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191.
Aurelia Santoro Valentina Balbi Elisa Balducci Chiara Pirazzini Francesca Rosini Francesca Tavano Alessandro Achilli Paola Siviero Nadia Minicuci Elena Bellavista Michele Mishto Stefano Salvioli Francesca Marchegiani Maurizio Cardelli Fabiola Olivieri Benedetta Nacmias Andrea Maria Chiamenti Luisa Benussi Roberta Ghidoni Giuseppina Rose Carlo Gabelli Giuliano Binetti Sandro Sorbi Gaetano Crepaldi Giuseppe Passarino Antonio Torroni Claudio Franceschi 《PloS one》2010,5(8)
Background
Alzheimer''s Disease (AD) is the most common neurodegenerative disease and the leading cause of dementia among senile subjects. It has been proposed that AD can be caused by defects in mitochondrial oxidative phosphorylation. Given the fundamental contribution of the mitochondrial genome (mtDNA) for the respiratory chain, there have been a number of studies investigating the association between mtDNA inherited variants and multifactorial diseases, however no general consensus has been reached yet on the correlation between mtDNA haplogroups and AD.Methodology/Principal Findings
We applied for the first time a high resolution analysis (sequencing of displacement loop and restriction analysis of specific markers in the coding region of mtDNA) to investigate the possible association between mtDNA-inherited sequence variation and AD in 936 AD patients and 776 cognitively assessed normal controls from central and northern Italy. Among over 40 mtDNA sub-haplogroups analysed, we found that sub-haplogroup H5 is a risk factor for AD (OR = 1.85, 95% CI:1.04–3.23) in particular for females (OR = 2.19, 95% CI:1.06–4.51) and independently from the APOE genotype. Multivariate logistic regression revealed an interaction between H5 and age. When the whole sample is considered, the H5a subgroup of molecules, harboring the 4336 transition in the tRNAGln gene, already associated to AD in early studies, was about threefold more represented in AD patients than in controls (2.0% vs 0.8%; p = 0.031), and it might account for the increased frequency of H5 in AD patients (4.2% vs 2.3%). The complete re-sequencing of the 56 mtDNAs belonging to H5 revealed that AD patients showed a trend towards a higher number (p = 0.052) of sporadic mutations in tRNA and rRNA genes when compared with controls.Conclusions
Our results indicate that high resolution analysis of inherited mtDNA sequence variation can help in identifying both ancient polymorphisms defining sub-haplogroups and the accumulation of sporadic mutations associated with complex traits such as AD. 相似文献192.
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Hong Ren Aurelia Schmalstieg Dorothy Yuan Richard B Gaynor 《Journal of immunology (Baltimore, Md. : 1950)》2002,168(2):577-587
The NF-kappaB proteins are critical in the regulation of the immune and inflammatory response. Stimulation of the NF-kappaB pathway leads to increases in I-kappaB kinase beta (IKKbeta) kinase activity to result in the enhanced phosphorylation and degradation of I-kappaB and the translocation of the NF-kappaB proteins from the cytoplasm to the nucleus. In this study, a dominant-negative IKKbeta mutant expressed from the IgH promoter was used to generate transgenic mice to address the role of IKKbeta on B cell function. Although these transgenic mice were defective in activating the NF-kappaB pathway in B cells, they exhibited no defects in B lymphocyte development or basal Ig levels. However, they exhibited defects in the cell cycle progression and proliferation of B cells in response to treatment with LPS, anti-CD40, and anti-IgM. Furthermore, selective defects in the production of specific Ig subclasses in response to both T-dependent and T-independent Ags were noted. These results suggest that IKKbeta is critical for the proliferation of B cells and the control of some aspects of the humoral response. 相似文献
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Aurelia Williams Gerhard Koekemoer Zander Lindeque Carolus Reinecke Debra Meyer 《Metabolomics : Official journal of the Metabolomic Society》2012,8(5):804-818
The first application of gas chromatography mass spectrometry (GC?CMS) metabolomics to the analysis of organic acid profiles in sera of asymptomatic human immunodeficiency virus (HIV)-infected individuals (n?=?18) compared to uninfected controls (n?=?21), is reported here. Several organic acids are well-established diagnostic biomarkers of mitochondrial dysfunction, making the analysis of the organic acid metabolome well suited to monitoring the progressive disruption of mitochondrial structure and function during HIV infection. Using a multifaceted analytical-bioinformatics procedure, at least 10 of these metabolites could be linked to (1) disrupted mitochondrial metabolism, (2) changes in lipid metabolism and (3) oxidative stress, all of which are aberrations caused by HIV infection. Because of the role of the mitochondria in apoptosis, higher levels of this type of cell death in infected (compared to uninfected) individuals was used to support GC?CMS data. This study demonstrates that mass spectrometry metabolomics detects biomarkers of mitochondrial dysfunction which could potentially be developed into indicators of HIV infection, perhaps also to monitor disease progression and the response to antiretroviral treatment. 相似文献
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Mihaela Gheorghiu Andreea Olaru Aurelia Tar Cristina Polonschii Eugen Gheorghiu 《Biosensors & bioelectronics》2009,24(12):3517-3523
A new and exciting biosensing avenue based on assessment of the non-monotonous, concentration dependent effect of pore formation is discussed. A novel kinetic model is advanced to relate surface plasmon resonance (SPR) data with actual concentrations of interacting partners. Lipid modified L1 sensor chip provide the accessible platform for SPR exploration of peptide–membrane interaction, with POPC and melittin as model systems. We show that quantitative assessment of the interaction between an antimicrobial peptide and lipid modified sensors is capable to provide both sensing avenues and detailed mechanistic insights into effects of pore-forming compounds. The proposed model combined with appropriate design of the experimental protocol adds a new depth to the classic SPR investigation of peptide–lipid interaction offering a quantitative platform for detection, improved understanding of the manifold facets of the interaction and for supporting the controlled design of novel antimicrobial compounds. This biosensing approach can be applied to an entire set of pore-forming compounds including antimicrobial peptides and exo-toxins. 相似文献
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