Altered splicing of the BIN1 muscle-specific exon in humans and dogs with highly progressive centronuclear myopathy

Amphiphysin 2, encoded by BIN1, is a key factor for membrane sensing and remodelling in different cell types. Homozygous BIN1 mutations in ubiquitously expressed exons are associated with autosomal recessive centronuclear myopathy (CNM), a mildly progressive muscle disorder typically showing abnormal nuclear centralization on biopsies. In addition, misregulation of BIN1 splicing partially accounts for the muscle defects in myotonic dystrophy (DM). However, the muscle-specific function of amphiphysin 2 and its pathogenicity in both muscle disorders are not well understood. In this study we identified and characterized the first mutation affecting the splicing of the muscle-specific BIN1 exon 11 in a consanguineous family with rapidly progressive and ultimately fatal centronuclear myopathy. In parallel, we discovered a mutation in the same BIN1 exon 11 acceptor splice site as the genetic cause of the canine Inherited Myopathy of Great Danes (IMGD). Analysis of RNA from patient muscle demonstrated complete skipping of exon 11 and BIN1 constructs without exon 11 were unable to promote membrane tubulation in differentiated myotubes. Comparative immunofluorescence and ultrastructural analyses of patient and canine biopsies revealed common structural defects, emphasizing the importance of amphiphysin 2 in membrane remodelling and maintenance of the skeletal muscle triad. Our data demonstrate that the alteration of the muscle-specific function of amphiphysin 2 is a common pathomechanism for centronuclear myopathy, myotonic dystrophy, and IMGD. The IMGD dog is the first faithful model for human BIN1-related CNM and represents a mammalian model available for preclinical trials of potential therapies

Dopamine, affordance and active inference.

The role of dopamine in behaviour and decision-making is often cast in terms of reinforcement learning and optimal decision theory. Here, we present an alternative view that frames the physiology of dopamine in terms of Bayes-optimal behaviour. In this account, dopamine controls the precision or salience of (external or internal) cues that engender action. In other words, dopamine balances bottom-up sensory information and top-down prior beliefs when making hierarchical inferences (predictions) about cues that have affordance. In this paper, we focus on the consequences of changing tonic levels of dopamine firing using simulations of cued sequential movements. Crucially, the predictions driving movements are based upon a hierarchical generative model that infers the context in which movements are made. This means that we can confuse agents by changing the context (order) in which cues are presented. These simulations provide a (Bayes-optimal) model of contextual uncertainty and set switching that can be quantified in terms of behavioural and electrophysiological responses. Furthermore, one can simulate dopaminergic lesions (by changing the precision of prediction errors) to produce pathological behaviours that are reminiscent of those seen in neurological disorders such as Parkinson's disease. We use these simulations to demonstrate how a single functional role for dopamine at the synaptic level can manifest in different ways at the behavioural level

Best practice for motor imagery: a systematic literature review on motor imagery training elements in five different disciplines

<p>Abstract</p> <p>Background</p> <p>The literature suggests a beneficial effect of motor imagery (MI) if combined with physical practice, but detailed descriptions of MI training session (MITS) elements and temporal parameters are lacking. The aim of this review was to identify the characteristics of a successful MITS and compare these for different disciplines, MI session types, task focus, age, gender and MI modification during intervention.</p> <p>Methods</p> <p>An extended systematic literature search using 24 databases was performed for five disciplines: Education, Medicine, Music, Psychology and Sports. References that described an MI intervention that focused on motor skills, performance or strength improvement were included. Information describing 17 MITS elements was extracted based on the PETTLEP (physical, environment, timing, task, learning, emotion, perspective) approach. Seven elements describing the MITS temporal parameters were calculated: study duration, intervention duration, MITS duration, total MITS count, MITS per week, MI trials per MITS and total MI training time.</p> <p>Results</p> <p>Both independent reviewers found 96% congruity, which was tested on a random sample of 20% of all references. After selection, 133 studies reporting 141 MI interventions were included. The locations of the MITS and position of the participants during MI were task-specific. Participants received acoustic detailed MI instructions, which were mostly standardised and live. During MI practice, participants kept their eyes closed. MI training was performed from an internal perspective with a kinaesthetic mode. Changes in MI content, duration and dosage were reported in 31 MI interventions. Familiarisation sessions before the start of the MI intervention were mentioned in 17 reports. MI interventions focused with decreasing relevance on motor-, cognitive- and strength-focused tasks. Average study intervention lasted 34 days, with participants practicing MI on average three times per week for 17 minutes, with 34 MI trials. Average total MI time was 178 minutes including 13 MITS. Reporting rate varied between 25.5% and 95.5%.</p> <p>Conclusions</p> <p>MITS elements of successful interventions were individual, supervised and non-directed sessions, added after physical practice. Successful design characteristics were dominant in the Psychology literature, in interventions focusing on motor and strength-related tasks, in interventions with participants aged 20 to 29 years old, and in MI interventions including participants of both genders. Systematic searching of the MI literature was constrained by the lack of a defined MeSH term.</p

Hadronic spectroscopy with Wilson valence quarks

We present preliminary results on hadronic spectrum measurements by the High Energy Monte Carlo Grand Challenge (HEMCGC) collaboration. The simulation, on a 124 lattice, uses the hybrid molecular dynamics algorithm with two flavors of staggered fermions at two quark mass values and 6/g2 = 5.6. This measurement uses Wilson valence quarks at three values of the hopping parameter on a lattice that is doubled in the time direction. Our work allows a comparative study of these two types of lattice fermions at the parameters used, and provides a check on whether the continuum limit has been reached. The results exhibit the correct trends as the chiral limit is approached. © 1990

Glueballs and topological charge in the presence of dynamical quarks

We have estimated the string tension and the masses of the 0++ and 2++ glueballs in lattice QCD with 2 light flavours of staggered quarks. In addition we have measured the topological charge and hence susceptibility of our gauge field configurations. The simulations were performed at 6/g2 = 5.6 and quark masses m = 0.01 and 0.025 (lattice units) on lattice sizes ranging from 124 to 164. © 1991

Hadronic spectroscopy at a ≈ 0.15 fm.

We discuss some aspects of the hadron spectrum with two flavors of Kogut-Susskind dynamical quarks at 6/g2 = 5.6 and amq = 0.01 and 0.025, using both Kogut-Susskind and Wilson valence quarks. Our high statistics simulations allow us to study systematic errors. Among the problematic features of our results are a dip in the pion effective mass which we ascribe to replicating the lattice in the time direction and large finite size effects in the baryon masses. We also compare the full QCD results to a quenched simulation at similar lattice spacing and quark masses to test whether the effects of dynamical fermions can be absorbed into renormalization of the lattice parameters. © 1991

QCD thermodynamics with Wilson quarks

We present results from a study of hadron thermodynamics with Wilson quarks. The crossover curve between the high and low temperature phases is determined as a function of the gauge coupling and hopping parameter on 83 × 4 lattices. Meson masses are calculated along the crossover curve, and screening lengths are determined in the vicinity of it on 83 × 16 and 82 × 16 × 4 lattices, respectively. © 1991

ImmunoNodes – graphical development of complex immunoinformatics workflows

Background: Immunoinformatics has become a crucial part in biomedical research. Yet many immunoinformatics tools have command line interfaces only and can be difficult to install. Web-based immunoinformatics tools, on the other hand, are difficult to integrate with other tools, which is typically required for the complex analysis and prediction pipelines required for advanced applications. Result We present ImmunoNodes, an immunoinformatics toolbox that is fully integrated into the visual workflow environment KNIME. By dragging and dropping tools and connecting them to indicate the data flow through the pipeline, it is possible to construct very complex workflows without the need for coding. Conclusion: ImmunoNodes allows users to build complex workflows with an easy to use and intuitive interface with a few clicks on any desktop computer