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Abstract Background Previous studies have found adverse effects on mental health following infection with SARS-CoV-2. This study investigates whether mental health is also impaired in unknowingly infected individuals. In addition, the relevance of the severity of the infection and the time since the onset of infection were analyzed. Methods Data from the population-representative Gutenberg COVID-19 Study (GCS) were used (N = 2,267). SARS-CoV-2 infection was determined multimodally by self-report, throat swabs (acute infections) and antibody measurements (previous infections). Participants completed self-report questionnaires on mental health. Results Neither unknowing nor knowing SARS-CoV-2 infection had an impact on mental health. However, symptom severity and previous depression or anxiety predicted higher levels of depressiveness, anxiety and somatic complaints. Our results confirm findings suggesting that the severity of the initial infection and previous mental illness, but not knowledge of the infection, are the most important predictors of negative mental health outcomes following SARS-CoV-2 infection. Conclusion The results suggest that mental health care should focus on individuals who suffer from a severe acute COVID-19 infection or have a history of mental illness.

Abstract Disturbances in the fatty acid lipidome are increasingly recognized as key drivers in the progression of various brain disorders. In this review article, we delve into the impact of Δ9 fatty acid desaturases, with a particular focus on stearoyl-CoA desaturase-1 (SCD1), within the setting of neuroinflammation, neurodegeneration, and brain repair. Over the past years, it was established that inhibition or deficiency of SCD1 not only suppresses neuroinflammation but also protects against neurodegeneration in conditions such as multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease. This protective effect is achieved through different mechanisms including enhanced remyelination, reversal of synaptic and cognitive impairments, and mitigation of α-synuclein toxicity. Intriguingly, metabolic rerouting of fatty acids via SCD1 improves the pathology associated with X-linked adrenoleukodystrophy, suggesting context-dependent benign and harmful effects of SCD1 inhibition in the brain. Here, we summarize and discuss the cellular and molecular mechanisms underlying both the beneficial and detrimental effects of SCD1 in these neurological disorders. We explore commonalities and distinctions, shedding light on potential therapeutic challenges. Additionally, we touch upon future research directions that promise to deepen our understanding of SCD1 biology in brain disorders and potentially enhance the clinical utility of SCD1 inhibitors.

Abstract Age-related cognitive decline has become an increasingly relevant public health issue. However, risk and protective factors of cognitive decline have yet to be investigated prospectively taking into account genetic, lifestyle, physical and mental health factors. Population-based data from middle-aged (40 to 59 years; N = 2,764) and older individuals (60 to 80 years; N = 1,254) were drawn from a prospective community cohort study using the Tower of London (TOL) planning task. Assessments were repeated at a 5-year interval to investigate age-related changes in planning performance and to determine the impact of risk and protective factors. Planning performance improved in middle-aged, but declined in older participants over 5 years. SNPs affecting the dopamine system (COMT, DRD2) and APOE polymorphisms differentially predicted cognitive performance in older vs. middle-aged individuals. For older individuals, high alcohol consumption, antidepressant medication and living without a partner had additional negative predictive power on cognition. In contrast, undiagnosed hypertension, no obstructive lung disease, and fewer years of education predicted cognitive decline in the middle-aged group. The results inform screening for individuals particularly vulnerable to cognitive decline and interventions (e.g., focusing on lifestyle factors) to help maintain cognitive performance into old age.

Ischiomysis proincisa sp. nov. is described from a comparatively large, semi-dark marine cave in sublittoral waters off the small island Ilhéu das Rolas, directly south of São Tomé Island in the Gulf of Guinea. As striking features, the new species is distinguished from both its congeners by an anteriorly incised rostrum in both sexes and by two versus only one modified flagellate spine on the ischium of the eighth thoracic endopod in males. The new species is sympatric yet ecologically remote from the congener I. telmatactiphila, which is associated with the sea anemone Telmatactis cricoides in brighter habitats. New records and morphological notes are given for I. telmatactiphila and I. peterwirtzi. An updated definition of the genus Ischiomysis and a key to its three species are given.

Abstract Background Self-rated physical health (SRPH) is known as an important predictor of mortality. Previous studies mostly used baseline values of self-rated health to predict long-term mortality. The effect of change in self-rated physical health on mortality during the course of aging has rarely been researched. The present study aimed to determine SRPH over time in women and men of an aging population, assess whether and how change in SRPH affects mortality while adjusting for known determinants of mortality, and test effect modification by sex on the relation between course of SRPH and mortality. Methods Data of N = 12,423 respondents of the 5-year follow-up of the Gutenberg Health Study (GHS) with participation at the baseline assessment were analysed. All-cause mortality from 5-year follow-up onwards was defined as the primary outcome. SRPH was assessed by a single item. Cox proportional hazards models with adjustment for age, sex, socio-economic status and physical diseases were fitted to assess the predictive power of baseline score and course of SRPH. Additionally, effect modification by sex was assessed. Results During a median follow-up period of 7.3 years (quartiles 6.0-8.5 years), 618 (5%) participants died. Overall, 70.9% of the participants indicated good or very good SRPH at baseline (T1) and follow-up (T2), 6.9% rated their SRPH as not so good at T1 and T2, and 0.6% reported bad SRPH at T1 and T2. An improvement of SRPH was indicated by 9.6% and 12.0% indicated deterioration of their SRPH. Change in SRPH added substantial predictive information to the Cox proportional hazards models, when adjusting for relevant covariates. In men, deterioration and constantly bad SRPH were associated with the strongest increase in risk of mortality by 87%, resp. 228%. While improvements increased mortality risk in men (67%), women with an improved SRPH had a lower risk (57%). Conclusion A sizeable subgroup of aging participants reported deterioration of SRPH over five years. The association between change of SRPH and mortality is modified by sex. Deterioration of SRPH predicts mortality over baseline-assessment even when adjusted for relevant covariates. SRPH should be assessed regularly as part of an older individual’s health evaluation. Deterioration, constantly bad and improved SRPH should be taken seriously as unfavorable prognostic indicators, the latter only in men.

Abstract Extracellularly released molecular inflammasome assemblies -ASC specks- cross-seed Aβ amyloid in Alzheimer’s disease. Here we show that ASC governs the extent of inflammation-induced amyloid A (AA) amyloidosis, a systemic disease caused by the aggregation and peripheral deposition of the acute-phase reactant serum amyloid A (SAA) in chronic inflammatory conditions. Using super-resolution microscopy, we found that ASC colocalized tightly with SAA in human AA amyloidosis. Recombinant ASC specks accelerated SAA fibril formation and mass spectrometry after limited proteolysis showed that ASC interacts with SAA via its pyrin domain (PYD). In a murine model of inflammatory AA amyloidosis, splenic amyloid load was conspicuously decreased in Pycard −/− mice which lack ASC. Treatment with anti-ASCPYD antibodies decreased amyloid loads in wild-type mice suffering from AA amyloidosis. The prevalence of natural anti-ASC IgG (−logEC50 ≥ 2) in 19,334 hospital patients was

Multiple myeloma (MM) patients are often refractory to targeted therapies including proteasome inhibitors (PIs). Here, analysis of RNA sequencing data derived from 672 patients with newly diagnosed or relapsed/refractory disease identified the acid ceramidase, ASAH1, as a key regulator of PI resistance. Genetic or pharmacological blockade of ASAH1 remarkably restored PI sensitivity and protected mice from resistant MM progression in vivo. Mechanistically, ASAH1 depletion of ceramide promoted SET inhibition of PP2A phosphatase activity thus facilitating the increased expression and activity of the pro-survival proteins, MCL-1, and BCL-2. We corroborated these findings in human MM datasets, and in ex vivo patient MM cells. These preclinical studies suggest that ASAH1 may be a potential therapeutic target for the treatment of relapsed/refractory MM (RRMM).

ABSTRACT Trichodesmium, a globally significant N2-fixing marine cyanobacterium, forms extensive surface blooms in nutrient-poor ocean regions. These blooms consist of a dynamic assemblage of Trichodesmium species that form distinct colony morphotypes and are inhabited by diverse microorganisms. Trichodesmium colony morphotypes vary in ecological niche, nutrient uptake, and organic molecule release, differentially impacting ocean carbon and nitrogen biogeochemical cycles. Here, we assessed the poorly studied spatial abundance of metabolites within and between three morphologically distinct Trichodesmium colonies collected from the Red Sea. We also compared these results with two morphotypes of the cultivable Trichodesmium strain IMS101. Using matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) coupled with liquid extraction surface analysis (LESA) tandem mass spectrometry (MS2), we identified and localized a wide range of small metabolites associated with single-colony Trichodesmium morphotypes. Our untargeted MALDI-MSI approach revealed 80 unique features (metabolites) shared between Trichodesmium morphotypes. Discrimination analysis showed spatial variations in 57 shared metabolites, accounting for 62% of the observed variation between morphotypes. The greatest variations in metabolite abundance were observed between the cultured morphotypes compared to the natural colony morphotypes, suggesting substantial differences in metabolite production between the cultivable strain IMS101 and the naturally occurring colony morphotypes that the cultivable strain is meant to represent. This study highlights the variations in metabolite abundance between natural and cultured Trichodesmium morphotypes and provides valuable insights into metabolites common to morphologically distinct Trichodesmium colonies, offering a foundation for future targeted metabolomic investigations.IMPORTANCEThis work demonstrates that the application of spatial mass spectrometry imaging at single-colony resolution can successfully resolve metabolite differences between natural and cultured Trichodesmium morphotypes, shedding light on their distinct biochemical profiles. Understanding the morphological differences between Trichodesmium colonies is crucial because they impact nutrient uptake, organic molecule production, and carbon and nitrogen export, and subsequently influence ocean biogeochemical cycles. As such, our study serves as an important initial assessment of metabolite differences between distinct Trichodesmium colony types, identifying features that can serve as ideal candidates for future targeted metabolomic studies.

Background & Aims: Elevated liver stiffness has been associated with atrial fibrillation (AFib) in the general population. The mechanism underlying this association is unclear. Methods: Participants were recruited from the general population and prospectively enrolled with follow-up for 5 years. The fibrosis-4 (FIB-4) index was used as a surrogate marker for liver fibrosis. Proteomics analysis was performed using the 92-target Olink inflammation panel. Validation was performed using the NAFLD fibrosis score (NFS), aspartate aminotransferase to platelet index (APRI), and repeat confirmation proteomics. Results: A sample of 11,509 participants with a mean age of 54.0 ± 11.1 years, 51.3% women, and a median FIB-4 index of 0.85 (0.65/1.12), was used. The FIB-4 index was predictive for prevalent (FIB-4 index adjusted odds ratio (aOR) per SD: 1.100 with 95% CI 1.011-1.196; p = 0.026), but not incident AFib (log[FIB-4 index]) adjusted hazard ratio: 1.125 with 95% CI 0.943-1.342, p = 0.19). Elastic net regularized regression identified CCL20, DNER, and CXCL10 for prevalent AFib, and AXIN1, CXCL10, and Flt3L for the log(FIB-4 index) (per SD) as most important in common regulated proteins. The relationship between the FIB-4 index, the identified proteins, and AFib was relevant and reproduced at the 5-year follow-up for CXCL10 after adjusting for confounders (log[FIB-4 index] per SD - CXCL10 [per SD] adjusted β 0.160 with 95% CI 0.127-0.194, p

Abstract Given the marginal penetration of most drugs across the blood-brain barrier, the efficacy of various agents remains limited for glioblastoma (GBM). Here we employ low-intensity pulsed ultrasound (LIPU) and intravenously administered microbubbles (MB) to open the blood-brain barrier and increase the concentration of liposomal doxorubicin and PD-1 blocking antibodies (aPD-1). We report results on a cohort of 4 GBM patients and preclinical models treated with this approach. LIPU/MB increases the concentration of doxorubicin by 2-fold and 3.9-fold in the human and murine brains two days after sonication, respectively. Similarly, LIPU/MB-mediated blood-brain barrier disruption leads to a 6-fold and a 2-fold increase in aPD-1 concentrations in murine brains and peritumoral brain regions from GBM patients treated with pembrolizumab, respectively. Doxorubicin and aPD-1 delivered with LIPU/MB upregulate major histocompatibility complex (MHC) class I and II in tumor cells. Increased brain concentrations of doxorubicin achieved by LIPU/MB elicit IFN-γ and MHC class I expression in microglia and macrophages. Doxorubicin and aPD-1 delivered with LIPU/MB results in the long-term survival of most glioma-bearing mice, which rely on myeloid cells and lymphocytes for their efficacy. Overall, this translational study supports the utility of LIPU/MB to potentiate the antitumoral activities of doxorubicin and aPD-1 for GBM.

Traumatic Brain Injury (TBI) is a debilitating condition that poses a significant public health concern. Historically linked to motor vehicle accidents, the epidemiology of TBI has evolved. Falls now emerge as the predominant cause, particularly among older adults. Sport-related TBIs have also garnered increased attention due to concerns regarding long-term neurological sequelae. To date, therapeutic interventions remain limited and have yet to yield substantial clinical benefits. Cell-based therapies offer promising avenues for neural repair and regeneration: endogenous stem cell therapies capitalize on endogenous pools that can be triggered by the injury and further enhanced by therapeutic approaches. In contrast, exogenous cell therapies provide an exogenous source of cells. However, challenges such as age-related decline in neurogenesis, age-related inflammation, and the heterogeneity of TBI present significant hurdles to overcome. Moreover, translating stem cell research from the laboratory to clinical applications necessitates the adherence to good manufacturing practice standards, which presents distinct obstacles. Addressing these challenges requires a multifaceted approach, including careful patient selection in clinical trials, appropriate experimental models, and the optimization of therapeutic techniques. Ultimately, a combination of strategies is likely to yield the most promising outcomes in the pursuit of effective TBI therapies.

Abstract Evidence from genetic and epidemiological studies point to lipid metabolism defects in both the brain and periphery being at the core of Alzheimer’s disease (AD) pathogenesis. Previously, we reported that central inhibition of the rate-limiting enzyme in monounsaturated fatty acid synthesis, stearoyl-CoA desaturase (SCD), improves brain structure and function in the 3xTg mouse model of AD (3xTg-AD). Here, we tested whether these beneficial central effects involve recovery of peripheral metabolic defects, such as fat accumulation and glucose and insulin handling. As early as 3 months of age, 3xTg-AD mice exhibited peripheral phenotypes including increased body weight and visceral and subcutaneous white adipose tissue as well as diabetic-like peripheral gluco-regulatory abnormalities. We found that intracerebral infusion of an SCD inhibitor that normalizes brain fatty acid desaturation, synapse loss and learning and memory deficits in middle-aged memory-impaired 3xTg-AD mice did not affect these peripheral phenotypes. This suggests that the beneficial effects of central SCD inhibition on cognitive function are not mediated by recovery of peripheral metabolic abnormalities. Given the widespread side-effects of systemically administered SCD inhibitors, these data suggest that selective inhibition of SCD in the brain may represent a clinically safer and more effective strategy for AD.

Abstract The vertebrate stress response (SR) is mediated by the hypothalamic–pituitary–adrenal (HPA) axis and contributes to generating context appropriate physiological and behavioral changes. Although the HPA axis plays vital roles both in stressful and basal conditions, research has focused on the response under stress. To understand broader roles of the HPA axis in a changing environment, we characterized an adaptive behavior of larval zebrafish during ambient illumination changes. Genetic abrogation of glucocorticoid receptor (nr3c1) decreased basal locomotor activity in light and darkness. Some key HPI axis receptors (mc2r [ACTH receptor], nr3c1), but not nr3c2 (mineralocorticoid receptor), were required to adapt to light more efficiently but became dispensable when longer illumination was provided. Such light adaptation was more efficient in dimmer light. Our findings show that the HPI axis contributes to the SR, facilitating the phasic response and maintaining an adapted basal state, and that certain adaptations occur without HPI axis activity.

IntroductionThe allocation of nitrogen (N) and phosphorus (P) among plant organs is an important strategy affecting growth and development as well as ecological processes in terrestrial ecosystems. However, due to lack of systematic investigation data, the allocation strategies of N and P in the three primary plant organs (e.g., leaves, stems and roots) are still unclear.MethodsA total of 912 individuals of 62 Artemisia species were examined across a broad environmental expanse in China, and the N and P concentrations of leaves, stems and roots were measured to explore the allocation strategies in different subgenera, ecosystem types, and local sites.Results and discussionAcross all 62 species, the N vs. P scaling exponents for leaves, stems and roots were 0.67, 0.59 and 0.67, respectively. However, these numerical values differed among subgenera, ecosystem types, and local sites. Overall, the numerical values of N vs. P scaling exponents comply with a 2/3-power function for each Artemisia organ-type reflecting a phylogenetically conserved allocation strategy that has nevertheless diversified with respect to local environmental conditions. These results inform our understanding of N and P stoichiometric patterns and responses to abiotic factors in an ecologically broadly distributed angiosperm genus.

Abstract Modifying the chemical environment of active surfaces with ionic liquids (IL) is an emerging strategy for tailoring novel electrocatalytic systems, including carbon dioxide reduction (CO2RR). Although copper (Cu) catalysts have recently gained more attention in this field, their modification with ILs is yet to be investigated. This work tested a range of common hydrophobic ILs impregnated into carbon‐supported Cu catalysts, following the “solid catalyst with ionic liquid layer” (SCILL) approach. The latter was used to showcase the applicability of real‐time product detection for CO2RR employing electrochemical mass spectrometry. The observed patterns of C1 to C3 product selectivity offered valuable insights into the intricate reaction mechanism. In addition, increasing the size of the IL cation showed an opposite and significant effect on the reaction selectivity. The obtained qualitative results were partially compared with conventional long‐term experiments.

Abstract The widespread application of green hydrogen production technologies requires cost reduction of crucial elements. To achieve this, a viable pathway to reduce the iridium loading in proton exchange membrane water electrolysis (PEMWE) is explored. Herein, a scalable synthesis method based on a photodeposition process for a TiO2@IrOx core–shell catalyst with a reduced iridium content as low as 40 wt.% is presented. Using this synthesis method, titania support particles homogeneously coated with a thin iridium oxide shell of only 2.1 ± 0.4 nm are obtained. The catalyst exhibits not only high ex situ activity, but also decent stability compared to commercially available catalysts. Furthermore, the unique core–shell structure provides a threefold increased electrical powder conductivity compared to structures without the shell. In addition, the low iridium content facilitates the fabrication of sufficiently thick catalyst layers at decreased iridium loadings mitigating the impact of crack formation in the catalyst layer during PEMWE operation. It is demonstrated that the novel TiO2@IrOx core–shell catalyst clearly outperforms the commercial reference in single‐cell tests with an iridium loading below 0.3 mgIr cm−2 exhibiting a superior iridium‐specific power density of 17.9 kW gIr−1 compared to 10.4 kW gIr−1 for the commercial reference.

The skeleton is a common site of cancer metastasis and malignancy with the resultant lesions often being incurable. Interactions between metastatic cancer cells and the bone microenvironment are critical for cancer cell survival, outgrowth, and progression. Mesenchymal Stem Cells (MSCs) are an essential stromal cell type in bone that are appreciated for their impacts on cancer-induced bone disease, however, newer evidence suggests that MSCs possess extensive roles in cancer-bone crosstalk, including cancer cell dormancy, metabolic demands, and immune-oncology. Emerging evidence has also identified the importance of MSC tissue source and the influence of ageing when studying MSC biology. Combining these considerations together with developing technologies such as spatial transcriptomics will contribute to defining the molecular mechanisms underlying complex stroma-cancer interactions in bone and assist with identification of therapeutically tractable targets.

Abstract Total leaf area per plant is an important measure of the photosynthetic capacity of an individual plant that together with plant density drives the canopy leaf area index, that is, the total leaf area per unit ground area. Because the total number of leaves per plant (or per shoot) varies among conspecifics and among mixed species communities, this variation can affect the total leaf area per plant and per canopy but has been little studied. Previous studies have shown a strong linear relationship between the total leaf area per plant (or per shoot) (AT) and the total number of leaves per plant (or per shoot) (NT) on a log–log scale for several growth forms. However, little is known whether such a scaling relationship also holds true for bamboos, which are a group of Poaceae plants with great ecological and economic importance in tropical, subtropical, and warm temperate regions. To test whether the scaling relationship holds true in bamboos, two dwarf bamboo species (Shibataea chinensis Nakai and Sasaella kongosanensis ‘Aureostriatus’) with a limited but large number of leaves per culm were examined. For the two species, the leaves from 480 and 500 culms, respectively, were sampled and AT was calculated by summing the areas of individual leaves per culm. Linear regression and correlation analyses reconfirmed that there was a significant log–log linear relationship between AT and NT for each species. For S. chinensis, the exponent of the AT versus NT scaling relationship was greater than unity, whereas that of S. kongosanensis ‘Aureostriatus’ was smaller than unity. The coefficient of variation in individual leaf area increased with increasing NT for each species. The data reconfirm that there is a strong positive power‐law relationship between AT and NT for each of the two species, which may reflect adaptations of plants in response to intra‐ and inter‐specific competition for light.

Abstract There is a lack of research on whether tree size affects lamina and petiole biomass allocation patterns, whereas the trade‐off between leaf biomass allocated to the lamina and the petiole is of significance when considering the hydraulic and mechanical function of the leaf as a whole. Here, Camptotheca acuminata Decne was selected for study because of the availability of trees differing in size growing under the same conditions. A total of 600 leaves for two tree size groups and 300 leaves per group differing in height and trunk diameter were collected. The lamina fresh mass (LFM), lamina dry mass (LDM), lamina area (LA), petiole fresh mass (PFM), and petiole length (PL) of each leaf was measured, and reduced major axis regression protocols were used to determine the scaling relationships among the five functional traits. The bootstrap percentile method was used to determine if the scaling exponents of the traits differed significantly between the two tree size groups. The results indicated that (i) there was a significant difference in the LFM, LDM, PFM, PL, LMA, LFMA and PFM/LFM between large and small trees, but no significant difference in LA; (ii) the LA versus LFM, LA versus LDM, LFM versus PFM, LA versus PFM, and PL versus PFM scaling relationships of the two groups were allometric (i.e., not isometric); (iii) there were significant differences in the scaling exponents of LA versus LFM, LA versus PFM, PL versus PFM between the two groups, but there was no significant difference in the LFM versus PFM scaling relationship between the two groups of trees. The data were also consistent with the phenomenon known as “diminishing returns”. These data indicate that tree size influences leaf biomass allocation patterns in ways that can potentially influence overall plant growth, and therefore have an important bearing on life‐history strategies.

Objective. This study investigated cardiorespiratory fitness (CRF) levels and the relationship with field-based measures of anthropometry in children aged 10 to 11 years. Methods . A total of 288 boys and 257 girls participated in the study. CRF (20 m shuttle run) and several field-based measures of anthropometry were assessed. Multiple regression was utilized for all data analysis. Results. Boys performed significantly better than girls on the CRF test ( P

Previous studies have validated a performance equation (PE) and its generalized version (GPE) in describing the rotated and right-shifted Lorenz curves of organ size (e.g., leaf area and fruit volume) distributions of herbaceous plants. Nevertheless, there are still two questions that have not been adequately addressed by prior work: (i) whether the PE and GPE apply to woody plant species and (ii) how do the PE and GPE perform in comparison with other Lorenz equations when fitting data. To address these deficiencies, we measured the lamina length and width of each leaf on 60 Alangium chinense saplings to compare the performance of the PE and GPE with three other Lorenz equations in quantifying the inequality of leaf area distributions across individual trees. Leaf area is shown to be the product of a proportionality coefficient (k) and leaf length and width. To determine the numerical value of k, we scanned 540 leaves to obtain the leaf area empirically. Using the estimated k, the leaf areas of 60 A. chinense saplings were calculated. Using these data, the two performance equations and three other Lorenz equations were then compared and assessed using the root-mean-square error (RMSE) and Akaike information criterion (AIC). The PE and GPE were found to be valid in describing the rotated and right-shifted Lorenz curves of the A. chinense leaf area distributions, and GPE has the lowest RMSE and AIC values. This work validates the GPE as the best model in gauging variations in leaf area of the woody species.

Abstract Multiple myeloma (MM) is an osteolytic malignancy that is incurable due to the emergence of treatment resistant disease. Defining how, when and where myeloma cell intrinsic and extrinsic bone microenvironmental mechanisms cause relapse is challenging with current biological approaches. Here, we report a biology-driven spatiotemporal hybrid agent-based model of the MM-bone microenvironment. Results indicate MM intrinsic mechanisms drive the evolution of treatment resistant disease but that the protective effects of bone microenvironment mediated drug resistance (EMDR) significantly enhances the probability and heterogeneity of resistant clones arising under treatment. Further, the model predicts that targeting of EMDR deepens therapy response by eliminating sensitive clones proximal to stroma and bone, a finding supported by in vivo studies. Altogether, our model allows for the study of MM clonal evolution over time in the bone microenvironment and will be beneficial for optimizing treatment efficacy so as to significantly delay disease relapse.

Abstract The relationship between noise annoyance and risk of cardiovascular disease (CVD) still needs to be fully elucidated. Thus, we examined the relationship between noise annoyance and CVD risk in a large population-based cohort study. Cross-sectional (N = 15,010, aged 35–74 years, baseline investigation period 2007–2012) and prospective data (5- and 10-year follow-up from 2012 to 2022) from the Gutenberg Health Study were used to examine the relationship between noise annoyance due to different sources and risk of prevalent and incident CVD comprising atrial fibrillation, coronary artery disease, myocardial infarction, stroke, chronic heart failure, peripheral artery disease, and venous thromboembolism. In cross-sectional analyses, noise annoyance was an independent risk factor for prevalent CVD, with the strongest associations seen for noise annoyance during sleep (e.g., neighborhood noise annoyance: odds ratio 1.20, 95% confidence interval 1.13–1.27, p

Abstract Background Depression is associated with an increased risk for type 2 diabetes mellitus. However, depression may take different courses, and it is not fully understood how these affect the development of diabetes. It is further to be determined whether sex modifies the association between depression and type 2 diabetes. Methods We analyzed data from the Gutenberg Health Study, a longitudinal and population-based cohort study (N = 15,010) in Germany. Depressive symptoms (measured by PHQ-9), history of depression, diabetes mellitus, and relevant covariates were assessed at baseline, and the outcomes of prediabetes and type 2 diabetes mellitus were evaluated 5 years later. Logistic regression was used to estimate odds ratios of incident prediabetes and type 2 diabetes mellitus, adjusting for potential confounders as identified in a Directed Acyclic Graph. Results In the confounder adjusted model, current depression (PHQ-9 ≥ 10 at baseline; OR = 1.79, 95% CI = 1.11 to 2.74, p = 0.011), and persistent depression had a statistically significant (OR = 2.44, 95% CI = 1.62 to 3.54, p = 0.005) effect on incident type 2 diabetes mellitus. A history of depression without current depression had no statistically significant effect on type 2 diabetes (OR = 1.00, 95% CI = 0.68 to 1.43, p = 0.999). The effect of depression on incident diabetes did not differ significantly between women (OR = 2.02; 95% CI = 1.32 to 3.09) and men (OR = 2.16; 95% CI = 1.41 to 3.31; p-value for interaction on the multiplicative scale p = 0.832 and on the additive scale p = 0.149). Depression did not have a significant effect on incident prediabetes. Conclusion This study shows how the history and trajectory of depression shape the risk for diabetes. This raises interesting questions on the cumulative effects of depression trajectories on diabetes and body metabolism in general. Depression can negatively affect physical health, contributing to increased morbidity and mortality in people with mental disorders.

Deep learning’s immense capabilities are often constrained by the complexity of its models, leading to an increasing demand for effective sparsification techniques. Bayesian sparsification for deep learning emerges as a crucial approach, facilitating the design of models that are both computationally efficient and competitive in terms of performance across various deep learning applications. The state-of-the-art – in Bayesian sparsification of deep neural networks – combines structural shrinkage priors on model weights with an approximate inference scheme based on stochastic variational inference. However, model inversion of the full generative model is exceptionally computationally demanding, especially when compared to standard deep learning of point estimates. In this context, we advocate for the use of Bayesian model reduction (BMR) as a more efficient alternative for pruning of model weights. As a generalization of the Savage-Dickey ratio, BMR allows a post-hoc elimination of redundant model weights based on the posterior estimates under a straightforward (non-hierarchical) generative model. Our comparative study highlights the advantages of the BMR method relative to established approaches, which are based on hierarchical horseshoe priors over model weights. We illustrate the potential of BMR across various deep learning architectures, from classical networks like LeNet to modern frameworks such as Vision Transformers and MLP-Mixers.

Abstract While microplastics have been recently detected in human blood and the placenta, their impact on human health is not well understood. Using a mouse model of environmental exposure during pregnancy, our group has previously reported that exposure to polystyrene micro- and nanoplastics throughout gestation results in fetal growth restriction. While polystyrene is environmentally relevant, polyethylene is the most widely produced plastic and amongst the most commonly detected microplastic in drinking water and human blood. In this study, we investigated the effect of maternal exposure to polyethylene micro- and nanoplastics on fetal growth and placental function. Healthy, pregnant CD-1 dams were divided into three groups: 106 ng/L of 740–4990 nm polyethylene with surfactant in drinking water (n = 12), surfactant alone in drinking water (n = 12) or regular filtered drinking water (n = 11). At embryonic day 17.5, high-frequency ultrasound was used to investigate the placental and fetal hemodynamic responses following exposure. While maternal exposure to polyethylene did not impact fetal growth, there was a significant effect on placental function with a 43% increase in umbilical artery blood flow in the polyethylene group compared to controls (p

Abstract High suicide risk represents a serious problem in patients with major depressive disorder (MDD), yet treatment options that could safely and rapidly ameliorate suicidal ideation remain elusive. Here, we tested the feasibility and preliminary efficacy of the Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) in reducing suicidal ideation in patients with MDD. Thirty-two MDD patients with moderate to severe suicidal ideation participated in the current study. Suicidal ideation and depression symptoms were assessed before and after 5 days of open-label SAINT. The neural pathways supporting rapid-acting antidepressant and suicide prevention effects were identified with dynamic causal modelling based on resting-state functional magnetic resonance imaging. We found that 5 days of SAINT effectively alleviated suicidal ideation in patients with MDD with a high response rate of 65.63%. Moreover, the response rates achieved 78.13% and 90.63% with 2 weeks and 4 weeks after SAINT, respectively. In addition, we found that the suicide prevention effects of SAINT were associated with the effective connectivity involving the insula and hippocampus, while the antidepressant effects were related to connections of the subgenual anterior cingulate cortex (sgACC). These results show that SAINT is a rapid-acting and effective way to reduce suicidal ideation. Our findings further suggest that distinct neural mechanisms may contribute to the rapid-acting effects on the relief of suicidal ideation and depression, respectively.

Twenty-one species of Mysidae were sampled by three ANDEEP expeditions to the Southern Ocean with epibenthic sledges dragged over the deep-sea floor in the realm of 58–71° S and 00–65° W, depth 774–5190 m. Previously known ranges are significantly extended southward for four species and to greater depth in the same four species plus two other species. Supplementary descriptions are given for Amblyops tattersalli and Dactylamblyops murrayi, and a first description of a (subadult) male for Thalassomysis tattersalli. The definitions of the genera Amphiakrops gen. nov., Chelamblyops gen. nov., Desmocornea gen. nov. and Schizurakrops gen. nov. are mainly based on the structure of the eyes as well as of the antennal peduncle, chelate second thoracic endopod and telson. These structures are also important for the descriptions of Amblyops arianii sp. nov., A. bipapillatus sp. nov., Amblyopsoides fenestragothica sp. nov., A. lepidophthalma sp. nov., Amphiakrops brandtae gen. et sp. nov., Dactylamblyops benthophilus sp. nov., Desmocornea subchelata gen. et sp. nov., Paramblyops petrescui sp. nov., Schizurakrops meesi gen. et sp. nov., Scolamblyops muehlenhardtae sp. nov., Stellamblyops doryphorus sp. nov. and Mysidella antarctica sp. nov. Six previously described taxa are recombined as Amblyopsoides laticauda comb. nov., Amphiakrops bidigitatus comb. nov., A. japonicus comb. nov., Chelamblyops globorostris comb. nov., Meierythrops tattersalli comb. nov. and M. triangulatus comb. nov. One species is revised back to the initial combination as Dactylamblyops japonicus. All except one (Mysidella antarctica sp. nov.) newly described (12), newly recombined (6) or back-combined (1) species belong to the Erythropinae. Keys to the resulting 61 genera and 263 species of Erythropinae and 18 species of Mysidellinae are given at the world-wide scale. Ocular papillae with a terminal pore (sensory pore organ) are recorded in nine ANDEEP species. The organ of Bellonci is identified on the reduced eyes in 16 species, among which D. subchelata gen. et sp. nov. has many ommatidia arranged in a self-contained ribbon which shows a banded rhabdom only in non-adults. Reduction of visual elements together with shrinking of ocular papillae during ontogenetic development suggest that non-adults of D. subchelata and T. tattersalli stay in the photic zone for feeding and growth and then descend only once during their lifetime to the abyss for reproduction.

While the ubiquity and importance of narratives for human adaptation is widely recognized, there is no integrative framework for understanding the roles of narrative in human adaptation. Research has identified several cognitive and social functions of narratives that are conducive to well-being and adaptation as well as to coordinated social practices and enculturation. In this paper, we characterize the cognitive and social functions of narratives in terms of active inference, to support the claim that one of the main adaptive functions of narrative is to generate more useful (i.e., accurate, parsimonious) predictions for the individual, as well as to coordinate group action (over multiple timescales) through shared predictions about collective behavior. Active inference is a theory that depicts the fundamental tendency of living organisms to adapt by proactively inferring the causes of their sensations (including their own actions). We review narrative research on identity, event segmentation, episodic memory, future projections, storytelling practices, enculturation, and master narratives. We show how this research dovetails with the active inference framework and propose an account of the cognitive and social functions of narrative that emphasizes that narratives are for the future—even when they are focused on recollecting or recounting the past. Understanding narratives as cognitive and cultural tools for mutual prediction in social contexts can guide research on narrative in adaptive behavior and psychopathology, based on a parsimonious mechanistic model of some of the basic adaptive functions of narrative.

Flow has been described as a state of optimal performance, experienced universally across a broad range of domains: from art to athletics, gaming to writing. However, its phenomenal characteristics can, at first glance, be puzzling. Firstly, individuals in flow supposedly report a loss of self-awareness, even though they perform in a manner which seems to evince their agency and skill. Secondly, flow states are felt to be effortless, despite the prerequisite complexity of the tasks that engender them. In this paper, we unpick these features of flow, as well as others, through the active inference framework, which posits that action and perception are forms of active Bayesian inference directed at sustained self-organisation; i.e., the minimisation of variational free energy. We propose that the phenomenology of flow is rooted in the deployment of high precision weight over (i) the expected sensory consequences of action and (ii) beliefs about how action will sequentially unfold. This computational mechanism thus draws the embodied cognitive system to minimise the ensuing (i.e., expected) free energy through the exploitation of the pragmatic affordances at hand. Furthermore, given the challenging dynamics the flow-inducing situation presents, attention must be wholly focussed on the unfolding task whilst counterfactual planning is restricted, leading to the attested loss of the sense of self-as-object. This involves the inhibition of both the sense of self as a temporally extended object and higher–order, meta-cognitive forms of self-conceptualisation. Nevertheless, we stress that self-awareness is not entirely lost in flow. Rather, it is pre-reflective and bodily. Our approach to bodily-action-centred phenomenology can be applied to similar facets of seemingly agentive experience beyond canonical flow states, providing insights into the mechanisms of so-called selfless experiences, embodied expertise and wellbeing.

Inflammatory macrophages are key drivers of atherosclerosis that can induce rupture-prone vulnerable plaques. Skewing the plaque macrophage population towards a more protective phenotype and reducing the occurrence of clinical events is thought to be a promising method of treating atherosclerotic patients. In the current study, we investigate the immunomodulatory properties of itaconate, an immunometabolite derived from the TCA cycle intermediate cis-aconitate and synthesised by the enzyme Aconitate Decarboxylase 1 (ACOD1, also known as IRG1), in the context of atherosclerosis. Ldlr−/− atherogenic mice transplanted with Acod1−/− bone marrow displayed a more stable plaque phenotype with smaller necrotic cores and showed increased recruitment of monocytes to the vessel intima. Macrophages from Acod1−/− mice contained more lipids whilst also displaying reduced induction of apoptosis. Using multi-omics approaches, we identify a metabolic shift towards purine metabolism, in addition to an altered glycolytic flux towards production of glycerol for triglyceride synthesis. Overall, our data highlight the potential of therapeutically blocking ACOD1 with the aim of stabilizing atherosclerotic plaques.

Abstract Objectives Vertigo describes symptoms of abnormal movement of the environment or the patient's own body. As such, it affects patients' quality of life, prevents them from following their daily activities, and increases healthcare utilization. The Global Burden of Disease Project aims to quantify morbidity and mortality worldwide. In 2013, a separate disability weight for vertigo was introduced. The aim of this study is to estimate the symptom burden of disease caused by vertigo. Methods This study analyzes data from the Gutenberg Health Study (GHS). The GHS is a population‐based cohort study representative of the city of Mainz and its district. Participants were asked whether they suffered from vertigo and, if so, how bothered they felt by it, rating their distress on a six‐level scale from 1 = little stressful to 6 = extremely stressful. Results Eight thousand five hundred and nineteen participants could be included in the study. The overall prevalence of vertigo was 21.6% (95%‐confidence interval [CI] [20.7%; 22.5%]). Vertigo prevalence peaked in the age group of 55–64 years. Vertigo annoyance averaged 2.42 (±1.28). When an annoyance of 3–6 was considered bothersome, the prevalence of bothersome vertigo was 8.1 % (95%‐CI [7.5%; 8.7%]). Age‐standardized to the European Standard Population 2013, vertigo caused a burden of 2102 years lived with disability per 100,000 population. Conclusion In this study, it was found that one in five people suffer at least occasionally from vertigo. This result suggests a significant burden of disease. This burden is reported at the symptom level. Future studies are needed to attribute the burden to specific causes. Level of Evidence 2.

Abstract Previous studies on self-rated health and mortality have usually not differentiated between physical and mental health, respectively have not considered physical diseases. This study aims to determine self-rated physical and mental health from middle to old age, examine associations with mortality adjusted for objective risk factors and assess effect modification by gender. In a large population-based sample (N = 14,993 at baseline), self-rated physical and mental health were rated separately by a single-item. Associations to mortality were modelled by Cox regressions, adjusting for potential confounding variables. Most participants rated their physical (79.4%), resp. mental health (82.3%) as good. Poor self-rated physical health was lowest in the youngest group (19.6%, age 35–44), and highest in midlife (29.1%, age 55–64). Poor self-rated mental health was lowest among the oldest (18.5%), and highest from 45 to 54 years (29.3%). Poor self-rated physical, but not mental health was predictive of mortality when adjusting for objective risk factors. Male gender and poor self-rated physical health interacted (RERI 0.43 95%-CI 0.02–0.85). Self-rated physical health was best in the youngest and worst in the midlife group, this pattern was reversed regarding self-rated mental health. Poor self-rated physical, but not mental health was predictive of mortality, adjusting for objective risk factors. It was more strongly predictive of mortality in men than in women. Poor subjective physical health ratings, should be taken seriously as an unfavorable prognostic sign, particularly in men.

Abstract Both classic and contemporary models of auditory word repetition involve at least four left hemisphere regions: primary auditory cortex for processing sounds; pSTS (within Wernicke’s area) for processing auditory images of speech; pOp (within Broca’s area) for processing motor images of speech; and primary motor cortex for overt speech articulation. Previous functional-MRI (fMRI) studies confirm that auditory repetition activates these regions, in addition to many others. Crucially, however, contemporary models do not specify how regions interact and drive each other during auditory repetition. Here, we used dynamic causal modelling, to test the functional interplay among the four core brain regions during single auditory word and pseudoword repetition. Our analysis is grounded in the principle of degeneracy—i.e., many-to-one structure-function relationships—where multiple neural pathways can execute the same function. Contrary to expectation, we found that, for both word and pseudoword repetition, (i) the effective connectivity between pSTS and pOp was predominantly bidirectional and inhibitory; (ii) activity in the motor cortex could be driven by either pSTS or pOp; and (iii) the latter varied both within and between individuals. These results suggest that different neural pathways can support auditory speech repetition. This degeneracy may explain resilience to functional loss after brain damage.

Abstract Myosin VI (Myo6) is the only minus-end directed nanomotor on actin, allowing it to uniquely contribute to numerous cellular functions. As for other nanomotors, the proper functioning of Myo6 relies on precise spatiotemporal control of motor activity via a poorly defined off-state and interactions with partners. Our structural, functional, and cellular studies reveal key features of myosin regulation and indicate that not all partners can activate Myo6. TOM1 and Dab2 cannot bind the off-state, while GIPC1 binds Myo6, releases its auto-inhibition and triggers proximal dimerization. Myo6 partners thus differentially recruit Myo6. We solved a crystal structure of the proximal dimerization domain, and show that its disruption compromises endocytosis in HeLa cells, emphasizing the importance of Myo6 dimerization. Finally, we show that the L926Q deafness mutation disrupts Myo6 auto-inhibition and indirectly impairs proximal dimerization. Our study thus demonstrates the importance of partners in the control of Myo6 auto-inhibition, localization, and activation.

Introduction: Overweight and obesity lead to numerous complications and their treatment. The associated costs represent a health and sociopolitical burden. Therefore, the development of overweight and obesity is of great importance for health policy. Methods: The Gutenberg Health Study (GHS), a population-based observational study of individuals aged 35–74 years in the city of Mainz and the district of Mainz-Bingen, examined current data on the prevalence and development of overweight and obesity and their association with concomitant diseases and medication use. Results: Among men, 48.1% were overweight and 26.3% had obesity. Among women, these proportions were 32.1% and 24.1%, respectively. Elevated body mass index (BMI) was associated with numerous complications, particularly insulin resistance and type 2 diabetes, arterial hypertension, elevated triglycerides and low HDL cholesterol, and cardiovascular disease. Accordingly, medications to treat these conditions were used significantly more often in individuals with elevated BMI. During the 10-year observation period, mean weight increased in the population. Both men and women had a moderate but significant increase in BMI compared to men and women of the same age at baseline. Individual weight changes over the 10-year observation period, on the other hand, were age-dependent. In the two younger age decades, weight gain was observed, while in the oldest age decade, mean body weight decreased. Conclusion: These current data confirm that overweight and obesity are associated with relevant complications and that these complications lead to significant use of appropriate medications. The study also suggests that there is a significant trend toward increased prevalence of obesity (BMI ≥30) over the 10-year period.

The “leafing intensity premium” hypothesis proposes that leaf size results from natural selection acting on different leafing intensities, i.e., the number of leaves per unit shoot volume or mass. The scaling relationships among various above-ground functional traits in the context of this hypothesis are important for understanding plant growth and ecology. Yet, they have not been sufficiently studied. In this study, we selected four bamboo species of the genus Indocalamus Nakai and measured the total leaf fresh mass per culm, total non-leaf above-ground fresh mass, total number of leaves per culm, and above-ground culm height of 90 culms from each species. These data were used to calculate leafing intensity (i.e., the total number of leaves per culm divided by the total non-leaf above-ground fresh mass) and mean leaf fresh mass per culm (i.e., the total leaf fresh mass per culm divided by the total number of leaves per culm). Reduced major axis regression protocols were then used to determine the scaling relationships among the various above-ground functional traits and leafing intensity. Among the four species, three exhibited an isometric (one-to-one) relationship between the total leaf fresh mass per culm and the total non-leaf above-ground fresh mass, whereas one species (Indocalamus pumilus) exhibited an allometric (not one-to-one) relationship. A negative isometric relationship was found between the mean leaf fresh mass per culm and the leafing intensity for one species (Indocalamus pedalis), whereas three negative allometric relationships between mean leaf fresh mass per culm and leafing intensity were observed for the other three species and the pooled data. An exploration of the alternative definitions of “leafing intensity” showed that the total number of leaves per culm divided by the above-ground culm height is superior because it facilitates the non-destructive calculation of leafing intensity for Indocalamus species. These results not only confirm the leafing intensity premium hypothesis for bamboo species but also highlight the interconnected scaling relationships among different functional traits, thereby contributing to our understanding of the ecological and evolutionary significance of leaf size variation and biomass investment strategies.

This Quality Improvement project evaluated the implementation of a virtual Tai Chi program for older Veterans (OVs) at risk of loneliness and/or physical deconditioning. A 12-week Tai Chi course was conducted virtually at three Veterans Affairs sites using VA Video Connect (VVC). Changes in physical function based on the 30-Second Chair Stand (30CST) and loneliness based on the De Jong Gierveld Loneliness Scale (DJGS) were measured, as were the OVs’ satisfaction and adherence. Of 109 OVs who enrolled, 74 completed the program with a mean attendance rate of 84%. Completers demonstrated a statistically significant improvement in the 30CST, and those who were moderately or severely lonely at baseline saw a statistically significant improvement in the DJGS. Course evaluations were generally very positive. Results suggest that a virtual Tai Chi program is an effective and very satisfying intervention for OVs at risk of loneliness or physical deconditioning.

Post-acute COVID-19 vaccination syndrome (PACVS) is a chronic disease triggered by SARS-CoV-2 vaccination (estimated prevalence 0.02%). PACVS is discriminated from the normal post-vaccination state by altered receptor antibodies, most notably angiotensin II type 1 and alpha-2B adrenergic receptor antibodies. Here, we investigate the clinical phenotype using a study registry encompassing 191 PACVS-affected persons (159 females/32 males; median ages: 39/42 years). Unbiased clustering (modified Jaccard index) of reported symptoms revealed a prevalent cross-cohort symptomatology of malaise and chronic fatigue (>80% of cases). Overlapping clusters of (i) peripheral nerve dysfunction, dysesthesia, motor weakness, pain, and vasomotor dysfunction; (ii) cardiovascular impairment; and (iii) cognitive impairment, headache, and visual and acoustic dysfunctions were also frequently represented. Notable abnormalities of standard serum markers encompassing increased interleukins 6 and 8 (>80%), low free tri-iodine thyroxine (>80%), IgG subclass imbalances (>50%), impaired iron storage (>50%), and increased soluble neurofilament light chains (>30%) were not associated with specific symptoms. Based on these data, 131/191 participants fit myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and simultaneously also several other established dysautonomia syndromes. Furthermore, 31/191 participants fit none of these syndromes. In conclusion, PACVS could either be an outlier of ME/CFS or a dysautonomia syndrome sui generis.

Abstract In optic neuropathies, including glaucoma, retinal ganglion cells (RGCs) die. Cell transplantation and endogenous regeneration offer strategies for retinal repair, however, developmental programs required for this to succeed are incompletely understood. To address this, we explored cellular reprogramming with transcription factor (TF) regulators of RGC development which were integrated into human pluripotent stem cells (PSCs) as inducible gene cassettes. When the pioneer factor NEUROG2 was combined with RGC-expressed TFs (ATOH7, ISL1, and POU4F2) some conversion was observed and when pre-patterned by BMP inhibition, RGC-like induced neurons (RGC-iNs) were generated with high efficiency in just under a week. These exhibited transcriptional profiles that were reminiscent of RGCs and exhibited electrophysiological properties, including AMPA-mediated synaptic transmission. Additionally, we demonstrated that small molecule inhibitors of DLK/LZK and GCK-IV can block neuronal death in two pharmacological axon injury models. Combining developmental patterning with RGC-specific TFs thus provided valuable insight into strategies for cell replacement and neuroprotection.

Abstract Biliary tract cancers are rare cancers with poor prognosis due to a lack of therapeutic options, especially after the failure of first-line systemic treatment. Targeted treatments for this clinical situation are promising and have entered clinical practice. We aimed to describe the overall survival of matched targeted treatment after first-line treatment in patients with biliary tract cancers in an Austrian real-world multicenter cohort. We performed a multicenter retrospective chart review of patients with biliary tract cancer between September 2015 and January 2022. Data, including comprehensive molecular characteristics—next generation sequencing (NGS) and immunohistochemistry (IHC), clinical history, surgical procedures, ablative treatments, patient history, and systemic chemotherapy, were extracted from the records of the participating institutions. Targeted treatment was matched according to the ESMO scale for the clinical actionability of molecular targets (ESCAT). We identified 159 patients with the available molecular characteristics. A total of 79 patients underwent second-line treatment. Of these, 36 patients received matched targeted treatment beyond the first-line and were compared with 43 patients treated with cytotoxic chemotherapy in terms of efficacy outcomes. For Tier I/II alterations, we observed a progression free survival ratio (PFStargeted/PFSpre-chemotherapy) of 1.86, p = 0.059. The overall survival for patients receiving at least two lines of systemic treatment significantly favored the targeted approach, with an overall survival of 22.3 months (95% CI 14.7–29.3) vs. 17.5 months (95% CI 1.7–19.8; p = 0.048). Our results underscore the value of targeted treatment approaches based on extended molecular characterization of biliary tract cancer to improve clinical outcomes.

Abstract Empirical applications of the free-energy principle are not straightforward because they entail a commitment to a particular process theory, especially at the cellular and synaptic levels. Using a recently established reverse engineering technique, we confirm the quantitative predictions of the free-energy principle using in vitro networks of rat cortical neurons that perform causal inference. Upon receiving electrical stimuli—generated by mixing two hidden sources—neurons self-organised to selectively encode the two sources. Pharmacological up- and downregulation of network excitability disrupted the ensuing inference, consistent with changes in prior beliefs about hidden sources. As predicted, changes in effective synaptic connectivity reduced variational free energy, where the connection strengths encoded parameters of the generative model. In short, we show that variational free energy minimisation can quantitatively predict the self-organisation of neuronal networks, in terms of their responses and plasticity. These results demonstrate the applicability of the free-energy principle to in vitro neural networks and establish its predictive validity in this setting.

Abstract Traumatic brain injury (TBI) is a leading cause of morbidity and mortality. The innate and adaptive immune responses play an important role in the pathogenesis of TBI. Gamma-delta (γδ) T cells have been shown to affect brain immunopathology in multiple different conditions, however, their role in acute and chronic TBI is largely unknown. Here, we show that γδ T cells affect the pathophysiology of TBI as early as one day and up to one year following injury in a mouse model. TCRδ−/− mice are characterized by reduced inflammation in acute TBI and improved neurocognitive functions in chronic TBI. We find that the Vγ1 and Vγ4 γδ T cell subsets play opposing roles in TBI. Vγ4 γδ T cells infiltrate the brain and secrete IFN-γ and IL-17 that activate microglia and induce neuroinflammation. Vγ1 γδ T cells, however, secrete TGF-β that maintains microglial homeostasis and dampens TBI upon infiltrating the brain. These findings provide new insights on the role of different γδ T cell subsets after brain injury and lay down the principles for the development of targeted γδ T-cell-based therapy for TBI.

Age-related hearing loss (ARHL) is a common sensory impairment with complex underlying mechanisms. In our previous study, we performed a meta-analysis of genome-wide association studies (GWAS) in mice and identified a novel locus on chromosome 18 associated with ARHL specifically linked to a 32 kHz tone burst stimulus. Consequently, we investigated the role of Formin Homology 2 Domain Containing 3 (Fhod3), a newly discovered candidate gene for ARHL based on the GWAS results. We observed Fhod3 expression in auditory hair cells (HCs) primarily localized at the cuticular plate (CP). To understand the functional implications of Fhod3 in the cochlea, we generated Fhod3 overexpression mice (Pax2-Cre+/-; Fhod3Tg/+) (TG) and HC-specific conditional knockout mice (Atoh1-Cre+/-; Fhod3fl/fl) (KO). Audiological assessments in TG mice demonstrated progressive high-frequency hearing loss, characterized by predominant loss of outer hair cells, and a decreased phalloidin intensities of CP. Ultrastructural analysis revealed loss of the shortest row of stereocilia in the basal turn of the cochlea, and alterations in the cuticular plate surrounding stereocilia rootlets. Importantly, the hearing and HC phenotype in TG mice phenocopied that of the KO mice. These findings suggest that balanced expression of Fhod3 is critical for proper CP and stereocilia structure and function. Further investigation of Fhod3 related hearing impairment mechanisms may lend new insight towards the myriad mechanisms underlying ARHL, which in turn could facilitate the development of therapeutic strategies for ARHL.