全文获取类型
收费全文 | 1588篇 |
免费 | 118篇 |
专业分类
1706篇 |
出版年
2023年 | 4篇 |
2022年 | 20篇 |
2021年 | 38篇 |
2020年 | 23篇 |
2019年 | 26篇 |
2018年 | 39篇 |
2017年 | 35篇 |
2016年 | 52篇 |
2015年 | 85篇 |
2014年 | 91篇 |
2013年 | 132篇 |
2012年 | 134篇 |
2011年 | 118篇 |
2010年 | 92篇 |
2009年 | 71篇 |
2008年 | 121篇 |
2007年 | 84篇 |
2006年 | 94篇 |
2005年 | 86篇 |
2004年 | 62篇 |
2003年 | 69篇 |
2002年 | 57篇 |
2001年 | 12篇 |
2000年 | 8篇 |
1999年 | 14篇 |
1998年 | 14篇 |
1997年 | 13篇 |
1996年 | 9篇 |
1995年 | 10篇 |
1994年 | 3篇 |
1993年 | 7篇 |
1992年 | 9篇 |
1991年 | 8篇 |
1990年 | 7篇 |
1989年 | 5篇 |
1988年 | 8篇 |
1987年 | 2篇 |
1986年 | 2篇 |
1985年 | 7篇 |
1984年 | 8篇 |
1983年 | 4篇 |
1982年 | 2篇 |
1981年 | 6篇 |
1980年 | 2篇 |
1976年 | 2篇 |
1975年 | 2篇 |
1974年 | 3篇 |
1972年 | 1篇 |
1970年 | 1篇 |
1965年 | 1篇 |
排序方式: 共有1706条查询结果,搜索用时 15 毫秒
81.
Daniela del Mauro Donatella Matteucci Simone Giannecchini Fabrizio Maggi Mauro Pistello Mauro Bendinelli 《Journal of virology》1998,72(3):2199-2207
Feline immunodeficiency virus (FIV) provides a model system with which the significance of neutralizing antibody (NA) in immunosuppressive lentivirus infections may be studied. To date, no detailed analysis of the neutralization properties of primary FIV isolates has been reported. In this study, we have conducted the first comprehensive study of the sensitivity to autologous and heterologous neutralization in a lymphoid cell-based assay of 15 primary FIV isolates and, for comparison, of one tissue culture-adapted strain. Primary isolates in general proved highly NA resistant, although there was considerable individual variation. Variation was also observed in the capacity of immune sera to neutralize heterologous FIV isolates. The ability of sera to neutralize isolates or for isolates to be neutralized by sera did not correlate with epidemiological and genetic relatedness or with the quasispecies complexity of the isolates. From the study of specific-pathogen-free cats experimentally infected with viral isolates associated with NA of different breadths, it appears that the development of FIV vaccines cannot rely on the existence of viral strains inherently capable of inducing especially broad NA responses.Feline immunodeficiency virus (FIV) is a lentivirus that is regarded as the feline counterpart of human immunodeficiency virus (HIV) because it produces persistent infections of domestic cats which, after an incubation period of several years, progress to clinical manifestations of immunodeficiency and neurological damage that closely resemble those observed in HIV-infected humans. FIV is therefore a valuable model for investigating many aspects of AIDS pathobiology and control, including vaccination (4, 11, 39, 56).Based on DNA phylogenesis, FIV isolates worldwide have been classified into at least five distinct genetic subtypes, designated A to E, with uneven geographical distributions (2). While there is little hope of developing a monovalent vaccine capable of protecting across different FIV subtypes, a more reasonable goal is the development of one or several protective immunogens for each subtype and subsequent selection of the immunogens on the basis of the subtypes prevalent in the area where the vaccine is to be used (56). However, because genetic diversity is also high within a subtype, especially in the env region (2, 42), successful vaccines will have to induce immune responses effective against a wide range of antigenically diverse strains. Mapping the immunological relatedness of FIV strains belonging to the same genetic subtype therefore represents a prerequisite for identifying shared critical protective epitopes and an essential step for ongoing vaccine development efforts. Similar problems exist for HIV vaccine development (33).Although the humoral and cell-mediated immune responses that will eventually prove important for vaccine-induced protection against lentiviruses are unresolved (3, 7, 17), the ability to evoke a broadly reactive neutralizing-antibody (NA) response would seem to be an advantageous feature of candidate immunogens because it would at least contrast the dissemination of the initial viral inoculum from the site of entry (8, 9). In previous studies, we found that cats immunized with a fixed-cell vaccine were protected against FIV challenge in the apparent absence of NA (27, 28), but it is possible that a detectable NA response could be elicited with improved vaccines, adjuvants, and immunization regimens.FIV vaccines must be designed to protect against strains of FIV as they circulate in nature. For this reason, it is important to learn more about the immunobiological properties of fresh clinical isolates, including their ability to evoke and interact with NA and their neutralizing determinant(s). Here we report on the sensitivity of 15 FIV isolates subjected to minimal passage in culture to neutralization by autologous and heterologous immune sera. Primary FIV isolates proved only slightly prone to inhibition by immune sera. However, certain isolates were more neutralizable by heterologous sera than others and certain infected cat sera neutralized fairly large numbers of primary isolates. A relationship was also sought between neutralization properties of the isolates and immune sera and a number of factors that theoretically might influence the induction or the activity of cross-reactive NA, including epidemiological and genetic relatedness and quasispecies complexity of the isolates. Finally, to ascertain whether the cross-neutralizing potency of anti-FIV antibody was dependent on properties of the viruses that had induced their formation, we studied the NA response of specific-pathogen-free (SPF) cats inoculated with selected FIV isolates. 相似文献
82.
Daniele Castagnolo Fabrizio Manetti Marco Radi Beatrice Bechi Mafalda Pagano Alessandro De Logu Rita Meleddu Manuela Saddi Maurizio Botta 《Bioorganic & medicinal chemistry》2009,17(15):5716-5721
Two series of novel rigid pyrazolone derivatives were synthesized and evaluated as inhibitors of Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis. Two of these compounds showed a high activity against MTB (MIC = 4 μg/mL). The newly synthesized pyrazolones were also computationally investigated to analyze if their properties fit the pharmacophoric model for antitubercular compounds previously built by us. The results are in agreement with those reported by us previously for a class of pyrazole analogues and confirm the fundamental role of the p-chlorophenyl moiety at C4 in the antimycobacterial activity. 相似文献
83.
Aron J. Huckaba Fabrizio Giordano Louis E. McNamara Katelyn M. Dreux Nathan I. Hammer Gregory S. Tschumper Shaik M. Zakeeruddin Michael Grätzel Mohammad K. Nazeeruddin Jared H. Delcamp 《Liver Transplantation》2015,5(7)
Strong electron‐donating functionality is desirable for many organic donor‐π‐bridge‐acceptor (D‐π‐A) dyes. Strategies for increasing the electron‐donating strength of common nitrogen‐based donors include planarization of nitrogen substituents and the use of low resonance‐stabilized energy aromatic ring‐substituted nitrogen atoms. Organic donor motifs based on the planar nitrogen containing heterocycle indolizine are synthesized and incorporated into dye‐sensitized solar cell (DSC) sensitizers. Resonance active substitutions at several positions on indolizine in conjugation with the D‐π‐A π‐system are examined computationally and experimentally. The indolizine‐based donors are observed to contribute electron density with strengths greater than triarylamines and diarylamines, as evidenced by UV/Vis, IR absorptions, and oxidation potential measurements. Fluorescence lifetime studies in solution and on TiO2 yield insights in understanding the performance of indolizine‐based dyes in DSC devices. 相似文献
84.
Scale-up of malaria preventive and control interventions over the last decade resulted in substantial declines in mortality and morbidity from the disease in sub-Saharan Africa and many other parts of the world. Sustaining these gains will depend on the health system performance. Treatment provides individual benefits by curing infection and preventing progression to severe disease as well as community-level benefits by reducing the infectious reservoir and averting emergence and spread of drug resistance. However many patients with malaria do not access care, providers do not comply with treatment guidelines, and hence, patients do not necessarily receive the correct regimen. Even when the correct regimen is administered some patients will not adhere and others will be treated with counterfeit or substandard medication leading to treatment failures and spread of drug resistance. We apply systems effectiveness concepts that explicitly consider implications of health system factors such as treatment seeking, provider compliance, adherence, and quality of medication to estimate treatment outcomes for malaria case management. We compile data for these indicators to derive estimates of effective coverage for 43 high-burden Sub-Saharan African countries. Parameters are populated from the Demographic and Health Surveys and other published sources. We assess the relative importance of these factors on the level of effective coverage and consider variation in these health systems indicators across countries. Our findings suggest that effective coverage for malaria case management ranges from 8% to 72% in the region. Different factors account for health system inefficiencies in different countries. Significant losses in effectiveness of treatment are estimated in all countries. The patterns of inter-country variation suggest that these are system failures that are amenable to change. Identifying the reasons for the poor health system performance and intervening to tackle them become key priority areas for malaria control and elimination policies in the region. 相似文献
85.
86.
Bruna Gigante Rona J. Strawbridge Ilais Moreno Velasquez Zahra Golabkesh Angela Silveira Anuj Goel Damiano Baldassarre Fabrizio Veglia Elena Tremoli Robert Clarke Hugh Watkins Anders Hamsten Steve E. Humphries Ulf de Faire 《PloS one》2015,10(3)
Variants at the interleukin 6 receptor (IL6R) gene regulate inflammation and are associated with risk of coronary heart disease (CHD). The aim of the present study was to investigate the effects of IL6R haplotypes on circulating levels of inflammatory biomarkers and risk of CHD. We performed a discovery analysis in SHEEP, a myocardial infarction (MI) case control study (n = 2,774) and replicated our results in two large, independent European populations, PROCARDIS, a CHD case control study (n = 7,998), and IMPROVE (n = 3,711) a prospective cardiovascular cohort study. Two major haplotype blocks (rs12083537A/G and rs4075015A/T—block 1; and rs8192282G/A, rs4553185T/C, rs8192284A/C, rs4240872T/C and rs7514452T/C—block 2) were identified in the IL6R gene. IL6R haplotype associations with C-reactive protein (CRP), fibrinogen, IL6, soluble IL6R (sIL6R), IL6, IL8 and TNF-α in SHEEP, CRP and fibrinogen in PROCARDIS and CRP in IMPROVE as well as association with risk of MI and CHD, were analyzed by THESIAS. Haplotypes in block 1 were associated neither with circulating inflammatory biomarkers nor with the MI/CHD risk. Haplotypes in block 2 were associated with circulating levels of CRP, in all three study populations, with fibrinogen in SHEEP and PROCARDIS, with IL8 and sIL6Rin SHEEP and with a modest, non significant, increase (7%) in MI/CHD risk in the three populations studied. Our results indicate that IL6R haplotypes regulate the circulating levels of inflammatory biomarkers. Lack of association with the risk of CHD may be explained by the combined effect of SNPs with opposite effect on the CHD risk, the sample size as well as by structural changes affecting sIL6R stability in the circulation. 相似文献
87.
Gianluigi Forloni Mauro Tettamanti Ugo Lucca Yasmin Albanese Elena Quaglio Roberto Chiesa Alessandra Erbetta Flavio Villani Veronica Redaelli Fabrizio Tagliavini Vladimiro Artuso Ignazio Roiter 《朊病毒》2015,9(2):75-79
The text describes a preventive clinical trial with drug treatment in a very rare neurodegenerative disease (Fatal familial Insomnia, FFI) designed with the help of individuals at genetic risk of developing the disease, asymptomatic carriers, who have agreed to be exposed over a 10-year period to doxycycline, an antibiotic with anti-prion activity. At least 10 carriers of the FFI mutation over 42 y old will be treated with doxycycline (100 mg/die) and the incidence of the disease will be compared to that of an historical dataset. For ethical reasons a randomized, double-blind, placebo-controlled trial was not feasible, however the study design and the statistical analysis ensure the scientific value of the results. This approach might represent an important breakthrough in terms of potential therapy and knowledge of rare diseases that could give some hopes to these neglected patients. 相似文献
88.
C. Simone Sutherland Joshua Yukich Ron Goeree Fabrizio Tediosi 《PLoS neglected tropical diseases》2015,9(2)
Human African trypanosomiasis (HAT) is a disease caused by infection with the parasite Trypanosoma brucei gambiense or T. b. rhodesiense. It is transmitted to humans via the tsetse fly. Approximately 70 million people worldwide were at risk of infection in 1995, and approximately 20,000 people across Africa are infected with HAT. The objective of this review was to identify existing economic evaluations in order to summarise cost-effective interventions to reduce, control, or eliminate the burden of HAT. The studies included in the review were compared and critically appraised in order to determine if there were existing standardised methods that could be used for economic evaluation of HAT interventions or if innovative methodological approaches are warranted. A search strategy was developed using keywords and was implemented in January 2014 in several databases. The search returned a total of 2,283 articles. After two levels of screening, a total of seven economic evaluations were included and underwent critical appraisal using the Scottish Intercollegiate Guidelines Network (SIGN) Methodology Checklist 6: Economic Evaluations. Results from the existing studies focused on the cost-effectiveness of interventions for the control and reduction of disease transmission. Modelling was a common method to forecast long-term results, and publications focused on interventions by category, such as case detection, diagnostics, drug treatments, and vector control. Most interventions were considered cost-effective based on the thresholds described; however, the current treatment, nifurtomix-eflornithine combination therapy (NECT), has not been evaluated for cost-effectiveness, and considerations for cost-effective strategies for elimination have yet to be completed. Overall, the current evidence highlights the main components that play a role in control; however, economic evaluations of HAT elimination strategies are needed to assist national decision makers, stakeholders, and key funders. These analyses would be of use, as HAT is currently being prioritized as a neglected tropical disease (NTD) to reach elimination by 2020. 相似文献
89.
Micheli F Antolini M Di Fabio R Pellacani A Pozzan A 《Bioorganic & medicinal chemistry letters》2010,20(22):6405-6407
A new class of selective orexin 2 antagonist was identified among commercial products. Initial SAR was obtained using commercial derivatives only prior to starting ad hoc medicinal chemistry activities. 相似文献
90.
Fabrizio Micheli Daniele Andreotti Simone Braggio Anna Checchia 《Bioorganic & medicinal chemistry letters》2010,20(15):4566-4568
A direct and specific comparison of a trifluoromethyl group with the corresponding pentafluorosulfanyl group is made in terms of primary affinity and pharmacokinetic properties. 相似文献