全文获取类型
收费全文 | 795篇 |
免费 | 66篇 |
专业分类
861篇 |
出版年
2024年 | 3篇 |
2023年 | 10篇 |
2022年 | 11篇 |
2021年 | 24篇 |
2020年 | 10篇 |
2019年 | 19篇 |
2018年 | 21篇 |
2017年 | 15篇 |
2016年 | 36篇 |
2015年 | 60篇 |
2014年 | 65篇 |
2013年 | 77篇 |
2012年 | 83篇 |
2011年 | 69篇 |
2010年 | 58篇 |
2009年 | 41篇 |
2008年 | 43篇 |
2007年 | 60篇 |
2006年 | 35篇 |
2005年 | 30篇 |
2004年 | 28篇 |
2003年 | 23篇 |
2002年 | 25篇 |
2001年 | 3篇 |
2000年 | 2篇 |
1999年 | 2篇 |
1998年 | 1篇 |
1997年 | 2篇 |
1996年 | 3篇 |
1994年 | 1篇 |
1992年 | 1篇 |
排序方式: 共有861条查询结果,搜索用时 15 毫秒
11.
12.
Cecilia Marini Barbara Salani Michela Massollo Adriana Amaro Alessia Isabella Esposito Anna Maria Orengo Selene Capitanio Laura Emionite Mattia Riondato Gianluca Bottoni Cinzia Massara Simona Boccardo Marina Fabbi Cristina Campi Silvia Ravera Giovanna Angelini Silvia Morbelli Michele Cilli Renzo Cordera Mauro Truini Davide Maggi Ulrich Pfeffer Gianmario Sambuceti 《Cell cycle (Georgetown, Tex.)》2013,12(22):3490-3499
Emerging evidence suggests that metformin, a widely used anti-diabetic drug, may be useful in the prevention and treatment of different cancers. In the present study, we demonstrate that metformin directly inhibits the enzymatic function of hexokinase (HK) I and II in a cell line of triple-negative breast cancer (MDA-MB-231). The inhibition is selective for these isoforms, as documented by experiments with purified HK I and II as well as with cell lysates. Measurements of 18F-fluoro-deoxyglycose uptake document that it is dose- and time-dependent and powerful enough to virtually abolish glucose consumption despite unchanged availability of membrane glucose transporters. The profound energetic imbalance activates phosphorylation and is subsequently followed by cell death. More importantly, the “in vivo” relevance of this effect is confirmed by studies of orthotopic xenografts of MDA-MB-231 cells in athymic (nu/nu) mice. Administration of high drug doses after tumor development caused an evident tumor necrosis in a time as short as 48 h. On the other hand, 1 mo metformin treatment markedly reduced cancer glucose consumption and growth. Taken together, our results strongly suggest that HK inhibition contributes to metformin therapeutic and preventive potential in breast cancer. 相似文献
13.
Gianguglielmo Zehender Erika Ebranati Renata Shkjezi Anna Papa Camilla Luzzago Elena Gabanelli Alessandra Lo Presti Alessia Lai Giovanni Rezza Massimo Galli Silvia Bino Massimo Ciccozzi 《PloS one》2013,8(11)
Crimean-Congo hemorrhagic fever (CCHF) is a zoonosis mainly transmitted by ticks that causes severe hemorrhagic fever and has a mortality rate of 5-60%. The first outbreak of CCHF occurred in the Crimean peninsula in 1944-45 and it has recently emerged in the Balkans and eastern Mediterranean. In order to reconstruct the origin and pathway of the worldwide dispersion of the virus at global and regional (eastern European) level, we investigated the phylogeography of the infection by analysing 121 publicly available CCHFV S gene sequences including two recently characterised Albanian isolates. The spatial and temporal phylogeny was reconstructed using a Bayesian Markov chain Monte Carlo approach, which estimated a mean evolutionary rate of 2.96 x 10-4 (95%HPD=1.6 and 4.7 x 10-4) substitutions/site/year for the analysed fragment. All of the isolates segregated into seven highly significant clades that correspond to the known geographical clades: in particular the two new isolates from northern Albania clustered significantly within the Europe 1 clade. Our phylogeographical reconstruction suggests that the global CCHFV clades originated about one thousand years ago from a common ancestor probably located in Africa. The virus then spread to Asia in the XV century and entered Europe on at least two occasions: the first in the early 1800s, when a still circulating but less or non-pathogenic virus emerged in Greece and Turkey, and the second in the early 1900s, when a pathogenic CCHFV strain began to spread in eastern Europe. The most probable location for the origin of this European clade 1 was Russia, but Turkey played a central role in spreading the virus throughout Europe. Given the close proximity of the infected areas, our data suggest that the movement of wild and domestic ungulates from endemic areas was probably the main cause of the dissemination of the virus in eastern Europe. 相似文献
14.
Beno?t de Chassey Anne Aublin-Gex Alessia Ruggieri Laurène Meyniel-Schicklin Fabrine Pradezynski Nathalie Davoust Thibault Chantier Lionel Tafforeau Philippe-Emmanuel Mangeot Claire Ciancia Laure Perrin-Cocon Ralf Bartenschlager Patrice André Vincent Lotteau 《PLoS pathogens》2013,9(7)
Influenza A NS1 and NS2 proteins are encoded by the RNA segment 8 of the viral genome. NS1 is a multifunctional protein and a virulence factor while NS2 is involved in nuclear export of viral ribonucleoprotein complexes. A yeast two-hybrid screening strategy was used to identify host factors supporting NS1 and NS2 functions. More than 560 interactions between 79 cellular proteins and NS1 and NS2 proteins from 9 different influenza virus strains have been identified. These interacting proteins are potentially involved in each step of the infectious process and their contribution to viral replication was tested by RNA interference. Validation of the relevance of these host cell proteins for the viral replication cycle revealed that 7 of the 79 NS1 and/or NS2-interacting proteins positively or negatively controlled virus replication. One of the main factors targeted by NS1 of all virus strains was double-stranded RNA binding domain protein family. In particular, adenosine deaminase acting on RNA 1 (ADAR1) appeared as a pro-viral host factor whose expression is necessary for optimal viral protein synthesis and replication. Surprisingly, ADAR1 also appeared as a pro-viral host factor for dengue virus replication and directly interacted with the viral NS3 protein. ADAR1 editing activity was enhanced by both viruses through dengue virus NS3 and influenza virus NS1 proteins, suggesting a similar virus-host co-evolution. 相似文献
15.
Alessia Belgi Ross A. D. Bathgate Geoffrey W. Tregear John D. Wade Mohammed Akhter Hossain 《International journal of peptide research and therapeutics》2013,19(1):71-79
Insulin-like peptide 5 (INSL5) is a two-chain, three-disulfide bonded member of insulin/relaxin superfamily of peptides that includes insulin, insulin-like growth factor I and II (IGFI and IGFII), insulin-like peptide 3, 4, 5 and 6 (INSL3, 4, 5 and 6), relaxin-1 (H1 relaxin), -2 (H2 relaxin) and -3 (H3 relaxin). Although it is expressed in relatively high levels in the gut, its biological function remains unclear. However, recent reports suggest a significant orexigenic action and a role in the regulation of insulin secretion and β-cell homeostasis, which implies that both agonists and antagonists of the peptide may have significant therapeutic applications. Modern solid phase synthesis techniques together with regioselective disulfide bond formation were employed for a preliminary structure–function relationship study of mouse INSL5. Two point mutated analogues, mouse INSL5 A-B(R24A, W25A) and mouse INSL5 A-B(K6A, R14A, Y18A) were chemically prepared, where the residues in the B-chain that may be involved in receptor activation and affinity binding, were respectively mutated. Synthetic mouse INSL5 A-B(R24A, W25A) analogue was inactive on RXFP4, the native receptor for INSL5, suggesting ArgB24 and TrpB25 are probably directly involved in INSL5 receptor activation. Mouse INSL5 A-B(K6A, R14A, Y18A) analogue had both decreased affinity and potency on RXFP4 (pIC50 7.7 ± 0.2, pEC50 7.87 ± 0.18) which indicated that one or more of these residues are critical for the binding to the receptor. 相似文献
16.
17.
Maria Maddalena Cavalluzzi Maurizio Viale Claudio Bruno Alessia Carocci Alessia Catalano Antonio Carrieri Carlo Franchini Giovanni Lentini 《Bioorganic & medicinal chemistry letters》2013,23(17):4820-4823
Lubeluzole, a neuroprotective anti-ischemic drug, and its enantiomer were prepared following a convenient procedure based on hydrolytic kinetic resolution. The ee values were >99% and 96%, respectively, as assessed by HPLC analysis. The chemosensitizing effects of both enantiomers were evaluated in combination with either doxorubicin (human ovarian adenocarcinoma A2780 cells) or paclitaxel (human lung carcinoma A549 cells) by the MTT assay. At the lowest concentrations used, lubeluzole showed an overall and remarkable tendency to synergize with both anticancer drugs. In ovarian cancer cells a clear prevalence of antagonistic effect was observed for the R-enantiomer. The synergistic effects of lubeluzole for both drugs were observed over a wide concentration window (0.005–5 μM), the lowest limit being at least 40 times lower than human plasma concentrations previously reported as causing serious side effects. 相似文献
18.
Federico Mussano Alberto Bartorelli Cusani Alessia Brossa Stefano Carossa Gianni Bussolati 《Bioscience, biotechnology, and biochemistry》2013,77(4):662-671
New approaches in the treatment of skeletal defects may benefit from the use of soluble biological factors. We previously standardized a derivative of bovine colostrum (SBCD), deprived of casein and fat and rich in cytokines. In the present study, we tested its possible use as an adjuvant in bone healing. SBCD contained factors involved in stromal cell stimulation and differentiation and induced cytokine production from stimulated mesenchymal stem cells (MSCs). In vitro, SBCD promoted proliferation, migration and, in association with osteogenic factors, osteogenic differentiation of osteoblastic and MSCs. In in vivo experiments of subcutaneous Matrigel injection in mice, SBCD plus hydroxyapatite, but not hydroxyapatite nor SBCD alone, induced recruitment of macrophages and stromal cells. After 60?days, plugs containing SBCD and hydroxyapatite were densely calcified and diffusely positive for osteocalcin, supporting the occurrence of an early osteogenic process. These results indicate that SBCD is a rich source of factors with osteoinductive properties. 相似文献
19.
20.
The extent of whole‐genome copy number alterations predicts aggressive features in primary melanomas 下载免费PDF全文
Greta Gandolfi Caterina Longo Elvira Moscarella Iris Zalaudek Valentina Sancisi Margherita Raucci Gloria Manzotti Mila Gugnoni Simonetta Piana Giuseppe Argenziano Alessia Ciarrocchi 《Pigment cell & melanoma research》2016,29(2):163-175
Recent evidence indicates that melanoma comprises distinct types of tumors and suggests that specific morphological features may help predict its clinical behavior. Using a SNP‐array approach, we quantified chromosomal copy number alterations (CNA) across the whole genome in 41 primary melanomas and found a high degree of heterogeneity in their genomic asset. Association analysis correlating the number and relative length of CNA with clinical, morphological, and dermoscopic attributes of melanoma revealed that features of aggressiveness were strongly linked to the overall amount of genomic damage. Furthermore, we observed that melanoma progression and survival were mainly affected by a low number of large chromosome losses and a high number of small gains. We identified the alterations most frequently associated with aggressive melanoma, and by integrating our data with publicly available gene expression profiles, we identified five genes which expression was found to be necessary for melanoma cells proliferation. In conclusion, this work provides new evidence that the phenotypic heterogeneity of melanoma reflects a parallel genetic diversity and lays the basis to define novel strategies for a more precise prognostic stratification of patients. 相似文献