全文获取类型
收费全文 | 277篇 |
免费 | 15篇 |
专业分类
292篇 |
出版年
2023年 | 6篇 |
2022年 | 4篇 |
2021年 | 9篇 |
2020年 | 6篇 |
2019年 | 2篇 |
2018年 | 3篇 |
2017年 | 6篇 |
2016年 | 14篇 |
2015年 | 13篇 |
2014年 | 21篇 |
2013年 | 21篇 |
2012年 | 28篇 |
2011年 | 22篇 |
2010年 | 12篇 |
2009年 | 9篇 |
2008年 | 10篇 |
2007年 | 18篇 |
2006年 | 18篇 |
2005年 | 17篇 |
2004年 | 10篇 |
2003年 | 11篇 |
2002年 | 10篇 |
2001年 | 1篇 |
2000年 | 1篇 |
1999年 | 3篇 |
1998年 | 3篇 |
1997年 | 3篇 |
1995年 | 2篇 |
1994年 | 1篇 |
1993年 | 1篇 |
1992年 | 3篇 |
1989年 | 2篇 |
1985年 | 1篇 |
1981年 | 1篇 |
排序方式: 共有292条查询结果,搜索用时 0 毫秒
1.
Carlos F. de Mello Diego D. De La Vega Leandro T. Pizutti Fabiane P. Lopes Maribel A. Rubin Jaime G. Homerich Dr. Carlos R. Melo Joana E. Somer Diogo O. Souza Moacir Wajner 《Neurochemical research》1995,20(12):1437-1441
The effect ofl-pyroglutamic acid, a metabolite that accumulates in pyroglutamic aciduria, on different neurochemical parameters was investigated in adult male Wistar rats. Glutamate binding, adenylate cyclase activity and G protein coupling to adenylate cyclase were assayed in the presence of the acid.l-pyroglutamic acid decreased Na+-dependent and Na+-independent glutamate binding Basal and GMP-PNP stimulated adenylate cyclase activity were not affected by the acid. Furthermore, rats received unilateral intrastriatal injections of 10–300 nmol of bufferedl-pyroglutamic acid. Vehicle (0.25 M Tris-Cl, pH 7.35–7.4) was injected into the contralateral striatum. Neurotoxic damage was assessed seven days after the injection by histological examination and by weighing both cerebral hemispheres. No difference in histology or weight could be identified between hemispheres. These results suggest that, although capable of interfering with glutamate binding, pyroglutamate did not cause a major lesion in the present model of neurotoxicity. 相似文献
2.
Xiaoyu Yang Wei Xu Svetlana Dukleska Sabrina Benchaar Selina Mengisen Valentyn Antochshuk Jason Cheung Leslie Mann Zulfia Babadjanova Jason Rowand Rico Gunawan Alexander McCampbell Maribel Beaumont David Meininger Daisy Richardson Alexandre Ambrogelly 《MABS-AUSTIN》2013,5(5):787-794
Monoclonal antibodies constitute a robust class of therapeutic proteins. Their stability, resistance to stress conditions and high solubility have allowed the successful development and commercialization of over 40 antibody-based drugs. Although mAbs enjoy a relatively high probability of success compared with other therapeutic proteins, examples of projects that are suspended due to the instability of the molecule are not uncommon. Developability assessment studies have therefore been devised to identify early during process development problems associated with stability, solubility that is insufficient to meet expected dosing or sensitivity to stress. This set of experiments includes short-term stability studies at 2−8 þC, 25 þC and 40 þC, freeze-thaw studies, limited forced degradation studies and determination of the viscosity of high concentration samples. We present here three case studies reflecting three typical outcomes: (1) no major or unexpected degradation is found and the study results are used to inform early identification of degradation pathways and potential critical quality attributes within the Quality by Design framework defined by US Food and Drug Administration guidance documents; (2) identification of specific degradation pathway(s) that do not affect potency of the molecule, with subsequent definition of proper process control and formulation strategies; and (3) identification of degradation that affects potency, resulting in program termination and reallocation of resources. 相似文献
3.
Marco Savioli Lorenzo Antonelli Gianfranco Bocchinfuso Francesca Cavalieri Rita Cimino Emanuela Gatto Ernesto Placidi Julio Raul Fernandez Masso Hilda Garay Perez Hector Santana Maribel Guerra-Vallespi Mariano Venanzi 《Journal of peptide science》2022,28(1):e3356
Synthetic therapeutic peptides (STP) are intensively studied as new-generation drugs, characterized by high purity, biocompatibility, selectivity and stereochemical control. However, most of the studies are focussed on the bioactivity of STP without considering how the formulation actually used for therapy administration could alter the physico-chemical properties of the active principle. The aggregation properties of a 20-mer STP (Ac-His-Ala-Arg-Ile-Lys-D-Pro-Thr-Phe-Arg-Arg-D-Leu-Lys-Trp-Lys-Tyr-Lys-Gly-Lys-Phe-Trp-NH2), showing antitumor activity, were investigated by optical spectroscopy and atomic force microscopy imaging, as itself (CIGB552) and in its therapeutic formulation (CIGB552TF). It has found that the therapeutic formulation deeply affects the aggregation properties of the investigated peptide and the morphology of the aggregates formed on mica by deposition of CIGB552 and CIGB552TF millimolar solutions. Molecular dynamics simulations studied the first steps of CIGB552 aggregation under physiological ionic strength conditions (NaCl 150 mM), showing that peptide oligomers, from dimers to tetramers, are preferentially formed in this environment. Interestingly, cell viability assays performed on H-460 cell lines indicate a major antiproliferative activity of the peptide in its therapeutic formulation with respect to the peptide aqueous solution. 相似文献
4.
Henar Hernando Claire Shannon-Lowe Abul B Islam Fatima Al-Shahrour Javier Rodríguez-Ubreva Virginia C Rodríguez-Cortez Biola M Javierre Cristina Mangas Agustín F Fernández Maribel Parra Henri-Jacques Delecluse Manel Esteller Eduardo López-Granados Mario F Fraga Nuria López-Bigas Esteban Ballestar 《Genome biology》2013,14(1):R3
5.
Comparative analysis reveals amino acids critical for anticancer activity of peptide CIGB‐552 下载免费PDF全文
Soledad Astrada Yolanda Gomez Exequiel Barrera Gonzalo Obal Otto Pritsch Sergio Pantano Maribel G. Vallespí Mariela Bollati‐Fogolín 《Journal of peptide science》2016,22(11-12):711-722
Because of resistance development by cancer cells against current anticancer drugs, there is a considerable interest in developing novel antitumor agents. We have previously demonstrated that CIGB‐552, a novel cell‐penetrating synthetic peptide, was effective in reducing tumor size and increasing lifespan in tumor‐bearing mice. Studies of protein–peptide interactions have shown that COMMD1 protein is a major mediator of CIGB‐552 antitumor activity. Furthermore, a typical serine‐protease degradation pattern for CIGB‐552 in BALB/c mice serum was identified, yielding peptides which differ from CIGB‐552 in size and physical properties. In the present study, we show the results obtained from a comparative analysis between CIGB‐552 and its main metabolites regarding physicochemical properties, cellular internalization, and their capability to elicit apoptosis in MCF‐7 cells. None of the analyzed metabolites proved to be as effective as CIGB‐552 in promoting apoptosis in MCF‐7. Taking into account these results, it seemed important to examine their cell‐penetrating capacity and interaction with COMMD1. We show that internalization, a lipid binding‐dependent process, is impaired as well as metabolite–COMMD1 interaction, key component of the apoptotic mechanism. Altogether, our results suggest that features conferred by the amino acid sequence are decisive for CIGB‐552 biological activity, turning it into the minimal functional unit. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd. 相似文献
6.
David García‐Bernal Marta Palomo Carlos M. Martínez Jos E. Milln‐Rivero Ana I. García‐Guilln Miguel Blanquer Maribel Díaz‐Ricart Robert Sackstein Enric Carreras Jose M. Moraleda 《Journal of cellular and molecular medicine》2020,24(14):8031-8044
Allogeneic hematopoietic stem cell transplantation (allo‐HCT) is an effective therapy for the treatment of high‐risk haematological malignant disorders and other life‐threatening haematological and genetic diseases. Acute graft‐versus‐host disease (aGvHD) remains the most frequent cause of non‐relapse mortality following allo‐HCT and limits its extensive clinical application. Current pharmacologic agents used for prophylaxis and treatment of aGvHD are not uniformly successful and have serious secondary side effects. Therefore, more effective and safe prophylaxis and therapy for aGvHD are an unmet clinical need. Defibrotide is a multi‐target drug successfully employed for prophylaxis and treatment of veno‐occlusive disease/sinusoidal obstruction syndrome. Recent preliminary clinical data have suggested some efficacy of defibrotide in the prevention of aGvHD after allo‐HCT. Using a fully MHC‐mismatched murine model of allo‐HCT, we report here that defibrotide, either in prophylaxis or treatment, is effective in preventing T cell and neutrophil infiltration and aGvHD‐associated tissue injury, thus reducing aGvHD incidence and severity, with significantly improved survival after allo‐HCT. Moreover, we performed in vitro mechanistic studies using human cells revealing that defibrotide inhibits leucocyte‐endothelial interactions by down‐regulating expression of key endothelial adhesion molecules involved in leucocyte trafficking. Together, these findings provide evidence that defibrotide may represent an effective and safe clinical alternative for both prophylaxis and treatment of aGvHD after allo‐HCT, paving the way for new therapeutic approaches. 相似文献
7.
8.
9.
Ajith?R?Vancha Suman?Govindaraju Kishore?VL?Parsa Madhuri?Jasti Maribel?González-García Rafael?P?BallesteroEmail author 《BMC biotechnology》2004,4(1):23