamarase-transducing nanoparticles impacted solid tumor development through the bystander effect of cyanide. 相似文献
146.
147.
Richards S Sorensen B Jae HS Winn M Chen Y Wang J Fung S Monzon K Frevert EU Jacobson P Sham H Link JT 《Bioorganic & medicinal chemistry letters》2006,16(24):6241-6245
High throughput screening efforts have identified a novel class of dichloroaniline amide 11β-HSD1 inhibitors. SAR studies initiated from dichloroaniline 4 focused on retaining the potency and selectivity profile of the lead. 相似文献
148.
Alpine meadows of high ecological value could be severely endangered by anthropogenic N enrichment, modifying the relationships between species and the environment. While a constraint exerted by N availability on alpine plant development has been demonstrated by some fertilization experiments, in others no effect was observed. Basically, the problem is that mineral N absorption has not been characterized in alpine plants. In growth chamber experiments, we investigated the component fluxes of 15NO3? and 15NH4+ uptake in a tussock grass (Festuca nigrescens) very common and representative of the dominant plant growth form in European alpine meadows. Rates of influx supported data already published for low elevation herbaceous species. These rates were up to ten times higher for NH4+ than for NO3? but rates of net uptake were similar for both ions demonstrating the occurrence of elevated NH4+ efflux (80% of primary influx). An increase in external N in the range of field-relevant concentrations did not substantially enhance net uptake. Thus, the alpine plant which is assumed to be adapted to relatively high soil NH4+ responded like an NH4+-sensitive species: as if it was unable to use the incoming nitrogen. It is suggested that the ability of this typical alpine grass to respond to increasing N availability due to global changes is limited. 相似文献
149.
Life with and without AtTIP1;1, an Arabidopsis aquaporin preferentially localized in the apposing tonoplasts of adjacent vacuoles 总被引:2,自引:0,他引:2
Azeez Beebo Dominique Thomas Christophe Der Lisa Sanchez Nathalie Leborgne-Castel Francis Marty Benoît Schoefs Karim Bouhidel 《Plant molecular biology》2009,70(1-2):193-209
The Arabidopsis thaliana Tonoplast Intrinsic Protein 1;1 (AtTIP1;1) is a member of the tonoplast aquaporin family. The tissue-specific expression pattern and intracellular localization of AtTIP1;1 were characterized using GUS and GFP fusion genes. Results indicate that AtTIP1;1 is expressed in almost all cell types with the notable exception of meristematic cells. The highest level of AtTIP1;1 expression was detected in vessel-flanking cells in vascular bundles. AtTIP1;1-GFP fusion protein labelled the tonoplast of the central vacuole and other smaller peripheral vacuoles. The fusion protein was not found evenly distributed along the tonoplast continuum but concentrated in contact zones of tonoplasts from adjacent vacuoles and in invaginations of the central vacuole. Such invaginations may result from partially engulfed small vacuoles. A knockout mutant was isolated and characterized to gain insight into AtTIP1;1 function. No phenotypic alteration was found under optimal growth conditions indicating that AtTIP1;1 function is not essential to the plant and that some members of the TIP family may act redundantly to facilitate water flow across the tonoplast. However, a conditional root phenotype was observed when mutant plants were grown on a glycerol-containing medium. 相似文献
150.
Amina Rhouati Georges Istamboulie Montserrat Cortina-Puig Jean-Louis Marty Thierry Noguer 《Enzyme and microbial technology》2010,46(3-4):212-216
Enzyme spectrophotometric assays based on acetylcholinesterase (AChE) inhibition were used in combination with Artificial Neural Network (ANN) chemometric analysis for the resolution of pesticides mixtures of chlorpyriphos, dichlorvos and carbofuran. Electric eel (EE) AChE and the recombinant B394-AChE from Drosophila melanogaster were selected due to their different sensitivities to insecticides. These enzymes were used in association with phosphotriesterase (PTE), an enzyme allowing to discriminate between organophosphate and carbamate insecticides. The combined response of three enzymes systems composed of EE-AChE, EE-AChE + PTE, and B394-AChE + PTE was modelled by means of ANN. Specifically, an ANN was constructed where the structure providing the best modelling was a single hidden layer containing four neurons. To prove the concept, a study to resolve pesticide mixtures was done with spectrophotometric measurements. Finally the developed system was successfully applied to the determination of carbofuran, CPO and dichlorvos pesticides in real water samples. 相似文献