全文获取类型
收费全文 | 1153篇 |
免费 | 57篇 |
出版年
2023年 | 5篇 |
2022年 | 5篇 |
2021年 | 26篇 |
2020年 | 15篇 |
2019年 | 21篇 |
2018年 | 23篇 |
2017年 | 32篇 |
2016年 | 34篇 |
2015年 | 47篇 |
2014年 | 55篇 |
2013年 | 74篇 |
2012年 | 92篇 |
2011年 | 93篇 |
2010年 | 61篇 |
2009年 | 60篇 |
2008年 | 70篇 |
2007年 | 73篇 |
2006年 | 71篇 |
2005年 | 47篇 |
2004年 | 61篇 |
2003年 | 49篇 |
2002年 | 49篇 |
2001年 | 10篇 |
2000年 | 10篇 |
1999年 | 15篇 |
1998年 | 7篇 |
1997年 | 11篇 |
1996年 | 11篇 |
1995年 | 7篇 |
1994年 | 10篇 |
1993年 | 7篇 |
1992年 | 7篇 |
1991年 | 4篇 |
1990年 | 6篇 |
1989年 | 5篇 |
1988年 | 3篇 |
1987年 | 3篇 |
1984年 | 3篇 |
1983年 | 2篇 |
1982年 | 5篇 |
1981年 | 2篇 |
1979年 | 2篇 |
1978年 | 2篇 |
1977年 | 1篇 |
1976年 | 3篇 |
1975年 | 2篇 |
1974年 | 3篇 |
1973年 | 1篇 |
1972年 | 1篇 |
1971年 | 2篇 |
排序方式: 共有1210条查询结果,搜索用时 15 毫秒
61.
Višnja B. Popović Silvana D. Petrović Marina T. Milenković Milica M. Drobac Maria A. Couladis Marjan S. Niketić 《化学与生物多样性》2015,12(1):170-177
The chemical composition and antimicrobial activity of essential oils of Laserpitium latifolium and L. ochridanum were investigated. The essential oils were isolated by steam distillation and characterized by GC‐FID and GC/MS analyses. All essential oils were distinguished by high contents of monoterpenes, and α‐pinene was the most abundant compound in the essential oils of L. latifolium underground parts and fruits (contents of 44.4 and 44.0%, resp.). The fruit essential oil was also rich in sabinene (26.8%). Regarding the L. ochridanum essential oils, the main constituents were limonene in the fruit oil (57.7%) and sabinene in the herb oil (25.9%). The antimicrobial activity of these essential oils as well as that of L. ochridanum underground parts, whose composition was reported previously, was tested by the broth‐microdilution method against four Gram‐positive and three Gram‐negative bacteria and two Candida albicans strains. Except the L. latifolium underground‐parts essential oil, the other investigated oils showed a high antimicrobial potential against Staphylococcus aureus, S. epidermidis, Micrococcus luteus, or Candida albicans (minimal inhibitory concentrations of 13.0–73.0 μg/ml), comparable to or even higher than that of thymol, which was used as reference compound. 相似文献
62.
Antimicrobial and Cytotoxic Activity of Extracts of Ferula heuffelii Griseb. ex Heuff. and Its Metabolites 下载免费PDF全文
Ivan Pavlović Silvana Petrović Marina Milenković Tatjana Stanojković Dejan Nikolić Aleksej Krunić Marjan Niketić 《化学与生物多样性》2015,12(10):1585-1594
The antimicrobial and cytotoxic activities of isolates (CHCl3 and MeOH extracts and selected metabolites) obtained from the underground parts of the Balkan endemic plant Ferula heuffelii Griseb . ex Heuff . were assessed. The CHCl3 and MeOH extracts exhibited moderate antimicrobial activity, being more pronounced against Gram‐positive than Gram‐negative bacteria, especially against Staphylococcus aureus (MIC=12.5 μg/ml for both extracts) and Micrococcus luteus (MIC=50 and 12.5 μg/ml, resp.). Among the tested metabolites, (6E)‐1‐(2,4‐dihydroxyphenyl)‐3,7,11‐trimethyl‐3‐vinyldodeca‐6,10‐dien‐1‐one ( 2 ) and (2S*,3R*)‐2‐[(3E)‐4,8‐dimethylnona‐3,7‐dien‐1‐yl]‐2,3‐dihydro‐7‐hydroxy‐2,3‐dimethylfuro[3,2‐c]coumarin ( 4 ) demonstrated the best antimicrobial activity. Compounds 2 and 4 both strongly inhibited the growth of M. luteus (MIC=11.2 and 5.2 μM , resp.) and Staphylococcus epidermidis (MIC=22.5 and 10.5 μM , resp.) and compound 2 additionally also the growth of Bacillus subtilis (MIC=11.2 μM ). The cytotoxic activity of the isolates was tested against three human cancer cell lines, viz., cervical adenocarcinoma (HeLa), chronic myelogenous leukemia (K562), and breast cancer (MCF‐7) cells. The CHCl3 extract exhibited strong cytotoxic activity against all cell lines (IC50<11.0 μg/ml). All compounds strongly inhibited the growth of the K562 and HeLa cell lines. Compound 4 exhibited also a strong activity against the MCF‐7 cell line, comparable to that of cisplatin (IC50=22.32±1.32 vs. 18.67±0.75μM ). 相似文献
63.
Silvana A. Rosú Omar J. Rimoldi Eduardo D. Prieto Lucrecia M. Curto José M. Delfino Nahuel A. Ramella M. Alejandra Tricerri 《PloS one》2015,10(5)
A number of naturally occurring mutations of human apolipoprotein A-I (apoA-I) have been associated with hereditary amyloidoses. The molecular mechanisms involved in amyloid-associated pathology remain largely unknown. Here we examined the effects of the Arg173Pro point mutation in apoA-I on the structure, stability, and aggregation propensity, as well as on the ability to bind to putative ligands. Our results indicate that the mutation induces a drastic loss of stability, and a lower efficiency to bind to phospholipid vesicles at physiological pH, which could determine the observed higher tendency to aggregate as pro-amyloidogenic complexes. Incubation under acidic conditions does not seem to induce significant desestabilization or aggregation tendency, neither does it contribute to the binding of the mutant to sodium dodecyl sulfate. While the binding to this detergent is higher for the mutant as compared to wt apoA-I, the interaction of the Arg173Pro variant with heparin depends on pH, being lower at pH 5.0 and higher than wt under physiological pH conditions. We suggest that binding to ligands as heparin or other glycosaminoglycans could be key events tuning the fine details of the interaction of apoA-I variants with the micro-environment, and probably eliciting the toxicity of these variants in hereditary amyloidoses. 相似文献
64.
Andrew Lucas Michaela Lucas Anette Strhyn Niamh M. Keane Elizabeth McKinnon Rebecca Pavlos Ellen M. Moran Viola Meyer-Pannwitt Silvana Gaudieri Lloyd D’Orsogna Spyros Kalams David A. Ostrov S?ren Buus Bjoern Peters Simon Mallal Elizabeth Phillips 《PloS one》2015,10(2)
BackgroundFifty-five percent of individuals with HLA-B*57:01 exposed to the antiretroviral drug abacavir develop a hypersensitivity reaction (HSR) that has been attributed to naïve T-cell responses to neo-antigen generated by the drug. Immunologically confirmed abacavir HSR can manifest clinically in less than 48 hours following first exposure suggesting that, at least in some cases, abacavir HSR is due to re-stimulation of a pre-existing memory T-cell population rather than priming of a high frequency naïve T-cell population.MethodsTo determine whether a pre-existing abacavir reactive memory T-cell population contributes to early abacavir HSR symptoms, we studied the abacavir specific naïve or memory T-cell response using HLA-B*57:01 positive HSR patients or healthy controls using ELISpot assay, intra-cellular cytokine staining and tetramer labelling.ResultsAbacavir reactive CD8+ T-cell responses were detected in vitro in one hundred percent of abacavir unexposed HLA-B*57:01 positive healthy donors. Abacavir-specific CD8+ T cells from such donors can be expanded from sorted memory, and sorted naïve, CD8+ T cells without need for autologous CD4+ T cells.ConclusionsWe propose that these pre-existing abacavir-reactive memory CD8+ T-cell responses must have been primed by earlier exposure to another foreign antigen and that these T cells cross-react with an abacavir-HLA-B*57:01-endogenous peptide ligand complex, in keeping with the model of heterologous immunity proposed in transplant rejection. 相似文献
65.
Katja Pfafferott Pooja Deshpande Elizabeth McKinnon Shahzma Merani Andrew Lucas David Heckerman Simon Mallal Mina John Silvana Gaudieri Michaela Lucas 《PloS one》2015,10(6)
Characterisation of Hepatitis C virus (HCV)-specific CD8+ T-cell responses in the context of multiple HCV exposures is critical to identify broadly protective immune responses necessary for an effective HCV vaccine against the different HCV genotypes. However, host and viral genetic diversity complicates vaccine development. To compensate for the observed variation in circulating autologous viruses and host molecules that restrict antigen presentation (human leucocyte antigens; HLA), this study used a reverse genomics approach that identified sites of viral adaptation to HLA-restricted T-cell immune pressure to predict genotype-specific HCV CD8+ T-cell targets. Peptides representing these putative HCV CD8+ T-cell targets, and their adapted form, were used in individualised IFN-γ ELISpot assays to screen for HCV-specific T-cell responses in 133 HCV-seropositive subjects with high-risk of multiple HCV exposures. The data obtained from this study i) confirmed that genetic studies of viral evolution is an effective approach to detect novel in vivo HCV T-cell targets, ii) showed that HCV-specific T-cell epitopes can be recognised in their adapted form and would not have been detected using wild-type peptides and iii) showed that HCV-specific T-cell (but not antibody) responses against alternate genotypes in chronic HCV-infected subjects are readily found, implying clearance of previous alternate genotype infection. In summary, HCV adaptation to HLA Class I-restricted T-cell responses plays a central role in anti-HCV immunity and multiple HCV genotype exposure is highly prevalent in at-risk exposure populations, which are important considerations for future vaccine design. 相似文献
66.
Adriana Echazú Daniela Bonanno Marisa Juarez Silvana P. Cajal Viviana Heredia Silvia Caropresi Ruben O. Cimino Nicolas Caro Paola A. Vargas Gladys Paredes Alejandro J. Krolewiecki 《PLoS neglected tropical diseases》2015,9(9)
BackgroundSoil-transmitted helminth (STH) infections are a public health problem in resource-limited settings worldwide. Chronic STH infection impairs optimum learning and productivity, contributing to the perpetuation of the poverty-disease cycle. Regular massive drug administration (MDA) is the cardinal recommendation for its control; along with water, sanitation and hygiene (WASH) interventions. The impact of joint WASH interventions on STH infections has been reported; studies on the independent effect of WASH components are needed to contribute with the improvement of current recommendations for the control of STH. The aim of this study is to assess the association of lacking access to water and sanitation with STH infections, taking into account the differences in route of infection among species and the availability of adequate water and sanitation at home.ConclusionsLack of safe water and proper sanitation pose a risk of STH infections that is distinct according to the route of entry to the human host used by each of the STH species. Interventions aimed to improve water and sanitation access should be highlighted in the recommendations for the control of STH. 相似文献
67.
Barbara Bottazzi Laura Santini Silvana Savino Marzia M. Giuliani Ana I. Due?as Díez Giuseppe Mancuso Concetta Beninati Marina Sironi Sonia Valentino Livija Deban Cecilia Garlanda Giuseppe Teti Mariagrazia Pizza Rino Rappuoli Alberto Mantovani 《PloS one》2015,10(3)
Long pentraxin 3 (PTX3) is a non-redundant component of the humoral arm of innate immunity. The present study was designed to investigate the interaction of PTX3 with Neisseria meningitidis. PTX3 bound acapsular meningococcus, Neisseria-derived outer membrane vesicles (OMV) and 3 selected meningococcal antigens (GNA0667, GNA1030 and GNA2091). PTX3-recognized microbial moieties are conserved structures which fulfil essential microbial functions. Ptx3-deficient mice had a lower antibody response in vaccination protocols with OMV and co-administration of PTX3 increased the antibody response, particularly in Ptx3-deficient mice. Administration of PTX3 reduced the bacterial load in infant rats challenged with Neisseria meningitidis. These results suggest that PTX3 recognizes a set of conserved structures from Neisseria meningitidis and acts as an amplifier/endogenous adjuvant of responses to this bacterium. 相似文献
68.
Paolo Cossu-Rocca Sandra Orrù Maria Rosaria Muroni Francesca Sanges Giovanni Sotgiu Sara Ena Giovanna Pira Luciano Murgia Alessandra Manca Maria Gabriela Uras Maria Giuseppina Sarobba Silvana Urru Maria Rosaria De Miglio 《PloS one》2015,10(11)
Background
Triple Negative Breast Cancer (TNBC) accounts for 12–24% of all breast carcinomas, and shows worse prognosis compared to other breast cancer subtypes. Molecular studies demonstrated that TNBCs are a heterogeneous group of tumors with different clinical and pathologic features, prognosis, genetic-molecular alterations and treatment responsivity. The PI3K/AKT is a major pathway involved in the regulation of cell survival and proliferation, and is the most frequently altered pathway in breast cancer, apparently with different biologic impact on specific cancer subtypes. The most common genetic abnormality is represented by PIK3CA gene activating mutations, with an overall frequency of 20–40%. The aims of our study were to investigate PIK3CA gene mutations on a large series of TNBC, to perform a wider analysis on genetic alterations involving PI3K/AKT and BRAF/RAS/MAPK pathways and to correlate the results with clinical-pathologic data.Materials and Methods
PIK3CA mutation analysis was performed by using cobas® PIK3CA Mutation Test. EGFR, AKT1, BRAF, and KRAS genes were analyzed by sequencing. Immunohistochemistry was carried out to identify PTEN loss and to investigate for PI3K/AKT pathways components.Results
PIK3CA mutations were detected in 23.7% of TNBC, whereas no mutations were identified in EGFR, AKT1, BRAF, and KRAS genes. Moreover, we observed PTEN loss in 11.3% of tumors. Deregulation of PI3K/AKT pathways was revealed by consistent activation of pAKT and p-p44/42 MAPK in all PIK3CA mutated TNBC.Conclusions
Our data shows that PIK3CA mutations and PI3K/AKT pathway activation are common events in TNBC. A deeper investigation on specific TNBC genomic abnormalities might be helpful in order to select patients who would benefit from current targeted therapy strategies. 相似文献69.