全文获取类型
收费全文 | 573篇 |
免费 | 59篇 |
国内免费 | 90篇 |
专业分类
722篇 |
出版年
2024年 | 3篇 |
2023年 | 9篇 |
2022年 | 17篇 |
2021年 | 30篇 |
2020年 | 23篇 |
2019年 | 34篇 |
2018年 | 26篇 |
2017年 | 22篇 |
2016年 | 20篇 |
2015年 | 37篇 |
2014年 | 40篇 |
2013年 | 43篇 |
2012年 | 36篇 |
2011年 | 39篇 |
2010年 | 35篇 |
2009年 | 27篇 |
2008年 | 30篇 |
2007年 | 20篇 |
2006年 | 30篇 |
2005年 | 21篇 |
2004年 | 18篇 |
2003年 | 25篇 |
2002年 | 17篇 |
2001年 | 14篇 |
2000年 | 22篇 |
1999年 | 10篇 |
1998年 | 12篇 |
1997年 | 6篇 |
1996年 | 7篇 |
1995年 | 3篇 |
1994年 | 4篇 |
1993年 | 2篇 |
1992年 | 4篇 |
1991年 | 5篇 |
1990年 | 4篇 |
1989年 | 2篇 |
1988年 | 1篇 |
1987年 | 4篇 |
1986年 | 4篇 |
1985年 | 3篇 |
1984年 | 3篇 |
1983年 | 1篇 |
1979年 | 1篇 |
1978年 | 1篇 |
1976年 | 2篇 |
1975年 | 4篇 |
1974年 | 1篇 |
排序方式: 共有722条查询结果,搜索用时 15 毫秒
31.
Philippe Truc Philippe Büscher Gérard Cuny Mary Isabel Gonzatti Jean Jannin Prashant Joshi Prayag Juyal Zhao-Rong Lun Raffaele Mattioli Etienne Pays Pere P. Simarro Marta Maria Geraldes Teixeira Louis Touratier Philippe Vincendeau Marc Desquesnes 《PLoS neglected tropical diseases》2013,7(9)
The two classical forms of human trypanosomoses are sleeping sickness due to Trypanosoma brucei gambiense or T. brucei rhodesiense, and Chagas disease due to T. cruzi. However, a number of atypical human infections caused by other T. species (or sub-species) have been reported, namely due to T. brucei brucei, T. vivax, T. congolense, T. evansi, T. lewisi, and T. lewisi-like. These cases are reviewed here. Some infections were transient in nature, while others required treatments that were successful in most cases, although two cases were fatal. A recent case of infection due to T. evansi was related to a lack of apolipoprotein L-I, but T. lewisi infections were not related to immunosuppression or specific human genetic profiles. Out of 19 patients, eight were confirmed between 1974 and 2010, thanks to improved molecular techniques. However, the number of cases of atypical human trypanosomoses might be underestimated. Thus, improvement, evaluation of new diagnostic tests, and field investigations are required for detection and confirmation of these atypical cases.
Key Learning Points
- The classical human trypanosomoses are human African trypanosomosis (HAT) or sleeping sickness, and Chagas disease, the Latin American human trypanosomosis.
- Atypical human infections caused by Trypanosoma species that normally are restricted to animals have been reported. These cases of atypical human trypanosomoses (a-HT) are mostly transient, but some require treatment and can be fatal.
- Only a few cases of a-HT have been fully confirmed, especially in Asia, leading to the hypothesis that the actual prevalence is probably underestimated.
- The detection of a case of a-HT should be based on observation of the parasite by direct microscopy. Evaluating/improving the diagnoses through serological and PCR assays would help in detecting and identifying atypical trypanosomosis infections in humans. These laboratory research and field activities are needed to evaluate the actual occurrence of atypical cases.
Top Five Papers
- Verma A, Manchanda S, Kumar N, Sharma A, Goel M, et al. (2011) Trypanosoma lewisi or Trypanosoma lewisi-like infection in a 37-day-old infant. Am J Trop Med Hyg 85: 221–224.
- Deborggraeve S, Koffi M, Jamonneau V, Bonsu FA, Queyson R, et al. (2008) Molecular analysis of archived blood slides reveals an atypical human Trypanosoma infection. Diagn Microbiol Infect Dis 61: 428–433.
- Vanhollebeke B, Truc P, Poelvoorde P, Pays A, Joshi PP, et al. (2006) Human Trypanosoma evansi infection linked to a lack of apolipoprotein L-I. N Engl J Med 355: 2752–2756.
- Joshi PP, Shegokar V, Powar S, Herder S, Katti R, et al. (2005) Human trypanosomiasis caused by Trypanosoma evansi in India: the first case report. Am J Trop Med Hyg 73: 491–495.
- Howie S, Guy M, Fleming L, Bailey W, Noyes H, et al. (2006) A Gambian infant with fever and an unexpected blood film. PLoS Med 3: e355. doi:10.1371/journal.pmed.0030355.
32.
Kejian Wang Jiazhi Sun Shufeng Zhou Chunling Wan Shengying Qin Can Li Lin He Lun Yang 《PLoS computational biology》2013,9(11)
Small drug molecules usually bind to multiple protein targets or even unintended off-targets. Such drug promiscuity has often led to unwanted or unexplained drug reactions, resulting in side effects or drug repositioning opportunities. So it is always an important issue in pharmacology to identify potential drug-target interactions (DTI). However, DTI discovery by experiment remains a challenging task, due to high expense of time and resources. Many computational methods are therefore developed to predict DTI with high throughput biological and clinical data. Here, we initiatively demonstrate that the on-target and off-target effects could be characterized by drug-induced in vitro genomic expression changes, e.g. the data in Connectivity Map (CMap). Thus, unknown ligands of a certain target can be found from the compounds showing high gene-expression similarity to the known ligands. Then to clarify the detailed practice of CMap based DTI prediction, we objectively evaluate how well each target is characterized by CMap. The results suggest that (1) some targets are better characterized than others, so the prediction models specific to these well characterized targets would be more accurate and reliable; (2) in some cases, a family of ligands for the same target tend to interact with common off-targets, which may help increase the efficiency of DTI discovery and explain the mechanisms of complicated drug actions. In the present study, CMap expression similarity is proposed as a novel indicator of drug-target interactions. The detailed strategies of improving data quality by decreasing the batch effect and building prediction models are also effectively established. We believe the success in CMap can be further translated into other public and commercial data of genomic expression, thus increasing research productivity towards valid drug repositioning and minimal side effects. 相似文献
33.
Shiu Lun Au Yeung Chaoqiang Jiang Kar Keung Cheng Benjamin J. Cowling Bin Liu Weisen Zhang Tai Hing Lam Gabriel M. Leung C. Mary Schooling 《PloS one》2013,8(7)
Background
Observational studies show moderate alcohol use negatively associated with ischemic heart disease (IHD) and cardiovascular disease (CVD). However, healthier attributes among moderate users compared to never users may confound the apparent association. A potentially less biased way to examine the association is Mendelian randomization, using alcohol metabolizing genes which influence alcohol use.Methods
We used instrumental variable analysis with aldehyde dehydrogenase 2 (ALDH2) genotypes (AA/GA/GG) as instrumental variables for alcohol use to examine the association of alcohol use (10 g ethanol/day) with CVD risk factors (blood pressure, lipids and glucose) and morbidity (self-reported IHD and CVD) among men in the Guangzhou Biobank Cohort Study.Results
ALDH2 genotypes were a credible instrument for alcohol use (F-statistic 74.6). Alcohol was positively associated with HDL-cholesterol (0.05 mmol/L per alcohol unit, 95% confidence interval (CI) 0.02 to 0.08) and diastolic blood pressure (1.15 mmHg, 95% CI 0.23 to 2.07) but not with systolic blood pressure (1.00 mmHg, 95% CI -0.74 to 2.74), LDL-cholesterol (0.03 mmol/L, 95% CI -0.03 to 0.08), log transformed triglycerides (0.03 mmol/L, 95% CI -0.01 to 0.08) or log transformed fasting glucose (0.01 mmol/L, 95% CI -0.006 to 0.03), self-reported CVD (odds ratio (OR) 0.98, 95% CI 0.76 to 1.27) or self-reported IHD (OR 1.10, 95% CI 0.83 to 1.45).Conclusion
Low to moderate alcohol use among men had the expected effects on most CVD risk factors but not fasting glucose. Larger studies are needed to confirm the null associations with IHD, CVD and fasting glucose. 相似文献34.
Van Lun Low Chee Dhang Chen Han Lim Lee Tiong Kai Tan Chin Fong Chen Cherng Shii Leong Yvonne Ai Lian Lim Phaik Eem Lim Yusoff Norma-Rashid Mohd Sofian-Azirun 《PloS one》2013,8(11)
Background
There has been no comprehensive study on biochemical characterization of insecticide resistance mechanisms in field populations of Malaysian Culex quinquefasciatus. To fill this void in the literature, a nationwide investigation was performed to quantify the enzyme activities, thereby attempting to characterize the potential resistance mechanisms in Cx. quinquefasciatus in residential areas in Malaysia.Methodology/Principal Findings
Culex quinquefasciatus from 14 residential areas across 13 states and one federal territory were subjected to esterases, mixed function oxidases, glutathione-S-transferase and insensitive acetylcholinesterase assays. Enzyme assays revealed that α-esterases and β-esterases were elevated in 13 populations and 12 populations, respectively. Nine populations demonstrated elevated levels of mixed function oxidases and glutathione-S-transferase. Acetylcholinesterase was insensitive to propoxur in all 14 populations. Activity of α-esterases associated with malathion resistance was found in the present study. In addition, an association between the activity of α-esterases and β-esterases was also demonstrated.Conclusions/Significance
The present study has characterized the potential biochemical mechanisms in contributing towards insecticide resistance in Cx. quinquefasciatus field populations in Malaysia. Identification of mechanisms underlying the insecticide resistance will be beneficial in developing effective mosquito control programs in Malaysia. 相似文献35.
Li Qifa Zhang Yue Ge Bi-Ying Li Na Sun Hai- Lun Ntim Michael Sun Yi-Ping Wu Xue-Fei Yang Jin-Yi Li Shao 《Neurochemical research》2020,45(10):2312-2323
Neurochemical Research - G protein-coupled receptor 50 (GPR50) belongs to the G protein-coupled receptor which is highly homologous with the sequence of melatonin receptor MT1 and MT2. GPR50... 相似文献
36.
Ming Gao Xiaoguang Li Wen Dong Rui Jin Hanghang Ma Pingxun Yang Meiru Hu Yi Li Yi Hao Shengtao Yuan Junjian Huang Lun Song 《Nucleic acids research》2013,41(10):5210-5222
The stress-responding protein, GADD45α, plays important roles in cell cycle checkpoint, DNA repair and apoptosis. In our recent study, we demonstrate that GADD45α undergoes a dynamic ubiquitination and degradation in vivo, which process can be blocked by the cytotoxic reagent, arsenite, resulting in GADD45α accumulation to activate JNKs cell death pathway, thereby revealing a novel mechanism for the cellular GADD45α functional regulation. But the factors involved in GADD45α stability modulations are unidentified. Here, we demonstrated that MDM2 was an E3 ubiquitin ligase for GADD45α. One of MDM2-binding partner, ribosomal protein S7, interacted with and stabilized GADD45α through preventing the ubiquitination and degradation of GADD45α mediated by MDM2. This novel function of S7 is unrelated to p53 but seems to depend on S7/MDM2 interaction, for the S7 mutant lacking MDM2-binding ability lost its function to stabilize GADD45α. Further investigations indicated that arsenite treatment enhanced S7–MDM2 interaction, resulting in attenuation of MDM2-dependent GADD45α ubiquitination and degradation, thereby leading to GADD45α-dependent cell death pathway activation. Silencing S7 expression suppressed GADD45α-dependent cytotoxicity induced by arsenite. Our findings thus identify a novel function of S7 in control of GADD45α stabilization under both basal and stress conditions and its significance in mediating arsenite-induced cellular stress. 相似文献
37.
An integrative gene expression system has been constructed for the directional assembly of biological components in Synechocystis PCC6803. We have characterized 11 promoter parts with various expression efficiencies for genetic engineering of Synechocystis for the production of fatty alcohols. This was achieved by integrating several genetic modifications including the expression of multiple-copies of fatty acyl-CoA reductase (FAR) under the control of strong promoters, disruption of the competing pathways for poly-β-hydroxybutyrate and glycogen synthesis, and for peptide truncation of the FAR. In shake-flask cultures, the production of fatty alcohols was significantly improved with a yield of 761 ± 216 μg/g cell dry weight in Synechocystis, which is the highest reported to date. 相似文献
38.
Aiqiu Liu Xiaoming Tan Lun Yao Xuefeng Lu 《Applied microbiology and biotechnology》2013,97(15):7061-7071
Although successful production of fatty alcohols in metabolically engineered Escherichia coli with heterologous expression of fatty acyl-CoA reductase has been reported, low biosynthetic efficiency is still a hurdle to be overcome. In this study, we examined the characteristics of two fatty acyl-CoA reductases encoded by Maqu_2220 and Maqu_2507 genes from Marinobacter aquaeolei VT8 on fatty alcohol production in E. coli. Fatty alcohols with diversified carbon chain length were obtained by co-expressing Maqu_2220 with different carbon chain length-specific acyl-ACP thioesterases. Both fatty acyl-CoA reductases displayed broad substrate specificities for C12–C18 fatty acyl chains in vivo. The optimized mutant strain of E. coli carrying the modified tesA gene and fadD gene from E. coli and Maqu_2220 gene from Marinobacter aquaeolei VT8 produced fatty alcohols at a remarkable level of 1.725 g/L under the fermentation condition. 相似文献
39.
Matthew I. Jackson Kristoffer Lunøe Charlotte Gabel-Jensen Bente Gammelgaard Gerald F. Combs 《The Journal of nutritional biochemistry》2013,24(12):2023-2030
Impaired S-adenosylmethionine (SAM)-dependent transmethylation and methylation capacity feature in diseases related to obesity or aging, and selenium (Se) metabolism is altered in these states. We tested the hypothesis that SAM metabolism is required for methylation and excretion of Se in a rat model. Four hours after selenite and periodate-oxidized adenosine (POA; an inhibitor of SAM metabolism) were administered, circulating markers of single-carbon status were unchanged, except for decreased circulating phosphatidylcholine (P<.05). In contrast, liver and kidney SAM and S-adenosylhomocysteine were elevated (P<.05 for all). Concentrations of total Se were significantly elevated in both liver (P<.001) and kidney (P<.01), however the degree of accumulation in liver was significantly greater than that of kidney (P<.05). Red blood cell Se levels were decreased (P=.01). Trimethylselenonium levels were decreased in liver and kidney (P=.001 for both tissues) and Se-methyl-N-acetylselenohexosamine selenosugar was decreased in liver (P=.001). Urinary output of both trimethylselenonium (P=.001) and selenosugar (P=.01) was decreased as well. Trimethylselenonium production is more inhibited by POA than is selenosugar production (P<.05). This work indicates that low molecular weight Se metabolism requires SAM-dependent methylation, and disrupting the conversion of SAM to S-adenosylhomocysteine prevents conversion of selenite and intermediate metabolites to final excretory forms, suggesting implications for selenium supplementation under conditions where transmethylation is suboptimal, such as in the case of obese or aging individuals. 相似文献
40.
Delong Zhao Xuefeng Sun Li Yao Hongli Lin Jijun Li Jiuyang Zhao Zhimin Zhang Lide Lun Jianrong Zhang Mingxu Li Qi Huang Yang Yang Shimin Jiang Yong Wang Hanyu Zhu Xiangmei Chen 《PloS one》2013,8(4)