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111.
Carsten Merkwirth Paola Martinelli Anne Korwitz Michela Morbin Hella S. Br?nneke Sabine D. Jordan Elena I. Rugarli Thomas Langer 《PLoS genetics》2012,8(11)
Fusion and fission of mitochondria maintain the functional integrity of mitochondria and protect against neurodegeneration, but how mitochondrial dysfunctions trigger neuronal loss remains ill-defined. Prohibitins form large ring complexes in the inner membrane that are composed of PHB1 and PHB2 subunits and are thought to function as membrane scaffolds. In Caenorhabditis elegans, prohibitin genes affect aging by moderating fat metabolism and energy production. Knockdown experiments in mammalian cells link the function of prohibitins to membrane fusion, as they were found to stabilize the dynamin-like GTPase OPA1 (optic atrophy 1), which mediates mitochondrial inner membrane fusion and cristae morphogenesis. Mutations in OPA1 are associated with dominant optic atrophy characterized by the progressive loss of retinal ganglion cells, highlighting the importance of OPA1 function in neurons. Here, we show that neuron-specific inactivation of Phb2 in the mouse forebrain causes extensive neurodegeneration associated with behavioral impairments and cognitive deficiencies. We observe early onset tau hyperphosphorylation and filament formation in the hippocampus, demonstrating a direct link between mitochondrial defects and tau pathology. Loss of PHB2 impairs the stability of OPA1, affects mitochondrial ultrastructure, and induces the perinuclear clustering of mitochondria in hippocampal neurons. A destabilization of the mitochondrial genome and respiratory deficiencies manifest in aged neurons only, while the appearance of mitochondrial morphology defects correlates with tau hyperphosphorylation in the absence of PHB2. These results establish an essential role of prohibitin complexes for neuronal survival in vivo and demonstrate that OPA1 stability, mitochondrial fusion, and the maintenance of the mitochondrial genome in neurons depend on these scaffolding proteins. Moreover, our findings establish prohibitin-deficient mice as a novel genetic model for tau pathologies caused by a dysfunction of mitochondria and raise the possibility that tau pathologies are associated with other neurodegenerative disorders caused by deficiencies in mitochondrial dynamics. 相似文献
112.
José A. G. Agúndez Pedro Ayuso José A. Cornejo-García Miguel Blanca María J. Torres Inmaculada Do?a María Salas Natalia Blanca-López Gabriela Canto Carmen Rondon Paloma Campo José J. Laguna Javier Fernández Carmen Martínez Elena García-Martín 《PloS one》2012,7(11)
Non-steroidal anti-inflammatory drugs (NSAIDs) are the drugs most frequently involved in hypersensitivity drug reactions. Histamine is released in the allergic response to NSAIDs and is responsible for some of the clinical symptoms. The aim of this study is to analyze clinical association of functional polymorphisms in the genes coding for enzymes involved in histamine homeostasis with hypersensitivity response to NSAIDs. We studied a cohort of 442 unrelated Caucasian patients with hypersensitivity to NSAIDs. Patients who experienced three or more episodes with two or more different NSAIDs were included. If this requirement was not met diagnosis was established by challenge. A total of 414 healthy unrelated controls ethnically matched with patients and from the same geographic area were recruited. Analyses of the SNPs rs17740607, rs2073440, rs1801105, rs2052129, rs10156191, rs1049742 and rs1049793 in the HDC, HNMT and DAO genes were carried out by means of TaqMan assays. The detrimental DAO 16 Met allele (rs10156191), which causes decreased metabolic capacity, is overrepresented among patients with crossed-hypersensitivity to NSAIDs with an OR = 1.7 (95% CI = 1.3–2.1; Pc = 0.0003) with a gene-dose effect (P = 0.0001). The association was replicated in two populations from different geographic areas (Pc = 0.008 and Pc = 0.004, respectively).
Conclusions and implications
The DAO polymorphism rs10156191 which causes impaired metabolism of circulating histamine is associated with the clinical response in crossed-hypersensitivity to NSAIDs and could be used as a biomarker of response. 相似文献113.
Sara Benedetti Pia Bernasconi Enrico Bertini Elena Biagini Giuseppe Boriani Cristina Capanni Nicola Carboni Giovanna Cenacchi Marta Columbaro Monica D’Adamo Adele D’Amico Maria Rosaria D’Apice Marianna Fontana Alessandra Gambineri Giovanna Lattanzi Rocco Liguori Nadir M Maraldi Laura Mazzanti Eugenio Mercuri Tiziana Mongini Lucia O Morandi Iria Neri Giovanni Nigro Giuseppe Novelli Michela Ortolani Renato Pasquali Antonella Pini Stefania Petrini Luisa Politano Stefano Previtali Lisa Pucci Claudio Rapezzi Giulia Ricci Carmelo Rodolico Paolo Sbraccia Emanuela Scarano Gabriele Siciliano Stefano Squarzoni Antonio Toscano Liliana Vercelli Matteo Ziacchi 《Orphanet journal of rare diseases》2012,7(1):1-3
The need for a collaborative approach to complex inherited diseases collectively referred to as laminopathies, encouraged Italian researchers, geneticists, physicians and patients to join in the Italian Network for Laminopathies, in 2009. Here, we highlight the advantages and added value of such a multidisciplinary effort to understand pathogenesis, clinical aspects and try to find a cure for Emery-Dreifuss muscular dystrophy, Mandibuloacral dysplasia, Hutchinson-Gilford Progeria and forms of lamin-linked cardiomyopathy, neuropathy and lipodystrophy. 相似文献
114.
Olga A. Romanova Timur H. Tenchurin Tatiana S. Demina Elena V. Sytina Alexey D. Shepelev Stanislav G. Rudyak Olga I. Klein Sergey V. Krasheninnikov Elizaveta I. Safronova Roman A. Kamyshinsky Vissarion G. Mamagulashvili Tatiana A. Akopova Sergey N. Chvalun Andrey A. Panteleyev 《Cell proliferation》2019,52(3)
115.
Armando Méndez-Garrido Maricarmen Hernández-Rodríguez Rafael Zamorano-Ulloa José Correa-Basurto Jessica Elena Mendieta-Wejebe Daniel Ramírez-Rosales Martha Cecilia Rosales-Hernández 《Neurochemical research》2014,39(11):2093-2104
It is well known that the principal biomolecules involved in Alzheimer’s disease (AD) are acetylcholinesterase (AChE), acetylcholine (ACh) and the amyloid beta peptide of 42 amino acid residues (Aβ42). ACh plays an important role in human memory and learning, but it is susceptible to hydrolysis by AChE, while the aggregation of Aβ42 forms oligomers and fibrils, which form senile plaques in the brain. The Aβ42 oligomers are able to produce hydrogen peroxide (H2O2), which reacts with metals (Fe2+, Cu2+, Cr3+, Zn2+, and Cd2+) present at high concentrations in the brain of AD patients, generating the hydroxyl radical (·OH) via Fenton (FR) and Fenton-like (FLR) reactions. This mechanism generates high levels of free radicals and, hence, oxidative stress, which has been correlated with the generation and progression of AD. Therefore, we have studied in vitro how AChE catalytic activity and ACh levels are affected by the presence of metals (Fe3+, Cu2+, Cr3+, Zn2+, and Cd2+), H2O2 (without Aβ42), and · OH radicals produced from FR and FLR. The results showed that the H2O2 and the metals do not modify the AChE catalytic activity, but the ·OH radical causes a decrease in it. On the other hand, metals, H2O2 and ·OH radicals, increase the ACh hydrolysis. This finding suggests that when H2O2, the metals and the ·OH radicals are present, both, the AChE catalytic activity and ACh levels diminish. Furthermore, in the future it may be interesting to study whether these effects are observed when H2O2 is produced directly from Aβ42. 相似文献
116.
Anastasia Chasapi Paulina Wachowicz Anne Niknejad Philippe Collin Andrea Krapp Elena Cano Viesturs Simanis Ioannis Xenarios 《PloS one》2015,10(8)
Cytokinesis in fission yeast is controlled by the Septation Initiation Network (SIN), a protein kinase signaling network using the spindle pole body as scaffold. In order to describe the qualitative behavior of the system and predict unknown mutant behaviors we decided to adopt a Boolean modeling approach. In this paper, we report the construction of an extended, Boolean model of the SIN, comprising most SIN components and regulators as individual, experimentally testable nodes. The model uses CDK activity levels as control nodes for the simulation of SIN related events in different stages of the cell cycle. The model was optimized using single knock-out experiments of known phenotypic effect as a training set, and was able to correctly predict a double knock-out test set. Moreover, the model has made in silico predictions that have been validated in vivo, providing new insights into the regulation and hierarchical organization of the SIN. 相似文献
117.
Outer-inner membrane vesicles (O-IMVs) were recently described as a new type of membrane vesicle secreted by the Antarctic bacterium Shewanella vesiculosa M7T. Their formation is characterized by the protrusion of both outer and plasma membranes, which pulls cytoplasmic components into the vesicles. To demonstrate that this is not a singular phenomenon in a bacterium occurring in an extreme environment, the identification of O-IMVs in pathogenic bacteria was undertaken. With this aim, a structural study by Transmission Electron Microscopy (TEM) and Cryo-transmission electron microscopy (Cryo-TEM) was carried out, confirming that O-IMVs are also secreted by Gram-negative pathogenic bacteria such as Neisseria gonorrhoeae, Pseudomonas aeruginosa PAO1 and Acinetobacter baumannii AB41, in which they represent between 0.23% and 1.2% of total vesicles produced. DNA and ATP, which are components solely found in the cell cytoplasm, were identified within membrane vesicles of these strains. The presence of DNA inside the O-IMVs produced by N. gonorrhoeae was confirmed by gold DNA immunolabeling with a specific monoclonal IgM against double-stranded DNA. A proteomic analysis of N. gonorrhoeae-derived membrane vesicles identified proteins from the cytoplasm and plasma membrane. This confirmation of O-IMV extends the hitherto uniform definition of membrane vesicles in Gram-negative bacteria and explains the presence of components in membrane vesicles such as DNA, cytoplasmic and inner membrane proteins, as well as ATP, detected for the first time. The production of these O-IMVs by pathogenic Gram-negative bacteria opens up new areas of study related to their involvement in lateral gene transfer, the transfer of cytoplasmic proteins, as well as the functionality and role of ATP detected in these new vesicles. 相似文献
118.
Jonna Engström-Öst Towe Holmborn Andreas Brutemark Hedvig Hogfors Anu Vehmaa Elena Gorokhova 《Marine and Freshwater Behaviour and Physiology》2014,47(3):173-183
This laboratory study reports some reproductive responses of the copepod Acartia bifilosa to rapid variations in pH. The imposed changes mimic those that copepods could experience due to coastal upwelling, changed mixing conditions or vertical migration. We measured effects of low pH on egg production, hatching and early nauplii development (H0: no effects on response variables between low and ambient pH). On treatment with low pH, we found positive effects on egg production rate and nauplii development time. The positive response to low pH could be an initial stress response or show that A. bifilosa is tolerant to the experimental pH values. The result suggests that A. bifilosa is adapted to pH changes as it performs daily migrations between the depths with differing pH. It could also be advantageous for population development if eggs hatch at high speed and so reduce the possibility that they will sink into anoxic and low pH waters. 相似文献
119.
120.
ABSTRACT: BACKGROUND: The exotic pepper species Capsicum baccatum, also known as the aji or Peruvian hot pepper, is comprised of wild and domesticated botanical forms. The species is a valuable source of new genes useful for improving fruit quality and disease resistance in C. annuum sweet bell and hot chile pepper. However, relatively little research has been conducted to characterize the species, thus limiting its utilization. The structure of genetic diversity in a plant germplasm collection is significantly influenced by its ecogeographical distribution. Together with DNA fingerprints derived from AFLP markers, we evaluated variation in fruit and plant morphology of plants collected across the species native range in South America and evaluated these characters in combination with the unique geography, climate and ecology at different sites where plants originated. RESULTS: The present study mapped the ecogeographic distribution, analyzed the spatial genetic structure, and assessed the relationship between the spatial genetic pattern and the variation of morphological traits in a diverse C. baccatum germplasm collection spanning the species distribution. A combined diversity analysis was carried out on the USDA-ARS C. baccatum germplasm collection using data from GIS, morphological traits and AFLP markers. The results demonstrate that the C. baccatum collection covers wide geographic areas and is adapted to divergent ecological conditions in South America ranging from cool Andean highland to Amazonia rainforest. A high level of morphological diversity was evident in the collection, with fruit weight the leading variable. The fruit weight distribution pattern was compatible to AFLP-based clustering analysis for the collection. A significant spatial structure was observed in the C. baccatum gene pool. Division of the domesticated germplasm into two major regional groups (Western and Eastern) was further supported by the pattern of spatial population structure. CONCLUSIONS: The results reported improve our understanding of the combined effects of geography, ecology and human intervention on organization of the C. baccatum genepool. The results will facilitate utilization of C. baccatum for crop improvement and species conservation by providing a framework for efficient germplasm collection management and guidance for future plant acquisitions. 相似文献