Pathogenic SCN2A variants cause early-stage dysfunction in patient-derived neurons.

Pathogenic heterozygous variants in SCN2A, which encodes the neuronal sodium channel NaV1.2, cause different types of epilepsy or intellectual disability (ID)/autism without seizures. Previous studies using mouse models or heterologous systems suggest that NaV1.2 channel gain-of-function typically causes epilepsy, whereas loss-of-function leads to ID/autism. How altered channel biophysics translate into patient neurons remains unknown. Here, we investigated iPSC-derived early-stage cortical neurons from ID patients harboring diverse pathogenic SCN2A variants [p.(Leu611Valfs*35); p.(Arg937Cys); p.(Trp1716*)] and compared them with neurons from an epileptic encephalopathy (EE) patient [p.(Glu1803Gly)] and controls. ID neurons consistently expressed lower NaV1.2 protein levels. In neurons with the frameshift variant, NaV1.2 mRNA and protein levels were reduced by ~ 50%, suggesting nonsense-mediated decay and haploinsufficiency. In other ID neurons, only protein levels were reduced implying NaV1.2 instability. Electrophysiological analysis revealed decreased sodium current density and impaired action potential (AP) firing in ID neurons, consistent with reduced NaV1.2 levels. In contrast, epilepsy neurons displayed no change in NaV1.2 levels or sodium current density, but impaired sodium channel inactivation. Single-cell transcriptomics identified dysregulation of distinct molecular pathways including inhibition of oxidative phosphorylation in neurons with SCN2A haploinsufficiency and activation of calcium signaling and neurotransmission in epilepsy neurons. Together, our patient iPSC-derived neurons reveal characteristic sodium channel dysfunction consistent with biophysical changes previously observed in heterologous systems. Additionally, our model links the channel dysfunction in ID to reduced NaV1.2 levels and uncovers impaired AP firing in early-stage neurons. The altered molecular pathways may reflect a homeostatic response to NaV1.2 dysfunction and can guide further investigations.

Rich forests, rich people? Sustainable finance and its links to forests.

Investment products labelled as sustainable, as well as regulations on sustainable finance, such as the EU taxonomy for sustainable activities, are on the rise globally. While some of these products and regulations include forests and forestry, the forest-sustainable finance nexus is largely unexplored in academic research. This paper systematically analyses the emerging expert debate spanning across the financial and forest sectors. We conducted 51 in-depth qualitative interviews with experts from financial institutions, timberland and impact investors, international organizations, civil society organizations and academia. We chose mainly experts from Europe, as one of the regions spearheading the topic globally. Based on these, we identify five main narratives on the nexus between sustainable finance and forests. These narratives are strikingly different regarding such dimensions as emphasis on risks versus opportunities, preference for public versus private governance and investments, as well as on the sustainability of forest-related investments per se. While financial sector experts are mainly concerned about financial risks, and only partially about deforestation risks, forest sector experts with financial expertise promote investment opportunities either for the asset class, or to increase private investment in tropical forests. In contrast, some experts from both the forest and financial sectors explicitly exclude forests as investable assets for the private sector, seeing them instead as pure public goods. We conclude with underlining the importance of more cross-sectoral dialogue, but also research, to both critically assess and advance the role of sustainable finance policy and practice in supporting forest conservation, restoration, and sustainable management.

De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy.

PURPOSE: Developmental and epileptic encephalopathies (DEEs) are severe clinical conditions characterized by stagnation or decline of cognitive and behavioral abilities preceded, accompanied or followed by seizures. Because DEEs are clinically and genetically heterogeneous, next-generation sequencing, especially exome sequencing (ES), is becoming a first-tier strategy to identify the molecular etiologies of these disorders. METHODS: We combined ES analysis and international data sharing. RESULTS: We identified 11 unrelated individuals with DEE and de novo heterozygous truncating variants in the interferon regulatory factor 2-binding protein-like gene (IRF2BPL). The 11 individuals allowed for delineation of a consistent neurodevelopmental disorder characterized by mostly normal initial psychomotor development followed by severe global neurological regression and epilepsy with nonspecific electroencephalogram (EEG) abnormalities and variable central nervous system (CNS) anomalies. IRF2BPL, also known as enhanced at puberty protein 1 (EAP1), encodes a transcriptional regulator containing a C-terminal RING-finger domain common to E3 ubiquitin ligases. This domain is required for its repressive and transactivating transcriptional properties. The variants identified are expected to encode a protein lacking the C-terminal RING-finger domain. CONCLUSIONS: These data support the causative role of truncating IRF2BPL variants in pediatric neurodegeneration and expand the spectrum of transcriptional regulators identified as molecular factors implicated in genetic developmental and epileptic encephalopathies.

[Memorandum IV: Theoretical and Normative Grounding of Health Services Research]. / Memorandum IV: Theoretische und normative Fundierung der Versorgungsforschung.

With Memoranda and other initiatives, the German Network for Health Service Research [Deutsches Netzwerk Versorgungsforschung e.V. (DNVF)] is fostering the methodological quality of care research studies for years. Compared to the standards of empirical research, questions concerning the role and function of theories, theoretical approaches and scientific principles have not been taken up on its own. Therefore, the DNVF e.V. has set up a working group in 2013, which was commissioned to prepare a memorandum on "theories in health care research". This now presented memorandum will primarily challenge scholars in health care services research to pay more attention to questions concerning the theoretical arsenal and the background assumptions in the research process. The foundation in the philosophy of science, the reference to normative principles and the theory-bases of the research process are addressed. Moreover, the memorandum will call on to advance the theorizing in health services research and to strengthen not empirical approaches, research on basic principles or studies with regard to normative sciences and to incorporate these relevant disciplines in health services research. Research structures and funding of health services research needs more open space for theoretical reflection and for self-observation of their own, multidisciplinary research processes.

[Does the Success of Work-related Interventions in the Rehabilitation of Neurological Diseases Depend on the Return-to-Work Prognosis? A Re-analysis of 2 Randomised Controlled Trials]. / Hängt der Erfolg arbeitsbezogener Leistungen in der Rehabilitation neurologischer Erkrankungen von der Wiedereingliederungsprognose ab? Eine Re-Analyse von 2 kontrolliert randomisierten Studien.

OBJECTIVE: The paper examines whether patients with neurological diseases and a poor return to work (RTW) prognosis gain more from work-related medical rehabilitation (WMR). METHODS: Re-analysis of matched samples of 2 randomised controlled trials (N=442; questionnaire at admission of rehabilitation and 15-month follow-up). Linear regression models were used calculating the effect of the WMR dependent on the RTW prognosis. Primary outcome was time of sick leave in the follow-up and physical and mental health measured by the SF-36. As secondary outcomes, strategies of coping skills and work-related attitudes were defined. RESULTS: Only for patients with a high non-RTW risk could positive effects of WMR be demonstrated on mental health, coping skills and the scale "work as a resource". In the 15-month follow-up, there were no differences in effects on duration of sick leave and physical health. CONCLUSIONS: The results based on this analysis indicate that patients with neurological diseases derive benefit from WMR only if their empirical RTW prognosis is poor. However, this only applies for the mental health in the medium term. Our study confirms the previous findings that suggest different effectiveness of the WMR for patients with different RTW risk.