全文获取类型
收费全文 | 2565篇 |
免费 | 164篇 |
国内免费 | 2篇 |
出版年
2023年 | 15篇 |
2022年 | 24篇 |
2021年 | 53篇 |
2020年 | 26篇 |
2019年 | 54篇 |
2018年 | 50篇 |
2017年 | 48篇 |
2016年 | 74篇 |
2015年 | 121篇 |
2014年 | 136篇 |
2013年 | 176篇 |
2012年 | 192篇 |
2011年 | 193篇 |
2010年 | 119篇 |
2009年 | 107篇 |
2008年 | 149篇 |
2007年 | 155篇 |
2006年 | 134篇 |
2005年 | 114篇 |
2004年 | 126篇 |
2003年 | 104篇 |
2002年 | 109篇 |
2001年 | 34篇 |
2000年 | 28篇 |
1999年 | 25篇 |
1998年 | 17篇 |
1997年 | 20篇 |
1996年 | 21篇 |
1995年 | 9篇 |
1994年 | 17篇 |
1993年 | 16篇 |
1992年 | 19篇 |
1991年 | 9篇 |
1990年 | 18篇 |
1989年 | 12篇 |
1988年 | 12篇 |
1987年 | 11篇 |
1986年 | 10篇 |
1985年 | 9篇 |
1984年 | 17篇 |
1983年 | 13篇 |
1982年 | 9篇 |
1981年 | 11篇 |
1980年 | 12篇 |
1979年 | 8篇 |
1978年 | 10篇 |
1977年 | 7篇 |
1975年 | 10篇 |
1974年 | 11篇 |
1966年 | 6篇 |
排序方式: 共有2731条查询结果,搜索用时 468 毫秒
71.
Irene Colavita Nicola Esposito Concetta Quintarelli Ersilia Nigro Fabrizio Pane Margherita Ruoppolo Francesco Salvatore 《Proteomics》2013,13(16):2414-2418
In the present study, we used a functional proteomic approach to identify Annexin A1 (Anxa1) interacting proteins in the Philadelphia‐positive KCL22 cell line. We focused on Anxa1 because it is one of the major proteins upregulated in imatinib‐sensitive KCL22S cells versus imatinib‐resistant KCL22R. Our proteomic strategy revealed 21 interactors. Bioinformatic analysis showed that most of these proteins are involved in cell death processes. Among the proteins identified, we studied the interaction of Anxa1 with two phosphatases, Shp1 and Shp2, which were recently identified as biomarkers of imatinib sensitivity in patients affected by chronic myeloid leukemia. Our data open new perspectives in the search for annexin‐mediated signaling pathways and may shed light on mechanisms of resistance to imatinib that are unrelated to Bcr‐Abl activity. All mass spectrometry data have been deposited in the ProteomeXchange with identifier PXD000030. 相似文献
72.
Rapha?l Laurenceau Gérard Péhau-Arnaudet Sonia Baconnais Joseph Gault Christian Malosse Annick Dujeancourt Nathalie Campo Julia Chamot-Rooke Eric Le Cam Jean-Pierre Claverys Rémi Fronzes 《PLoS pathogens》2013,9(6)
Natural genetic transformation is widely distributed in bacteria and generally occurs during a genetically programmed differentiated state called competence. This process promotes genome plasticity and adaptability in Gram-negative and Gram-positive bacteria. Transformation requires the binding and internalization of exogenous DNA, the mechanisms of which are unclear. Here, we report the discovery of a transformation pilus at the surface of competent Streptococcus pneumoniae cells. This Type IV-like pilus, which is primarily composed of the ComGC pilin, is required for transformation. We provide evidence that it directly binds DNA and propose that the transformation pilus is the primary DNA receptor on the bacterial cell during transformation in S. pneumoniae. Being a central component of the transformation apparatus, the transformation pilus enables S. pneumoniae, a major Gram-positive human pathogen, to acquire resistance to antibiotics and to escape vaccines through the binding and incorporation of new genetic material. 相似文献
73.
Context
Medical centers worldwide report an increased frequency of Hashimoto''s thyroiditis (HT) and thyroid cancer (TC), two environmentally influenced diseases. In Sicily, data on HT are available for the province of Messina (1975–2005); data on TC are available for the whole island (2002–2004), with the volcanic province of Catania having the highest incidence.Objective
To replicate in Catania, on comparable years, the HT data of Messina.Design, Methods, Setting
Review of the clinical records of patients in years 1995–2005 to compare presentation and yearly changes of HT. During 1995–2005, records were computer stored in the Endocrine Divisions of the University Hospitals of Catania and Messina, two tertiary referral centers.Results
Catania is outnumbered by Messina (742 vs. 3,409 HT patients). Similar were the linear increase in the yearly number of HT patients, rates of thyroid dysfunctions though with different proportions of subclinical and overt hypothyroidism, and rates of positiveness for TgAb or TPOAb. Different were age and its yearly trend; gender distribution and rates of the sonography variants, though yearly trends were similar.Conclusion
The HT epidemics is smaller in Catania, with changes in presentation overlapping partially those in Messina. Whatever environmental factors might be involved, they (and/or their intensity) were not necessarily the same in these provinces. Intriguingly, the expected number of TC in HT patients with thyroid nodules in Catania is congruent with that of the general population of this province, but it is far less than in the Messina province. Thus, TC and HT incidences could be influenced by distinct environmental factors. 相似文献74.
Giovanna Poce Robert H. Bates Salvatore Alfonso Martina Cocozza Giulio Cesare Porretta Lluís Ballell Joaquin Rullas Fátima Ortega Alessandro De Logu Emanuela Agus Valentina La Rosa Maria Rosalia Pasca Edda De Rossi Baojie Wae Scott G. Franzblau Fabrizio Manetti Maurizio Botta Mariangela Biava 《PloS one》2013,8(2)
1,5-Diphenyl pyrroles were previously identified as a class of compounds endowed with high in vitro efficacy against M. tuberculosis. To improve the physical chemical properties and drug-like parameters of this class of compounds, a medicinal chemistry effort was undertaken. By selecting the optimal substitution patterns for the phenyl rings at N1 and C5 and by replacing the thiomorpholine moiety with a morpholine one, a new series of compounds was produced. The replacement of the sulfur with oxygen gave compounds with lower lipophilicity and improved in
vitro microsomal stability. Moreover, since the parent compound of this family has been shown to target MmpL3, mycobacterial mutants resistant to two compounds have been isolated and characterized by sequencing the mmpL3 gene; all the mutants showed point mutations in this gene. The best compound identified to date was progressed to dose-response studies in an acute murine TB infection model. The resulting ED99 of 49 mg/Kg is within the range of commonly employed tuberculosis drugs, demonstrating the potential of this chemical series. The in vitro and in vivo target validation evidence presented here adds further weight to MmpL3 as a druggable target of interest for anti-tubercular drug discovery. 相似文献
75.
Ana Aranda Paloma Campo Arantxa Palacin Inmaculada Do?a Cristina Gomez-Casado Luisa Galindo Araceli Díaz-Perales Miguel Blanca 《PloS one》2013,8(1)
Background
Obeche wood dust is a known cause of occupational asthma where an IgE-mediated mechanism has been demonstrated.Objective
To characterize the allergenic profile of obeche wood dust and evaluate the reactivity of the proteins by in vitro, ex vivo and in vivo assays in carpenters with confirmed rhinitis and/or asthmaMaterials and methods
An in-house obeche extract was obtained, and two IgE binding bands were purified (24 and 12 kDa) and sequenced by N-terminal identity. Specific IgE and IgG, basophil activation tests and skin prick tests (SPTs) were performed with whole extract and purified proteins. CCD binding was analyzed by ELISA inhibition studies.Results
Sixty-two subjects participated: 12 with confirmed occupational asthma/rhinitis (ORA+), 40 asymptomatic exposed (ORA−), and 10 controls. Of the confirmed subjects, 83% had a positive SPT to obeche. There was a 100% recognition by ELISA in symptomatic subjects vs. 30% and 10% in asymptomatic exposed subjects and controls respectively (p<0.05). Two new proteins were purified, a 24 kDa protein identified as a putative thaumatin-like protein and a 12 kDa gamma-expansin. Both showed allergenic activity in vitro, with the putative thaumatin being the most active, with 92% recognition by ELISA and 100% by basophil activation test in ORA+ subjects. Cross-reactivity due to CCD was ruled out in 82% of cases.Conclusions
Two proteins of obeche wood were identified and were recognized by a high percentage of symptomatic subjects and by a small proportion of asymptomatic exposed subjects. Further studies are required to evaluate cross reactivity with other plant allergens. 相似文献76.
Juan P. de-Torres David Blanco Ana B. Alcaide Luis M. Seijo Gorka Bastarrika María José Pajares Arrate Mu?oz-Barrutia Carlos Ortiz-de-Solorzano Ruben Pio Arantza Campo Usua Montes Victor Segura Jesús Pueyo Luis M. Montuenga Javier J. Zulueta 《PloS one》2013,8(4)
Rationale
Low-grade inflammation and emphysema have been shown to be associated with an increased risk of lung cancer. However, the systemic inflammatory response in patients with emphysema is still unknown.Objective
To compare the plasma cytokine profiles in two groups of current or former smokers without airway obstruction: a control group of individuals without computed tomography (CT) detected emphysema vs. a study group of individuals with CT detected emphysema.Methods
Subjects underwent a chest CT, spirometry, and determination of EGF, IL-15, IL-1ra, IL-8, MCP-1, MIP-1β, TGFα, TNFα, and VEGF levels in plasma. Cytokine levels in each group were compared adjusting for confounding factors.Results
160 current smokers and former smokers without airway obstruction participated in the study: 80 without emphysema and 80 subjects with emphysema. Adjusted group comparisons revealed significant reductions in EGF (−0.317, p = 0.01), IL-15 (−0.21, p = 0.01), IL-8 (−0.180, p = 0.02) and IL-1ra (−0.220, p = 0.03) in subjects with emphysema and normal spirometry.Conclusions
Current or former smokers expressing a well-defined disease characteristic such as emphysema, has a specific plasma cytokine profile. This includes a decrease of cytokines mainly implicated in activation of apoptosis or decrease of immunosurveillance. This information should be taken into account when evaluated patients with tobacco respiratory diseases. 相似文献77.
78.
79.
80.
Polito Francesca Famà Fausto Oteri Rosaria Raffa Giovanni Vita Gianluca Conti Alfredo Daniele Sacco Macaione Vincenzo Passalacqua Marcello Cardali Salvatore Di Giorgio Rosa Maria Gioffrè Maria Angileri Flavio F. Germanò Antonino Aguennouz M’Hammed 《Molecular biology reports》2020,47(4):2941-2949
Molecular Biology Reports - TBI is the main cause of death and disability in individuals aged 1–45 in Western countries. One of the main challenges of TBI at present is the lack of specific... 相似文献