Action plan co-optimization reveals the parallel encoding of competing reach movements.

Several influential cognitive theories propose that in situations affording more than one possible target of action, we prepare multiple competing movements before selecting one. Here we provide direct evidence for this provocative but largely untested idea and demonstrate why preparing multiple movements is computationally advantageous. Using a reaching task in which movements are initiated after one of two potential targets is cued, we show that the movement generated for the cued target borrows components of the movement that would have been required for the other, competing target. This interaction can only arise if multiple potential movements are fully specified in advance and we demonstrate that it reduces the time required to launch a given action plan. Our findings suggest that this co-optimization of motor plans is highly automatic and largely occurs outside conscious awareness.The study was supported by the Natural Sciences and Engineering Research Council of Canada; the Wellcome Trust; the Human Frontiers Science Program; and the Royal Society. J.P.G. was supported by Banting postdoctoral fellowship and CIHR postdoctoral fellowship awards.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms842

Rapid Automatic Motor Encoding of Competing Reach Options.

Mounting neural evidence suggests that, in situations in which there are multiple potential targets for action, the brain prepares, in parallel, competing movements associated with these targets, prior to implementing one of them. Central to this interpretation is the idea that competing viewed targets, prior to selection, are rapidly and automatically transformed into corresponding motor representations. Here, by applying target-specific, gradual visuomotor rotations and dissociating, unbeknownst to participants, the visual direction of potential targets from the direction of the movements required to reach the same targets, we provide direct evidence for this provocative idea. Our results offer strong empirical support for theories suggesting that competing action options are automatically represented in terms of the movements required to attain them. The rapid motor encoding of potential targets may support the fast optimization of motor costs under conditions of target uncertainty and allow the motor system to inform decisions about target selection.Funding from the Natural Sciences and Engineering Research Council of Canada (NSERC), the Wellcome Trust, the Royal Society Noreen Murray Professorship in Neurobiology (to D.M.W.), the Canadian Foundation for Innovation, and the Ontario Innovation Trust supported this study. J.P.G. was supported by an NSERC Banting Postdoctoral Fellowship and a Canadian Institutes of Health Research Postdoctoral Fellowship. B.M.S. was supported by an NSERC graduate scholarship

Inference and Visualization of Information Flow in the Visual Pathway using dMRI and EEG

International audienceWe propose a method to visualize information flow in the visual pathway following a visual stimulus. Our method estimates structural connections using diffusion magnetic resonance imaging and functional connections using electroencephalography. First, a Bayesian network which represents the cortical regions of the brain and their connections is built from the structural connections. Next, the functional information is added as evidence into the network and the posterior probability of activation is inferred using a maximum entropy on the mean approach. Finally, projecting these posterior probabilities back onto streamlines generates a visual depiction of pathways used in the network. We first show the effect of noise in a simulated phantom dataset. We then present the results obtained from left and right visual stimuli which show expected information flow traveling from eyes to the lateral geniculate nucleus and to the visual cortex. Information flow visualiza-tion along white matter pathways has potential to explore the brain dynamics in novel ways

Polycation-π Interactions Are a Driving Force for Molecular Recognition by an Intrinsically Disordered Oncoprotein Family

Molecular recognition by intrinsically disordered proteins (IDPs) commonly involves specific localized contacts and target-induced disorder to order transitions. However, some IDPs remain disordered in the bound state, a phenomenon coined "fuzziness", often characterized by IDP polyvalency, sequence-insensitivity and a dynamic ensemble of disordered bound-state conformations. Besides the above general features, specific biophysical models for fuzzy interactions are mostly lacking. The transcriptional activation domain of the Ewing's Sarcoma oncoprotein family (EAD) is an IDP that exhibits many features of fuzziness, with multiple EAD aromatic side chains driving molecular recognition. Considering the prevalent role of cation-π interactions at various protein-protein interfaces, we hypothesized that EAD-target binding involves polycation- π contacts between a disordered EAD and basic residues on the target. Herein we evaluated the polycation-π hypothesis via functional and theoretical interrogation of EAD variants. The experimental effects of a range of EAD sequence variations, including aromatic number, aromatic density and charge perturbations, all support the cation-π model. Moreover, the activity trends observed are well captured by a coarse-grained EAD chain model and a corresponding analytical model based on interaction between EAD aromatics and surface cations of a generic globular target. EAD-target binding, in the context of pathological Ewing's Sarcoma oncoproteins, is thus seen to be driven by a balance between EAD conformational entropy and favorable EAD-target cation-π contacts. Such a highly versatile mode of molecular recognition offers a general conceptual framework for promiscuous target recognition by polyvalent IDPs. © 2013 Song et al

Measuring organisational readiness for patient engagement (MORE) : an international online Delphi consensus study

Date of Acceptance: 28/01/2015. © 2015 Oostendorp et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise statedWidespread implementation of patient engagement by organisations and clinical teams is not a reality yet. The aim of this study is to develop a measure of organisational readiness for patient engagement designed to monitor and facilitate a healthcare organisation’s willingness and ability to effectively implement patient engagement in healthcarePeer reviewedFinal Published versio

Meet the researchers: an alternative method of engaging patients with research in mesothelioma.

There are new ways to engage people with science and research but many patient support groups and charitable organisations still hold traditional meetings to provide updates on their activities and to report new developments in their field of interest. These meetings often feature presentations given by medical doctors or, in the case of research-focussed organisations, by research scientists.Receiving feedback from people who are confused and sometimes upset by some types of information, and the way it is presented at meetings, made us think about better ways for researchers to discuss their ideas for new research, or share the findings from completed projects, with patients and members of the public.This article describes a method of public engagement called "Meet the Researchers" that enables people to hear about current trends in research face to face with the researchers planning or conducting it. "Meet the Researchers" is designed to promote discussion and allow questions to be asked in a relaxed and informal way, in small groups, which is less daunting than asking questions in front of a conference audience. The aim is to break down the barriers between researchers and patients, and enable conversations that will lead to meaningful engagement and a better understanding of research. Additionally we aim to improve understanding of how results are passed on to doctors and nurses and translated into improvements in patient care.The method was tested with patients and was rated very highly by them in the feedback they gave. Abstract:Background Innovative approaches to engaging people with science exist but are often framed around interactive events or social media technologies. Notwithstanding the availability of novel approaches, many patient support groups and charitable organisations continue to hold traditional meetings and seminars to provide information and updates on their activities, and report on developments in their field of interest. In the case of research-focussed organisations, these meetings often take the form of presentations delivered by clinical experts or research scientists.Observation of mesothelioma patients, their relatives, friends and carers attending scientific or clinical-themed meetings has shown that they can be confused, and sometimes distressed, by presentations. This can be due to didactic presentations that are not properly targeted to this audience and a lack of a general overview or summary at the end of meetings that would provide some simple take home messages. This experience motivated the development of a less formal method of sharing complex information and ideas in a simplified manner. "Meet the Researchers" aims to make researchers accessible to patients in order to raise awareness and understanding of research and to explain how research translates into, and informs practice. This approach encourages the use of plain English, removes the tendency to rely on PowerPoint slides to convey the message and moreover, provides an opportunity for researchers to hear patients' views. Methods Small groups of participants met face to face with the researchers planning or conducting research into their condition, and discussed the topics in a relaxed and informal way. The researchers spent a minimum of 20-min with each group before moving on to the next. Info-graphics on a portable device or printed hand-outs in plain English were allowed but no formal presentations were made. Results Our method has been evaluated using feedback data from three annual events held from 2016 to 2018: 100% of participants indicated that they liked the format "very much"(76.0%) or "quite a lot"(24.0%); 80.4% found the topics "very interesting" and 75.9% found it "very easy" to ask questions. Free text comments revealed themes of 'hope' and 'altruism'. Researchers also reported benefits from participation such as learning about patient' priorities and networking. Conclusion "Meet the Researchers" provides a unique opportunity for mesothelioma researchers and patients, relatives and carers to interact on a more equal footing. It stimulates discussion, promotes understanding and provides a more informal setting for non-professional participants to ask questions. It is a format that could easily be adapted for use in other conditions

Design Principles for Ligand-Sensing, Conformation-Switching Ribozymes

Nucleic acid sensor elements are proving increasingly useful in biotechnology and biomedical applications. A number of ligand-sensing, conformational-switching ribozymes (also known as allosteric ribozymes or aptazymes) have been generated by some combination of directed evolution or rational design. Such sensor elements typically fuse a molecular recognition domain (aptamer) with a catalytic signal generator (ribozyme). Although the rational design of aptazymes has begun to be explored, the relationships between the thermodynamics of aptazyme conformational changes and aptazyme performance in vitro and in vivo have not been examined in a quantitative framework. We have therefore developed a quantitative and predictive model for aptazymes as biosensors in vitro and as riboswitches in vivo. In the process, we have identified key relationships (or dimensionless parameters) that dictate aptazyme performance, and in consequence, established equations for precisely engineering aptazyme function. In particular, our analysis quantifies the intrinsic trade-off between ligand sensitivity and the dynamic range of activity. We were also able to determine how in vivo parameters, such as mRNA degradation rates, impact the design and function of aptazymes when used as riboswitches. Using this theoretical framework we were able to achieve quantitative agreement between our models and published data. In consequence, we are able to suggest experimental guidelines for quantitatively predicting the performance of aptazyme-based riboswitches. By identifying factors that limit the performance of previously published systems we were able to generate immediately testable hypotheses for their improvement. The robust theoretical framework and identified optimization parameters should now enable the precision design of aptazymes for biotechnological and clinical applications

Analyzing GPCR-Ligand Interactions with the Fragment Molecular Orbital (FMO) Method

G-protein-coupled receptors (GPCRs) have enormous physiological and biomedical importance, and therefore it is not surprising that they are the targets of many prescribed drugs. Further progress in GPCR drug discovery is highly dependent on the availability of protein structural information. However, the ability of X-ray crystallography to guide the drug discovery process for GPCR targets is limited by the availability of accurate tools to explore receptor-ligand interactions. Visual inspection and molecular mechanics approaches cannot explain the full complexity of molecular interactions. Quantum mechanics (QM) approaches are often too computationally expensive to be of practical use in time-sensitive situations, but the fragment molecular orbital (FMO) method offers an excellent solution that combines accuracy, speed, and the ability to reveal key interactions that would otherwise be hard to detect. Integration of GPCR crystallography or homology modelling with FMO reveals atomistic details of the individual contributions of each residue and water molecule toward ligand binding, including an analysis of their chemical nature. Such information is essential for an efficient structure-based drug design (SBDD) process. In this chapter, we describe how to use FMO in the characterization of GPCR-ligand interactions

Mechanisms of Allergen-Antibody Interaction of Cockroach Allergen Bla g 2 with Monoclonal Antibodies That Inhibit IgE Antibody Binding

BACKGROUND: Cockroach allergy is strongly associated with asthma, and involves the production of IgE antibodies against inhaled allergens. Reports of conformational epitopes on inhaled allergens are limited. The conformational epitopes for two specific monoclonal antibodies (mAb) that interfere with IgE antibody binding were identified by X-ray crystallography on opposite sites of the quasi-symmetrical cockroach allergen Bla g 2. METHODOLOGY/PRINCIPAL FINDINGS: Mutational analysis of selected residues in both epitopes was performed based on the X-ray crystal structures of the allergen with mAb Fab/Fab' fragments, to investigate the structural basis of allergen-antibody interactions. The epitopes of Bla g 2 for the mAb 7C11 or 4C3 were mutated, and the mutants were analyzed by SDS-PAGE, circular dichroism, and/or mass spectrometry. Mutants were tested for mAb and IgE antibody binding by ELISA and fluorescent multiplex array. Single or multiple mutations of five residues from both epitopes resulted in almost complete loss of mAb binding, without affecting the overall folding of the allergen. Preventing glycosylation by mutation N268Q reduced IgE binding, indicating a role of carbohydrates in the interaction. Cation-π interactions, as well as electrostatic and hydrophobic interactions, were important for mAb and IgE antibody binding. Quantitative differences in the effects of mutations on IgE antibody binding were observed, suggesting heterogeneity in epitope recognition among cockroach allergic patients. CONCLUSIONS/SIGNIFICANCE: Analysis by site-directed mutagenesis of epitopes identified by X-ray crystallography revealed an overlap between monoclonal and IgE antibody binding sites and provided insight into the B cell repertoire to Bla g 2 and the mechanisms of allergen-antibody recognition, including involvement of carbohydrates

Characterizing Protein-Protein Interactions with the Fragment Molecular Orbital Method

Proteins are vital components of living systems, serving as building blocks, molecular machines, enzymes, receptors, ion channels, sensors, and transporters. Protein-protein interactions (PPIs) are a key part of their function. There are more than 645,000 reported disease-relevant PPIs in the human interactome, but drugs have been developed for only 2% of these targets. The advances in PPI-focused drug discovery are highly dependent on the availability of structural data and accurate computational tools for analysis of this data. Quantum mechanical approaches are often too expensive computationally, but the fragment molecular orbital (FMO) method offers an excellent solution that combines accuracy, speed and the ability to reveal key interactions that would otherwise be hard to detect. FMO provides essential information for PPI drug discovery, namely, identification of key interactions formed between residues of two proteins, including their strength (in kcal/mol) and their chemical nature (electrostatic or hydrophobic). In this chapter, we have demonstrated how three different FMO-based approaches (pair interaction energy analysis (PIE analysis), subsystem analysis (SA) and analysis of protein residue networks (PRNs)) have been applied to study PPI in three protein-protein complexes