Molecular modeling of a tandem two pore domain potassium channel reveals a putative binding Site for general anesthetics

[Image: see text] Anesthetics are thought to mediate a portion of their activity via binding to and modulation of potassium channels. In particular, tandem pore potassium channels (K2P) are transmembrane ion channels whose current is modulated by the presence of general anesthetics and whose genetic absence has been shown to confer a level of anesthetic resistance. While the exact molecular structure of all K2P forms remains unknown, significant progress has been made toward understanding their structure and interactions with anesthetics via the methods of molecular modeling, coupled with the recently released higher resolution structures of homologous potassium channels to act as templates. Such models reveal the convergence of amino acid regions that are known to modulate anesthetic activity onto a common three- dimensional cavity that forms a putative anesthetic binding site. The model successfully predicts additional important residues that are also involved in the putative binding site as validated by the results of suggested experimental mutations. Such a model can now be used to further predict other amino acid residues that may be intimately involved in the target-based structure–activity relationships that are necessary for anesthetic binding

OPA1-related dominant optic atrophy is not strongly influenced by mitochondrial DNA background

<p>Abstract</p> <p>Background</p> <p>Leber's hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (ADOA) are the most frequent forms of hereditary optic neuropathies. LHON is associated with mitochondrial DNA (mtDNA) mutations whereas ADOA is mainly due to mutations in the OPA1 gene that encodes a mitochondrial protein involved in the mitochondrial inner membrane remodeling. A striking influence of mtDNA haplogroup J on LHON expression has been demonstrated and it has been recently suggested that this haplogroup could also influence ADOA expression. In this study, we have tested the influence of mtDNA backgrounds on OPA1 mutations.</p> <p>Methods</p> <p>To define the relationships between OPA1 mutations and mtDNA backgrounds, we determined the haplogroup affiliation of 41 French patients affected by OPA1-related ADOA by control-region sequencing and RFLP survey of their mtDNAs.</p> <p>Results</p> <p>The comparison between patient and reference populations did not revealed any significant difference.</p> <p>Conclusion</p> <p>Our results argue against a strong influence of mtDNA background on ADOA expression. These data allow to conclude that OPA1 could be considered as a "severe mutation", directly responsible of the optic atrophy, whereas OPA1-negative ADOA and LHON mutations need an external factor(s) to express the pathology (i.e. synergistic interaction with mitochondrial background).</p

Mutation Rate Switch inside Eurasian Mitochondrial Haplogroups: Impact of Selection and Consequences for Dating Settlement in Europe

R-lineage mitochondrial DNA represents over 90% of the European population and is significantly present all around the planet (North Africa, Asia, Oceania, and America). This lineage played a major role in migration “out of Africa” and colonization in Europe. In order to determine an accurate dating of the R lineage and its sublineages, we analyzed 1173 individuals and complete mtDNA sequences from Mitomap. This analysis revealed a new coalescence age for R at 54.500 years, as well as several limitations of standard dating methods, likely to lead to false interpretations. These findings highlight the association of a striking under-accumulation of synonymous mutations, an over-accumulation of non-synonymous mutations, and the phenotypic effect on haplogroup J. Consequently, haplogroup J is apparently not a Neolithic group but an older haplogroup (Paleolithic) that was subjected to an underestimated selective force. These findings also indicated an under-accumulation of synonymous and non-synonymous mutations localized on coding and non-coding (HVS1) sequences for haplogroup R0, which contains the major haplogroups H and V. These new dates are likely to impact the present colonization model for Europe and confirm the late glacial resettlement scenario

General Anesthetics Predicted to Block the GLIC Pore with Micromolar Affinity

Although general anesthetics are known to modulate the activity of ligand-gated ion channels in the Cys-loop superfamily, there is at present neither consensus on the underlying mechanisms, nor predictive models of this modulation. Viable models need to offer quantitative assessment of the relative importance of several identified anesthetic binding sites. However, to date, precise affinity data for individual sites has been challenging to obtain by biophysical means. Here, the likely role of pore block inhibition by the general anesthetics isoflurane and propofol of the prokaryotic pentameric channel GLIC is investigated by molecular simulations. Microscopic affinities are calculated for both single and double occupancy binding of isoflurane and propofol to the GLIC pore. Computations are carried out for an open-pore conformation in which the pore is restrained to crystallographic radius, and a closed-pore conformation that results from unrestrained molecular dynamics equilibration of the structure. The GLIC pore is predicted to be blocked at the micromolar concentrations for which inhibition by isofluorane and propofol is observed experimentally. Calculated affinities suggest that pore block by propofol occurs at signifcantly lower concentrations than those for which inhibition is observed: we argue that this discrepancy may result from binding of propofol to an allosteric site recently identified by X-ray crystallography, which may cause a competing gain-of-function effect. Affinities of isoflurane and propofol to the allosteric site are also calculated, and shown to be 3 mM for isoflurane and for propofol; both anesthetics have a lower affinity for the allosteric site than for the unoccupied pore

The Railway and the River: Conduits of Dickens’s Imaginary City

This chapter analyses the railway and the river as two key conduits of Dickens’ imaginary city, arguing that each simultaneously connects and fractures the modern urban world that he depicts. Focusing on Dombey and Son and Our Mutual Friend, the chapter explores how railway and river combine modernity with the primordial past, arguing that these are not separable but overlay and interpenetrate one another, forming a spatio-temporal palimpsest. Drawing on Walter Benjamin, the chapter proposes that these conduits are signs of a spatial or architectural unconscious that thrusts to the surface the ruination that the city tries to repress. Through this drawing together of new and old, known and unknown, the railway and the river come to embody Dickens’ vision of modernity

VI. Données morphologiques

L’analyse des caractères métriques participe à la reconstitution du profil biologique d’une population. L’interprétation de leurs variations permet dans un premier temps de souligner l’homogénéité ou, au contraire, l’hétérogénéité morphologique d’une série, et dans un second temps d’étudier la variabilité au sein d’une région ou d’une époque à l’aide de comparaisons. Quatre sites ont fait l’objet de cette étude, Saint-Bertrand-de-Comminges, Venerque, Vindrac et l’Isle-Jourdain. VI. 1. Les car..

V. Organisation : répartition biologique au sein de l’espace funéraire

V. 1. Etude du nombre de sépultures individuelles et multiples Les sites de Saint-Bertrand-de-Comminges, de Lunel-Viel Les Horts, Saint-Brice-de-Cassan, Venerque, Vindrac et La Gravette ont une répartition proche du nombre de sujets par tombe (fig. 112 et 113). Le site de Lunel-Viel l’Eglise se différencie par un nombre plus élevé de sujets par tombe, pratiquement le double. Selon le nombre de sujets dans des tombes individuelles ou multiples, les sites de Lunel-Viel l’Église et de Venerque, ..

IV. Recrutement

IV. 1. La mortalité des immatures En appliquant le principe de conformité (Sellier 1996), nous avons réparti ces données biologiques brutes en classes d’âges identiques à celles utilisées dans les tables types de Ledermann (1969) (fig. 105). IV. 1.1. Analyse des quotients de mortalité Les quotients de mortalité des enfants ont été calculés pour une espérance de vie à la naissance de 25 ans (e°0=25 ans) (fig. 106), et comparés aux tables types pour une espérance de vie comprise entre 25 et 30 ..