全文获取类型
收费全文 | 93篇 |
免费 | 6篇 |
出版年
2022年 | 1篇 |
2020年 | 3篇 |
2019年 | 2篇 |
2018年 | 1篇 |
2017年 | 4篇 |
2016年 | 6篇 |
2015年 | 3篇 |
2014年 | 2篇 |
2013年 | 8篇 |
2012年 | 17篇 |
2011年 | 6篇 |
2010年 | 1篇 |
2009年 | 2篇 |
2008年 | 5篇 |
2007年 | 7篇 |
2006年 | 2篇 |
2005年 | 2篇 |
2004年 | 5篇 |
2003年 | 2篇 |
2001年 | 1篇 |
2000年 | 3篇 |
1999年 | 1篇 |
1998年 | 1篇 |
1997年 | 1篇 |
1996年 | 1篇 |
1994年 | 2篇 |
1993年 | 3篇 |
1989年 | 2篇 |
1988年 | 1篇 |
1987年 | 1篇 |
1986年 | 1篇 |
1984年 | 2篇 |
排序方式: 共有99条查询结果,搜索用时 628 毫秒
61.
Wood-Kaczmar A Gandhi S Yao Z Abramov AY Abramov AS Miljan EA Keen G Stanyer L Hargreaves I Klupsch K Deas E Downward J Mansfield L Jat P Taylor J Heales S Duchen MR Latchman D Tabrizi SJ Wood NW 《PloS one》2008,3(6):e2455
Parkinson's disease (PD) is a common age-related neurodegenerative disease and it is critical to develop models which recapitulate the pathogenic process including the effect of the ageing process. Although the pathogenesis of sporadic PD is unknown, the identification of the mendelian genetic factor PINK1 has provided new mechanistic insights. In order to investigate the role of PINK1 in Parkinson's disease, we studied PINK1 loss of function in human and primary mouse neurons. Using RNAi, we created stable PINK1 knockdown in human dopaminergic neurons differentiated from foetal ventral mesencephalon stem cells, as well as in an immortalised human neuroblastoma cell line. We sought to validate our findings in primary neurons derived from a transgenic PINK1 knockout mouse. For the first time we demonstrate an age dependent neurodegenerative phenotype in human and mouse neurons. PINK1 deficiency leads to reduced long-term viability in human neurons, which die via the mitochondrial apoptosis pathway. Human neurons lacking PINK1 demonstrate features of marked oxidative stress with widespread mitochondrial dysfunction and abnormal mitochondrial morphology. We report that PINK1 plays a neuroprotective role in the mitochondria of mammalian neurons, especially against stress such as staurosporine. In addition we provide evidence that cellular compensatory mechanisms such as mitochondrial biogenesis and upregulation of lysosomal degradation pathways occur in PINK1 deficiency. The phenotypic effects of PINK1 loss-of-function described here in mammalian neurons provides mechanistic insight into the age-related degeneration of nigral dopaminergic neurons seen in PD. 相似文献
62.
Bacterial ghosts--biological particles as delivery systems for antigens, nucleic acids and drugs 总被引:4,自引:0,他引:4
Tabrizi CA Walcher P Mayr UB Stiedl T Binder M McGrath J Lubitz W 《Current opinion in biotechnology》2004,15(6):167-537
Despite the exponential rate of discovery of new antigens and DNA vaccines resulting from modern molecular biology and proteomics, the lack of effective delivery technology is a major limiting factor in their application. The bacterial ghost system represents a platform technology for antigen, nucleic acid and drug delivery. Bacterial ghosts have significant advantages over other engineered biological delivery particles, owing to their intrinsic cellular and tissue tropic abilities, ease of production and the fact that they can be stored and processed without the need for refrigeration. These particles have found both veterinary and medical applications for the vaccination and treatment of tumors and various infectious diseases. 相似文献
63.
Baraldi PG Romagnoli R Tabrizi MA Falzoni S di Virgilio F 《Bioorganic & medicinal chemistry letters》2000,10(7):681-684
Conformationally constrained analogues of KN62 containing 1,2,3,4-tetrahydro-7-hydroxyisoquinoline-3-carboxylic acid with S configuration in position 3 were synthesized and their antagonist activities were tested on human macrophage cells. While KN62 is a potent antagonist of the P2X7 receptor, these analogues were inactive as antagonists and only one compound showed appreciable activity as P2X7 antagonist, which was 30 times weaker than that reported for KN62. 相似文献
64.
65.
Baraldi PG Romagnoli R Saponaro G Aghazadeh Tabrizi M Baraldi S Pedretti P Fusi C Nassini R Materazzi S Geppetti P Preti D 《Bioorganic & medicinal chemistry》2012,20(5):1690-1698
The transient receptor potential ankyrin 1 (TRPA1) channel is activated by a series of by-products of oxidative/nitrative stress, produced under inflammatory conditions or in the case of tissue damage, thus generating inflammatory and neuropathic pain and neurogenic inflammatory responses. These findings have identified TRPA1 as an emerging opportunity for the design and synthesis of selective inhibitors as potential analgesic and antiinflammatory agents. Herein we present the synthesis and functional evaluation of a new series of 7-substituted-1,3-dimethyl-1,5-dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione derivatives designed as TRPA1 antagonists. A small library of compounds has been built by the introduction of differently substituted N(7)-phenylacetamide or N(7)-[4-(substituted-phenyl)-thiazol-2-yl]-acetamide chains. All the synthesized compounds were assayed to evaluate their ability to block acrolein-mediated activation of native human and rat TRPA1 channels employing a fluorometric calcium imaging assay. Our study led us to the identification of compound 3h which showed considerably improved potency (IC(50)=400nM) against human TRPA1 with regard to some of the most representative antagonists previously reported and integrated in our screening program as reference compounds. In addition, 3h proved to maintain its efficacy toward rTRPA1, which designates it as a possible candidate for future evaluation of in vivo efficacy in rodent animal model of inflammatory and neuropathic pain. 相似文献
66.
Baraldi PG Saponaro G Aghazadeh Tabrizi M Baraldi S Romagnoli R Moorman AR Varani K Borea PA Preti D 《Bioorganic & medicinal chemistry》2012,20(2):1046-1059
The discovery and development of adenosine receptor antagonists have represented for years an attractive field of research from the perspective of identifying new drugs for the treatment of widespread disorders such as inflammation, asthma and Parkinson's disease. The present work can be considered as an extension of our structure-activity relationship studies on the pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine (PTP) nucleus, extensively investigated by us as a useful template, in particular, for the identification of A(2A) and A(3) adenosine receptor antagonists. In order to explore the role of the nitrogen at the 7-position, we performed a new synthetic strategy for the preparation of pyrrolo[3,4-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives which can be considered as 7-deaza analogues of the parent PTPs. We also synthesised a novel series of pyrazolo[3,4-e][1,2,4]triazolo[1,5-c]pyrimidines as junction isomers of the reference compounds. In both cases we obtained some examples of potent antagonists (K(i) in the low nanomolar range) with variable selectivity profiles in relation to the nature of substituents introduced at the C(5)-, N(8)- and/or N(9)-positions. The pyrrolo-triazolo-pyrimidine derivative 9b appeared to be a potent A(3) adenosine receptor antagonist (K(i)=10 nM) with good selectivity over hA(1) (74-fold) and hA(2A) (20-fold) adenosine receptors combined with low activity at the hA(2B) subtype (IC(50)=906 nM). Moreover, some examples of high-affinity A(1)/A(2A) dual antagonists have been identified in both series. This work constitutes a new and important contribution for the comprehension of the interaction between PTPs and adenosine receptors. 相似文献
67.
Ghanizadeh A 《Neurochemical research》2011,36(5):922-923
The exact pathophysiology of the neurodevelopment disorder of autism is not clear and there is not any curative approach for
it. There is only one FDA-approved medication for its management. Therefore, providing of novel treatments is highly required.
The hypofunction of GABAergic system and glutamate toxicity are generally believed to have a causal role for autism. The antagonist
of the N-methyl-d-aspartic acid (NMDA) glutamate receptor improves autism. Glycine is required for the activation of NMDA receptor. The antagonist
of glycine site decreases NMDA receptor conductance. It is hypothesis that glycine site antagonists can be tested as a new
strategy for the management of autism. 相似文献
68.
Zuccato C Marullo M Vitali B Tarditi A Mariotti C Valenza M Lahiri N Wild EJ Sassone J Ciammola A Bachoud-Lèvi AC Tabrizi SJ Di Donato S Cattaneo E 《PloS one》2011,6(8):e22966
Reduced Brain-Derived Neurotrophic Factor (BDNF) levels have been described in a number of patho-physiological conditions, most notably, in Huntington's disease (HD), a progressive neurodegenerative disorder. Since BDNF is also produced in blood, we have undertaken the measurement of its peripheral levels in the attempt to identify a possible link with HD prognosis and/or its progression. Here we evaluated BDNF level in 398 blood samples including 138 controls, 56 preHD, and 204 HD subjects. We found that BDNF protein levels were not reliably different between groups, whether measured in plasma (52 controls, 26 preHD, 105 HD) or serum (39 controls, 5 preHD, 29 HD). Our experience, and a re-analysis of the literature highlighted that intra-group variability and methodological aspects affect this measurement, especially in serum. We also assessed BDNF mRNA levels in blood samples from 47 controls, 25 preHD, and 70 HD subjects, and found no differences among the groups. We concluded that levels of BDNF in human blood were not informative (mRNA levels or plasma protein level) nor reliable (serum protein levels) as HD biomarkers. We also wish to warn the scientific community in interpreting the significance of changes measured in BDNF protein levels in serum from patients suffering from different conditions. 相似文献
69.
Ahmad Ghanizadeh Michael Berk Hassan Farrashbandi Ali Alavi shoushtari Kristi-Ann Villagonzalo 《Mitochondrion》2013,13(5):515-519
Autism is a complex developmental disorder with an unknown etiology and without any curative treatment. The mitochondrial electron transfer chains play a major role in the production of ATP, and the generation and management of reactive oxidative stress (ROS). This paper is a systematic review of the role of the mitochondrial electron transport chain in autism, and a consequent hypothesis for treating autism is synthesized.An electronic search with pre-specified inclusion criteria was conducted in order to retrieve all the published articles about the mitochondrial electron transport chain in autism. The two databases of PUBMED and Google Scholar were searched.From one hundred twenty five retrieved titles, 12 (three case control study and 9 case reports) articles met inclusion criteria. All of the included studies indicated dysfunction of electron transport chain in autism.The mitochondrial electron transfer chain seems impaired in some children with autism and ROS production is additionally enhanced. It is hypothesized that interventions involving alternative electron shuttling may improve autism through lowering the production of ROS. In addition, it is expected that this alternative electron shuttling to cytochrome c might enhance the production of ATP which is impaired in the disorder. 相似文献
70.
Surabhi S. Liyanage Bayzidur Rahman Iman Ridda Anthony T. Newall Sepehr N. Tabrizi Suzanne M. Garland Eva Segelov Holly Seale Philip J. Crowe Aye Moa C. Raina MacIntyre 《PloS one》2013,8(7)