全文获取类型
收费全文 | 1144篇 |
免费 | 101篇 |
国内免费 | 49篇 |
出版年
2023年 | 23篇 |
2022年 | 28篇 |
2021年 | 45篇 |
2020年 | 58篇 |
2019年 | 50篇 |
2018年 | 57篇 |
2017年 | 37篇 |
2016年 | 50篇 |
2015年 | 49篇 |
2014年 | 95篇 |
2013年 | 99篇 |
2012年 | 58篇 |
2011年 | 72篇 |
2010年 | 60篇 |
2009年 | 47篇 |
2008年 | 61篇 |
2007年 | 69篇 |
2006年 | 38篇 |
2005年 | 35篇 |
2004年 | 31篇 |
2003年 | 30篇 |
2002年 | 33篇 |
2001年 | 21篇 |
2000年 | 15篇 |
1999年 | 10篇 |
1998年 | 8篇 |
1997年 | 5篇 |
1996年 | 6篇 |
1995年 | 13篇 |
1994年 | 8篇 |
1993年 | 7篇 |
1992年 | 6篇 |
1991年 | 9篇 |
1990年 | 9篇 |
1989年 | 5篇 |
1988年 | 1篇 |
1987年 | 2篇 |
1986年 | 1篇 |
1985年 | 3篇 |
1984年 | 8篇 |
1983年 | 6篇 |
1982年 | 8篇 |
1981年 | 1篇 |
1980年 | 2篇 |
1978年 | 4篇 |
1977年 | 4篇 |
1976年 | 3篇 |
1975年 | 2篇 |
1974年 | 2篇 |
排序方式: 共有1294条查询结果,搜索用时 31 毫秒
1.
2.
Irene Jao Vicki Marsh Primus Che Chi Melissa Kapulu Mainga Hamaluba Sassy Molyneux Philip Bejon Dorcas Kamuya 《Bioethics》2020,34(8):819-832
Controlled human malaria infection (CHMI) studies involve the deliberate infection of healthy volunteers with malaria parasites under controlled conditions to study immune responses and/or test drug or vaccine efficacy. An empirical ethics study was embedded in a CHMI study at a Kenyan research programme to explore stakeholders’ perceptions and experiences of deliberate infection and moral implications of these. Data for this qualitative study were collected through focus group discussions, in-depth interviews and non-participant observation. Sixty-nine participants were involved, including CHMI study volunteers, community representatives and research staff. Data were managed using QSR Nvivo 10 and analysed using an inductive-deductive approach, guided by ethics literature. CHMI volunteers had reasonable understanding of the study procedures. Decisions to join were influenced by study incentives, trust in the research institution, their assessment of associated burdens and motivation to support malaria vaccine development. However, deliberate malaria infection was a highly unusual research strategy for volunteers, community representatives and some study staff. Volunteers’ experiences of physical, emotional and social burdens or harms were often greater than anticipated initially, and fluctuated over time, related to specific procedures and events. Although unlikely to deter volunteers' participation in similar studies in furture, we argue that the dissonance between level of understanding of the burdens involved and actual experiences are morally relevant in relation to community engagement, informed consent processes, and ongoing support for volunteers and research staff. We further argue that ethics oversight of CHMI studies should take account of these issues in deciding whether consent, engagement and the balance of benefits and harms are reasonable in a given context. 相似文献
3.
4.
《Bioscience, biotechnology, and biochemistry》2013,77(7):1564-1570
A novel technique is reported for softening plant tissues while retaining their shape by impregnating them with macerating enzymes under reduced pressure after defrosting the frozen plants. Samples were removed immediately from the enzyme solution after the freeze-infusion treatment, and the hardness was measured. Six enzymes and three enzymes were respectively chosen from 18 commercial enzymes for softening burdock roots and bamboo shoots. The tissue degradation due to impregnation of the tissues with the enzymes and the reaction time were investigated. Burdock roots and bamboo shoots were progressively softened during the reaction: the hardness reached 1.0×104 N/m2 or less. The water-soluble dietary fiber contents increased as a result of the freeze-infusion treatment. This softening technique, which retained the food shape, could enhance the production of food products for elderly persons and those under nursing care. Foods produced by this method can replace current minced and liquid dietary components. 相似文献
5.
Rebecca Pastrana-Mena Rhoel R. Dinglasan Blandine Franke-Fayard Joel Vega-Rodr��guez Mariela Fuentes-Caraballo Abel Baerga-Ortiz Isabelle Coppens Marcelo Jacobs-Lorena Chris J. Janse Adelfa E. Serrano 《The Journal of biological chemistry》2010,285(35):27045-27056
Malaria parasites contain a complete glutathione (GSH) redox system, and several enzymes of this system are considered potential targets for antimalarial drugs. Through generation of a γ-glutamylcysteine synthetase (γ-GCS)-null mutant of the rodent parasite Plasmodium berghei, we previously showed that de novo GSH synthesis is not critical for blood stage multiplication but is essential for oocyst development. In this study, phenotype analyses of mutant parasites lacking expression of glutathione reductase (GR) confirmed that GSH metabolism is critical for the mosquito oocyst stage. Similar to what was found for γ-GCS, GR is not essential for blood stage growth. GR-null parasites showed the same sensitivity to methylene blue and eosin B as wild type parasites, demonstrating that these compounds target molecules other than GR in Plasmodium. Attempts to generate parasites lacking both GR and γ-GCS by simultaneous disruption of gr and γ-gcs were unsuccessful. This demonstrates that the maintenance of total GSH levels required for blood stage survival is dependent on either de novo GSH synthesis or glutathione disulfide (GSSG) reduction by Plasmodium GR. Our studies provide new insights into the role of the GSH system in malaria parasites with implications for the development of drugs targeting GSH metabolism. 相似文献
6.
7.
《Bioorganic & medicinal chemistry》2016,24(15):3291-3303
The characterization of the target proteins of drug molecules has become an important goal in understanding its mode of action and origin of side effects due to off-target binding. This is especially important for covalently binding drugs usually containing electrophilic moieties, which potentially can react with nucleophilic residues found in many proteins. This review gives a comprehensive overview of the use of activity-based protein profiling (ABPP) as an efficient tool for the target identification of covalently binding drugs. 相似文献
8.
Click chemistry is fundamentally important to medicinal chemistry and chemical biology. It represents a powerful and versatile tool, which can be exploited to develop novel Pt-based anticancer drugs and to better understand the biological effects of Pt-based anticancer drugs at a cellular level. Innovative azide–alkyne cycloaddition–based approaches are being used to functionalise Pt-based complexes with biomolecules to enhance tumour targeting. Valuable information in relation to the mechanisms of action and resistance of Pt-based drugs is also being revealed through click-based detection, isolation and tracking of Pt drug surrogates in biological and cellular environments. Although less well-explored, inorganic Pt-click reactions enable synthesis of novel (potentially multimetallic) Pt complexes and provide plausible routes to introduce functional groups and monitoring Pt-azido drug localisation. 相似文献
9.
《Bioorganic & medicinal chemistry》2019,27(20):114962
The global emergence of antibiotic resistance is one of the most serious challenges facing modern medicine. There is an urgent need for validation of new drug targets and the development of small molecules with novel mechanisms of action. We therefore sought to inhibit bacterial DNA repair mediated by the AddAB/RecBCD protein complexes as a means to sensitize bacteria to DNA damage caused by the host immune system or quinolone antibiotics. A rational, hypothesis-driven compound optimization identified IMP-1700 as a cell-active, nanomolar potency compound. IMP-1700 sensitized multidrug-resistant Staphylococcus aureus to the fluoroquinolone antibiotic ciprofloxacin, where resistance results from a point mutation in the fluoroquinolone target, DNA gyrase. Cellular reporter assays indicated IMP-1700 inhibited the bacterial SOS-response to DNA damage, and compound-functionalized Sepharose successfully pulled-down the AddAB repair complex. This work provides validation of bacterial DNA repair as a novel therapeutic target and delivers IMP-1700 as a tool molecule and starting point for therapeutic development to address the pressing challenge of antibiotic resistance. 相似文献
10.
Risks and benefit evaluation for controlled human infection studies, where healthy volunteers are deliberately exposed to infectious agents to evaluate vaccine efficacy, should be explicit, systematic, thorough, and non-arbitrary. Decision analysis promotes these qualities using four steps: (1) determining explicit criteria and measures for evaluation, (2) identifying alternatives to the study, (3) defining the models used to estimate the measures for each alternative, and (4) running the models to produce the estimates and compare the alternatives. In this paper, we describe how decision analysis might be applied by funders and regulators, as well as by others contemplating the use of novel controlled human infection studies for vaccine development and evaluation. 相似文献