全文获取类型
收费全文 | 422篇 |
免费 | 37篇 |
出版年
2021年 | 6篇 |
2020年 | 4篇 |
2019年 | 3篇 |
2017年 | 6篇 |
2016年 | 8篇 |
2015年 | 14篇 |
2014年 | 19篇 |
2013年 | 15篇 |
2012年 | 18篇 |
2011年 | 23篇 |
2010年 | 19篇 |
2009年 | 17篇 |
2008年 | 21篇 |
2007年 | 16篇 |
2006年 | 12篇 |
2005年 | 14篇 |
2004年 | 19篇 |
2003年 | 13篇 |
2002年 | 17篇 |
2001年 | 13篇 |
2000年 | 17篇 |
1999年 | 13篇 |
1998年 | 10篇 |
1997年 | 4篇 |
1996年 | 8篇 |
1995年 | 5篇 |
1994年 | 7篇 |
1993年 | 6篇 |
1992年 | 6篇 |
1991年 | 9篇 |
1990年 | 5篇 |
1989年 | 10篇 |
1988年 | 3篇 |
1987年 | 3篇 |
1986年 | 6篇 |
1984年 | 3篇 |
1981年 | 3篇 |
1979年 | 2篇 |
1978年 | 6篇 |
1977年 | 3篇 |
1976年 | 4篇 |
1975年 | 4篇 |
1972年 | 2篇 |
1971年 | 2篇 |
1968年 | 8篇 |
1967年 | 4篇 |
1966年 | 3篇 |
1965年 | 3篇 |
1963年 | 2篇 |
1959年 | 2篇 |
排序方式: 共有459条查询结果,搜索用时 875 毫秒
51.
52.
53.
A novel conjugate of human hemoglobin (Hb) and the nucleoside analogue ribavirin (RBV) was synthesized to demonstrate the utility of Hb as a biocompatible drug carrier for improved drug delivery in the treatment of liver disease. RBV is used in combination with interferon for the treatment of hepatitis C, but its side effects can result in dose limitation or discontinuation of treatment. Targeted delivery of RBV may help to prevent or minimize its toxicity. The hemoglobin-ribavirin conjugate (Hb-RBV) was designed to release bioactive drug upon endocytosis by cells and tissues involved in extracellular Hb catabolism and clearance. Ribavirin-5'-monophosphate (RBV-P) was prepared from RBV and activated as the 5'-monophosphorimidazolide (RBV-P-Im) for reaction with carbonmonoxyhemoglobin to yield Hb-RBV consisting of multiple RBV drugs covalently attached as physiologically labile phosphoramidates via their 5'-hydroxyl groups. A molar drug ratio of six to eight RBV molecules per Hb tetramer was obtained with near complete haptoglobin (Hp) binding of the drug modified Hb maintained. The conjugate complex (Hp-Hb-RBV) was selectively taken up in vitro by cells that express the hemoglobin-haptoglobin receptor, CD163. Recovered ribavirin enzymatically cleaved from Hb-RBV showed equipotent antiproliferative activity compared to control unconjugated RBV against human HepG2 and mouse AML12 liver cell lines. Based upon the reported high level of Hb uptake in the liver, Hb-RBV may be useful in the treatment of certain liver diseases, as well as inflammatory disorders associated with CD163-positive macrophages. 相似文献
54.
Suzanne V Frankfort Valerie D Doodeman Remco Bakker Linda R Tulner Jos PCM van Campen Paul HM Smits Jos H Beijnen 《Molecular neurodegeneration》2006,1(1):1-5
Amyloid β is an in vitro substrate for P-glycoprotein (P-gp), an efflux pump at the blood brain barrier (BBB). The Multi Drug Resistance (ABCB1) gene, encoding for P-gp, is highly polymorphic and this may result in a changed function of P-gp and may possibly interfere with the pathogenesis of Alzheimer's disease. This study investigates to what extent ABCB1 Single Nucleotide Polymorphisms (SNPs; C1236T in exon 12, G2677T/A in exon 21 and C3435T in exon 26) and inferred haplotypes exist in an elderly population and if these SNPs and haplotypes differ between patients with dementia and age-matched non-demented control patients. ABCB1 genotype, allele and haplotype frequencies were neither significantly different between patients with dementia and age-matched controls, nor between subgroups of different types of dementia nor age-matched controls. This study shows ABCB1 genotype frequencies to be comparable with described younger populations. To our knowledge this is the first study on ABCB1 genotypes in dementia. ABCB1 genotypes are presently not useful as a biomarker for dementia, as they were not significantly different between demented patients and age-matched control subjects. 相似文献
55.
Blomqvist ME Reynolds C Katzov H Feuk L Andreasen N Bogdanovic N Blennow K Brookes AJ Prince JA 《Human genetics》2006,119(1-2):29-37
Most genetic sequence variants that contribute to variability in complex human traits will have small effects that are not
readily detectable with population samples typically used in genetic association studies. A potentially valuable tool in the
gene discovery process is meta-analysis of the accumulated published data, but in order to be valid these require a sample
of studies representative of the true genetic effect and thus hypothetically should include some positive and an abundance
of negative reports. A survey of the literature on association studies for Alzheimer disease (AD) from January 2004–April
2005, identified 138 studies, 86 of which reported positive findings other than for apolipoprotein E (APOE), strongly indicative of publication bias. We report here an analysis of 62 genetic markers, tested for association with
AD risk as well as for possible effects upon quantitative indices of AD severity (mini-mental state examination scores, age-at-onset,
and cerebrospinal fluid (CSF) β-amyloid (Aβ) and CSF tau proteins). Within this set, only modest signals were present that,
with the exception of APOE are easily lost when corrections for multiple hypotheses are applied. In isolation, results are thus broadly negative. Genes
studied encompass both novel candidates as well as several recently claimed to be associated with AD (e.g. urokinase plasminogen
activator (PLAU) and acetyl-coenzyme A acetyltransferase 1 (ACAT1)). By reporting these data we hope to encourage the publication of gene compendia to guide further studies and aid future
meta-analyses aimed at resolving the involvement of genes in complex human traits. 相似文献
56.
57.
Nelli RK Dunham SP Kuchipudi SV White GA Baquero-Perez B Chang P Ghaemmaghami A Brookes SM Brown IH Chang KC 《Journal of virology》2012,86(17):9201-9210
58.
This paper updates the assessment of the impact commercialized agricultural biotechnology is having on global agriculture, from some important environmental perspectives. It focuses on the impact of changes in pesticide use and greenhouse gas emissions arising from the use of biotech crops. The technology has reduced pesticide spraying by 443 million kg (-9.1%) and, as a result, decreased the environmental impact associated with herbicide and insecticide use on these crops [as measured by the indicator the Environmental Impact Quotient (EIQ)] by 17.9%. The technology has also significantly reduced the release of greenhouse gas emissions from this cropping area, which, in 2010, was equivalent to removing 8.6 million cars from the roads. 相似文献
59.
Warrell MJ Riddell A Yu LM Phipps J Diggle L Bourhy H Deeks JJ Fooks AR Audry L Brookes SM Meslin FX Moxon R Pollard AJ Warrell DA 《PLoS neglected tropical diseases》2008,2(4):e224
Background
The need for economical rabies post-exposure prophylaxis (PEP) is increasing in developing countries. Implementation of the two currently approved economical intradermal (ID) vaccine regimens is restricted due to confusion over different vaccines, regimens and dosages, lack of confidence in intradermal technique, and pharmaceutical regulations. We therefore compared a simplified 4-site economical PEP regimen with standard methods.Methods
Two hundred and fifty-four volunteers were randomly allocated to a single blind controlled trial. Each received purified vero cell rabies vaccine by one of four PEP regimens: the currently accepted 2-site ID; the 8-site regimen using 0.05 ml per ID site; a new 4-site ID regimen (on day 0, approximately 0.1 ml at 4 ID sites, using the whole 0.5 ml ampoule of vaccine; on day 7, 0.1 ml ID at 2 sites and at one site on days 28 and 90); or the standard 5-dose intramuscular regimen. All ID regimens required the same total amount of vaccine, 60% less than the intramuscular method. Neutralising antibody responses were measured five times over a year in 229 people, for whom complete data were available.Findings
All ID regimens showed similar immunogenicity. The intramuscular regimen gave the lowest geometric mean antibody titres. Using the rapid fluorescent focus inhibition test, some sera had unexpectedly high antibody levels that were not attributable to previous vaccination. The results were confirmed using the fluorescent antibody virus neutralisation method.Conclusions
This 4-site PEP regimen proved as immunogenic as current regimens, and has the advantages of requiring fewer clinic visits, being more practicable, and having a wider margin of safety, especially in inexperienced hands, than the 2-site regimen. It is more convenient than the 8-site method, and can be used economically with vaccines formulated in 1.0 or 0.5 ml ampoules. The 4-site regimen now meets all requirements of immunogenicity for PEP and can be introduced without further studies.Trial Registration
Controlled-Trials.com ISRCTN 30087513 相似文献60.
Lynn PA Chen BN Zagorodnyuk VP Costa M Brookes SJ 《American journal of physiology. Gastrointestinal and liver physiology》2008,295(4):G862-G871
The effects of trinitrobenzene sulfonic acid (TNBS)-induced inflammation on specialized, low-threshold, slowly adapting rectal mechanoreceptors were investigated in the guinea pig. Under isoflurane anesthesia, 300 microl saline or TNBS (15 mg/ml) in 30% ethanol was instilled 7 cm from the anal sphincter. Six or 30 days later, single unit extracellular recordings were made from rectal nerve trunks in flat-sheet in vitro preparations attached to a mechanical tissue stretcher. TNBS treatment caused macroscopic ulceration of the rectal mucosa at 6 days, which fully resolved by 30 days. Muscle contractility was unaffected by TNBS treatment. At 6 days posttreatment, responses of low-threshold rectal mechanoreceptors to circumferential stretch were increased, and the proportion of afferents responding with von Frey hair thresholds 相似文献