Restless Legs Syndrome-associated intronic common variant in Meis1 alters enhancer function in the developing telencephalon

This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported).-- et al.Genome-wide association studies (GWAS) identified the MEIS1 locus for Restless Legs Syndrome (RLS), but causal single nucleotide polymorphisms (SNPs) and their functional relevance remain unknown. This locus contains a large number of highly conserved noncoding regions (HCNRs) potentially functioning as cis-regulatory modules. We analyzed these HCNRs for allele-dependent enhancer activity in zebrafish and mice and found that the risk allele of the lead SNP rs12469063 reduces enhancer activity in the Meis1 expression domain of the murine embryonic ganglionic eminences (GE). CREB1 binds this enhancer and rs12469063 affects its binding in vitro. In addition, MEIS1 target genes suggest a role in the specification of neuronal progenitors in the GE, and heterozygous Meis1-deficient mice exhibit hyperactivity, resembling the RLS phenotype. Thus, in vivo and in vitro analysis of a common SNP with small effect size showed allele-dependent function in the prospective basal ganglia representing the first neurodevelopmental region implicated in RLS.The project was supported by Fritz-Thyssen-Stiftung, Cologne, Germany (10.09.2.146; 10.12.2.183), KKF-TUM (8766156), DAAD (0811963), and COST (“HOX and TALE homeoproteins in Development and Disease”). B.S. was partially supported by DFG grants (WI 1820/4-1; WI 1820/5-1) and a TUM-Excellence stipend. The KORA study was financed by the Helmholtz Zentrum München, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. KORA research was supported within the Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. J.L.G.-S. and F.C. acknowledge funding of the Spanish and the Andalusian Governments and the Feder program for grants (BFU2010-14839, BFU2009-07044, CSD2007-00008, and Proyectos de Excelencia CVI-3488 and CVI 2658). This work was funded in part by a grant from the German Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research (DZD), to the German Mouse Clinic (Infrafrontier: 01KX1012), to the German Center for Neurodegenerative Diseases (DZNE), Germany; by the Initiative and Networking Fund of the Helmholtz Association in the framework of the Helmholtz Alliance for Mental Research in an Ageing Society (HA-215); and the Munich Cluster for Systems Neurology (EXC 1010 SyNergy) and its Collaborative Research Center (CRC) 870/2 “Assembly and Function of Neuronal Circuits.”Peer Reviewe

CMView: Interactive contact map visualization and analysis

Summary: Contact maps are a valuable visualization tool in structural biology. They are a convenient way to display proteins in two dimensions and to quickly identify structural features such as domain architecture, secondary structure and contact clusters. We developed a tool called CMView which integrates rich contact map analysis with 3D visualization using PyMol. Our tool provides functions for contact map calculation from structure, basic editing, visualization in contact map and 3D space and structural comparison with different built-in alignment methods. A unique feature is the interactive refinement of structural alignments based on user selected substructures. Availability: CMView is freely available for Linux, Windows and MacOS. The software and a comprehensive manual can be downloaded from http://www.bioinformatics.org/cmview/. The source code is licensed under the GNU General Public License. Contact: [email protected], [email protected]

Perspective: lessons from COVID-19 of countries in the European region in light of findings from the health system response monitor

Introduction: Decision-makers initially had limited data to inform their policy responses to the COVID-19 pandemic. The research community developed several online databases to track cases, deaths, and hospitalizations; however, a major deficiency was the lack of detailed information on how health systems were responding to the pandemic and how they would need to be transformed going forward. Approach: In an eort to fill this information gap, in March 2020, the European Observatory on Health Systems and Policies, the WHO European Regional Oce and the European Commission created the COVID-19 Health System Response Monitor (HSRM) to collect and organise up-to-date information on how health systems, mainly in the WHO European Region, were responding to the COVID-19 pandemic. Findings: The HSRM analysis and broader Observatory work on COVID-19 shone light on a range of health system challenges and weaknesses and catalogued policy options countries put in place during the pandemic to address these. Countries prioritised policies on investing in public health, supporting the workforce, maintaining financial stability, and strengthening governance in their response to COVID-19. Outlook: COVID-19 is likely to continue to impact health systems for the foreseeable future; the ability to cope with this pressure, and other shocks, depends on having good information on what other countries have done so that health systems develop adequate policy options. In support of this, the country information on the COVID-19 HSRM will remain available as a repository to inform decision makers on options for actions and possible measures against COVID-19 and other public health emergencies. Building on its previous work on health systems resilience, the European Observatory on Health Systems and Policies will sustain its focus on analysing key issues relate to the recovery from the pandemic and making health systems more resilient. This includes policy knowledge transfer between countries and systematic resilience testing, aiming at contributing to an improved understanding of health system response, recovery, and preparedness. Contribution to the literature in non-technical language: The COVID-19 Health System Response Monitor (HSRM) was the first database in the WHO European Region to collect and organise up-to-date information on how health systems were responding to the COVID-19 pandemic. The HSRM provides a repository of policies which can be used to inform decision makers in health and other policy domains on options for action and possible measures against COVID-19 and other public health emergencies. This initiative proved particularly valuable, especially during the early phases of the pandemic, when there was limited information for countries to draw on as they formulated their own policy response to the pandemic. Our perspectives paper highlights some key challenges within health systems that the HSRM was able to identify during the pandemic and considers policy options countries put in place in response. Our research contributes to literature on emergency responses and recovery, health systems performance assessment, particularly health system resilience, and showcases the Observatory experience on how to design such a data collection tool, as well as how to leverage its findings to support cross-country learning

Perspective: Lessons from COVID-19 of countries in the European region in light of findings from the health system response monitor

IntroductionDecision-makers initially had limited data to inform their policy responses to the COVID-19 pandemic. The research community developed several online databases to track cases, deaths, and hospitalizations; however, a major deficiency was the lack of detailed information on how health systems were responding to the pandemic and how they would need to be transformed going forward.ApproachIn an effort to fill this information gap, in March 2020, the European Observatory on Health Systems and Policies, the WHO European Regional Office and the European Commission created the COVID-19 Health System Response Monitor (HSRM) to collect and organise up-to-date information on how health systems, mainly in the WHO European Region, were responding to the COVID-19 pandemic.FindingsThe HSRM analysis and broader Observatory work on COVID-19 shone light on a range of health system challenges and weaknesses and catalogued policy options countries put in place during the pandemic to address these. Countries prioritised policies on investing in public health, supporting the workforce, maintaining financial stability, and strengthening governance in their response to COVID-19.OutlookCOVID-19 is likely to continue to impact health systems for the foreseeable future; the ability to cope with this pressure, and other shocks, depends on having good information on what other countries have done so that health systems develop adequate policy options. In support of this, the country information on the COVID-19 HSRM will remain available as a repository to inform decision makers on options for actions and possible measures against COVID-19 and other public health emergencies. Building on its previous work on health systems resilience, the European Observatory on Health Systems and Policies will sustain its focus on analysing key issues related to the recovery from the pandemic and making health systems more resilient. This includes policy knowledge transfer between countries and systematic resilience testing, aiming at contributing to an improved understanding of health system response, recovery, and preparedness.Contribution to the literature in non-technical languageThe COVID-19 Health System Response Monitor (HSRM) was the first database in the WHO European Region to collect and organise up-to-date information on how health systems were responding to the COVID-19 pandemic. The HSRM provides a repository of policies which can be used to inform decision makers in health and other policy domains on options for action and possible measures against COVID-19 and other public health emergencies. This initiative proved particularly valuable, especially during the early phases of the pandemic, when there was limited information for countries to draw on as they formulated their own policy response to the pandemic. Our perspectives paper highlights some key challenges within health systems that the HSRM was able to identify during the pandemic and considers policy options countries put in place in response. Our research contributes to literature on emergency responses and recovery, health systems performance assessment, particularly health system resilience, and showcases the Observatory experience on how to design such a data collection tool, as well as how to leverage its findings to support cross-country learning

Predictors of social leisure activities in older Europeans with and without multimorbidity

Older people spend much time participating in leisure activities, such as taking part in organized activities and going out, but the extent of participation may differ according to both individual and environmental resources available. Chronic health problems become more prevalent at higher ages and likely necessitate tapping different resources to maintain social participation. This paper compares predictors of participation in social leisure activities between older people with and those without multimorbidity. The European Project on Osteoarthritis (EPOSA) was conducted in Germany, UK, Italy, The Netherlands, Spain and Sweden (N = 2942, mean age 74.2 (5.2)). Multivariate regression was used to predict social leisure participation and degree of participation in people with and without multimorbidity. Fewer older people with multimorbidity participated in social leisure activities (90.6 %), compared to those without multimorbidity (93.9 %). The frequency of participation was also lower compared to people without multimorbidity. Higher socioeconomic status, widowhood, a larger network of friends, volunteering, transportation possibilities and having fewer depressive symptoms were important for (the degree of) social leisure participation. Statistically significant differences between the multimorbidity groups were observed for volunteering and driving a car, which were more important predictors of participation in those with multimorbidity. In contrast, self-reported income appeared more important for those without multimorbidity, compared to those who had multimorbidity. Policies focusing on social (network of friends), physical (physical performance) and psychological factors (depressive symptoms) and on transportation possibilities are recommended to enable all older people to participate in social leisure activities

Variant recurrence confirms the existence of a FBXO31-related spastic-dystonic cerebral palsy syndrome

The role of genetics in the causation of cerebral palsy has become the focus of many studies aiming to unravel the heterogeneous etiology behind this frequent neurodevelopmental disorder. A recent paper reported two unrelated children with a clinical diagnosis of cerebral palsy, who carried the same de novo c.1000G \u3e A (p.Asp334Asn) variant in FBXO31, encoding a widely studied tumor suppressor not previously implicated in monogenic disease. We now identified a third individual with the recurrent FBXO31 de novo missense variant, featuring a spastic-dystonic phenotype. Our data confirm a link between variant FBXO31 and an autosomal dominant neurodevelopmental disorder characterized by prominent motor dysfunction

Association between usual dietary intake of food groups and DNA methylation and effect modification by metabotype in the KORA FF4 cohort

Associations between diet and DNA methylation may vary among subjects with different metabolic states, which can be captured by clustering populations in metabolically homogenous subgroups, called metabotypes. Our aim was to examine the relationship between habitual consumption of various food groups and DNA methylation as well as to test for effect modification by metabotype. A cross-sectional analysis of participants (median age 58 years) of the population-based prospective KORA FF4 study, habitual dietary intake was modeled based on repeated 24-h diet recalls and a food frequency questionnaire. DNA methylation was measured using the Infinium MethylationEPIC BeadChip providing data on >850,000 sites in this epigenome-wide association study (EWAS). Three metabotype clusters were identified using four standard clinical parameters and BMI. Regression models were used to associate diet and DNA methylation, and to test for effect modification. Few significant signals were identified in the basic analysis while many significant signals were observed in models including food group-metabotype interaction terms. Most findings refer to interactions of food intake with metabotype 3, which is the metabotype with the most unfavorable metabolic profile. This research highlights the importance of the metabolic characteristics of subjects when identifying associations between diet and white blood cell DNA methylation in EWAS

Identification of Autophagy as a Functional Target Suitable for the Pharmacological Treatment of Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN) In Vitro

Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a relentlessly progressive neurodegenerative disorder caused by mutations in the C19orf12 gene. C19orf12 has been implicated in playing a role in lipid metabolism, mitochondrial function, and autophagy, however, the precise functions remain unknown. To identify new robust cellular targets for small compound treatments, we evaluated reported mitochondrial function alterations, cellular signaling, and autophagy in a large cohort of MPAN patients and control fibroblasts. We found no consistent alteration of mitochondrial functions or cellular signaling messengers in MPAN fibroblasts. In contrast, we found that autophagy initiation is consistently impaired in MPAN fibroblasts and show that C19orf12 expression correlates with the amount of LC3 puncta, an autophagy marker. Finally, we screened 14 different autophagy modulators to test which can restore this autophagy defect. Amongst these compounds, carbamazepine, ABT-737, LY294002, oridonin, and paroxetine could restore LC3 puncta in the MPAN fibroblasts, identifying them as novel potential therapeutic compounds to treat MPAN. In summary, our study confirms a role for C19orf12 in autophagy, proposes LC3 puncta as a functionally robust and consistent readout for testing compounds, and pinpoints potential therapeutic compounds for MPAN.</p