Bernstein Center for Computational Neuroscience Tübingen

Rhodopsin-mediated autosomal dominant retinitis pigmentosa (RHO-adRP) is a progressive inherited retinal degenerative disorder currently lacking effective treatments. A recurrent 3-base pair deletion in the RHO gene, resulting in the loss of isoleucine at codon 255 or 256 (RHO∆I255 or RHO∆I256), has been identified in patients from the United Kingdom, Germany, Belgium, China, and Korea, suggesting a broad geographic distribution. This mutation leads to rhodopsin (RHO) misfolding, its retention in the endoplasmic reticulum (ER), and aggregation with wild-type (WT) RHO, ultimately triggering ER stress and photoreceptor degeneration. These aggregates are primarily cleared via the ER-associated degradation (ERAD) pathway, with valosin-containing protein (VCP) playing a key role in their retrotranslocation and proteasomal degradation. Pharmacological or genetic inhibition of VCP has shown neuroprotective effects in other models of adRP, but the poor aqueous solubility of VCP inhibitors and challenges in retinal drug delivery hinder clinical translation. To overcome these limitations, we evaluated and compared three VCP-targeted therapeutic strategies in Rho∆I255 knock-in mouse retinae: (1) small-molecule inhibitors (ML240, NMS-873) solubilized in DMSO, (2) ML240 encapsulated in monomethoxy-polyethylene glycol (mPEG)-cholane nanoparticles, and (3) small interfering RNA (siRNA) targeting VCP, delivered via magnetic nanoparticles. Neuroprotective effects were assessed in vitro in retinal explants and in vivo following intravitreal injection. Our findings provide the first evidence that VCP inhibition restores RHO trafficking to the outer segments and prevents photoreceptor cell death in the Rho∆I255 model. Among the three approaches, nanocarrier-encapsulated ML240 exhibited superior efficacy, enabling sustained drug delivery and enhanced photoreceptor protection. These results establish a preclinical proof-of-concept for nanocarrier-mediated VCP inhibition as a promising therapeutic strategy for RHO-adRP and potentially other ER-stress-related retinal degenerations.

Abstract Age-specific fertility rates (ASFRs) provide the most extensive record of reproductive change, but their aggregate nature obscures the individual-level behavioural mechanisms that drive fertility trends. To bridge this micro–macro divide, we introduce a simulation-based Bayesian framework that couples a demographically interpretable, individual-level simulation model of the reproductive process with sequential neural posterior estimation (SNPE). We show that this framework successfully recovers core behavioural parameters governing contemporary fertility, including preferences for family size, reproductive timing, and contraceptive failure, using only ASFRs. The framework’s effectiveness is validated on cohorts from four countries with diverse fertility regimes. Most compellingly, the model, estimated solely on aggregate data, successfully predicts out-of-sample distributions of individual-level outcomes, including age at first sex, desired family size, and birth intervals. Because our framework yields complete synthetic life histories, it significantly reduces the data requirements for building microsimulation models and enables behaviourally explicit demographic forecasts.

Uncertainty is an inherent part of geoscience research and arises at multiple stages of the scientific process, from data collection and modelling to analysis and interpretation. In recent years, growing attention has been devoted to uncertainty quantification and assessment, alongside increasing recognition of the importance of uncertainty communication. These aspects are closely linked, as robust characterization of uncertainty provides an essential basis for transparent communication within the scientific community and beyond it.Communicating uncertainty not only plays a key role in improving the understanding of how scientific knowledge is produced, but can also help to foster trust by increasing transparency and contextualizing results. Nevertheless, reluctance to explicitly assess and communicate uncertainty persists, particularly when addressing non-expert audiences. This challenge is especially relevant in the context of natural hazard risk assessment and management: Here, adequate communication of uncertainties can add particularly valuable information for decision-making, risk governance, and a better understanding of the risks at hand among public audiences.This contribution presents an exploratory, database-driven overview of the scientific literature on uncertainty communication in geoscience, with a particular focus on natural hazards. Using structured queries in the Web of Science database, we examine publication trends over time, disciplinary distributions, thematic emphases, and possible blind spots. Keyword combinations range from general terms such as “uncertainty communication” and “multi-hazard communication” to more specific queries combining uncertainty, communication, and individual natural hazards (e.g., floods, earthquakes, droughts).Preliminary results indicate that uncertainty communication spans a broad range of scientific categories, while the level of attention varies substantially across hazard types, with flood-related studies being more prominent than others. Initial findings also suggest that multi-hazard uncertainty communication remains comparatively underrepresented, despite the increasing emphasis on multi-hazard and multi-risk assessments in recent research and policy frameworks. The growing volume of publications further highlights the need for systematic approaches to literature mapping, as well as the potential role of data-driven and AI-assisted tools in supporting such analyses.This research was partially funded by the European Civil Protection and Humanitarian Aid Operations (ECHO) of the European Commission (EC) through the VOLCAN project (ref. 101193100) and by the 2024 Research Prize of the Dr. K. H. Eberle Foundation to Mohadjer, Pelzer and Dietrich.

Transsphenoidal surgery (TSS) is the recommended treatment for Cushing's disease (CD). While low morning serum cortisol (MSeC) indicates early remission, the predictive value of an early postoperative overnight 2mg low-dose dexamethasone suppression test (LDDST) remains unclear. This study compares the accuracy of early postoperative MSeC and LDDST for predicting early and long-term remission after TSS. We retrospectively analysed 342 CD surgical cases, who underwent TSS in our department between 2004 and 2024. Morning cortisol measurements were obtained postoperatively. An overnight 2mg LDDST was performed on postoperative day five, in selected cases, preferentially in those without immediate postoperative biochemical remission (MSeC > 50 nmol/L), rather than as a universal screening test. Immediate postoperative biochemical remission (IPBR; MSeC < 50 nmol/L) was achieved in 170 cases (49.7%). LDDST was performed in 197 cases (57.6%), with complete suppression (< 50 nmol/L) in 137 (69.5%). Remission at first follow-up (3-6 months) was significantly higher in cases with IPBR (99.4%) and/or complete LDDST suppression (98.5%) compared to those without (45.0%; p < .0001*). Long-term remission also correlated significantly with postoperative MSeC and LDDST (p < .0001*). ROC analyses confirmed strong predictive accuracy for remission during first FU (AUC MSeC: 0.9229; LDDST: 0.9413) and long-term (AUC MSeC: 0.8267; LDDST: 0.8058). Five-year recurrence risk was 71.1% without LDDST suppression versus 6.8% with suppression. Early postoperative MSeC and LDDST are reliable predictors of remission after TSS in CD. MSeC < 50 nmol/L safely define biochemical remission. LDDST adds diagnostic value, particularly in cases with borderline, normal or elevated MSeC, and should be included in routine postoperative assessment.

Wood ash from small-scale (<1 MW) wood-fired heating plants represents a valuable secondary resource containing essential plant nutrients such as Ca, K, and P, but may also harbor potentially hazardous elements. Its current utilization and disposal are typically based solely on total elemental composition, disregarding element mobility and environmental behavior. This study introduces element mobility as an additional criterion for assessing ash quality and suitability for recycling. Sequential extraction using a modified BCR (Community Bureau of Reference) protocol with four solvents (water, acetic acid, hydroxylamine hydrochloride, and ammonium acetate) was applied to evaluate the leachability of 26 elements. Results indicate high extractabilities for several potentially hazardous elements—Sr (54 %), B (48 %), V (44 %), Cd (38 %), and Tl (27 %)—suggesting potential environmental risks despite low total concentrations. In contrast, key plant nutrients, especially P (15 %) were less mobile but could be mobilized under oxidizing conditions. While dissolution of K (74 %) and Ca (12 %) in water and weak organic acid indicates partial plant-availability already in the untreated ash, 26 % resp. 88 % remained in the residual fraction, indicating only long-term plant availability through weathering. The findings demonstrate that both total concentrations and leaching behavior must be considered in environmental assessments. For fertilizer production, pretreatment to remove Tl and enhance P solubility is recommended. From a waste management perspective, controlled ash processing can promote nutrient recovery and support circular economy objectives. These insights contribute to optimizing wood ash management strategies and minimizing environmental risks associated with its reuse. • Element mobility as a new criterion for assessment of wood ash as fertilizer. • Sequential extraction reveals wide variation of element leachability from ash. • P becomes extractable via oxidation with hydrogen peroxide and ammonium acetate. • Only Tl exceeds limits among toxic elements but can be selectively removed.

Abstract Many students disengage from mathematics throughout their school careers, a pattern often attributed to declines in motivation. While long-term motivational trajectories are well documented, far less is known about short-term motivational fluctuations in self-paced online courses; a setting that becomes increasingly popular in mathematics education and which places high demands on learners’ autonomy, possibly increasing the risk of disengagement when motivation decreases. Drawing on situated expectancy-value theory, we investigated the relations between dispositional (trait-like) motivation, situational (state-like) motivation, and parental help in an extracurricular enrichment online course designed to foster children’s proof competency. Longitudinal data from 159 talented primary school students indicated considerable within-person variability in motivation. Dispositional motivation at the beginning of the course was only modestly related to children’s average situational motivation during the course. Notably, across different course sections, motivational declines seemed more pronounced when students encountered cognitively demanding content (e.g., construction of formal-deductive proofs). For situational utility value—children’s perceived usefulness of the specific course section for school life—parental help emerged as a critical moderator, significantly buffering declines between two mid-course sections. Critically, our data indicated high dropout rates among children. Survival analyses suggested that greater situational motivation (particularly self-concept), but not greater dispositional motivation, reduced the risk of dropout, highlighting the importance of momentary motivational states in sustaining engagement.

Major depressive disorder (MDD) is a common severe mental disorder with enormous socioeconomic costs for the patient and society alike. Current pharmacological and psychotherapeutic treatments are ineffective in a substantial fraction of patients and can be accompanied by unwanted side effects. Using a novel non-invasive brain stimulation method to specifically target and modulate dysfunctional brain oscillations with high spatial and temporal precision this study will investigate the efficacy of EEG-triggered transcranial magnetic stimulation (TMS) to alleviate depressive symptoms in 28 patients with MDD in a 1:1-randomized, double blind, standard treatment-controlled pilot trial. In the experimental condition, stimulation will be brain oscillation-synchronized based on the EEG-extracted endogenous theta oscillation over left dorsomedial prefrontal cortex (DMPFC). The control condition will consist of standard TMS therapy following an FDA-approved intermittent theta-burst stimulation (iTBS) protocol over left dorsolateral prefrontal cortex (DLPFC). The treatment will be performed over four consecutive weeks (20 sessions) and the primary outcome will be the change in the Montgomery-Åsberg Depression Rating Scale (MADRS) after the last versus before the first treatment session. The aim of the study is to gain exploratory evidence for the feasibility and efficacy of EEG-synchronized TBS of left DMPFC compared to a standard FDA-approved treatment (iTBS of left DLPFC) in a double-blind randomized parallel-design pilot clinical trial. Positive results will pave the way for a larger RCT to prove the superiority of personalized, brain oscillation-synchronized non-invasive brain stimulation therapies as novel, effective and well-tolerated treatment in MDD. Trial Registration: NCT06345651, date of registration: 2024-01-08, https://clinicaltrials.gov/study/NCT06345651 The trial is conducted in accord with protocol version number 2022-09, Version 3. Recruitment started in January 2024, and recruitment is ongoing. The recruitment phase is projected to conclude by December 2026.

In plants, multiple cell types contribute to immunity, but what division of labor exists among cell types when immunity is activated? We compared, at single-cell resolution, the response of Arabidopsis thaliana leaf cells during pattern-triggered and effector-triggered immunity (PTI/ETI), sampled at 3 and 5 h after infection with Pseudomonas syringae DC3000. Core defense modules were broadly shared across cell clusters, but their activation varied in timing and intensity, with key immune receptors also showing cell type-specific expression dynamics. Mesophyll cell populations could be distinguished based on their resilience patterns: after the initial response, some populations continue to express defense genes at high levels during both PTI and ETI, while others quickly reinitiate growth-related gene expression programs but only during PTI. Gene regulatory network inference revealed WRKY-regulated modules enriched in cells sensing effectors, while salicylic acid biosynthesis regulators were activated in complementary clusters. Analysis of cue1 mutants demonstrated that core immune responses are robust to altered leaf architecture. In addition, we uncovered cryptic defense pathways, including sucrose-responsive modules, in this mutant. By capturing early immune responses at high resolution, our study reveals cell type-specific coordination of plant immunity and provides a framework for decoding immune signaling networks.

SummaryAltered microglial lipid metabolism is heavily implicated in Alzheimer’s disease (AD) and aging. Recently, protocols were developed to generate human induced pluripotent stem cell-derived microglia-like cells (iMGL) to study microglial function in vitro, including embryoid body-based methods and induced transcription factor (iTF)-dependent approaches. Here, we performed comparative lipidomics on iMGL from these methods and report major differences in multiple lipid classes, including triglycerides (TGs), a storage form of fatty acids implicated in microglial reactivity. TGs are strongly increased in iTF microglia due to the absence of a media supplement (B-27). Supplementing iTF microglia with B-27, or its component L-carnitine, reduces TGs and promotes a homeostatic state. B-27 also renders iTF microglia metabolically responsive to immune stimuli. Overall, our data show that iMGL differentiation methods have a major impact on microglial lipidomes and warrant attention when studying AD and neuroinflammatory processes involving lipids.

Abstract Litter decomposition, a key component of the global carbon cycle, is greatly affected by climate. Our current understanding of climate change effects on decomposition stems from (1) spatial observational studies along climate gradients, where direct and indirect effects of climate on litter decomposition are confounded; (2) reciprocal litter translocations and common garden experiments, where biotic interactions are disrupted; or (3) manipulation experiments, which can be less realistic than observational studies. Experimental studies combining all of the above mentioned methods can separate indirect from direct climate effects on decomposition, as the confounding effects of one method can be explained with another method. Additionally, this setup can directly test if observations along a spatial gradient can predict responses to climate change, that is the validity of the space‐for‐time approach. However, studies combining the different methods are still scarce. We combined a pronounced climate gradient, large‐ and small‐scale reciprocal litter translocations (local litter and standard litter, i.e. tea), and in situ precipitation manipulation for studying soil moisture effects on litter decomposition. All our experiments (translocation of litter and tea across the gradient, slope comparisons within sites and rainfall exclusions) indicated positive direct effects of climate on litter decomposition. However, as local litter quality decreased with increasing precipitation, litter from species of the drier sites decomposed quicker than litter from species of the wetter sites across the gradient. In other words, while the direct effects of climate favoured litter decomposition in wetter sites, its indirect effect (i.e. litter quality) favoured the decomposition of litter from species of the drier sites within each site. Synthesis : Our results highlight the need for experimental evidence from reciprocal translocations and climate manipulations in litter decomposition studies as they indicate that space cannot always substitute for time. Such evidence would improve predictions of models of the global carbon cycle that include interactions between climate and vegetation.