全文获取类型
收费全文 | 874篇 |
免费 | 64篇 |
国内免费 | 4篇 |
出版年
2023年 | 9篇 |
2022年 | 11篇 |
2021年 | 26篇 |
2020年 | 19篇 |
2019年 | 15篇 |
2018年 | 30篇 |
2017年 | 34篇 |
2016年 | 49篇 |
2015年 | 37篇 |
2014年 | 59篇 |
2013年 | 55篇 |
2012年 | 49篇 |
2011年 | 47篇 |
2010年 | 37篇 |
2009年 | 34篇 |
2008年 | 27篇 |
2007年 | 34篇 |
2006年 | 22篇 |
2005年 | 25篇 |
2004年 | 34篇 |
2003年 | 29篇 |
2002年 | 24篇 |
2001年 | 18篇 |
2000年 | 16篇 |
1999年 | 8篇 |
1998年 | 11篇 |
1995年 | 5篇 |
1994年 | 9篇 |
1992年 | 7篇 |
1991年 | 11篇 |
1990年 | 6篇 |
1989年 | 4篇 |
1988年 | 11篇 |
1987年 | 7篇 |
1986年 | 11篇 |
1985年 | 8篇 |
1984年 | 5篇 |
1983年 | 9篇 |
1982年 | 9篇 |
1981年 | 8篇 |
1980年 | 6篇 |
1979年 | 10篇 |
1978年 | 6篇 |
1976年 | 4篇 |
1975年 | 4篇 |
1974年 | 7篇 |
1973年 | 5篇 |
1969年 | 4篇 |
1968年 | 6篇 |
1966年 | 5篇 |
排序方式: 共有942条查询结果,搜索用时 15 毫秒
141.
Philippe Marullo Chantal Mansour Matthieu Dufour Warren Albertin Delphine Sicard Marina Bely & Denis Dubourdieu 《FEMS yeast research》2009,9(8):1148-1160
During red wine fermentation, high temperatures may cause stuck fermentation by affecting the physiology of fermenting yeast. This deleterious effect is the result of the complex interaction of temperature with other physicochemical parameters of grape juice, such as sugar and lipid content. The genetic background of fermenting yeast also interacts with this complex matrix and some strains are more resistant to high temperatures than others. Here, the temperature tolerance of nine commercial starters was evaluated, demonstrating that, at high sugar concentrations, half of them are sensitive to temperature. Using a classical backcross approach, one thermo-sensitive commercial starter was genetically improved by introducing quantitative trait loci conferring resistance to temperature. With this breeding program it is possible to obtain a thermo-resistant strain sharing most of its genome with the initial commercial starter. The parental and improved strains were compared for population growth and fermentation ability in various conditions. Despite their common genetic background, these two strains showed slight physiological differences in response to environmental changes that enable identification of the key physiological parameters influencing stuck fermentation. 相似文献
142.
Background
In view of the current widespread use of and reliance on a single schistosomicide, praziquantel, there is a pressing need to discover and develop alternative drugs for schistosomiasis. One approach to this is to develop High Throughput in vitro whole organism screens (HTS) to identify hits amongst large compound libraries.Methodology/Principal Findings
We have been carrying out low throughput (24-well plate) in vitro testing based on microscopic evaluation of killing of ex-vivo adult S. mansoni worms using selected compound collections mainly provided through the WHO-TDR Helminth Drug Initiative. To increase throughput, we introduced a similar but higher throughput 96-well primary in vitro assay using the schistosomula stage which can be readily produced in vitro in large quantities. In addition to morphological readout of viability we have investigated using fluorometric determination of the reduction of Alamar blue (AB), a redox indicator of enzyme activity widely used in whole organism screening. A panel of 7 known schistosome active compounds including praziquantel, produced diverse effects on larval morphology within 3 days of culture although only two induced marked larval death within 7 days. The AB assay was very effective in detecting these lethal compounds but proved more inconsistent in detecting compounds which damaged but did not kill. The utility of the AB assay in detecting compounds which cause severe morbidity and/or death of schistosomula was confirmed in testing a panel of compounds previously selected in library screening as having activity against the adult worms. Furthermore, in prospective library screening, the AB assay was able to detect all compounds which induced killing and also the majority of compounds designated as hits based on morphological changes.Conclusion
We conclude that an HTS combining AB readout and image-based analysis would provide an efficient and stringent primary assay for schistosome drug discovery. 相似文献143.
El‐Sayed M. El‐Sayed Ahmed M. Mansour Waleed S. El‐Sawy 《Journal of biochemical and molecular toxicology》2017,31(11)
Doxorubicin (DOX) exerts toxic effects in several organs particularly kidney. The present study aimed to assess the protective effect of proanthocyanidins (PAs) against DOX‐induced nephrotoxicity in rats. A single dose of DOX (7.5 mg/kg, i.v.) significantly increased kidney weight, kidney/body weight ratio, serum urea, creatinine, tumor necrosis factor alpha levels, and kidney contents of malondialdehyde, nitric oxide, cyclooxygenase‐2, and caspase‐3 activity with significant reduction in final body weight, serum albumin, kidney contents of reduced glutathione (GSH), and superoxide dismutase activity as compared with control group. In contrast, pretreatment with PAs (200 mg/kg, p.o.) for 14 days before DOX and for 7 days after DOX ameliorated kidney function and oxidative stress parameters. Histopathological evidence confirmed the protective effects of PAs from the tissue damage induced by DOX. In conclusion, PAs have a multi‐nephroprotective effect that might be attributed to its antioxidant, anti‐inflammatory, and antiapoptoic activities. 相似文献
144.
145.
Ilse M. Boudewijn Alen Faiz Katrina Steiling Erica van der Wiel Eef D. Telenga Susan J. M. Hoonhorst Nick H. T. ten Hacken Corry-Anke Brandsma Huib A. M. Kerstjens Wim Timens Irene H. Heijink Marnix R. Jonker Harold G. de Bruin J. Sebastiaan Vroegop Henk R. Pasma Wim G. Boersma Pascal Wielders Frank van den Elshout Khaled Mansour Avrum Spira Marc E. Lenburg Victor Guryev Dirkje S. Postma Maarten van den Berge 《Respiratory research》2017,18(1):213
Background
Nasal gene expression profiling is a promising method to characterize COPD non-invasively. We aimed to identify a nasal gene expression profile to distinguish COPD patients from healthy controls. We investigated whether this COPD-associated gene expression profile in nasal epithelium is comparable with the profile observed in bronchial epithelium.Methods
Genome wide gene expression analysis was performed on nasal epithelial brushes of 31 severe COPD patients and 22 controls, all current smokers, using Affymetrix Human Gene 1.0 ST Arrays. We repeated the gene expression analysis on bronchial epithelial brushes in 2 independent cohorts of mild-to-moderate COPD patients and controls.Results
In nasal epithelium, 135 genes were significantly differentially expressed between severe COPD patients and controls, 21 being up- and 114 downregulated in COPD (false discovery rate?<?0.01). Gene Set Enrichment Analysis (GSEA) showed significant concordant enrichment of COPD-associated nasal and bronchial gene expression in both independent cohorts (FDRGSEA <?0.001).Conclusion
We identified a nasal gene expression profile that differentiates severe COPD patients from controls. Of interest, part of the nasal gene expression changes in COPD mimics differentially expressed genes in the bronchus. These findings indicate that nasal gene expression profiling is potentially useful as a non-invasive biomarker in COPD.Trial registration
ClinicalTrials.gov registration number NCT01351792 (registration date May 10, 2011), ClinicalTrials.gov registration number NCT00848406 (registration date February 19, 2009), ClinicalTrials.gov registration number NCT00807469 (registration date December 11, 2008).146.
Rajesh Abraham Jacob Cassandra R. Edgar Jrmie Prvost Steven M. Trothen Antony Lurie Mitchell J. Mumby Alexa Galbraith Frank Kirchhoff S.M. Mansour Haeryfar Andrs Finzi Jimmy D. Dikeakos 《The Journal of biological chemistry》2021,297(3)
Prolonged immune activation drives the upregulation of multiple checkpoint receptors on the surface of virus-specific T cells, inducing their exhaustion. Reversing HIV-1-induced T cell exhaustion is imperative for efficient virus clearance; however, viral mediators of checkpoint receptor upregulation remain largely unknown. The enrichment of checkpoint receptors on T cells upon HIV-1 infection severely constrains the generation of an efficient immune response. Herein, we examined the role of HIV-1 Nef in mediating the upregulation of checkpoint receptors on peripheral blood mononuclear cells. We demonstrate that the HIV-1 accessory protein Nef upregulates cell surface levels of the checkpoint receptor T-cell immunoglobulin mucin domain-3 (Tim-3) and that this is dependent on Nef''s dileucine motif LL164/165. Furthermore, we used a bimolecular fluorescence complementation assay to demonstrate that Nef and Tim-3 form a complex within cells that is abrogated upon mutation of the Nef dileucine motif. We also provide evidence that Nef moderately promotes Tim-3 shedding from the cell surface in a dileucine motif–dependent manner. Treating HIV-1-infected CD4+ T cells with a matrix metalloprotease inhibitor enhanced cell surface Tim-3 levels and reduced Tim-3 shedding. Finally, Tim-3-expressing CD4+ T cells displayed a higher propensity to release the proinflammatory cytokine interferon-gamma. Collectively, our findings uncover a novel mechanism by which HIV-1 directly increases the levels of a checkpoint receptor on the surface of infected CD4+ T cells. 相似文献
147.
Kallert DM Bauer W Haas W El-Matbouli M 《International journal for parasitology》2011,41(3-4):271-276
This work reports the discovery of an hitherto unknown chemical recognition trait enabling a parasitic life cycle in aquatic habitats. We believe this is the first record of a natural, host-derived chemical molecule identified as a recognition cue for the phylum Myxozoa. The actinospores of these parasites attach to fish hosts via polar filaments that are extruded upon mechanical stimulation after preceding recognition of a chemical trigger contained in surface mucus. Our goal was to identify this signal. We separated compounds from a purified active fraction derived from trout mucus by a novel HPLC method. By subsequent nuclear magnetic resonance analysis of distinct components and testing in bioassays we elicited stimulation of polar filament discharge and sporoplasm emission in actinospores of three myxozoan spp., Myxobolus cerebralis, Myxobolus pseudodispar and Henneguya nuesslini, by the free nucleosides inosine, 2'-deoxyinosine and guanosine. These nucleosides also activated sporoplasm emission. Nucleosides appear to be appropriate cues for rapid host recognition by the waterborne parasite stages since they are continuously released into surface mucus. The recognition mechanism is not specific for susceptible host species, at least in the myxozoan spp. examined. In addition, a novel function of nucleobase derivatives as semiochemicals was uncovered and a wider impact of this molecule class in parasite recognition systems and aquatic chemical ecology is predicted. The relevance for disease prevention and cell culturing remains to be explored. 相似文献
148.
149.
Twelve randomly-selected isolates of Fusarium graminearum that produce 3-acetyl-deoxynivalenol (3-ADON) or 15-acetyl-deoxynivalenol (15-ADON) were screened by thin-layer chromatography
(TLC) for their ability to produce ADON and zearalenone (ZEA) mycotoxins when grown on water agar containing different concentrations
of sucrose. The results showed the ability of the F. graminearum 3-ADON chemotype population to produce DON and ZEA at a lower concentration range of sucrose (5-7%) compared with the 15-ADON
chemotype (30-40%). The former distinction allows for sucrose-water agar to be employed as a rapid and simple differential
medium, where two separate sucrose-gradient concentrations discriminate 3-ADON from 15-ADON populations. In the light of the
shift in sugar concentrations occurring during the process of grain formation and maturation, the difference in mycotoxin
production between the two populations is discussed with respect to predicting Fusarium head blight (FHB) epidemiology and
accumulation of DON and ZEA. 相似文献
150.
Wright SW Carlo AA Danley DE Hageman DL Karam GA Mansour MN McClure LD Pandit J Schulte GK Treadway JL Wang IK Bauer PH 《Bioorganic & medicinal chemistry letters》2003,13(12):2055-2058
3-(2-Carboxyethyl)-4,6-dichloro-1H-indole-2-carboxylic acid (MDL-29951), an antagonist of the glycine site of the NMDA receptor, has been found to be an allosteric inhibitor of the enzyme fructose 1,6-bisphosphatase. The compound binds at the AMP regulatory site by X-ray crystallography. This represents a new approach to inhibition of fructose 1,6-bisphosphatase and serves as a lead for further drug design. 相似文献