Complementation between mouse Mfn1 and Mfn2 protects mitochondrial fusion defects caused by CMT2A disease mutations

Mfn2, an oligomeric mitochondrial protein important for mitochondrial fusion, is mutated in Charcot-Marie-Tooth disease (CMT) type 2A, a peripheral neuropathy characterized by axonal degeneration. In addition to homooligomeric complexes, Mfn2 also associates with Mfn1, but the functional significance of such heterooligomeric complexes is unknown. Also unknown is why Mfn2 mutations in CMT2A lead to cell type–specific defects given the widespread expression of Mfn2. In this study, we show that homooligomeric complexes formed by many Mfn2 disease mutants are nonfunctional for mitochondrial fusion. However, wild-type Mfn1 complements mutant Mfn2 through the formation of heterooligomeric complexes, including complexes that form in trans between mitochondria. Wild-type Mfn2 cannot complement the disease alleles. Our results highlight the functional importance of Mfn1–Mfn2 heterooligomeric complexes and the close interplay between the two mitofusins in the control of mitochondrial fusion. Furthermore, they suggest that tissues with low Mfn1 expression are vulnerable in CMT2A and that methods to increase Mfn1 expression in the peripheral nervous system would benefit CMT2A patients

Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development

Mitochondrial morphology is determined by a dynamic equilibrium between organelle fusion and fission, but the significance of these processes in vertebrates is unknown. The mitofusins, Mfn1 and Mfn2, have been shown to affect mitochondrial morphology when overexpressed. We find that mice deficient in either Mfn1 or Mfn2 die in midgestation. However, whereas Mfn2 mutant embryos have a specific and severe disruption of the placental trophoblast giant cell layer, Mfn1-deficient giant cells are normal. Embryonic fibroblasts lacking Mfn1 or Mfn2 display distinct types of fragmented mitochondria, a phenotype we determine to be due to a severe reduction in mitochondrial fusion. Moreover, we find that Mfn1 and Mfn2 form homotypic and heterotypic complexes and show, by rescue of mutant cells, that the homotypic complexes are functional for fusion. We conclude that Mfn1 and Mfn2 have both redundant and distinct functions and act in three separate molecular complexes to promote mitochondrial fusion. Strikingly, a subset of mitochondria in mutant cells lose membrane potential. Therefore, mitochondrial fusion is essential for embryonic development, and by enabling cooperation between mitochondria, has protective effects on the mitochondrial population

Guided random walk calculation of energies and <\sq {r^2} > values of the 1Σg^1\Sigma_g state of H_2 in a magnetic field

Energies and spatial observables for the $^1\Sigma_g$ state of the hydrogen molecule in magnetic fields parallel to the proton-proton axis are calculated with a guided random walk Feynman-Kac algorithm. We demonstrate that the accuracy of the results and the simplicity of the method may prove it a viable alternative to large basis set expansions for small molecules in applied fields.Comment: 10 pages, no figure

Exchange and correlation energies of ground states of atoms and molecules in strong magnetic fields

Using a Hartree-Fock mesh method and a configuration interaction approach based on a generalized Gaussian basis set we investigate the behaviour of the exchange and correlation energies of small atoms and molecules, namely th e helium and lithium atom as well as the hydrogen molecule, in the presence of a magnetic field covering the regime B=0-100a.u. In general the importance of the exchange energy to the binding properties of at oms or molecules increases strongly with increasing field strength. This is due to the spin-flip transitions and in particular due to the contributions of the tightly bound hydrogenic state s which are involved in the corresponding ground states of different symmetries. In contrast to the exchange energy the correlation energy becomes less relevant with increasing field strength. This holds for the individual configurations constituting the ground state and for the crossovers of the global ground state.Comment: 4 Figures acc.f.publ.in Phys.Rev.

A stimulus to define informatics and health information technology

<p>Abstract</p> <p>Background</p> <p>Despite the growing interest by leaders, policy makers, and others, the terminology of health information technology as well as biomedical and health informatics is poorly understood and not even agreed upon by academics and professionals in the field.</p> <p>Discussion</p> <p>The paper, presented as a Debate to encourage further discussion and disagreement, provides definitions of the major terminology used in biomedical and health informatics and health information technology. For informatics, it focuses on the words that modify the term as well as individuals who practice the discipline. Other categories of related terms are covered as well, from the associated disciplines of computer science, information technolog and health information management to the major application categories of applications used. The discussion closes with a classification of individuals who work in the largest segment of the field, namely clinical informatics.</p> <p>Summary</p> <p>The goal of presenting in Debate format is to provide a starting point for discussion to reach a documented consensus on the definition and use of these terms.</p

Cytokinesis in bloodstream stage Trypanosoma brucei requires a family of katanins and spastin

Microtubule severing enzymes regulate microtubule dynamics in a wide range of organisms and are implicated in important cell cycle processes such as mitotic spindle assembly and disassembly, chromosome movement and cytokinesis. Here we explore the function of several microtubule severing enzyme homologues, the katanins (KAT80, KAT60a, KAT60b and KAT60c), spastin (SPA) and fidgetin (FID) in the bloodstream stage of the African trypanosome parasite, Trypanosoma brucei. The trypanosome cytoskeleton is microtubule based and remains assembled throughout the cell cycle, necessitating its remodelling during cytokinesis. Using RNA interference to deplete individual proteins, we show that the trypanosome katanin and spastin homologues are non-redundant and essential for bloodstream form proliferation. Further, cell cycle analysis revealed that these proteins play essential but discrete roles in cytokinesis. The KAT60 proteins each appear to be important during the early stages of cytokinesis, while downregulation of KAT80 specifically inhibited furrow ingression and SPA depletion prevented completion of abscission. In contrast, RNA interference of FID did not result in any discernible effects. We propose that the stable microtubule cytoskeleton of T. brucei necessitates the coordinated action of a family of katanins and spastin to bring about the cytoskeletal remodelling necessary to complete cell divisio

Heuristic Reasoning and the Observer's View: The Influence of Example-Availability on ad-hoc Frequency Judgments in Sport

Drawing upon evidence from broader social psychology, and an illustrative study of frequency estimation during a simple, sport-specific observe-and-recall task, this paper makes the case for the more thorough investigation of the availability heuristic (Tversky & Kahneman, 1973) on practical state-of-play reasoning in largely observational sporting activities. It is argued that this evidence particularly substantiates a need for a more robust body of research in two primary domains: (a) the gatekeeping tasks pertinent (and usually preliminary) to an individual’s sporting performance such as talent scouting, team selection, and substitution decisions, and (b) the business of officiating in high-tempo environments

Evaluation of a Web Portal for Improving Public Access to Evidence-Based Health Information and Health Literacy Skills: A Pragmatic Trial

Background: Using the conceptual framework of shared decision-making and evidence-based practice, a web portal was developed to serve as a generic (non disease-specific) tailored intervention to improve the lay public’s health literacy skills. Objective: To evaluate the effects of the web portal compared to no intervention in a real-life setting. Methods: A pragmatic randomised controlled parallel trial using simple randomisation of 96 parents who had children aged ,4 years. Parents were allocated to receive either access to the portal or no intervention, and assigned three tasks to perform over a three-week period. These included a searching task, a critical appraisal task, and reporting on perceptions about participation. Data were collected from March through June 2011. Results: Use of the web portal was found to improve attitudes towards searching for health information. This variable was identified as the most important predictor of intention to search in both samples. Participants considered the web portal to have good usability, usefulness, and credibility. The intervention group showed slight increases in the use of evidencebased information, critical appraisal skills, and participation compared to the group receiving no intervention, but these differences were not statistically significant. Conclusion: Despite the fact that the study was underpowered, we found that the web portal may have a positive effect on attitudes towards searching for health information. Furthermore, participants considered the web portal to be a relevant tool. It is important to continue experimenting with web-based resources in order to increase user participation in health care decision-making. Trial Registration: ClinicalTrials.gov NCT0126679

OXPHOS Supercomplexes as a Hallmark of the Mitochondrial Phenotype of Adipogenic Differentiated Human MSCs

Mitochondria are essential organelles with multiple functions, especially in energy metabolism. Recently, an increasing number of data has highlighted the role of mitochondria for cellular differentiation processes. Metabolic differences between stem cells and mature derivatives require an adaptation of mitochondrial function during differentiation. In this study we investigated alterations of the mitochondrial phenotype of human mesenchymal stem cells undergoing adipogenic differentiation. Maturation of adipocytes is accompanied by mitochondrial biogenesis and an increase of oxidative metabolism. Adaptation of the mt phenotype during differentiation is reflected by changes in the distribution of the mitochondrial network as well as marked alterations of gene expression and organization of the oxidative phosphorylation system (OXPHOS). Distinct differences in the supramolecular organization forms of cytochrome c oxidase (COX) were detected using 2D blue native (BN)-PAGE analysis. Most remarkably we observed a significant increase in the abundance of OXPHOS supercomplexes in mitochondria, emphasizing the change of the mitochondrial phenotype during adipogenic differentiation