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The Mariana Trough is the youngest back‐arc basin in a series of basins and arcs that developed behind the Mariana subduction zone in the western Pacific. Active seafloor spreading is ongoing at a spreading axis close to the Mariana Arc, resulting in a pronounced asymmetric configuration (double rate to the west 2:1) at 17°N. The formation of back‐arc basins is controlled by the subducting slab, which regulates the temporal development of mantle flow, entrainment of fluids, and hydrous melts together with the magma generation. To better understand the formation process of back‐arc basin asymmetry in the central Mariana Trough, we combined 2‐D P‐wave traveltime tomography results with high‐resolution bathymetric data. Here, we show that the crust in the central Mariana Trough is 6.5–9.5 km thick, which is unusually thick for oceanic crust. While the lower crust exhibits average seismic velocities of 6.5–7.2 km/s, high‐velocity anomalies occur at the margins of the Mariana Trough, indicating that magmatic accretion was affected by hydrous melting during rifting. While the Mariana Trough developed from a rather symmetric rifting (0.89:1) to a strongly asymmetric seafloor spreading stage (5.33:1), the contribution of hydrous melts declined and the opening direction changed at ∼5 Ma. Asymmetric basin opening is potentially driven by the far‐field stress effect of the subduction zones on the western boundary of the Philippine Sea Plate. Plain Language Summary: The Mariana Trough is a young ocean basin that formed above the Mariana subduction zone in the western Pacific Ocean. Active seafloor spreading occurs close to the Mariana Arc, resulting in an asymmetric shape of the basin at ∼17°N. The opening of back‐arc basins is controlled by the downgoing plate in the subduction zone, which also affects how magma and fluids move in the mantle. To understand how the Mariana Trough formed and what caused the asymmetric shape, we used seismic subsurface imaging and detailed mapping techniques of the seafloor. The crust is 6.5–9.5 km thick, and seismic waves travel through the lower crust at normal speed for the oceanic crust. The fact that seismic waves travel faster at the basin margins suggests that magma was influenced by fluid‐rich‐molten rocks during early formation. As the Mariana Trough developed over time, it changed from a more symmetrical rift configuration to a very asymmetrical seafloor spreading. This change affected the amount of water‐induced melting and changed the direction and speed at which the seafloor spread apart. The asymmetry is likely caused by an additional pull from the subduction zones on the western margin of the Philippine Sea Plate. Key Points: The Central Mariana Trough developed from rather symmetric rifting (0.89:1) to a strongly asymmetric seafloor spreading stage (5.33:1)Strong crustal variability with unusual thickness indicates temporal heterogeneity of the mantle compositionSeismic high‐velocity zones at the basin margins indicate that magma generation was affected by slab‐derived hydrous fluids and/or melts [ABSTRACT FROM AUTHOR]

Selenium-dependent glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis, preventing unrestrained (phospho)lipid peroxidation by reducing phospholipid hydroperoxides (PLOOH). However, the contribution of other phospholipid peroxidases in ferroptosis protection remains unclear. We show that cells lacking GPX4 still exhibit substantial PLOOH-reducing capacity, suggesting a contribution of alternative PLOOH peroxidases. By scrutinizing potential candidates, we found that although overexpression of peroxiredoxin 6 (PRDX6), a thiol-specific antioxidant enzyme with reported PLOOH-reducing activity, failed to prevent ferroptosis, its genetic loss sensitizes cancer cells to ferroptosis. Mechanistically, we uncover that PRDX6, beyond its known peroxidase activity, acts as a selenium-acceptor protein, facilitating intracellular selenium utilization and efficient selenium incorporation into selenoproteins, including GPX4. Its physiological significance was demonstrated by reduced GPX4 expression in Prdx6-deficient mouse brains and increased sensitivity to ferroptosis in PRDX6-deficient tumor xenografts in mice. Our study highlights PRDX6 as a critical player in directing cellular selenium utilization and dictating ferroptosis sensitivity., Competing Interests: Declaration of interests M.C. is a co-founder and shareholder of ROSCUE Therapeutics GmbH. M.C., B.P., and T.N. hold patents for some of the compounds described herein. M.C. is a member of the journal advisory board., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Studies have shown improvement in overall survival with anti-PD1/PD-L1 molecules in combination with cisplatin/carboplatin and etoposide as a first-line treatment for Small Cell Lung Cancer (SCLC). However, first-line efficacy remains limited and well below that observed in Non-Small Cell Lung Cancer (NSCLC). Etoposide may have a detrimental effect on lymphocyte activation, which could explain the limited benefit of immunotherapy in the first line and the lack of benefit in the second line for patients previously exposed to high levels of etoposide., Methods: We initiated a multicenter, single-arm, open-label phase II study of a chemotherapy regimen with durvalumab, combined with carboplatin and paclitaxel for extensive disease SCLC. Eligible patients will receive durvalumab plus carboplatin and paclitaxel every 3 weeks for up to 4 cycles, followed by durvalumab every 4 weeks until progression or unacceptable toxicity. A total of 67 patients will be enrolled in this study, with a 12-month enrollment period and 36-month follow-up. The primary endpoint is Overall Survival (OS) rate at 12 months. Secondary endpoints are best response rate, OS, OS at 24- and 36 months, progression free survival (PFS), duration of response, quality of life and safety., Results: This study aims to establish the efficacy of durvalumab combined with carboplatin and paclitaxel in patients with extensive disease Small Cell Lung Cancer., Clinical Trial Registration: EU CT: 2023-504670-38-00., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: French intergroup IFCT reports financial support was provided by AstraZeneca Pharmaceuticals LP. Denis Moro-Sibilot reports a relationship with ASTRA ZENECA that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Denis Moro-Sibilot reports a relationship with Bristol Myers Squibb Co that includes: consulting or advisory, funding grants, speaking and lecture fees, and travel reimbursement. Denis Moro-Sibilot reports a relationship with MSD France SAS that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Denis Moro-Sibilot reports a relationship with Roche that includes: consulting or advisory, funding grants, speaking and lecture fees, and travel reimbursement. Virginie Westeel reports a relationship with Roche that includes: funding grants, speaking and lecture fees, and travel reimbursement. Virginie Westeel reports a relationship with MSD France SAS that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Virginie Westeel reports a relationship with ASTRA ZENECA that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Virginie Westeel reports a relationship with Bristol Myers Squibb Co that includes: consulting or advisory, funding grants, speaking and lecture fees, and travel reimbursement. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Glioblastoma (GBM) is the most commonly occurring and most aggressive primary brain tumor. Transcriptomics-based tumor subtype classification has established the mesenchymal lineage of GBM (MES-GBM) as cancers with particular aggressive behavior and high levels of therapy resistance. Previously it was show that Trihexyphenidyl (THP), a market approved M1 muscarinic receptor-targeting oral drug can suppress proliferation and survival of GBM stem cells from the classical transcriptomic subtype. In a series of in vitro experiments, this study confirms the therapeutic potential of THP, by effectively suppressing the growth, proliferation and survival of MES-GBM cells with limited effects on non-tumor cells. Transcriptomic profiling of treated cancer cells identified genes and associated metabolic signaling pathways as possible underlying molecular mechanisms responsible for THP-induced effects. In vivo trials of THP in immunocompromised mice carry orthotopic MES-GBMs showed moderate response to the drug. This study further highlights the potential of THP repurposing as an anti-cancer treatment regimen but mode of action and d optimal treatment procedures for in vivo regimens need to be investigated further., Competing Interests: Authors JA and WW were employed by Experimental Pharmacology and Oncology Berlin-Buch GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Du, Sanin, Shi, Huang, Nickel, Vargas-Toscano, Huo, Nickl-Jockschat, Dumitru, Hu, Duan, Sandalcioglu, Croner, Alcaniz, Walther, Berndt and Kahlert.)

Ferroptosis is a pervasive non-apoptotic form of cell death highly relevant in various degenerative diseases and malignancies. The hallmark of ferroptosis is uncontrolled and overwhelming peroxidation of polyunsaturated fatty acids contained in membrane phospholipids, which eventually leads to rupture of the plasma membrane. Ferroptosis is unique in that it is essentially a spontaneous, uncatalyzed chemical process based on perturbed iron and redox homeostasis contributing to the cell death process, but that it is nonetheless modulated by many metabolic nodes that impinge on the cells' susceptibility to ferroptosis. Among the various nodes affecting ferroptosis sensitivity, several have emerged as promising candidates for pharmacological intervention, rendering ferroptosis-related proteins attractive targets for the treatment of numerous currently incurable diseases. Herein, the current members of a Germany-wide research consortium focusing on ferroptosis research, as well as key external experts in ferroptosis who have made seminal contributions to this rapidly growing and exciting field of research, have gathered to provide a comprehensive, state-of-the-art review on ferroptosis. Specific topics include: basic mechanisms, in vivo relevance, specialized methodologies, chemical and pharmacological tools, and the potential contribution of ferroptosis to disease etiopathology and progression. We hope that this article will not only provide established scientists and newcomers to the field with an overview of the multiple facets of ferroptosis, but also encourage additional efforts to characterize further molecular pathways modulating ferroptosis, with the ultimate goal to develop novel pharmacotherapies to tackle the various diseases associated with - or caused by - ferroptosis., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SJD is a co-founder of Prothegen, Inc. and holds patents related to ferroptosis. XJ is an inventor on patents related to autophagy and cell death and holds equity of and consults for Exarta Therapeutics and Lime Therapeutics. JAO is a member of the scientific advisory board for Vicinitas Therapeutics and has patent applications related to ferroptosis. TP reports grants from Dracen Pharmaceuticals, Kymera Therapeutics, Bristol-Myers Squibb, Agios Pharmaceuticals, personal fees from Vividion Therapeutics, Tohoku University, and personal fees from Faeth Therapeutics outside the submitted work; in addition, TP has a patent for US-20210361603-A1 pending and a patent for US-20210085763-A1 pending. BRS is an inventor on patents and patent applications involving ferroptosis, holds equity in and serves as a consultant to Exarta Therapeutics, and ProJenX Inc, holds equity in Sonata Therapeutics, and serves as a consultant to Weatherwax Biotechnologies Corporation and Akin Gump Strauss Hauer & Feld LLP. TVB holds patents related to ferroptosis inhibitors. CWil is a consultant for Odyssey Therapeutics and Orphagen Pharmaceuticals. YZ is a consultant for Keen Therapeutics. BP and MC hold patents for some of the compounds described herein, and is co-founder and shareholder of ROSCUE Therapeutics., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Redox control seems to be indispensable for proper embryonic development. The ratio between glutathione (GSH) and its oxidized disulfide (GSSG) is the most abundant cellular redox circuit., Methods: We used zebrafish harboring the glutaredoxin 1-redox sensitive green fluorescent protein (Grx1-roGFP) probe either in mitochondria or cytosol to test the hypothesis that the GSH:GSSG ratio is strictly regulated through zebrafish embryogenesis to sustain the different developmental processes of the embryo., Results: Following the GSSG:GSH ratio as a proxy for the GSH-dependent reduction potential (E hGSH ) revealed increasing mitochondrial and cytosolic E hGSH during cleavage and gastrulation. During organogenesis, cytosolic E hGSH decreased, while that of mitochondria remained high. The similarity between E hGSH in brain and muscle suggests a central regulation. Modulation of GSH metabolism had only modest effects on the GSSG:GSH ratios of newly hatched larvae. However, inhibition of GSH reductase directly after fertilization led to dead embryos already 10 h later. Exposure to the emerging environmental pollutant Perfluorooctane Sulfonate (PFOS) disturbed the apparent regulated E hGSH as well., Conclusions: Mitochondrial and cytosolic GSSG:GSH ratios are almost identical in different organs during zebrafish development indicating that the E hGSH might follow H 2 O 2 levels and rather indirectly affect specific enzymatic activities needed for proper embryogenesis., General Significance: Our data confirm that vertebrate embryogenesis depends on strictly regulated redox homeostasis. Disturbance of the GSSG:GSH circuit, e.g. induced by environmental pollution, leads to malformation and death., Competing Interests: Declaration of competing interest No competing interest declared., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Besides vaccines, the development of antiviral drugs targeting SARS-CoV-2 is critical for preventing future COVID outbreaks. The SARS-CoV-2 main protease (M pro ), a cysteine protease with essential functions in viral replication, has been validated as an effective drug target. Here, we show that M pro is subject to redox regulation in vitro and reversibly switches between the enzymatically active dimer and the functionally dormant monomer through redox modifications of cysteine residues. These include a disulfide-dithiol switch between the catalytic cysteine C145 and cysteine C117, and generation of an allosteric cysteine-lysine-cysteine SONOS bridge that is required for structural stability under oxidative stress conditions, such as those exerted by the innate immune system. We identify homo- and heterobifunctional reagents that mimic the redox switching and inhibit M pro activity. The discovered redox switches are conserved in main proteases from other coronaviruses, e.g. MERS-CoV and SARS-CoV, indicating their potential as common druggable sites., (© 2024. The Author(s).)

Early identification and intervention of individuals with an increased risk for bipolar disorder (BD) may improve the course of illness and prevent long‑term consequences. Early-BipoLife, a multicenter, prospective, naturalistic study, examined risk factors of BD beyond family history in participants aged 15-35 years. At baseline, positively screened help-seeking participants (screenBD at-risk) were recruited at Early Detection Centers and in- and outpatient depression and attention-deficit/hyperactivity disorder (ADHD) settings, references (Ref) drawn from a representative cohort. Participants reported sociodemographics and medical history and were repeatedly examined regarding psychopathology and the course of risk factors. N = 1,083 screenBD at-risk and n = 172 Ref were eligible for baseline assessment. Within the first two years, n = 31 screenBD at-risk (2.9 %) and none of Ref developed a manifest BD. The cumulative transition risk was 0.0028 at the end of multistep assessment, 0.0169 at 12 and 0.0317 at 24 months (p = 0.021). The transition rate with a BD family history was 6.0 %, 4.7 % in the Early Phase Inventory for bipolar disorders (EPIbipolar), 6.6 % in the Bipolar Prodrome Interview and Symptom Scale-Prospective (BPSS-FP) and 3.2 % with extended Bipolar At-Risk - BARS criteria). In comparison to help-seeking young patients from psychosis detection services, transition rates in screenBD at-risk participants were lower. The findings of Early-BipoLife underscore the importance of considering risk factors beyond family history in order to improved early detection and interventions to prevent/ameliorate related impairment in the course of BD. Large long-term cohort studies are crucial to understand the developmental pathways and long-term course of BD, especially in people at- risk., Competing Interests: Declaration of Competing Interest JM, KLB, CB, KL, CS, JM, GJ, AJF, ML, AB, AR, SM, TS, TK, IF, AJ, UD, SKÖ, PFP, LMH, PR, SB, PM, BM and AP state to have no conflict of interest. SKS has received author's and advisory honoraria from Takeda/Shire and Medice Arzneimittel Pütter GmbH in the last 3 years. AR serves on advisory boards and receives speaker's honoraria from Medice, Shire/Takeda, Janssen, neuraxpharm, Servier and SAGE. MB has received grant support from the Deutsche Forschungsgemeinschaft, the Bundesministerium für Bildung und Forschung, and the European Commission. He served as a consultant to GH Research, Janssen-Cilag, neuraxpharm, Novartis, Shire International, Sunovion, and Takeda, and received fees from Aristo, Hexal, Janssen-Cilag, and Sunovion. CU Correll has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, SK Life Science, Sunovion, Sun Pharma, Supernus, Takeda, Teva, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Compass, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Mindpax, LB Pharma and Quantic., (Copyright © 2023. Published by Elsevier B.V.)

Background: Individuals with bipolar disorder are commonly correctly diagnosed a decade after symptom onset. Machine learning techniques may aid in early recognition and reduce the disease burden. As both individuals at risk and those with a manifest disease display structural brain markers, structural magnetic resonance imaging may provide relevant classification features., Methods: Following a pre-registered protocol, we trained linear support vector machine (SVM) to classify individuals according to their estimated risk for bipolar disorder using regional cortical thickness of help-seeking individuals from seven study sites ( N = 276). We estimated the risk using three state-of-the-art assessment instruments (BPSS-P, BARS, EPI bipolar )., Results: For BPSS-P, SVM achieved a fair performance of Cohen's κ of 0.235 (95% CI 0.11-0.361) and a balanced accuracy of 63.1% (95% CI 55.9-70.3) in the 10-fold cross-validation. In the leave-one-site-out cross-validation, the model performed with a Cohen's κ of 0.128 (95% CI -0.069 to 0.325) and a balanced accuracy of 56.2% (95% CI 44.6-67.8). BARS and EPI bipolar could not be predicted. In post hoc analyses, regional surface area, subcortical volumes as well as hyperparameter optimization did not improve the performance., Conclusions: Individuals at risk for bipolar disorder, as assessed by BPSS-P, display brain structural alterations that can be detected using machine learning. The achieved performance is comparable to previous studies which attempted to classify patients with manifest disease and healthy controls. Unlike previous studies of bipolar risk, our multicenter design permitted a leave-one-site-out cross-validation. Whole-brain cortical thickness seems to be superior to other structural brain features.

Volcanic eruptions can trigger tsunamis, which may cause significant damage to coastal communities and infrastructure. Tsunami generation during volcanic eruptions is complex and often due to a combination of processes. The 1650 eruption of the Kolumbo submarine volcano triggered a tsunami causing major destruction on surrounding islands in the Aegean Sea. However, the source mechanisms behind the tsunami have been disputed due to difficulties in sampling and imaging submarine volcanoes. Here we show, based on three-dimensional seismic data, that ~1.2 km³ of Kolumbo's northwestern flank moved 500-1000 m downslope along a basal detachment surface. This movement is consistent with depressurization of the magma feeding system, causing a catastrophic explosion. Numerical tsunami simulations indicate that only the combination of flank movement followed by an explosive eruption can explain historical eyewitness accounts. This cascading sequence of natural hazards suggests that assessing submarine flank movements is critical for early warning of volcanogenic tsunamis., (© 2023. Springer Nature Limited.)

With a global increase in chronic kidney disease patients, alternatives to dialysis and organ transplantation are needed. Stem cell-based therapies could be one possibility to treat chronic kidney disease. Here, we used multipotent urine-derived renal progenitor cells (UdRPCs) to study nephrogenesis. UdRPCs treated with the JNK inhibitor-AEG3482 displayed decreased proliferation and downregulated transcription of cell cycle-associated genes as well as the kidney progenitor markers-SIX2, SALL1 and VCAM1. In addition, levels of activated SMAD2/3, which is associated with the maintenance of self-renewal in UdRPCs, were decreased. JNK inhibition resulted in less efficient oxidative phosphorylation and more lipid peroxidation via ferroptosis, an iron-dependent non-apoptotic cell death pathway linked to various forms of kidney disease. Our study is the first to describe the importance of JNK signalling as a link between maintenance of self-renewal and protection against ferroptosis in SIX2-positive renal progenitor cells.

The pathophysiology of bipolar disorder (BD) remains mostly unclear. Yet, a valid biomarker is necessary to improve upon the early detection of this serious disorder. Patients with manifest BD display reduced volumes of the hippocampal subfields and amygdala nuclei. In this pre-registered analysis, we used structural MRI ( n = 271, 7 sites) to compare volumes of hippocampus, amygdala and their subfields/nuclei between help-seeking subjects divided into risk groups for BD as estimated by BPSS-P, BARS and EPI bipolar . We performed between-group comparisons using linear mixed effects models for all three risk assessment tools. Additionally, we aimed to differentiate the risk groups using a linear support vector machine. We found no significant volume differences between the risk groups for all limbic structures during the main analysis. However, the SVM could still classify subjects at risk according to BPSS-P criteria with a balanced accuracy of 66.90% (95% CI 59.2-74.6) for 10-fold cross-validation and 61.9% (95% CI 52.0-71.9) for leave-one-site-out. Structural alterations of the hippocampus and amygdala may not be as pronounced in young people at risk; nonetheless, machine learning can predict the estimated risk for BD above chance. This suggests that neural changes may not merely be a consequence of BD and may have prognostic clinical value.

Despite their global societal importance, the volumes of large-scale volcanic eruptions remain poorly constrained. Here, we integrate seismic reflection and P-wave tomography datasets with computed tomography-derived sedimentological analyses to estimate the volume of the iconic Minoan eruption. Our results reveal a total dense-rock equivalent eruption volume of 34.5 ± 6.8 km³, which encompasses 21.4 ± 3.6 km³ of tephra fall deposits, 6.9 ± 2 km³ of ignimbrites, and 6.1 ± 1.2 km³ of intra-caldera deposits. 2.8 ± 1.5 km³ of the total material consists of lithics. These volume estimates are in agreement with an independent caldera collapse reconstruction (33.1 ± 1.2 km³). Our results show that the Plinian phase contributed most to the distal tephra fall, and that the pyroclastic flow volume is significantly smaller than previously assumed. This benchmark reconstruction demonstrates that complementary geophysical and sedimentological datasets are required for reliable eruption volume estimates, which are necessary for regional and global volcanic hazard assessments., (© 2023. The Author(s).)

Introduction: In factor VIII (FVIII) prophylaxis for haemophilia A, cost comparisons have used price per international unit (IU) based on the once reasonable assumption of equivalent outcome per IU. Now, with several extended half-life (EHL) products available, new outcome-oriented ways to compare products are needed. Area under the curve (AUC) quantifies FVIII levels over time after infusion providing comparable data., Aim: To develop a decision analytical model for making indirect comparisons of FVIII replacement products based on AUC., Methods: A literature search identified 11 crossover studies with relevant pharmacokinetic data. A common comparator FVIII level curve was calculated using pooled data from selected studies. Absolute curves for other products were estimated based on relative differences to the common comparator (% difference vs the anchor). Three scenarios were investigated: (1) Kogenate ® versus Kovaltry ® and Jivi ® ; (2) Advate ® versus Elocta ® , NovoEight ® , Kovaltry, Adynovate ® , Afstyla ® , and ReFacto ® ; and (3) Jivi versus Elocta, Adynovate, and Kogenate. Sensitivity analyses investigated effects of assay type and dose., Results: In scenario 1, Jivi (+50%) and Kovaltry (+14%) showed larger AUCs versus Kogenate. In scenario 2, EHL products, Elocta and Adynovate, had the largest AUC (+64% and +58%, respectively) versus Advate. Compared with all other products in scenario 3, Jivi had the largest AUC by +13%-28%., Conclusion: This analysis concludes that EHL products differ in relative AUC, have a larger AUC compared with standard half-life, and thus, different FVIII levels over time after infusion. This model may aid decision makers in the absence of head-to-head data., (© 2022 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Throughout the COVID-19 pandemic, mental health of individuals with bipolar disorders (BD) is potentially more vulnerable, especially regarding COVID-19-related regulations and associated symptomatic changes. A multicentric online study was conducted in Austria, Germany, and Denmark during the COVID-19 pandemic. Overall, data from 494 participants were collected (203 individuals with BD, 291 healthy controls (HC)). Participants filled out questionnaires surveying emotional distress due to social distancing, fear of COVID-19, and the Brief Symptom Inventory-18 to assess symptom severity at four points of measurement between 2020 and 2021. General linear mixed models were calculated to determine the difference between the groups in these pandemic specific factors. Individuals with BD reported higher distress due to social distancing than HC, independently of measurement times. Fear of COVID-19 did not differ between groups; however, it was elevated in times of higher infection and mortality due to COVID-19. Individuals with BD reported higher psychiatric symptom severity than HC; however, symptom severity decreased throughout the measured time in the pandemic. Overall, individuals with BD experienced more distress due to the COVID-19 situation than HC. A supportive mental health system is thus recommended to ensure enhanced care, especially in times of strict COVID-19-related regulations.

The COVID-19 pandemic affects both mentally healthy and ill individuals. Individuals with bipolar disorder (BD) constitute an especially vulnerable group. A multicentric online study was conducted in Austria, Denmark, and Germany after the first lockdown phase in 2020. In total, 117 healthy controls (HC) were matched according to age and sex to 117 individuals with BD. The survey included the Brief Symptom Inventory-18, Beck Depression Inventory-2, Pittsburgh Sleep Quality Index, and a self-constructed questionnaire assessing COVID-19 fears, emotional distress due to social distancing, lifestyle, and compliance to governmental measures. In individuals with BD, increased symptoms of depression, somatization, anxiety, distress due to social distancing, and poorer sleep quality were related to emotional distress due to social distancing. The correlation between emotional distress due to social distancing and anxiety showed 26% of shared variance in BD and 11% in HC. Negative lifestyle changes and lower compliance with COVID-19 regulatory measures were more likely to be observed in individuals with BD than in HC. These findings underscore the need for ongoing mental health support during the pandemic. Individuals with BD should be continuously supported during periods of social distancing to maintain a stable lifestyle and employ strategies to cope with COVID-19 fears., (Copyright © 2022. Published by Elsevier B.V.)

Redox regulation of specific cysteines via oxidoreductases of the thioredoxin family is increasingly being recognized as an important signaling pathway. Here, we demonstrate that the cytosolic isoform of the vertebrate-specific oxidoreductase Glutaredoxin 2 (Grx2c) regulates the redox state of the transcription factor SP-1 and thereby its binding affinity to both the promoter and an enhancer region of the CSPG4 gene encoding chondroitin sulfate proteoglycan nerve/glial antigen 2 (NG2). This leads to an increased number of NG2 glia during in vitro oligodendroglial differentiation and promotes migration of these wound healing cells. On the other hand, we found that the same mechanism also leads to increased invasion of glioma tumor cells. Using in vitro (human cell lines), ex vivo (mouse primary cells), and in vivo models (zebrafish), as well as glioblastoma patient tissue samples we provide experimental data highlighting the Yin and Yang of redox signaling in the central nervous system and the enzymatic Taoism of Grx2c., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)