MEGS
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BACKGROUND: Maternally inherited complex I deficiencies due to mutations in MT-ND genes represent a heterogeneous group of multisystem mitochondrial disorders (MD) with a unfavourable prognosis. The aim of the study was to characterize the impact of the mutations in MT-ND genes, including the novel m.13091 T > C variant, on the course of the disease, and to analyse the activities of respiratory chain complexes, the amount of protein subunits, and the mitochondrial energy-generating system (MEGS) in available muscle biopsies and cultivated fibroblasts. METHODS: The respiratory chain complex activities were measured by spectrophotometry, MEGS were analysed using radiolabelled substrates, and protein amount by SDS-PAGE or BN-PAGE in muscle or fibroblasts. RESULTS: In our cohort of 106 unrelated families carrying different mtDNA mutations, we found heteroplasmic mutations in the genes MT-ND1, MT-ND3, and MT-ND5, including the novel variant m.13091 T > C, in 13 patients with MD from 12 families. First symptoms developed between early childhood and adolescence and progressed to multisystem disease with a phenotype of Leigh or MELAS syndromes. MRI revealed bilateral symmetrical involvement of deep grey matter typical of Leigh syndrome in 6 children, cortical/white matter stroke-like lesions suggesting MELAS syndrome in 3 patients, and a combination of cortico-subcortical lesions and grey matter involvement in 4 patients. MEGS indicated mitochondrial disturbances in all available muscle samples, as well as a significantly decreased oxidation of [1-14C] pyruvate in fibroblasts. Spectrophotometric analyses revealed a low activity of complex I and/or complex I + III in all muscle samples except one, but the activities in fibroblasts were mostly normal. No correlation was found between complex I activities and mtDNA mutation load, but higher levels of heteroplasmy were generally found in more severely affected patients. CONCLUSIONS: Maternally inherited complex I deficiencies were found in 11% of families with mitochondrial diseases in our region. Six patients manifested with Leigh, three with MELAS. The remaining four patients presented with an overlap between these two syndromes. MEGS, especially the oxidation of [1-14C] pyruvate in fibroblasts might serve as a sensitive indicator of functional impairment due to MT-ND mutations. Early onset of the disease and higher level of mtDNA heteroplasmy were associated with a worse prognosis.
- Klíčová slova
- Complex I, Leigh syndrome, MEGS, MELAS syndrome, MT-ND genes, Mitochondria, mtDNA,
- MeSH
- biopsie MeSH
- dítě MeSH
- dospělí MeSH
- fibroblasty metabolismus MeSH
- kojenec MeSH
- kosterní svaly metabolismus MeSH
- kultivované buňky MeSH
- Leighova nemoc genetika MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- mitochondriální DNA * MeSH
- mitochondriální nemoci genetika MeSH
- mladiství MeSH
- mozek diagnostické zobrazování patologie MeSH
- mutace * MeSH
- novorozenec MeSH
- respirační komplex I nedostatek genetika metabolismus MeSH
- syndrom MELAS genetika MeSH
- věk při počátku nemoci MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- novorozenec MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- mitochondriální DNA * MeSH
- respirační komplex I MeSH
Genome sequencing of the human parasite Schistosoma mansoni revealed an interesting gene superfamily, called micro-exon gene (meg), that encodes secreted MEG proteins. The genes are composed of short exons (3-81 base pairs) regularly interspersed with long introns (up to 5 kbp). This article recollects 35 S. mansoni specific meg genes that are distributed over 7 autosomes and one pair of sex chromosomes and that code for at least 87 verified MEG proteins. We used various bioinformatics tools to produce an optimal alignment and propose a phylogenetic analysis. This work highlighted intriguing conserved patterns/motifs in the sequences of the highly variable MEG proteins. Based on the analyses, we were able to classify the verified MEG proteins into two subfamilies and to hypothesize their duplication and colonization of all the chromosomes. Together with motif identification, we also proposed to revisit MEGs' common names and annotation in order to avoid duplication, to help the reproducibility of research results and to avoid possible misunderstandings.
- Klíčová slova
- Schistosoma mansoni, gene annotation, micro-exon genes (MEG), phylogeny,
- MeSH
- exony genetika MeSH
- fylogeneze MeSH
- lidé MeSH
- mapování chromozomů MeSH
- reprodukovatelnost výsledků MeSH
- Schistosoma mansoni * genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Magnetoencephalography (MEG) is the recording of the magnetic field produced by the flowing of ions in the brain. This article reports our experience in the application of MEG in patients and healthy volunteers in the Greek population. We provide a brief description of our research work. The MEG data were recorded in a magnetically shielded room with a whole-head 122 channel or an one-channel biomagnetometer. Our results lead us to believe that the MEG is an important research field which is evolving quickly with a number of interesting findings with respect to normal and abnormal functions of the human brain. It could provide clinical practice with an easy to perform non invasive method, which could be adjunct to conventional methods for the evaluation of brain disorders.
- Klíčová slova
- Alzheimer, Epilepsy, Febrile seizures, MEG, Multiple sclerosis, Parkinson, SQUID,
- MeSH
- lidé MeSH
- magnetoencefalografie přístrojové vybavení MeSH
- nemoci mozku diagnóza MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Geografické názvy
- Řecko MeSH
The accurate solution of the forward electrostatic problem is an essential first step before solving the inverse problem of magneto- and electroencephalography (MEG/EEG). The symmetric Galerkin boundary element method is accurate but cannot be used for very large problems because of its computational complexity and memory requirements. We describe a fast multipole-based acceleration for the symmetric boundary element method (BEM). It creates a hierarchical structure of the elements and approximates far interactions using spherical harmonics expansions. The accelerated method is shown to be as accurate as the direct method, yet for large problems it is both faster and more economical in terms of memory consumption.
Accurate geometrical models of the head are necessary for solving the forward and inverse problems of magneto- and electro-encephalography (MEG/EEG). Boundary element methods (BEMs) require a geometrical model describing the interfaces between different tissue types. Classically, head models with a nested volume topology have been used. In this paper, we demonstrate how this constraint can be relaxed, allowing us to model more realistic head topologies. We describe the symmetric BEM for this new model. The symmetric BEM formulation uses both potentials and currents at the interfaces as unknowns and is in general more accurate than the alternative double-layer formulation.
Micro-Exon Genes are a widespread class of genes known for their high variability, widespread in the genome of parasitic trematodes such as Schistosoma mansoni. In this study, we present a strategy that allowed us to solve the structures of three alternatively spliced isoforms from the Schistoma mansoni MEG 2.1 family for the first time. All isoforms are hydrophobic, intrinsically disordered, and recalcitrant to be expressed in high yield in heterologous hosts. We resorted to the chemical synthesis of shorter pieces, before reconstructing the entire sequence. Here, we show that isoform 1 partially folds in a-helix in the presence of trifluoroethanol while isoform 2 features two rigid elbows, that maintain the peptide as disordered, preventing any structuring. Finally, isoform 3 is dominated by the signal peptide, which folds into a-helix. We demonstrated that combining biophysical techniques, like circular dichroism and nuclear magnetic resonance at natural abundance, with in silico molecular dynamics simulation for isoform 1 only, was the key to solve the structure of MEG 2.1. Our results provide a crucial piece to the puzzle of this elusive and highly variable class of proteins.
- MeSH
- exony genetika MeSH
- peptidy * metabolismus MeSH
- protein - isoformy genetika MeSH
- Schistosoma mansoni * genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- peptidy * MeSH
- protein - isoformy MeSH
BACKGROUND: Although they form a unitary phenomenon, the relationship between extracranial M/EEG and transmembrane ion flows is understood only as a general principle rather than as a well-articulated and quantified causal chain. METHOD: We present an integrated multiscale model, consisting of a neural simulation of thalamus and cortex during stage N2 sleep and a biophysical model projecting cortical current densities to M/EEG fields. Sleep spindles were generated through the interactions of local and distant network connections and intrinsic currents within thalamocortical circuits. 32,652 cortical neurons were mapped onto the cortical surface reconstructed from subjects' MRI, interconnected based on geodesic distances, and scaled-up to current dipole densities based on laminar recordings in humans. MRIs were used to generate a quasi-static electromagnetic model enabling simulated cortical activity to be projected to the M/EEG sensors. RESULTS: The simulated M/EEG spindles were similar in amplitude and topography to empirical examples in the same subjects. Simulated spindles with more core-dominant activity were more MEG weighted. COMPARISON WITH EXISTING METHODS: Previous models lacked either spindle-generating thalamic neural dynamics or whole head biophysical modeling; the framework presented here is the first to simultaneously capture these disparate scales. CONCLUSIONS: This multiscale model provides a platform for the principled quantitative integration of existing information relevant to the generation of sleep spindles, and allows the implications of future findings to be explored. It provides a proof of principle for a methodological framework allowing large-scale integrative brain oscillations to be understood in terms of their underlying channels and synapses.
- Klíčová slova
- Cortex, EEG, Forward model, Human, MEG, Sleep, Spindle, Thalamus,
- MeSH
- biologické modely * MeSH
- dospělí MeSH
- elektroencefalografie * MeSH
- iontové kanály MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- magnetoencefalografie * MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mozková kůra * MeSH
- nervová síť MeSH
- počítačová simulace MeSH
- stadia spánku * MeSH
- thalamus * MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
- Názvy látek
- iontové kanály MeSH
BACKGROUND: Huntington disease (HD) is a fatal neurodegenerative disorder involving reduced muscle coordination, mental and behavioral changes, and testicular degeneration. In order to further clarify the decreased fertility and penetration ability of the spermatozoa of transgenic HD minipig boars (TgHD), we applied a set of mitochondrial metabolism (MM) parameter measurements to this promising biological material, which can be collected noninvasively in longitudinal studies. OBJECTIVE: We aimed to optimize methods for MM measurements in spermatozoa and to establish possible biomarkers of HD in TgHD spermatozoa expressing the N-terminal part of mutated human huntingtin. METHODS: Semen samples from 12 TgHD and wild-type animals, aged 12-65 months, were obtained repeatedly during the study. Respiration was measured by polarography, MM was assessed by the detection of oxidation of radiolabeled substrates (mitochondrial energy-generating system; MEGS), and the content of the oxidative phosphorylation system subunits was detected by Western blot. Three possibly interfering factors were statistically analyzed: the effect of HD, generation and aging. RESULTS: We found 5 MM parameters which were significantly diminished in TgHD spermatozoa and propose 3 specific MEGS incubations and complex I-dependent respiration as potential biomarkers of HD in TgHD spermatozoa. CONCLUSIONS: Our results suggest a link between the gain of toxic function of mutated huntingtin in TgHD spermatozoa and the observed MM and/or glycolytic impairment. We determined 4 biomarkers useful for HD phenotyping and experimental therapy monitoring studies in TgHD minipigs.
- Klíčová slova
- Huntington disease, Large-animal model, Mitochondrial metabolism, Mutant huntingtin, Spermatozoa,
- MeSH
- dýchání MeSH
- geneticky modifikovaná zvířata MeSH
- Huntingtonova nemoc komplikace genetika patologie MeSH
- kyseliny trikarboxylové metabolismus MeSH
- lidé MeSH
- miniaturní prasata MeSH
- mitochondriální proteiny metabolismus MeSH
- mitochondrie metabolismus MeSH
- mutace genetika MeSH
- oxidativní fosforylace MeSH
- prasata MeSH
- protein huntingtin genetika MeSH
- pyruvátdehydrogenasový komplex metabolismus MeSH
- sperma metabolismus MeSH
- spermie metabolismus patologie MeSH
- trinukleotidové repetice genetika MeSH
- věkové faktory MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- HTT protein, human MeSH Prohlížeč
- kyseliny trikarboxylové MeSH
- mitochondriální proteiny MeSH
- protein huntingtin MeSH
- pyruvátdehydrogenasový komplex MeSH
Mycobacterium tuberculosis O(6)-methylguanine-DNA methyltransferase (MtOGT) contributes to protect the bacterial GC-rich genome against the pro-mutagenic potential of O(6)-methylated guanine in DNA. Several strains of M. tuberculosis found worldwide encode a point-mutated O(6)-methylguanine-DNA methyltransferase (OGT) variant (MtOGT-R37L), which displays an arginine-to-leucine substitution at position 37 of the poorly functionally characterized N-terminal domain of the protein. Although the impact of this mutation on the MtOGT activity has not yet been proved in vivo, we previously demonstrated that a recombinant MtOGT-R37L variant performs a suboptimal alkylated-DNA repair in vitro, suggesting a direct role for the Arg(37)-bearing region in catalysis. The crystal structure of MtOGT complexed with modified DNA solved in the present study reveals details of the protein-protein and protein-DNA interactions occurring during alkylated-DNA binding, and the protein capability also to host unmodified bases inside the active site, in a fully extrahelical conformation. Our data provide the first experimental picture at the atomic level of a possible mode of assembling three adjacent MtOGT monomers on the same monoalkylated dsDNA molecule, and disclose the conformational flexibility of discrete regions of MtOGT, including the Arg(37)-bearing random coil. This peculiar structural plasticity of MtOGT could be instrumental to proper protein clustering at damaged DNA sites, as well as to protein-DNA complexes disassembling on repair.
- Klíčová slova
- DNA repair, DNA-binding protein, Mycobacterium tuberculosis, O6-methylguanine-DNA methyltransferase, co-operativity, crystal structure,
- MeSH
- bakteriální proteiny chemie genetika MeSH
- bodová mutace genetika MeSH
- krystalografie MeSH
- Mycobacterium tuberculosis genetika MeSH
- O(6)-methylguanin-DNA-methyltransferasa chemie genetika MeSH
- poškození DNA genetika MeSH
- sekundární struktura proteinů MeSH
- terciární struktura proteinů MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- bakteriální proteiny MeSH
- O(6)-methylguanin-DNA-methyltransferasa MeSH
We report on the effects of prenatal alcohol exposure on resting-state brain activity as measured by magnetoencephalography (MEG). We studied 37 subjects diagnosed with fetal alcohol spectrum disorder in one of three categories: fetal alcohol syndrome, partial fetal alcohol syndrome, and alcohol-related neurodevelopmental disorder. For each subject, the MEG signal was recorded for 60 s during rest while subjects lay supine. Using time series analysis, we calculated the synchronous neural interactions for all pair-wise combinations of 248 MEG sensors resulting in 30,628 partial correlations for each subject. We found significant differences from control subjects in 6.19 % of the partial zero-lag crosscorrelations (synchronous neural interactions; Georgopoulos et al. in J Neural Eng 4:349-355, 2007), with these differences localized in the right posterior frontal, right parietal, and left parietal/posterior frontal regions. These results show that MEG can detect functional brain differences in the individuals affected by prenatal exposure to alcohol. Furthermore, these differences may serve as a biomarker for future studies linking symptoms and signs to specific brain areas. This may lead to new insights into the neuropathology of fetal alcohol spectrum disorders.
- Klíčová slova
- Fetal alcohol syndrome, Magnetoencephalography, Resting state, Synchronous neural interactions,
- MeSH
- alkoholy škodlivé účinky MeSH
- analýza rozptylu MeSH
- časové faktory MeSH
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- magnetoencefalografie MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mozková kůra patofyziologie MeSH
- neurovývojové poruchy etiologie MeSH
- spektrum vrozených alkoholových poruch etiologie MeSH
- studie případů a kontrol MeSH
- těhotenství MeSH
- zpožděný efekt prenatální expozice patologie MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
- Názvy látek
- alkoholy MeSH
