全文获取类型
收费全文 | 2996篇 |
免费 | 157篇 |
专业分类
3153篇 |
出版年
2022年 | 22篇 |
2021年 | 30篇 |
2020年 | 19篇 |
2019年 | 32篇 |
2018年 | 44篇 |
2017年 | 45篇 |
2016年 | 79篇 |
2015年 | 111篇 |
2014年 | 111篇 |
2013年 | 207篇 |
2012年 | 212篇 |
2011年 | 193篇 |
2010年 | 120篇 |
2009年 | 115篇 |
2008年 | 181篇 |
2007年 | 183篇 |
2006年 | 182篇 |
2005年 | 163篇 |
2004年 | 150篇 |
2003年 | 135篇 |
2002年 | 128篇 |
2001年 | 29篇 |
2000年 | 27篇 |
1999年 | 31篇 |
1998年 | 25篇 |
1997年 | 32篇 |
1996年 | 27篇 |
1995年 | 28篇 |
1994年 | 23篇 |
1993年 | 33篇 |
1992年 | 30篇 |
1991年 | 27篇 |
1990年 | 31篇 |
1989年 | 17篇 |
1988年 | 23篇 |
1987年 | 20篇 |
1986年 | 17篇 |
1985年 | 19篇 |
1984年 | 30篇 |
1983年 | 27篇 |
1982年 | 19篇 |
1981年 | 17篇 |
1980年 | 21篇 |
1979年 | 21篇 |
1978年 | 23篇 |
1977年 | 11篇 |
1976年 | 11篇 |
1975年 | 12篇 |
1974年 | 9篇 |
1973年 | 12篇 |
排序方式: 共有3153条查询结果,搜索用时 15 毫秒
991.
Tafuri S Martinelli D Grimaldi A Lopatriello A Giorgio V Prato R 《The new microbiologica》2011,34(4):417-420
We report a clinical failure of a pneumococcal vaccine in a patient who developed pneumococcal pneumonia. In 2008, an 85-year-old Italian woman was admitted to the Respiratory Disease Unit of a hospital in Southern Italy. The 23-valent pneumococcal vaccine had been administered to the patient 50 days earlier. The chest x-ray disclosed a right basal bronchopneumonic focus. Streptococcus Pneumoniae serotype 19A, a strain included in the 23-valent pneumococcal vaccine, was isolated from the sputum. There is a need for more efficacious conjugated vaccines covering the majority of the pneumococcal serotypes that cause serious illness in older children and adults worldwide. 相似文献
992.
Yu SS Koblin RL Zachman AL Perrien DS Hofmeister LH Giorgio TD Sung HJ 《Biomacromolecules》2011,12(12):4357-4366
Chronic inflammation-mediated oxidative stress is a common mechanism of implant rejection and failure. Therefore, polymer scaffolds that can degrade slowly in response to this environment may provide a viable platform for implant site-specific, sustained release of immunomodulatory agents over a long time period. In this work, proline oligomers of varying lengths (P(n)) were synthesized and exposed to oxidative environments, and their accelerated degradation under oxidative conditions was verified via high performance liquid chromatography and gel permeation chromatography. Next, diblock copolymers of poly(ethylene glycol) (PEG) and poly(ε-caprolactone) (PCL) were carboxylated to form 100 kDa terpolymers of 4%PEG-86%PCL-10%cPCL (cPCL = poly(carboxyl-ε-caprolactone); i% indicates molar ratio). The polymers were then cross-linked with biaminated PEG-P(n)-PEG chains, where P(n) indicates the length of the proline oligomer flanked by PEG chains. Salt-leaching of the polymeric matrices created scaffolds of macroporous and microporous architecture, as observed by scanning electron microscopy. The degradation of scaffolds was accelerated under oxidative conditions, as evidenced by mass loss and differential scanning calorimetry measurements. Immortalized murine bone-marrow-derived macrophages were then seeded on the scaffolds and activated through the addition of γ-interferon and lipopolysaccharide throughout the 9-day study period. This treatment promoted the release of H(2)O(2) by the macrophages and the degradation of proline-containing scaffolds compared to the control scaffolds. The accelerated degradation was evidenced by increased scaffold porosity, as visualized through scanning electron microscopy and X-ray microtomography imaging. The current study provides insight into the development of scaffolds that respond to oxidative environments through gradual degradation for the controlled release of therapeutics targeted to diseases that feature chronic inflammation and oxidative stress. 相似文献
993.
994.
Leo L Gherardini L Barone V De Fusco M Pietrobon D Pizzorusso T Casari G 《PLoS genetics》2011,7(6):e1002129
Familial hemiplegic migraine type 2 (FHM2) is an autosomal dominant form of migraine with aura that is caused by mutations of the α2-subunit of the Na,K-ATPase, an isoform almost exclusively expressed in astrocytes in the adult brain. We generated the first FHM2 knock-in mouse model carrying the human W887R mutation in the Atp1a2 orthologous gene. Homozygous Atp1a2(R887/R887) mutants died just after birth, while heterozygous Atp1a2(+/R887) mice showed no apparent clinical phenotype. The mutant α2 Na,K-ATPase protein was barely detectable in the brain of homozygous mutants and strongly reduced in the brain of heterozygous mutants, likely as a consequence of endoplasmic reticulum retention and subsequent proteasomal degradation, as we demonstrate in transfected cells. In vivo analysis of cortical spreading depression (CSD), the phenomenon underlying migraine aura, revealed a decreased induction threshold and an increased velocity of propagation in the heterozygous FHM2 mouse. Since several lines of evidence involve a specific role of the glial α2 Na,K pump in active reuptake of glutamate from the synaptic cleft, we hypothesize that CSD facilitation in the FHM2 mouse model is sustained by inefficient glutamate clearance by astrocytes and consequent increased cortical excitatory neurotransmission. The demonstration that FHM2 and FHM1 mutations share the ability to facilitate induction and propagation of CSD in mouse models further support the role of CSD as a key migraine trigger. 相似文献
995.
Sonia Fabris Valentina Bollati Luca Agnelli Fortunato Morabito Valeria Motta Giovanna Cutrona Serena Matis Anna Grazia Recchia Vincenzo Gigliotti Massimo Gentile Giorgio Lambertenghi Deliliers Pier Alberto Bertazzi Manlio Ferrarini Antonino Neri Andrea Baccarelli 《Epigenetics》2011,6(2):188-194
Global DNA hypomethylation affecting repeat sequences has been reported in different cancer types. Herein, we investigated the methylation levels of repetitive DNA elements in chronic lymphocytic leukemia (CLL), their correlation with the major cytogenetic and molecular features, and clinical relevance in predicting therapy-free survival (TFS). A quantitative bisulfite-PCR Pyrosequencing method was used to evaluate methylation of Alu, long interspersed nuclear elements-1 (LINE-1) and satellite-α (SAT-α) sequences in 77 untreated early-stage (Binet A) CLL patients. Peripheral B-cells from 7 healthy donors were used as controls. Methylation levels (median %5mC) were lower in B-CLLs compared with controls (21.4 vs. 25.9; 66.8 vs. 85.7; 84.0, vs. 88.2 for Alu, LINE-1 and SAT-α, respectively) (p < 0.001). Among CLL patients, a significant association was observed with 17p13.1 deletion (16.8 vs. 22.4; 51.2 vs. 68.5; 52.6 vs. 85.0, for Alu, LINE-1 and SAT-α) but not with other major genetic lesions, IgVH mutation status, CD38 or ZAP-70 expression. Follow-up analyses showed that lower SAT-α methylation levels appeared to be an independent prognostic marker significantly associated with shorter TFS. Our study extended previous limited evidences in methylation of repetitive sequences in CLL suggesting an important biological and clinical relevance in the disease. 相似文献
996.
Henry RR Buse JB Sesti G Davies MJ Jensen KH Brett J Pratley RE 《Endocrine practice》2011,17(6):906-913
ObjectiveTo compare Iiraglutide versus common antihyperglycemic treatments in reducing hemoglobin A1c (A1C) values across multiple levels of baseline glycemic control and in reaching glycemic targets.MethodsPooled patient data from 7 phase 3, multinational, randomized controlled trials in patients with type 2 diabetes were stratified by baseline A1C values into 5 categories: ≤ 7.5%, > 7.5% to 8.0%, > 8.0% to 8.5%, > 8.5% to 9.0%, and > 9.0%. The changes in A1C from baseline to week 26 of treatment and patient proportions reaching A1C targets of < 7.0% and ≤ 6.5% were compared between liraglutide (1.8 mg daily) and sitagliptin, glimepiride, rosiglitazone, exenatide, and insulin glargine across all baseline A1C categories.ResultsIrrespective of treatment, reductions in A1C levels were generally greater in groups with higher baseline A1C values. After 26 weeks of treatment, liraglutide produced the greatest reductions in A1C values across all baseline categories, ranging from 0.7% to 1.8% (baseline A1C categories ≤ 7.5% to > 9.0%, respectively), followed by insulin glargine (0.3% to 1.5%) and then by glimepiride (0.4% to 1.3%). Generally, larger percentages of patients achieved the A1C target of ≤ 6.5% with liraglutide therapy across all baseline categories (from 62% of patients with A1C values ≤ 7.5% to 10% of patients with A1C values > 9.0%) in comparison with other treatments (ranging from 49% to 0% of patients, respectively). Similarly, greater proportions of patients also reached the A1C target of < 7.0% with liraglutide therapy across all baseline categories (from 83% of patients with A1C values ≤ 7.5% to 25% of patients with A1C values > 9.0%) versus comparators (from 74% to 5% of patients, respectively).ConclusionAcross a wide spectrum of baseline A1C categories, liraglutide is an efficacious treatment option for patients with type 2 diabetes. (Endocr Pract. 2011;17: 906-913) 相似文献
997.
Milli A Perego P Beretta GL Corvo A Righetti PG Carenini N Corna E Zuco V Zunino F Cecconi D 《Journal of proteome research》2011,10(3):1191-1207
Novel agents characterized by the scaffold of the atypical retinoid ST1926, but containing different chemical functions (carboxylic or hydroxamic acid), exhibit potent proapoptotic activity. In the present paper, we show that the treatment of the IGROV-1 ovarian cancer cell line with compounds sharing structural features with ST1926 (ST1898, ST3595, ST3056) determines a strong inhibition of proliferation mainly due to apoptotic cell death. In an effort to understand the mechanism of action of these compounds, we performed a proteomics analysis of IGROV-1 total lysates and nuclear extracts. Using this approach, we found that deregulation of calcium homeostasis, oxidative stress, cytoskeleton reorganization, and deregulation of proteasome function may represent important pathways involved in response of IGROV-1 cells to the studied compounds. The most prominent effect was down-regulation of factors involved in protein degradation, an event more marked in cells treated with ST3595. In addition, we identified proteins specifically modulated by each treatment, including prohibitin and cochaperone P23 (ST1898), pre-mRNA splicing factor SF2p32 and clathrin light chain (ST3595), as well as Far upstream element (FUSE) binding protein 1 and DNA-binding protein B (ST3056). By identifying proteins modulated by novel proapoptotic agents, this study provides insights into critical aspects of their mechanism of action. 相似文献
998.
999.
1000.
The identification of biomarkers is one of the leading research areas in proteomics. When biomarkers have to be searched for in spot volume datasets produced by 2D gel-electrophoresis, problems may arise related to the large number of spots present in each map and the small number of samples available in each class (control/pathological). In such cases multivariate methods are usually exploited together with variable selection procedures, to provide a set of possible biomarkers: they are however usually aimed to the selection of the smallest set of variables (spots) providing the best performances in prediction. This approach seems not to be suitable for the identification of potential biomarkers since in this case all the possible candidate biomarkers have to be identified to provide a general picture of the "pathological state": in this case exhaustivity has to be preferred to provide a complete understanding of the mechanisms underlying the pathology. We propose here a ranking and classification method, "Ranking-PCA", based on Principal Component Analysis and variable selection in forward search: the method selects one variable at a time as the one providing the best separation of the two classes investigated in the space given by the relevant PCs. The method was applied to an artificial dataset and a real case-study: Ranking-PCA exhaustively identified the potential biomarkers and provided reliable and robust results. 相似文献