Search

Ecuador has one of the most progressive constitutions in Latin America. It defines the state as plurinational and guarantees collective rights to Indigenous people and even to Nature itself. At the same time, the oil sector has been of strategic importance and “national interest” to both right‐ and left‐wing governments for the last decades, contributing with its rents and revenues to around one‐third of the state coffers. Therefore, the extractivist model remains unchallenged and still promises development—while reproducing systemic inequalities and a “continuum of violence.” In June 2022, the Indigenous movement called for a nationwide strike to draw attention to the socio‐economic crisis following the pandemic. The authorities harshly repressed the mobilization and a racializing media discourse demarcated the “Indigenous” agenda from the needs of “all Ecuadorians,” classifying the protesters as “terrorists” and thus, a threat to the nation. Drawing on ethnographic research, this article discusses the role of extractivism in social mobilization. Exploring the future of social protest in Ecuador in the face of new pressures like climate change and the energy transition, it argues that extractivist patterns will change globally and amplify social discontent and mobilization.

Introduction: Connected landscapes can increase the effectiveness of protected areas by facilitating individual movement and gene flow between populations, thereby increasing the persistence of species even in fragmented habitats. Connectivity planning is often based on modeling connectivity for a limited number of species, i.e., “connectivity umbrellas”, which serve as surrogates for co-occurring species. Connectivity umbrellas are usually selected a priori, based on a few life history traits and often without evaluating other species. Methods: We developed a quantitative method to identify connectivity umbrellas at multiple scales. We demonstrate the approach on the terrestrial large mammal community (24 species) in continental Europe at two scales: 13 geographic biomes and 36 ecoregions, and evaluate the interaction of landscape characteristics on the selection of connectivity umbrellas. Results: We show that the number, identity, and attributes of connectivity umbrellas are sensitive to spatial scale and human influence on the landscape. Multiple species were selected as connectivity umbrellas in 92% of the geographic biomes (average of 4.15 species) and 83% of the ecoregions (average of 3.16 species). None of the 24 species evaluated is by itself an effective connectivity umbrella across its entire range. We identified significant interactions between species and landscape attributes. Species selected as connectivity umbrellas in regions with low human influence have higher mean body mass, larger home ranges, longer dispersal distances, smaller geographic ranges, occur at lower population densities, and are of higher conservation concern than connectivity umbrellas in more human-influenced regions. More species are required to meet connectivity targets in regions with high human influence (average of three species) in comparison to regions with low human influence (average of 1.67 species). Discussion: We conclude that multiple species selected in relation to l

Neurodevelopmental disorders (NDDs), including severe pediatric epilepsy, autism, and intellectual disabilities are heterogeneous conditions in which clinical genetic testing can often identify a pathogenic variant. For many of them, genetic therapies will be tested in this or the coming years in clinical trials. In contrast to first-generation symptomatic treatments, the new disease-modifying precision medicines require a genetic test-informed diagnosis before a patient can be enrolled in a clinical trial. However, even in 2022, most identified genetic variants in NDD genes are ‘Variants of Uncertain Significance’. To safely enroll patients in precision medicine clinical trials, it is important to increase our knowledge about which regions in NDD-associated proteins can ‘tolerate’ missense variants and which ones are ‘essential’ and will cause a NDD when mutated. In addition, knowledge about functionally indispensable regions in the three-dimensional (3D) structure context of proteins can also provide insights into the molecular mechanisms of disease variants. We developed a novel consensus approach that overlays evolutionary, and population based genomic scores to identify 3D essential sites (Essential3D) on protein structures. After extensive benchmarking of AlphaFold predicted and experimentally solved protein structures, we generated the currently largest expert curated protein structure set for 242 NDDs and identified 14,377 Essential3D sites across 189 gene disorders associated proteins. We demonstrate that the consensus annotation of Essential3D sites improves prioritization of disease mutations over single annotations. The identified Essential3D sites were enriched for functional features such as intermembrane regions or active sites and discovered key inter-molecule interactions in protein complexes that were otherwise not annotated. Using the currently largest autism, developmental disorders, and epilepsies exome sequencing studies including >360,000 NDD

Pathogenic copy number variants (CNVs) can cause a heterogeneous spectrum of rare and severe disorders. However, most CNVs are benign and are part of natural variation in human genomes. CNV pathogenicity classification, genotype-phenotype analyses, and therapeutic target identification are challenging and time-consuming tasks that require the integration and analysis of information from multiple scattered sources by experts.Here, we introduce the CNV-ClinViewer, an open-source web-application for clinical evaluation and visual exploration of CNVs. The application enables real-time interactive exploration of large CNV datasets in a user-friendly designed interface and facilitates semi-automated clinical CNV interpretation following the ACMG guidelines by integrating the ClassifCNV tool. In combination with clinical judgment the application enables clinicians and researchers to formulate novel hypotheses and guide their decision-making process. Subsequently, the CNV-ClinViewer enhances for clinical investigators patient care and for basic scientists translational genomic research.The web-application is freely available at https://cnv-ClinViewer.broadinstitute.org and the open-source code can be found at https://github.com/LalResearchGroup/CNV-clinviewer.Supplementary data are available at Bioinformatics online.

Biallelic mutations in PINK1/PRKN cause recessive Parkinson’s disease. Given the established role of PINK1/Parkin in regulating mitochondrial dynamics, we explored mitochondrial DNA (mtDNA) integrity and inflammation as disease modifiers in carriers of mutations in these genes. MtDNA integrity was investigated in a large collection of biallelic (n = 84) and monoallelic (n = 170) carriers of PINK1/PRKN mutations, idiopathic Parkinson’s disease patients (n = 67) and controls (n = 90). In addition, we studied global gene expression and serum cytokine levels in a subset. Affected and unaffected PINK1/PRKN monoallelic mutation carriers can be distinguished by heteroplasmic mtDNA variant load (AUC = 0.83, CI:0.74-0.93). Biallelic PINK1/PRKN mutation carriers harbor more heteroplasmic mtDNA variants in blood (p = 0.0006, Z = 3.63) compared to monoallelic mutation carriers. This enrichment was confirmed in iPSC-derived (controls, n = 3; biallelic PRKN mutation carriers, n = 4) and postmortem (control, n = 1; biallelic PRKN mutation carrier, n = 1) midbrain neurons. Lastly, the heteroplasmic mtDNA variant load correlated with IL6 levels in PINK1/PRKN mutation carriers (r = 0.57, p = 0.0074). PINK1/PRKN mutations predispose individuals to mtDNA variant accumulation in a dose- and disease-dependent manner.

Purpose The majority of missense variants in clinical genetic tests are classified as variants of uncertain significance. Broadening the evidence of the PS1 and PM5 criteria has the potential to increase conclusive variant interpretation. Methods We hypothesized that incorporation of pathogenic missense variants in conserved residues across paralogous genes can increase the number of variants where ACMG PS1/PM5 criteria can be applied. We mapped over 2.5 million pathogenic and general population variants from ClinVar, HGMD, and gnomAD databases onto 9,990 genes and aligned these by gene families. Subsequently, we developed a novel framework to extend PS1/PM5 by incorporating pathogenic paralogous variants annotations (para-PS1/PM5). Results We demonstrate that para-PS1/PM5 criteria increase the number of classifiable amino acids 3.6-fold compared to PS1 and PM5. Across all gene families with at least two disease-associated genes, the calculated likelihood ratios suggest moderate evidence for pathogenicity. Moreover, for 36 genes, the extended para-PS1/PM5 criteria reach strong evidence level. Conclusion We show that single pathogenic paralogous variants incorporation at paralogous protein positions increases the applicability of the PS1 and PM5 criteria, likely leading to a reduction of variants of uncertain significance across many monogenic disorders. Future iterations of the ACMG guidelines may consider para-PS1 and para-PM5.

Pseudomonas aeruginosa (PA) is an opportunistic human pathogen, which is involved in a wide range of dangerous infections. It develops alarming resistances toward antibiotic treatment. Therefore, alternative strategies, which suppress pathogenicity or synergize with antibiotic treatments are in great need to combat these infections more effectively. One promising approach is to disarm the bacteria by interfering with their quorum sensing (QS) system, which regulates the release of various virulence factors as well as biofilm formation. Herein, this work reports the rational design, optimization, and in-depth profiling of a new class of Pseudomonas quinolone signaling receptor (PqsR) inverse agonists. The resulting frontrunner compound features a pyrimidine-based scaffold, high in vitro and in vivo efficacy, favorable pharmacokinetics as well as clean safety pharmacology characteristics, which provide the basis for potential pulmonary as well as systemic routes of administration. An X-ray crystal structure in complex with PqsR facilitated further structure-guided lead optimization. The compound demonstrates potent pyocyanin suppression, synergizes with aminoglycoside antibiotic tobramycin against PA biofilms, and is active against a panel of clinical isolates from bronchiectasis patients. Importantly, this in vitro effect translated into in vivo efficacy in a neutropenic thigh infection model in mice providing a proof-of-principle for adjunctive treatment scenarios.

Invasive alien species are one of the major threats to global biodiversity, ecosystem integrity, nature's contributions to people and human health. While scenarios about potential future developments have been available for other global change drivers for quite some time, we largely lack an understanding of how biological invasions might unfold in the future across spatial scales. Based on previous work on global invasion scenarios, we developed a workflow to downscale global scenarios to a regional and policy-relevant context. We applied this workflow at the European scale to create four European scenarios of biological invasions until 2050 that consider different environmental, socio-economic and socio-cultural trajectories, namely the European Alien Species Narratives (Eur-ASNs). We compared the Eur-ASNs with their previously published global counterparts (Global-ASNs), assessing changes in 26 scenario variables. This assessment showed a high consistency between global and European scenarios in the logic and assumptions of the scenario variables. However, several discrepancies in scenario variable trends were detected that could be attributed to scale differences. This suggests that the workflow is able to capture scale-dependent differences across scenarios. We also compared the Global- and Eur-ASNs with the widely used Global and European Shared Socioeconomic Pathways (SSPs), a set of scenarios developed in the context of climate change to capture different future socio-economic trends. Our comparison showed considerable divergences in the scenario space occupied by the different scenarios, with overall larger differences between the ASNs and SSPs than across scales (global vs. European) within the scenario initiatives. Given the differences between the ASNs and SSPs, it seems that the SSPs do not adequately capture the scenario space relevant to understanding the complex future of biological invasions. This underlines the importance of developing independent b

To effectively cope with the intermittency of VRE, power systems will need different flexibility options. The future portfolio of flexibility options will differ among countries, as it will be determined by the political, economic, social, technological, legal, and environmental factors of a country. Thus, some countries might have a greater need for flexibility options than others. Generation and expansion planning for renewable power systems on a national level are complex and require large long-term investments. Therefore, it is crucial to estimate the "need for flexibility" in energy systems from a macro-level. By assessing relevant indicators (e.g., economic) and different boundary conditions (e.g., VRE capacity), power system planners, policymakers, operators, and regulators can evaluate the need for flexibility in power systems and prioritize the needed actions. Published research and international reports do not refer to the countries with the highest need for flexibility options in respective power systems. In this regard, the aim of this paper is to answer the following question: "Which countries in the world have the highest need for flexibility options from a macro-energy systems point of view?" To answer our question, first, we have identified relevant indicators from the literature that can help us to estimate the "need for flexibility" in national power systems. Second, we weighed the different indicators according to their importance by using the analytical hierarchy process (AHP) of the multi-criteria decision analysis (MCDA) process. Finally, this paper proposes a “global index for flexibility need” using these indicators. As for the results, countries were ranked in this index based on indicators and already show us the promising countries with the top 10 dominated by European countries. This index works as a macro-level assessment framework that provides the comparative position of countries with regard to the need for flexibility. This index wil

Biallelic mutations in PINK1/PRKN cause recessive Parkinson’s disease. Given the established role of PINK1/Parkin in regulating mitochondrial dynamics, we explored mitochondrial DNA (mtDNA) integrity and inflammation as disease modifiers in carriers of mutations in these genes. MtDNA integrity was investigated in a large collection of biallelic (n = 84) and monoallelic (n = 170) carriers of PINK1/PRKN mutations, idiopathic Parkinson’s disease patients (n = 67) and controls (n = 90). In addition, we studied global gene expression and serum cytokine levels in a subset. Affected and unaffected PINK1/PRKN monoallelic mutation carriers can be distinguished by heteroplasmic mtDNA variant load (AUC = 0.83, CI:0.74-0.93). Biallelic PINK1/PRKN mutation carriers harbor more heteroplasmic mtDNA variants in blood (p = 0.0006, Z = 3.63) compared to monoallelic mutation carriers. This enrichment was confirmed in iPSC-derived (controls, n = 3; biallelic PRKN mutation carriers, n = 4) and postmortem (control, n = 1; biallelic PRKN mutation carrier, n = 1) midbrain neurons. Lastly, the heteroplasmic mtDNA variant load correlated with IL6 levels in PINK1/PRKN mutation carriers (r = 0.57, p = 0.0074). PINK1/PRKN mutations predispose individuals to mtDNA variant accumulation in a dose- and disease-dependent manner.

There are different flexibility options to align power systems to volatile feed-in of renewable electricity sources. The flexibility options differ in the dimensions of time, spatiality, and resource type. To make policy decisions on future energy systems, it is necessary to get a top-down indication of how much power system flexibility is needed. With the ongoing energy transition, there is yet no comprehensive overview of indicators that describe which dimension of flexibility will be necessary to what extent for different energy systems. Therefore, this paper provides a first overview of indicators that can be used to assess the necessity of power system flexibility. Thus, we do a systematic literature review to identify indicators that allow us to estimate the necessity of power system flexibility. We conduct a meta-analysis of these indicators and categorize them as indicators that either stand for an increasing or decreasing necessity of power system flexibility. Our paper can help inform policy, assess needed changes to system operations, increase stakeholder acceptance and investor confidence in implementing new technology and measures.

Co-authored research articles in the disciplinarily heterogeneous field of higher education have dramatically increased in this century, largely driven, as in other fields, by rising international co-authorships. We examine this evolving international collaboration network in higher education research over two decades. To do so, we apply automated bibliometric topic identification and social network analysis of 9,067 papers in 13 core higher education journals (1998–2018). Remarkable expansion in the volume of papers and co-authorships has, surprisingly, not resulted in a more diverse network. Rather, existing co-authorship patterns are strengthened, with the dominance of scholars from a few Anglophone countries largely maintained. Researchers globally seek to co-author with leading scholars in these countries, especially the US, UK, and Australia—at least when publishing in the leading general HE journals based there. Further, the two-mode social network analysis of countries and topics suggests that while Anglophone countries have led the development of higher education research, China and Germany, as leading research-producing countries, are increasingly influential within this world-spanning network. Topically, the vast majority of co-authored papers in higher education research focuses on individual-level phenomena, with organizational and system-level or country-level analysis constituting a (much) smaller proportion, despite policymakers’ emphasis on cross-national comparisons and the growing importance of university actorhood. We discuss implications thereof for the future of the multidisciplinary higher education field.

Purpose Large copy number variants (CNVs) can cause a heterogeneous spectrum of rare and severe disorders. However, most CNVs are benign and are part of natural variation in human genomes. CNV pathogenicity classification, genotype-phenotype analyses, and therapeutic target identification are challenging and time-consuming tasks that require the integration and analysis of information from multiple scattered sources by experts. Methods We developed a web-application combining >250,000 patient and population CNVs together with a large set of biomedical annotations and provide tools for CNV classification based on ACMG/ClinGen guidelines and gene-set enrichment analyses. Results Here, we introduce the CNV-ClinViewer (https://cnv-ClinViewer.broadinstitute.org), an open-source web-application for clinical evaluation and visual exploration of CNVs. The application enables real-time interactive exploration of large CNV datasets in a user-friendly designed interface. Conclusion Overall, this resource facilitates semi-automated clinical CNV interpretation and genomic loci exploration and, in combination with clinical judgment, enables clinicians and researchers to formulate novel hypotheses and guide their decision-making process. Subsequently, the CNV-ClinViewer enhances for clinical investigators patient care and for basic scientists translational genomic research.

Flexibility has risen as a potential solution and complement for system operators’ current and future problems (e.g., congestion, voltage) caused by integrating distributed renewable resources (e.g., wind, solar) and electric vehicles. In parallel, local flexibility markets (LFM) emerge as a possible smart grid solution to bridge between flexibility-seeking customers and flexibility-offering customers in localized areas. Nevertheless, there is no unique, standard, or simple solution to tackle all the problems system operators and other energy actors face. Therefore, many local flexibility market concepts, initiatives (projects), and companies have developed various solutions over the last few years. At the same time, they increased the complexity of the topic. Thus, this research paper aims to describe several local flexibility market concepts, initiatives (projects), and companies in Europe. To do so, we propose a taxonomy derived from LFMs descriptions. We use the taxonomy-building research method proposed by [1] to develop our taxonomy. Moreover, we use the smart grid architecture model (SGAM) as a structural and foundation guideline. Given the numerous and diverse LFM solutions, we delimit the taxonomy by considering solutions focused on congestion management on medium and low voltage (meta-characteristic).

The energy transition into a modern power system requires energy flexibility. Demand Response (DR) is one promising option for providing this flexibility. With the highest share of final energy consumption, the industry has the potential to offer DR and contribute to the energy transition by adjusting its energy demand. This paper proposes a mathematical optimization model that uses a generic data model for flexibility description. The optimization model supports industrial companies to select when (i.e., at which time), where (i.e., in which market), and how (i.e., the schedule) they should market their flexibility potential to optimize profit. We evaluate the optimization model under several synthetic use cases developed upon the learnings over several workshops and bilateral discussions with industrial partners from the paper and aluminum industry. The results of the optimization model evaluation suggest the model can fulfill its purpose under different use cases even with complex use cases such as various loads and storages. However, the optimization model computation time grows as the complexity of use cases grows.

We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel NaV1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups could be identified: 1) Benign familial infantile epilepsy (BFIE) (n = 15, normal cognition, treatable seizures), 2) intermediate epilepsy (n = 33, mild ID, partially pharmaco-responsive), 3) developmental and epileptic encephalopathy (DEE, n = 177, severe ID, majority pharmaco-resistant), 4) generalized epilepsy (n = 20, mild to moderate ID, frequently with absence seizures), 5) unclassifiable epilepsy (n = 127), and 6) neurodevelopmental disorder without epilepsy (n = 20, mild to moderate ID). Groups 1–3 presented with focal or multifocal seizures (median age of onset: four months) and focal epileptiform discharges, whereas the onset of seizures in group 4 was later (median: 42 months) with generalized epileptiform discharges. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin-insensitive human NaV1.6 channels and whole-cell patch-clamping. Two variants causing DEE showed a strong gain-of-function (GOF, hyperpolarising shift of steady-state activation, strongly increased neuronal firing rate), and one variant causing BFIE or intermediate epilepsy showed a mild GOF (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (LOF, reduced current amplitudes, depolarising shift of steady-state activation, reduced neuronal firing). Including previous studies, functional effects were known for 170 individuals. All 136 individuals carrying a functionally tested GOF variant had either focal (97, groups 1–3), or unclassifiable epilepsy (39), whereas 34 with a LOF variant had either generalized (14), no

Many epilepsy-associated genes have been identified over the last three decades, revealing a remarkable molecular heterogeneity with the shared outcome of recurrent seizures. Information about the genetic landscape of epilepsies is scattered throughout the literature and answering the simple question of how many genes are associated with epilepsy is not straightforward. Here, we present a computationally driven analytical review of epilepsy-associated genes using the complete scientific literature in PubMed. Based on our search criteria, we identified a total of 738 epilepsy-associated genes. We further classified these genes into two Tiers. A broad gene list of 738 epilepsy-associated genes (Tier 2) and a narrow gene list composed of 143 epilepsy-associated genes (Tier 1). Our search criteria do not reflect the degree of association. The average yearly number of identified epilepsy-associated genes between 1992 and 2021 was 4.8. However, most of these genes were only identified in the last decade (2010–2019). Ion channels represent the largest class of epilepsy-associated genes. For many of these, both gain- and loss-of-function effects have been associated with epilepsy in recent years. We identify 28 genes frequently reported with heterogenous variant effects which should be considered for variant interpretation. Overall, our study provides an updated and manually curated list of epilepsy-related genes together with additional annotations and classifications reflecting the current genetic landscape of epilepsy.

Species introduced through human-related activities beyond their native range, termed alien species, have various impacts worldwide. The IUCN Environmental Impact Classification for Alien Taxa (EICAT) is a global standard to assess negative impacts of alien species on native biodiversity. Alien species can also positively affect biodiversity (for instance, through food and habitat provisioning or dispersal facilitation) but there is currently no standardized and evidence-based system to classify positive impacts. We fill this gap by proposing EICAT+, which uses 5 semiquantitative scenarios to categorize the magnitude of positive impacts, and describes underlying mechanisms. EICAT+ can be applied to all alien taxa at different spatial and organizational scales. The application of EICAT+ expands our understanding of the consequences of biological invasions and can inform conservation decisions.

It is well established that quizzing fosters learning. However, some gaps in the literature relating to the fit of quizzing to learner characteristics and learner perceptions during quizzing still need to be addressed. The present study focuses on two of these aspects: achievement motives and perceptions of cognitive load. First, quizzing entails that learners’ performance is judged against some standard of excellence. This might make it appealing and effective for learners with high hope of success and low fear of failure in particular. Second, it is an open question whether providing quiz questions that are adapted to learners’ perceived level of cognitive load during quizzing would be beneficial. To address these questions, we randomly assigned learners to either non-adaptive quizzing, adaptive quizzing, or note-taking. We found that quizzing benefits concerning learning outcomes were moderated by hope of success. Furthermore, the adaptation via cognitive load ratings substantially increased the quizzing effect.

Volunteering plays a central role in cultural and arts education in rural areas in Germany. However, a decrease in the number of volunteers in structurally weak regions can be observed in recent years. This poses existential challenges for cultural and arts education. The promotion of social networks and regional cooperation, as well as a sense of place, can counteract this decline. This article aims to explore how sense of place influence cooperation and thus social networks between actors of different institutions in the context of cultural and arts education in rural areas. A total of 34 interviews and egocentric network maps were conducted with different local actors (e.g., volunteers in the theatre association, mayors, etc.) in four municipalities. The data were analysed using qualitative content analysis. Our results show that, through active participation in cultural events and associations, new cooperation is created and maintained, which also expands the social network. This active participation can be positively influenced by the existing attachment to the region and cultural places.

The peptidyl-prolyl-cis/trans-isomerase (PPIase) macrophage infectivity potentiator (Mip) contributes to the pathogenicity and fitness of L. pneumophila, the causative agent of Legionnaires’ disease. Here, we identified the stringent starvation protein SspB, hypothetical protein Lpc2061, and flagellin FlaA as bacterial interaction partners of Mip. The macrolide FK506, which inhibits the PPIase activity of Mip, interfered with the binding of Lpc2061. Moreover, we demonstrated that the N-terminal dimerization region and amino acid Y185 in the C-terminal PPIase domain of Mip are required for the binding of Lpc2061 and FlaA. The modeling of the interaction partners and global docking with Mip suggested nonoverlapping binding interfaces, and a molecular dynamic simulation predicted an increased stability for the tripartite interaction of Lpc2061, Mip, and FlaA. On the functional level, we demonstrated that Mip promotes L. pneumophila flagellation, which is positively influenced by the binding of Lpc2061 and reduced by FK506. Also, L. pneumophila mutants expressing the Y185A or the monomeric Mip variant, which bind less Lpc2061, were nonmotile, were less flagellated, and yielded less FlaA when quantified. To our knowledge, this is the first report in which a PPIase and its bacterial interaction partners were demonstrated to influence flagellation.

Fungi and bacteria often engage in complex interactions, such as the formation of multicellular biofilms within the human body. Knowledge about how interkingdom biofilms initiate and coalesce into higher-level communities and which functions the different species carry out during biofilm formation remain limited. We found native-state assemblages of Candida albicans (fungi) and Streptococcus mutans (bacteria) with highly structured arrangement in saliva from diseased patients with childhood tooth decay. Further analyses revealed that bacterial clusters are attached within a network of fungal yeasts, hyphae, and exopolysaccharides, which bind to surfaces as a preassembled cell group. The interkingdom assemblages exhibit emergent functions, including enhanced surface colonization and growth rate, stronger tolerance to antimicrobials, and improved shear resistance, compared to either species alone. Notably, we discovered that the interkingdom assemblages display a unique form of migratory spatial mobility that enables fast spreading of biofilms across surfaces and causes enhanced, more extensive tooth decay. Using mutants, selective inactivation of species, and selective matrix removal, we demonstrate that the enhanced stress resistance and surface mobility arise from the exopolymeric matrix and require the presence of both species in the assemblage. The mobility is directed by fungal filamentation as hyphae extend and contact the surface, lifting the assemblage with a “forward-leaping motion.” Bacterial cell clusters can “hitchhike” on this mobile unit while continuously growing, to spread across the surface three-dimensionally and merge with other assemblages, promoting community expansion. Together, our results reveal an interkingdom assemblage in human saliva that behaves like a supraorganism, with disease-causing emergent functionalities that cannot be achieved without coassembly.

INTRODUCTION The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. RATIONALE To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. RESULTS We identified 369 nominally genome-wide significant loci (P < 5 × 10−8) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 360 loci for which replication data were available, 241 loci influencing surface area and 66 influencing thickness remained significant after replication, with 237 loci passing multiple testing correction (P < 8.3 × 10−10; 187 influencing surface area and 50 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness; surface area and thickness showed a negative genetic correlation (rG = −0.32, SE = 0.05, P = 6.5 × 10−12), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When co

In this article we discuss the contribution of digitalisation for equal participation in higher education. Its potential is often postulated, but accessibility is seldom examined in this context. Despite the challenges and difficulties created in the summer term of 2020, this semester has provided a great opportunity to collect data on digital teaching, as face‐to‐face teaching needed to be transformed into digital teaching. Based on two surveys conducted in the summer of 2020, current practices and students’ needs regarding accessibility are outlined. Despite the circumstances, it can be derived from the surveys that digital teaching generally provides a variety of advantages for students with disabilities, although some tools and platforms remain not fully accessible to them. Additionally, the results indicate that not only students with sensory impairments benefit from the principles of the Web Content Accessibility Guidelines (2018). In particular, the principles ‘operable’ and ‘understandable’ are beneficial for students with mental health difficulties. Regarding the assessment of accessibility features, the study shows that the perception of students with and without impairments is very similar.

Providing quiz questions has emerged as a powerful means to support learning. However, it is still unclear whether adaptive practice quizzing will enhance beneficial effects in authentic contexts. To address this question, university students (N = 188; n = 155 female) were randomly assigned to employ either adaptive practice quizzing, nonadaptive practice quizzing, or note-taking following three consecutive sessions of a standard psychology university lecture for undergraduate pre-service teachers. In the adaptive practice quizzing condition, quiz questions were adapted to learners’ expertise via cognitive demand ratings, whereas in the non-adaptive condition quiz questions followed a fixed sequence. Students in the adaptive practice quizzing condition outperformed those in the nonadaptive condition after a two-week delay, but not after a one-week delay. Exploratory mediation analyses show that performance on the quiz questions during the learning phase seems to be partly responsible for this effect.

peer-reviewed, Introduction: Over 40 million deaths annually are due to noncommunicable diseases, 15 million of these are premature deaths and physical inactivity contributes an estimated 9% to this figure. Global responses have included the Sustainable Development Goals (SDGs) and the Global Action Plan on Physical Activity (GAPPA). Both point to policy action on physical activity (PA) to address change, yet the impact of policy on PA outcomes is unknown. The protocol described outlines the methodology for systematic literature reviews that will be undertaken by the Policy Evaluation Network (PEN) to address this knowledge gap. Methods: The seven best investments for promotion of population PA identified in the Toronto Charter highlighted seven policy domains (schools, transport, urban design, primary health care systems, public education, community-wide programmes and sport) which will form the basis of these PEN reviews. Seven individual scientific literature searches across six electronic databases will be conducted. Each will use the key concepts of policy, PA, evaluation and a distinct concept for each of the seven policy domains. This will be supplemented with a search of the reference list of included articles. Methodological quality will be assessed and overall effectiveness for each included study will be described according to pre-determined criteria. Conclusions: Each review will provide policy makers with a list of policy statements and corresponding actions which the evidence has determined impact on PA directly or indirectly. By collating the evidence, and demonstrating the depth of the science base which informs these policy recommendations, each review will provide guidance to policymakers to use evidence-based or evidenceinformed policies to achieve the 15% relative reduction in physical inactivity as defined by GAPPA., PUBLISHED, peer-reviewed

Objective: De novo missense variants in KCNQ5, encoding the voltage gated K+ channel KV7.5, have been described as a cause of developmental and epileptic encephalopathy (DEE) or intellectual disability (ID). We set out to identify disease-related KCNQ5 variants in genetic generalized epilepsy (GGE) and their underlying mechanisms. Methods: 1292 families with GGE were studied by next-generation sequencing. Whole-cell patch-clamp recordings, biotinylation and phospholipid overlay assays were performed in mammalian cells combined with docking and homology modeling. Results: We identified three deleterious heterozygous missense variants, one truncation and one splice site alteration in five independent families with GGE with predominant absence seizures, two variants were also associated with mild to moderate ID. All three missense variants displayed a strongly decreased current density indicating a loss-of-function (LOF). When mutant channels were co-expressed with wild-type (WT) KV7.5 or KV7.5 and KV7.3 channels, three variants also revealed a significant dominant-negative effect on WT channels. Other gating parameters were unchanged. Biotinylation assays indicated a normal surface expression of the variants. The p.Arg359Cys variant altered PI(4,5)P2-interaction, presumably in the non-conducting preopen-closed state. Interpretation: Our study indicates that specific deleterious KCNQ5 variants are associated with GGE, partially combined with mild to moderate ID. The disease mechanism is a LOF partially with dominant-negative effects through functional, rather than trafficking deficits. LOF of KV7.5 channels will reduce the M-current, likely resulting in increased excitability of KV7.5-expressing neurons. Further studies on a network level are necessary to understand which circuits are affected and how the variants induce generalized seizures.

Speeding up the energy transition in the European Union (EU) is a major task to quickly reduce harmful greenhouse gas emissions. Market design plays a crucial role in the decarbonization of the European energy system, driving the expansion of both Renewable Energy Sources (RES) and accompanying flexibility sources. In particular, demand flexibility by energy-intensive industrial companies can play a key role. By flexibilizing their production processes, industrial companies can contribute to an increased use of variable RES (in the following referred to as Variable Renewable Energy (VRE)) to lower the CO2 footprint of their products with positive effects on economic competitiveness. Together with other flexibility sources like electric vehicles, the EU can transition to a just, low-carbon society and economy with benefits for all. However, to actually realize these benefits, market design must account for the changing production and consumption characteristics, e.g., the intermittency of VRE. Starting with current challenges of the energy transition that need to be solved with a future market designin the EU, the whitepaper takes alternative market design options and recent technological developments into account, which are highly intertwined. The whitepaper elaborates on the role of, for instance, flexibility, digital technologies, market design with locational incentives, and possible transition pathways in a European context. The “Clean energy for all Europeans” package offers a new opportunity to deepen the integration of different national electricity systems, whereby Transmission System Operators (TSOs) are required to reserve at least 70% of transmission capacities for cross-border trades from 2025 onwards. The corresponding scarcity of transmission capacities on the national level, however, may aggravate congestion to a critical extent, calling for transformational changes in market design involving, e.g., a redefinition of bidding zones close to the network

Driven by the climate conference in Paris in December 2015 countries worldwide are confronted with the question of how to shape their power system and how to establish alternative technologies to reduce harmful CO2 emissions. The German government plans that even before the year 2050, all electricity generated and consumed in Germany should be greenhouse gas neutral [1]. To successfully integrate renewable energies, a future energy system must be able to handle the intermittent nature of renewable energy sources such as wind and solar. One important means to address such electricity production variability is demand-side flexibility. Here, industry plays a major role in responding to variable electricity supply with adequate flexibility. This is where the Kopernikus project SynErgie comes in with more than 80 project partners from academia, industry, governmental, and non-governmental organizations as well as energy suppliers and network operators. The Kopernikus project SynErgie investigates how to best leverage demand-side flexibility in the German industry. The current electricity market design in Germany is not well suited to deal with increasing levels of re- newable energy, and it does not embrace demand-side flexibility. Almost 6 GW of curtailed power in 2019 provide evidence that changes are needed with respect to the rules governing electricity markets. These rules were designed at a time when electricity generation was concentrated on a few large and dispatchable conventional power plants and demand was considered inelastic. The SynErgie Cluster IV investigates how a future-proof electricity market design should be organized. The corresponding Work Package IV.3.1 more specifically deals with analyzing and designing allocation and pricing rules on electricity spot markets. The resulting design must be well suited to accommodate demand-side flexibility and address the intermittent nature of important renewable energy sources. This whitepaper is the result of

Background: Burden analysis in epilepsy has shown an excess of deleterious ultra-rare variants (URVs) in few gene-sets, such as known epilepsy genes, constrained genes, ion channel or GABAA receptor genes. We set out to investigate the burden of URVs in a comprehensive range of gene-sets presumed to be implicated in epileptogenesis. Methods: We investigated several constraint and conservation-based strategies to study whole exome sequencing data from European individuals with developmental and epileptic encephalopathies (DEE, n = 1,003), genetic generalized epilepsy (GGE, n = 3,064), and non-acquired focal epilepsy (NAFE, n = 3,522), collected by the Epi25 Collaborative, compared to 3,962 ancestry-matched controls. The burden of 12 URVs types in 92 gene-sets was compared between epilepsy cases (DDE, GGE, NAFE) and controls using logistic regression analysis. Results: Burden analysis of brain-expressed genes revealed an excess of different URVs types in all three epilepsy categories which was largest for constrained missense variants. The URVs burden was prominent in neuron-specific, synaptic and developmental genes as well as genes encoding ion channels and receptors, and it was generally higher for DEE and GGE compared to NAFE. The patterns of URVs burden in gene-sets expressed in inhibitory vs. excitatory neurons or receptors suggested a high burden in both in DEE but a differential involvement of inhibitory genes in GGE, while excitatory genes were predominantly affected in NAFE. Top ranking susceptibility genes from a recent genome-wide association study (GWAS) of generalized and focal epilepsies displayed a higher URVs burden in constrained coding regions in GGE and NAFE, respectively. Conclusions: Using exome-based gene-set burden analysis, we demonstrate that missense URVs affecting mainly constrained sites are enriched in neuronal genes in both common and rare severe epilepsy syndromes. Our results indicate a differential impact of these URVs in genes expres

The mixed‐methods project WeGe investigates key factors for refugees’ integration into pre‐study programs and conditions for successful transitions to higher education institutions (HEIs). In this article, we first examine the dropout intentions of international students and refugee students participating in formal pre‐study programs at German HEIs to disclose both barriers and resources. We use insights from migration research to extend theoretical student dropout models and analyse novel data from a quantitative survey with international and refugee students in pre‐study programs. Our findings show that refugee students intend to drop out from pre‐study programs more often than other international students. This difference disappears when other characteristics are controlled for. Effect decomposition shows that financial problems and perceived exclusion are driving dropout intentions of refugee students, whereas German language use in everyday life and a strong connection to the prospective field of study function as a resource and reduce the dropout risk. Depending on the reference group, deficits or resources of refugee students become apparent. This result suggests that refugees should be addressed as a student group in their own right. As a second step, we analyse qualitative expert interviews to reconstruct the staff’s perspectives on barriers and resources of refugee students to analyse how the driving factors of dropout intentions are represented in their knowledge. In particular, we show if and how this knowledge is used to address refugees and to develop inclusive educational concepts within pre‐study programs.

Countries around the world have emulated Germany’s model of the university devoted to research-based teaching. The independent, extra-university research institute led by a leading “genius” scientist was also developed in Germany. In recent decades, Germany’s research budget and science system continue to be split between its universities, which are relatively underresourced, and institutes enjoying favored sponsorship and significant funding. We argue that Germany could be even more prouctive with stronger support for its research universities.

Climate change and ambitious emission-reduction targets call for an extensive decarbonization of electricity systems, with increasing levels of Renewable Energy Sources (RES) and demand flexibility to balance the variable and intermittent electricity supply. A successful energy transition will lead to an economically and ecologically sustainable future with an affordable, reliable, and carbon-neutral supply of electricity. In order to achieve these objectives, a consistent and enabling market design is required. The Kopernikus Project SynErgie investigates how demand flexibility of the German industry can be leveraged and how a future-proof electricity market design should be organized, with more than 80 project partners from academia, industry, governmental and non-governmental organizations, energy suppliers, and network operators. In our SynErgie Whitepaper Electricity Spot Market Design 2030-2050 [1], we argued for a transition towards Locational Marginal Prices (LMPs) (aka. nodal prices) in Germany in a single step as a core element of a sustainable German energy policy. We motivated a well-designed transition towards LMPs, discussed various challenges, and provided a new perspective on electricity market design in terms of technological opportunities, bid languages, and strategic implications. This second SynErgie Whitepaper Electricity Market Design 2030-2050: Moving Towards Implementation aims at further concretizing the future German market design and provides first guidelines for an implementation of LMPs in Germany. Numerical studies –while not being free of abstractions –give evidence that LMPs generate efficient locational price signals and contribute to manage the complex coordination challenge in (long-term) electricity markets, ultimately reducing price differences between nodes. Spot and derivatives markets require adjustments in order to enable an efficient dispatch and price discovery, while maintaining high liquidity and low transaction costs. Mo

Background KCNC2 encodes a member of the shaw-related voltage-gated potassium channel family (KV3.2), which are important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain.Methods Individuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic and functional analysis. The cases were referred through clinical and research collaborations in our study. Four de novo variants were examined electrophysiologically in Xenopus laevis oocytes.Results We identified novel KCNC2 variants in 27 patients with various forms of epilepsy. Functional analysis demonstrated gain-of-function in severe and loss-of-function in milder phenotypes as the underlying pathomechanisms with specific response to valproic acid.Conclusion These findings implicate KCNC2 as a novel causative gene for epilepsy emphasizing the critical role of KV3.2 in the regulation of brain excitability with an interesting genotype-phenotype correlation and a potential concept for precision medicine.