Accurate template-based modeling in CASP12 using the IntFOLD4-TS, ModFOLD6, and ReFOLD methods.

Our aim in CASP12 was to improve our Template-Based Modeling (TBM) methods through better model selection, accuracy self-estimate (ASE) scores and refinement. To meet this aim, we developed two new automated methods, which we used to score, rank, and improve upon the provided server models. Firstly, the ModFOLD6_rank method, for improved global Quality Assessment (QA), model ranking and the detection of local errors. Secondly, the ReFOLD method for fixing errors through iterative QA guided refinement. For our automated predictions we developed the IntFOLD4-TS protocol, which integrates the ModFOLD6_rank method for scoring the multiple-template models that were generated using a number of alternative sequence-structure alignments. Overall, our selection of top models and ASE scores using ModFOLD6_rank was an improvement on our previous approaches. In addition, it was worthwhile attempting to repair the detected errors in the top selected models using ReFOLD, which gave us an overall gain in performance. According to the assessors' formula, the IntFOLD4 server ranked 3rd/5th (average Z-score > 0.0/-2.0) on the server only targets, and our manual predictions (McGuffin group) ranked 1st/2nd (average Z-score > -2.0/0.0) compared to all other groups.

IntFOLD: an integrated server for modelling protein structures and functions from amino acid sequences.

IntFOLD is an independent web server that integrates our leading methods for structure and function prediction. The server provides a simple unified interface that aims to make complex protein modelling data more accessible to life scientists. The server web interface is designed to be intuitive and integrates a complex set of quantitative data, so that 3D modelling results can be viewed on a single page and interpreted by non-expert modellers at a glance. The only required input to the server is an amino acid sequence for the target protein. Here we describe major performance and user interface updates to the server, which comprises an integrated pipeline of methods for: tertiary structure prediction, global and local 3D model quality assessment, disorder prediction, structural domain prediction, function prediction and modelling of protein-ligand interactions. The server has been independently validated during numerous CASP (Critical Assessment of Techniques for Protein Structure Prediction) experiments, as well as being continuously evaluated by the CAMEO (Continuous Automated Model Evaluation) project. The IntFOLD server is available at: http://www.reading.ac.uk/bioinf/IntFOLD/.

Disorder Prediction Methods, Their Applicability to Different Protein Targets and Their Usefulness for Guiding Experimental Studies.

The role and function of a given protein is dependent on its structure. In recent years, however, numerous studies have highlighted the importance of unstructured, or disordered regions in governing a protein's function. Disordered proteins have been found to play important roles in pivotal cellular functions, such as DNA binding and signalling cascades. Studying proteins with extended disordered regions is often problematic as they can be challenging to express, purify and crystallise. This means that interpretable experimental data on protein disorder is hard to generate. As a result, predictive computational tools have been developed with the aim of predicting the level and location of disorder within a protein. Currently, over 60 prediction servers exist, utilizing different methods for classifying disorder and different training sets. Here we review several good performing, publicly available prediction methods, comparing their application and discussing how disorder prediction servers can be used to aid the experimental solution of protein structure. The use of disorder prediction methods allows us to adopt a more targeted approach to experimental studies by accurately identifying the boundaries of ordered protein domains so that they may be investigated separately, thereby increasing the likelihood of their successful experimental solution.

Feasibility of Acquiring Neuroimaging Data from Adults with Acquired Brain Injuries before and after a Yoga Intervention.

BACKGROUND: To date, no one has prospectively evaluated yoga intervention-induced changes in brain structure or function in adults with acquired brain injuries (ABI). Thus, this study was conducted to test the feasibility of acquiring neuroimaging data from adults with ABI before and after a yoga intervention. METHODS: This was a single-arm intervention feasibility study that included 12 adults with chronic (i.e., greater than 6 months post-injury) ABI and self-reported limitations in balance. Neuroimaging data were acquired before and after yoga. The yoga intervention was completed once per week for eight weeks. Feasibility objectives and benchmarks were established a priori. RESULTS: Most feasibility objectives and benchmarks were achieved. The goal of recruiting 12 participants was successfully achieved, and 75% of participants were retained throughout the study (goal of 80%). All imaging feasibility benchmarks were met; rs-fMRI and fNIRS data were acquired safely, data were of acceptable quality, and data pre-processing procedures were successful. Additionally, improvements were detected in balance after yoga, as group-level balance was significantly better post-yoga compared to pre-yoga, p = 0.043. CONCLUSIONS: These findings indicate it is feasible to acquire neuroimaging data from adults with ABI before and after a yoga intervention. Thus, future prospective studies are warranted.

Coming and going: dietetic students' experience of their education.

PURPOSE: Nutrition students' expectations for and experiences of their education were explored, as was the influence of the educational process on the students. METHODS: In this qualitative research guided by a phenomenological approach, eight students in the first year and six in the final year of an undergraduate program completed semi-structured interviews. RESULTS: Although the students were diverse in terms of age, ethnicity, and class background, all stated that they wanted to become dietitians. Our findings illuminate the ways in which dietetic education influences students' relationship with food, their bodies, bodies of knowledge, and family and friends. Professionalization, as initiated through discourse, necessitates a particular loss of relationship with the self. Although students enter with an awareness of professional norms and discourses, their education fosters an identity shift based on the kinds of nutrition knowledge and discourses they are learning, as these are performed by educators. CONCLUSIONS: Acknowledging that an embodied curriculum has an impact on professionalization is important for educators and students because education is a critical site for developing a professional identity; this identity then influences how dietitians practise. This research has implications for recruitment language, professional practice curricula, faculty development, the scholarship of teaching and learning, and ongoing support for students as they enter practice contexts.

Heat shock protein-based therapy as a potential candidate for treating the sphingolipidoses.

Lysosomal storage diseases (LSDs) often manifest with severe systemic and central nervous system (CNS) symptoms. The existing treatment options are limited and have no or only modest efficacy against neurological manifestations of disease. We demonstrate that recombinant human heat shock protein 70 (HSP70) improves the binding of several sphingolipid-degrading enzymes to their essential cofactor bis(monoacyl)glycerophosphate in vitro. HSP70 treatment reversed lysosomal pathology in primary fibroblasts from 14 patients with eight different LSDs. HSP70 penetrated effectively into murine tissues including the CNS and inhibited glycosphingolipid accumulation in murine models of Fabry disease (Gla(-/-)), Sandhoff disease (Hexb(-/-)), and Niemann-Pick disease type C (Npc1(-/-)) and attenuated a wide spectrum of disease-associated neurological symptoms in Hexb(-/-) and Npc1(-/-) mice. Oral administration of arimoclomol, a small-molecule coinducer of HSPs that is currently in clinical trials for Niemann-Pick disease type C (NPC), recapitulated the effects of recombinant human HSP70, suggesting that heat shock protein-based therapies merit clinical evaluation for treating LSDs.