Power provides protection : genetic robustness in yeast depends on the capacity to generate energy

The functional basis of genetic robustness, the ability of organisms to suppress the effects of mutations, remains incompletely understood. We exposed a set of 15 strains of Saccharomyces cerevisiae form diverse environments to increasing doses of the chemical mutagen EMS. The number of the resulting random mutations was similar for all tested strains. However, there were differences in immediate mortality after the mutagenic treatment and in defective growth of survivors. An analysis of gene expression revealed that immediate mortality was lowest in strains with lowest expression of transmembrane proteins, which are rich in thiol groups and thus vulnerable to EMS. A signal of genuine genetic robustness was detected for the other trait, the ability to grow well despite bearing non-lethal mutations. Increased tolerance of such mutations correlated with high expression of genes responsible for the oxidative energy metabolism, suggesting that the negative effect of mutations can be buffered if enough energy is available. We confirmed this finding in three additional tests of the ability to grow on (i) fermentable or non-fermentable sources of carbon, (ii) under chemical inhibition of the electron transport chain and (iii) during overexpression of its key component, cytochrome c. Our results add the capacity to generate energy as a general mechanism of genetic robustness

Advanced Electrocardiographic Predictors of Sudden Death in Familial Dysautonomia

To identify accurate predictors for the risk of sudden death in patients with familial dysautonomia (FD). Ten-minute resting high-fidelity 12-lead ECGs were obtained from 14 FD patients and 14 age/gender-matched healthy subjects. Multiple conventional and advanced ECG parameters were studied for their ability to predict sudden death in FD over a subsequent 4.5-year period, including multiple indices of linear and non-linear heart rate variability (HRV); QT variability; waveform complexity; high frequency QRS; and derived Frank-lead parameters. Four of the 14 FD patients died suddenly during the follow-up period, usually with concomitant pulmonary disorder. The presence of low vagally-mediated HRV was the ECG finding most predictive of sudden death. Concomitant left ventricular hypertrophy and other ECG abnormalities such as increased QTc and JTc intervals, spatial QRS-T angles, T-wave complexity, and QT variability were also present in FD patients, suggesting that structural heart disease is fairly common in FD. Although excessive or unopposed cardiac vagal (relative to sympathetic) activity has been postulated as a contributor to sudden death in FD, the presence of low vagally-mediated HRV was paradoxically the best predictor of sudden death. However, we suggest that low vagally-mediated HRV be construed not as a direct cause of sudden death in FD, but rather as an effect of concurrent pathological processes, especially hypoxia due to pulmonary disorders and sleep apnea, that themselves increase the risk of sudden death in FD and simultaneously diminish HRV. We speculate that adenosine may play a role in sudden death in FD, possibly independently of vagal activity, and that adenosine inhibitors such as theophylline might therefore be useful as prophylaxis in this disorder

The Rat Genome Database Pathway Portal

The set of interacting molecules collectively referred to as a pathway or network represents a fundamental structural unit, the building block of the larger, highly integrated networks of biological systems. The scientific community's interest in understanding the fine details of how pathways work, communicate with each other and synergize, and how alterations in one or several pathways may converge into a disease phenotype, places heightened demands on pathway data and information providers. To meet such demands, the Rat Genome Database [(RGD) http://rgd.mcw.edu] has adopted a multitiered approach to pathway data acquisition and presentation. Resources and tools are continuously added or expanded to offer more comprehensive pathway data sets as well as enhanced pathway data manipulation, exploration and visualization capabilities. At RGD, users can easily identify genes in pathways, see how pathways relate to each other and visualize pathways in a dynamic and integrated manner. They can access these and other components from several entry points and effortlessly navigate between them and they can download the data of interest. The Pathway Portal resources at RGD are presented, and future directions are discussed

Clinical autonomic nervous system laboratories in Europe. A joint survey of the European Academy of Neurology and the European Federation of Autonomic Societies

Background and purpose: Disorders of the autonomic nervous system (ANS) are common conditions, but it is unclear whether access to ANS healthcare provision is homogeneous across European countries. The aim of this study was to identify neurology-driven or interdisciplinary clinical ANS laboratories in Europe, describe their characteristics and explore regional differences. Methods: We contacted the European national ANS and neurological societies, as well as members of our professional network, to identify clinical ANS laboratories in each country and invite them to answer a web-based survey. Results: We identified 84 laboratories in 22 countries and 46 (55%) answered the survey. All laboratories perform cardiovascular autonomic function tests, and 83% also perform sweat tests. Testing for catecholamines and autoantibodies are performed in 63% and 56% of laboratories, and epidermal nerve fiber density analysis in 63%. Each laboratory is staffed by a median of two consultants, one resident, one technician and one nurse. The median (interquartile range [IQR]) number of head-up tilt tests/laboratory/year is 105 (49–251). Reflex syncope and neurogenic orthostatic hypotension are the most frequently diagnosed cardiovascular ANS disorders. Thirty-five centers (76%) have an ANS outpatient clinic, with a median (IQR) of 200 (100–360) outpatient visits/year; 42 centers (91%) also offer inpatient care (median 20 [IQR 4–110] inpatient stays/year). Forty-one laboratories (89%) are involved in research activities. We observed a significant difference in the geographical distribution of ANS services among European regions: 11 out of 12 countries from North/West Europe have at least one ANS laboratory versus 11 out of 21 from South/East/Greater Europe (p = 0.021). Conclusions: This survey highlights disparities in the availability of healthcare services for people with ANS disorders across European countries, stressing the need for improved access to specialized care in South, East and Greater Europe

Alliance of Genome Resources Portal: unified model organism research platform

The Alliance of Genome Resources (Alliance) is a consortium of the major model organism databases and the Gene Ontology that is guided by the vision of facilitating exploration of related genes in human and well-studied model organisms by providing a highly integrated and comprehensive platform that enables researchers to leverage the extensive body of genetic and genomic studies in these organisms. Initiated in 2016, the Alliance is building a central portal (www.alliancegenome.org) for access to data for the primary model organisms along with gene ontology data and human data. All data types represented in the Alliance portal (e.g. genomic data and phenotype descriptions) have common data models and workflows for curation. All data are open and freely available via a variety of mechanisms. Long-term plans for the Alliance project include a focus on coverage of additional model organisms including those without dedicated curation communities, and the inclusion of new data types with a particular focus on providing data and tools for the non-model-organism researcher that support enhanced discovery about human health and disease. Here we review current progress and present immediate plans for this new bioinformatics resource

Alliance of Genome Resources Portal: unified model organism research platform

The Alliance of Genome Resources (Alliance) is a consortium of the major model organism databases and the Gene Ontology that is guided by the vision of facilitating exploration of related genes in human and well-studied model organisms by providing a highly integrated and comprehensive platform that enables researchers to leverage the extensive body of genetic and genomic studies in these organisms. Initiated in 2016, the Alliance is building a central portal (www.alliancegenome.org) for access to data for the primary model organisms along with gene ontology data and human data. All data types represented in the Alliance portal (e.g. genomic data and phenotype descriptions) have common data models and workflows for curation. All data are open and freely available via a variety of mechanisms. Long-term plans for the Alliance project include a focus on coverage of additional model organisms including those without dedicated curation communities, and the inclusion of new data types with a particular focus on providing data and tools for the non-model-organism researcher that support enhanced discovery about human health and disease. Here we review current progress and present immediate plans for this new bioinformatics resource

EFAS/EAN survey on the influence of the COVID-19 pandemic on European clinical autonomic education and research

© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Purpose: To understand the influence of the coronavirus disease 2019 (COVID-19) pandemic on clinical autonomic education and research in Europe. Methods: We invited 84 European autonomic centers to complete an online survey, recorded the pre-pandemic-to-pandemic percentage of junior participants in the annual congresses of the European Federation of Autonomic Societies (EFAS) and European Academy of Neurology (EAN) and the pre-pandemic-to-pandemic number of PubMed publications on neurological disorders. Results: Forty-six centers answered the survey (55%). Twenty-nine centers were involved in clinical autonomic education and experienced pandemic-related didactic interruptions for 9 (5; 9) months. Ninety percent (n = 26/29) of autonomic educational centers reported a negative impact of the COVID-19 pandemic on education quality, and 93% (n = 27/29) established e-learning models. Both the 2020 joint EAN-EFAS virtual congress and the 2021 (virtual) and 2022 (hybrid) EFAS and EAN congresses marked higher percentages of junior participants than in 2019. Forty-one respondents (89%) were autonomic researchers, and 29 of them reported pandemic-related trial interruptions for 5 (2; 9) months. Since the pandemic begin, almost half of the respondents had less time for scientific writing. Likewise, the number of PubMed publications on autonomic topics showed the smallest increase compared with other neurological fields in 2020-2021 and the highest drop in 2022. Autonomic research centers that amended their trial protocols for telemedicine (38%, n = 16/41) maintained higher clinical caseloads during the first pandemic year. Conclusions: The COVID-19 pandemic had a substantial negative impact on European clinical autonomic education and research. At the same time, it promoted digitalization, favoring more equitable access to autonomic education and improved trial design.info:eu-repo/semantics/publishedVersio

The Gene Ontology knowledgebase in 2023

The Gene Ontology (GO) knowledgebase (http://geneontology.org) is a comprehensive resource concerning the functions of genes and gene products (proteins and noncoding RNAs). GO annotations cover genes from organisms across the tree of life as well as viruses, though most gene function knowledge currently derives from experiments carried out in a relatively small number of model organisms. Here, we provide an updated overview of the GO knowledgebase, as well as the efforts of the broad, international consortium of scientists that develops, maintains, and updates the GO knowledgebase. The GO knowledgebase consists of three components: (1) the GO-a computational knowledge structure describing the functional characteristics of genes; (2) GO annotations-evidence-supported statements asserting that a specific gene product has a particular functional characteristic; and (3) GO Causal Activity Models (GO-CAMs)-mechanistic models of molecular "pathways" (GO biological processes) created by linking multiple GO annotations using defined relations. Each of these components is continually expanded, revised, and updated in response to newly published discoveries and receives extensive QA checks, reviews, and user feedback. For each of these components, we provide a description of the current contents, recent developments to keep the knowledgebase up to date with new discoveries, and guidance on how users can best make use of the data that we provide. We conclude with future directions for the project