Introduction to Markov state modeling with the PyEMMA software — v1.0

This tutorial provides an introduction to the construction of Markov models of molec- ular kinetics from molecular dynamics trajectory data with the PyEMMA software. Using tutorial notebooks, we will guide the user through the basic functionality as well as the more common advanced mechanisms. Short exercises to self check the learning progress and a notebook on troubleshooting complete this basic introduction

Navigating protein landscapes with a machine-learned transferable coarse-grained model

The most popular and universally predictive protein simulation models employ all-atom molecular dynamics (MD), but they come at extreme computational cost. The development of a universal, computationally efficient coarse-grained (CG) model with similar prediction performance has been a long-standing challenge. By combining recent deep learning methods with a large and diverse training set of all-atom protein simulations, we here develop a bottom-up CG force field with chemical transferability, which can be used for extrapolative molecular dynamics on new sequences not used during model parametrization. We demonstrate that the model successfully predicts folded structures, intermediates, metastable folded and unfolded basins, and the fluctuations of intrinsically disordered proteins while it is several orders of magnitude faster than an all-atom model. This showcases the feasibility of a universal and computationally efficient machine-learned CG model for proteins

Consequences of chronic diseases and other limitations associated with old age - A scoping review

Funding Information: This work supported in part by the LTC INTER COST, Evaluation of the Potential for Reducing Health and Social Expenses for Elderly People Using the Smart Environment, through the Ministry of Education, Youth and Sports, Czech Republic, under Project LTC18035; and in part by the project of Excellence, University of Hradec Kralove, FIM, Czech Republic (ID: 2205–2019). First author – Petra Maresova is principle investigator of LTC18035 INTER COST project, from which Petra Maresova, Ondrej Krejcar and Kamil Kuca are funded for all expenses including personal costs. Ehsan Javanmardi is funded from project of Excellence ID: 2205–2019 for personal costs. Sabina Barakovic, Jasmina Barakovic Husic and Signe Tomsone are members of COST ACTION 16226 of which also Petra Maresova and Ondrej Krejcar are paticipants, while this article also ACKnowledge this project CA16226. Funding Information: The authors would like to hereby acknowledge COST Action CA16226 for their networking support. The Indoor Living Space Improvement: Smart Habitat for the Elderly played a role of networking platform for knowledge sharing and interchanging ideas for joint research and publication, what was the base for creating this study. Based on CA16226 project LTC18035 INTER COST was proposed for national funding support of COST ACTION Framework. COST is a funding agency that helps innovation and research networks. Our Action was instrumental in connecting research programmes throughout the EU region. Their contribution has made it possible for scientists to connect with each other and share their ideas and findings. This allows for more research and better innovation. More information can be found at www.cost.eu. The authors would also like to acknowledge the Excellence 2019 internal research project, Faculty of Informatics and Management, University of Hradec Kralove, Czech Republic. Publisher Copyright: © 2019 The Author(s).Background: The phenomenon of the increasing number of ageing people in the world is arguably the most significant economic, health and social challenge that we face today. Additionally, one of the major epidemiologic trends of current times is the increase in chronic and degenerative diseases. This paper tries to deliver a more up to date overview of chronic diseases and other limitations associated with old age and provide a more detailed outlook on the research that has gone into this field. Methods: First, challenges for seniors, including chronic diseases and other limitations associated with old age, are specified. Second, a review of seniors' needs and concerns is performed. Finally, solutions that can improve seniors' quality of life are discussed. Publications obtained from the following databases are used in this scoping review: Web of Science, PubMed, and Science Direct. Four independent reviewers screened the identified records and selected relevant publications published from 2010 to 2017. A total of 1916 publications were selected. In all, 52 papers were selected based on abstract content. For further processing, 21 full papers were screened." Results: The results indicate disabilities as a major problem associated with seniors' activities of daily living dependence. We founded seven categories of different conditions - psychological problems, difficulties in mobility, poor cognitive function, falls and incidents, wounds and injuries, undernutrition, and communication problems. In order to minimize ageing consequences, some areas require more attention, such as education and training; technological tools; government support and welfare systems; early diagnosis of undernutrition, cognitive impairment, and other diseases; communication solutions; mobility solutions; and social contributions. Conclusions: This scoping review supports the view on chronic diseases in old age as a complex issue. To prevent the consequences of chronic diseases and other limitations associated with old age related problems demands multicomponent interventions. Early recognition of problems leading to disability and activities of daily living (ADL) dependence should be one of essential components of such interventions.publishersversionPeer reviewe

Importance of Post-Translational Modifications for Functionality of a Chloroplast-Localized Carbonic Anhydrase (CAH1) in Arabidopsis thaliana

Background: The Arabidopsis CAH1 alpha-type carbonic anhydrase is one of the few plant proteins known to be targeted to the chloroplast through the secretory pathway. CAH1 is post-translationally modified at several residues by the attachment of N-glycans, resulting in a mature protein harbouring complex-type glycans. The reason of why trafficking through this non-canonical pathway is beneficial for certain chloroplast resident proteins is not yet known. Therefore, to elucidate the significance of glycosylation in trafficking and the effect of glycosylation on the stability and function of the protein, epitope-labelled wild type and mutated versions of CAH1 were expressed in plant cells. Methodology/Principal Findings: Transient expression of mutant CAH1 with disrupted glycosylation sites showed that the protein harbours four, or in certain cases five, N-glycans. While the wild type protein trafficked through the secretory pathway to the chloroplast, the non-glycosylated protein formed aggregates and associated with the ER chaperone BiP, indicating that glycosylation of CAH1 facilitates folding and ER-export. Using cysteine mutants we also assessed the role of disulphide bridge formation in the folding and stability of CAH1. We found that a disulphide bridge between cysteines at positions 27 and 191 in the mature protein was required for correct folding of the protein. Using a mass spectrometric approach we were able to measure the enzymatic activity of CAH1 protein. Under circumstances where protein N-glycosylation is blocked in vivo, the activity of CAH1 is completely inhibited. Conclusions/Significance: We show for the first time the importance of post-translational modifications such as N-glycosylation and intramolecular disulphide bridge formation in folding and trafficking of a protein from the secretory pathway to the chloroplast in higher plants. Requirements for these post-translational modifications for a fully functional native protein explain the need for an alternative route to the chloroplast.This work was supported by the Swedish Research Council (VR), the Kempe Foundations and Carl Tryggers Foundation to GS, and grant numbers BIO2006-08946 and BIO2009-11340 from the Spanish Ministerio de Ciencia e Innovación (MICINN) to A