bluuebunny/crossref_metadata_2025 huggingface dataset:
Stable primary brain cell cultures from zebrafish reveal hyperproliferation of non-neuronal cells fromscn1labmutants
Authors: Lorenzo Odierna G. , Stednitz Sarah , Pruitt April , Arnold Joshua , Hoffman Ellen J. , Scott Ethan K.
Published: October 2024

Zebrafish are a popular model system for studying the genetic and neural underpinnings of perception and behavior, both in wild-type animals and in the context of disease modelling. Cultured primary neurons provide a key complementary tool for such studies, but existing protocols for culturing embryonic zebrafish primary neurons are limited by short cell survival and low neuronal purity. In this study, we set out to establish a protocol to produce long lived, pure neuronal cultures from zebrafish that could be used to study the mechanistic contributions of genes to neuronal networks. We then used these primary cultures to characterize cell proliferation and differentiation in primary neurons derived fromscn1labmutant embryos, which lack a sodium channel relevant to Dravet syndrome and autism. Using our optimized protocol, we generated cultures that proliferate, diversify, and form stable networks of neurons surviving for months. These stable cultures allowed us to perform genetic experiments, in this case revealing dramatic differences in the cellular composition of cultures derived fromscn1labmutant embryos versus their wild type siblings. Specifically, we find that loss ofscn1labpromotes hyperproliferation of non-neuronal cells in mixed cultures of brain cells. In pure neuronal cultures, we find alterations in neurotransmitter subtypes consistent with known effects ofscn1labloss of function. Validating the utility of this approach, we then identify a corresponding hyperproliferation phenotype in livescn1labmutant embryos, shedding light on potential mechanisms that may be relevant for Dravet syndrome.

Significance statement

Most existing embryonic zebrafish primary neuron culture protocols describe growing mixed cell types for restricted durations. Here, we report generation of zebrafish mixed type or pure neuronal cultures that are viable for over 100 days. We apply these cultures to gain new insight intoscn1lab, a zebrafish orthologue of the Dravet Syndrome-associated sodium channel geneSCN1A. We report that loss ofscn1labresults in hyperproliferation of non-neuronal cells, revealing an underappreciated mechanism by which mutations inSCN1Aimpact the structure and function of neuronal networks. Ourin vitrocultures thus faithfully recapitulatein vivoneurobiology and provide a powerful platform to interrogate brain function in health and disease.
Students’ perspectives on communication skills’ course learning modes in two medical schools in Zambia: An interview-based descriptive study
Authors: Ezeala Mercy Ijeoma Okwudili , Volk John
Published: October 2024

Introduction

This study sought the views of undergraduate medical students on the effectiveness of their modes of instruction in communication skills knowledge and skills acquisition and transfer. Understanding the teaching-learning experiences from the students’ viewpoint could influence communication skills course facilitators to adopt instructional modes and learning experiences that enhance competency development in communication skills. It could also emphasize the need for curriculum developers to review the medical school curriculum, specifying student-centered and active learning pedagogical practices.

Methods

The descriptive study involved an in-depth semi-structured interview of eight undergraduate medical students from two medical schools in Zambia, who participated in communication skills training, selected through a purposive nonprobability sampling. The study mostly appropriated Tracy’s phronetic iterative analysis during its thematic analysis of the textual data collected between April and May 2022.

Results

The participants affirmed the importance of communication skills to their medical training but, decried the dominance of lecture-based delivery, limited interactive sessions, untimely and inadequate feedback from teachers and peers, inefficacy of teaching communication skills as theory, and limited understanding and distraction from online delivery as factors that hindered communication skills teaching-learning.

Conclusion

Although the students expressed communication skills as pivotal to their training and medical practice, their experiences of learning the skills through non-experiential and traditional lecture-based methods did not facilitate the motivation required for mastery and competency, suggesting that facilitators and curriculum planners should reevaluate the teaching-learning modes and process.
The multivariate genetic architecture of psychiatric and insulin resistance multimorbidity
Authors: Mota Nina Roth , Fanelli Giuseppe , Erdogan Izel , Klein Marieke , Sprooten Emma , Fóthi Ábel , Ruisch I. Hyun , Poelmans Geert , Alam Kazi Asraful , Haavik Jan , Wimberley Theresa , Arenella Martina , Serretti Alessandro , Fabbri Chiara , Franke Barbara , Bralten Janita
Published: October 2024

Psychiatric disorders frequently co-occur with insulin resistance (IR)-related conditions, including obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome (MetS). Although pairwise genetic correlations have been observed, the shared genetics underlying this multimorbidity remains underexplored. Here, we investigate the joint genetic architecture of psychiatric-IR multimorbidity, explore tissue-specific gene expression associations, and identify potential underlying biological mechanisms and repurposable drugs. We applied genomic structural equation modeling (SEM) to genome-wide association study (GWAS) data (N=9,725–933,970) from five psychiatric disorders (attention-deficit/hyperactivity disorder, anorexia nervosa, major depressive disorder, obsessive-compulsive disorder, and schizophrenia) and three IR-related conditions (MetS, obesity, T2DM). Factor analyses revealed a 2-factor solution, where one of the factors was composed by all psychiatric disorders (excluding schizophrenia) and IR-related conditions (the Psych-IR factor), representing the shared genetics of these psychiatric and IR-conditions. This factor showed genetic correlations with the inferior temporal, lateral occipital, and total cortical brain surface areas. A multivariate GWAS of the Psych-IR factor identified 150 risk loci and 366 associated genes (128 novel). The significant gene-set associations included the insulin binding and the Notch signaling pathways, while the gene-property tissue expression implicated the cerebellum, brain cortex, and pituitary gland, particularly involving the brain during prenatal development stages. Transcriptome-wide SEM (T-SEM) assessed tissue-specific gene expression associations and identified 499 genes (191 novel), including MHC-related genes. Drug repurposing analysis using PharmOmics suggested six potential candidates, including memantine and rosiglitazone. Associated genes derived from the Psych-IR factor multivariate GWAS and T-SEM results were combined for enrichment analyses, which highlighted the involvement of the chr16p11.2 region, BDNF signaling, and lipid metabolism. The identified Psych-IR factor offers novel insights into the shared genetic and biological mechanisms underlying psychiatric-IR multimorbidity, providing a foundation for future research on precision medicine and prevention approaches.
Gamma-hydroxybutyrate to promote slow-wave sleep in major depressive disorder: a randomized crossover trial
Authors: Bavato Francesco , Schnider Laura K. , Dornbierer Dario A. , Di Floriano Julia R. , Friedli Nicole , Janki Marina , Quednow Boris B. , Landolt Hans-Peter , Bosch Oliver G. , Seifritz Erich
Published: October 2024

In major depressive disorder (MDD), main clinical features include insomnia and increased daytime sleepiness. However, specific treatment options to promote sleep in MDD are limited. Gamma-hydroxybutyrate (GHB, clinically administered as sodium oxybate) is a GHB/GABABreceptor agonist used clinically in narcolepsy, where it promotes restorative slow-wave sleep (SWS) while reducing next-day sleepiness. Therefore, we performed a randomized, placebo- and active comparator-controlled, double-blind, crossover trial to investigate the sleep-promoting properties of GHB in individuals with MDD. Outpatients aged 20-65 years fulfilling the DSM-V criteria for MDD were enrolled. A single dose of GHB (50mg/kg) was compared with a single dose of the clinical competitor trazodone (1.5 mg/kg) and placebo. Of 29 randomized patients, 23 received at least one intervention and were included in the analysis. Primary outcomes were slow wave sleep ([SWS], as % of total sleep time [TST]) assessed by polysomnography and next-day vigilance (median response time and number of lapses in the psychomotor vigilance test [PVT]). GHB robustly prolonged SWS compared to both trazodone and placebo. GHB also prolonged TST and enhanced sleep efficiency (TST % of time-in-bed), while reducing sleep stages N1, N2, and wake-after-sleep-onset. While the median response time on the PVT was unaffected, GHB reduced the number of lapses compared to trazodone and placebo. No serious adverse events occurred. A single nocturnal dose of GHB effectively promotes SWS and shows more favorable effects on next-day vigilance than trazodone and placebo. Future studies should investigate GHB in clinical settings, including repeated administration.
Increasing Representativeness in theAll of UsCohort Using Inverse Probability Weighting
Authors: Kambara Manoj S. , Sharma Shivam , Spouge John L. , Jordan I. King , Mariño-Ramírez Leonardo
Published: October 2024

Large-scale population biobanks rely on volunteer participants, which may introduce biases that compromise the external validity of epidemiological studies. We characterized the volunteer participant bias for theAll of UsResearch Program cohort and developed a set of inverse probability (IP) weights that can be used to mitigate this bias. TheAll of Uscohort is older, more female, more educated, more likely to be covered by health insurance, less White, less likely to drink or smoke, and less healthy compared to the US population. IP weights developed via comparison of a nationally representative database eliminated the observed biases for all demographic and lifestyle characteristics and reduced the observed disease prevalence differences. IP weights also impact genetic associations with type 2 diabetes across diverse ancestry cohorts. We provide our IP weights as a community resource to increase the representativeness and external validity of theAll of Uscohort.
The Multidimensional Assessment of Parenting Scale: Youth Report Form in a Clinical Sample
Authors: Hogan Christina M , Beckmann Emily , Maron Micaela , Sutton Kelsey , Highlander April , Pielech Melissa , Wolff Jennifer C , Davis Thamara , Parent Justin
Published: October 2024

Objective

The Multidimensional Assessment of Parenting Scale (MAPS) was developed to assess a wide range of behaviors across positive and negative domains of parenting. This study aims to expand the utility of the MAPS by evaluating a youth-report version which provides an additional perspective on parenting practices.

Method

The study evaluated the youth-report form of the MAPS (MAPS-Y) in a large clinical population (N= 628) ranging from middle childhood (8-12) to adolescence (13-17) who were admitted to partial and inpatient psychiatric units. Youth and their caregivers completed the parent and youth versions of the MAPS questionnaire, and measures of child and adolescent psychopathology, emotion regulation, family context, and adversity. Analyses of factor structure, reliability, agreement, and validity were performed. The study also examined a short form of the MAPS-Y for reliability and validity.

Results

CFA and model fit indices indicated that all items loaded as expected onto subscales and with good fit. Analyses support strong reliability. The factor structure of the youth-report was invariant across developmental stages, included both positive and negative domains, and demonstrated strong psychometric properties. The MAPS-Y short form demonstrated strong validity and reliability.

Conclusion

The youth-report of the MAPS and its short form are appropriate for use among children and adolescents experiencing acute clinical symptoms. The MAPS youth-report will allow for nuanced, in-depth assessment of the parenting behaviors beyond parent-report that are critical to treatment outcomes in youth.
Early Prenatal Nitrate Exposure and Birth Outcomes: A Study of Iowa’s Public Drinking Water (1970-1988)
Authors: Semprini Jason
Published: October 2024

Background

Despite the biological mechanisms linking prenatal nitrate exposure to birth outcomes, epidemiological research has been inconclusive. The evidence-base has been limited by where and how nitrate exposure was measured, and the spurious correlation between geotemporal nitrate heterogeneity and unmeasurable factors contributing to gestational age and birth weight.

Objective

We linked Iowa water quality data and birth records to estimate the independent association between early prenatal nitrate exposure and birth outcomes.

Methods

Accessing Community Water Supply Quality Data, we calculated the median nitrate (mg/L) level for each county-date. With birth certificate microdata from the National Center for Health Statistics, we linked every Iowa birth (1970-1988) to a county-level nitrate measure within thirty days of conception. The outcomes were gestational age (weeks), preterm birth (< 37 weeks), birth weight (g), and low birth weight (< 2500 g). Nitrate exposure was first measured as a “dose-response” continuous variable, then as four binary variables (>10 mg/L, >5 mg/L, > 0.1 mg/L, > 0.0 mg/L). We constructed linear regression models which controlled for maternal and paternal characteristics, and county-year and year-month fixed-effects to account for unobservable annual variation between counties and longitudinal variation within all counties.

Results

Among 357,741 births, mean nitrate exposure was 4.2 mg/L. Early prenatal exposure to >0.1 mg/L nitrate was associated preterm birth (Est. = +0.66%-points; C.I. = 0.31, 1.01). Early prenatal exposure to 5 mg/L nitrate was associated with low birth weight (Est. = +0.33%-points; C.I. = 0.03, 0.63). The associations between elevated exposure to nitrate and any birth outcomes did not differ from lower levels of exposure.

Discussion

Prenatal exposure to nitrate below the >10 mg/L standard may cause harm. Since establishing this standard in 1992, groundwater nitrate levels have risen. Our results warrant greater scholarly and policymaking attention to understand and combat the adverse effects of nitrate.
Inconsistency detection in cancer data classification using explainable-AI
Authors: Mortezaagha Pouria , Rahgozar Arya
Published: October 2024

Abstract

This paper presents a novel approach to improving text-based cancer data classification by integrating BERTopic clustering with Support Vector Machine (SVM) classifiers, combined with the Explainable Inconsistency Algorithm (EIA). The proposed method leverages advanced preprocessing techniques, including Node2Vec embeddings, to enhance both clustering and classification performance. Through the introduction of EIA, we automatically identify and eliminate outliers and discordant data points, thus improving classification accuracy and providing valuable insights into underlying data relation-ships. A key innovation in this work is the use of recommender systems for mapping clusters to labels, which improves label assignment through collaborative filtering techniques. Our experimental results show a significant increase in both accuracy and F1-score after addressing data inconsistencies, with improvements validated through statistical tests, including t-tests. This paper contributes a robust, explainable, and scalable framework for cancer data analysis, offering potential applications in other domains requiring high-precision text classification. Future work will focus on extending the EIA to other biomedical datasets, optimizing hyperparameters, and deploying the framework in real-time clinical decision-support systems.
Longitudinal modeling of multimorbidity trajectories using large language models
Authors: Yang Lu , Bolton Elliot , Nayar Gowri , Altman Russ B.
Published: October 2024

Multimorbidity, the co-occurrence of two or more chronic conditions within an individual, is a major and escalating global health challenge, complicating treatment regimens, straining healthcare resources, and worsening patient outcomes. The complex interplay of shared genetic predispositions, biological pathways, and socioeconomic factors underpins its development, but clinical and research efforts have largely focused on managing diseases in isolation. Understanding multimorbidity trajectories—the accumulation and interaction of chronic diseases over time—is essential to improving preventive strategies and optimizing personalized care. Here, we introduce ForeSITE (Forecasting Susceptibility to Illness with Transformer Embeddings), a novel, transformer-based framework that harnesses advanced machine learning to predict multimorbidity progression. By analyzing longitudinal data from 480,000 participants in the UK Biobank, ForeSITE identifies distinct patterns in the co-occurrence and timing of diseases. Our temporal disease network provides insights into how certain diseases might share common genetic, environmental, or socioeconomic factors, offering more specific guidance for earlier detection and more effective disease management.
The Impact of Clinical and Molecular Variant Properties on Calibration and Performance of Variant Effect Prediction Tools
Authors: Isakov Ofer , Fluss Reut , Marek-Yagel Dina , Ben Shachar Shay
Published: October 2024

Background

Variant Effect Prediction (VEP) tools are essential for determining the potential pathogenicity of genetic variants, aiding clinical diagnostics and genetic counseling. However, their performance can vary depending on molecular and clinical contexts, complicating variant classification.

Aim

This study aims to assess the performance variability of commonly used VEP tools under different conditions. Additionally, the study aims to recalibrate score thresholds to better reflect evidence of pathogenicity.

Methods

ClinVar variants classified as pathogenic (P), likely pathogenic (LP), benign (B), or likely benign (LB) were analyzed using 25 VEP tools. Tools were evaluated based on discriminatory performance. Data were stratified by variant creation date, allele frequency, conservation level, mode of inheritance (MOI), and disease category. For each subset, Bayesian methods were employed to recalibrate score thresholds corresponding to the levels of evidence defined by the American College of Medical Genetics (ACMG).

Results

The performance of VEP tools varied significantly across different subsets. Variants created after 2020 showed a mild yet significant decrease in the performance of certain VEP tools, particularly those trained on earlier datasets. VEP tools exhibited reduced accuracy for variants with higher allele frequencies, particularly those exceeding a frequency of 10−4, suggesting a need for recalibration when assessing more common variants. Tools demonstrated lower discriminatory performance for variants located in regions with high conservation, mostly due to a decrease in specificity. Variants affecting autosomal recessive (AR) and X-linked (XL) genes were more accurately classified compared to those affecting autosomal dominant (AD) genes by most tools. Differences in MOI and conservation levels within certain disease categories were shown to correlate with overall performance. Recalibration of prediction scores resulted in lower score thresholds in low conservation regions compared to high and uncovered subsets in which higher levels of evidence may be achieved.

Conclusion

VEP tools exhibit context-dependent performance variability, necessitating score recalibration for accurate classification.
Intellectual disability-causing mutations in KIF11 impair microtubule dynamics and dendritic arborization
Authors: Wingfield Jenna L. , Niese Lukas , Grover Rahul , Diez Stefan , Puthanveettil Sathyanarayanan V
Published: October 2024

Precise control of axonal and dendritic architecture is vital for proper brain function, with microtubule (MT) dynamics playing a central role in this process. Here, we uncover a previously unrecognized function of the molecular motor protein KIF11, which acts as a MT dynamics rheostat in hippocampal neurons to modulate dendritic branching. Known for its role in mitotic spindle bipolarity, KIF11 is also implicated in Microcephaly with or without chorioretinopathy, lymphedema, or intellectual disabilities (MCLID). However, the specific neuronal functions of KIF11 and the impact of its mutations in MCLID have remained largely unexplored. Our studies, using quantitative imaging of MT dynamics following KIF11 inhibition, indicate that KIF11 preferentially binds to parallel MTs in mature neurons. This binding is associated with a marked increase in minus-end-out MT dynamics in both axons and dendrites upon KIF11 loss of function, coupled with enhanced MT flux and extended growth in tertiary dendrites. These changes suggest a novel role for KIF11 in orchestrating dendritic branching. Moreover, introducing MCLID-associated KIF11 mutations, KIF11Y82F, and KIF11ΔCterm, which cause minor microcephaly but severe intellectual disabilities, leads to significantly reduced MT dynamics and impaired dendritic arborization. In a microtubule sliding assay, KIF11Y82Fsignificantly reduced KIF11 velocity while KIF11ΔCtermincreased it. Temporal inhibition of KIF11 using a photo-inhibitable KIF11, show increased MT dynamics and dendritic growth, while activation results in kinked and twisted branches. Together, these data reveal that KIF11 is MT dynamics rheostat and regulator of dendritic arborization in mature neurons and provide new insights into the molecular mechanisms driving MCLID.
Co-cultivating rice plants withAzolla filiculoidesmodifies root architecture and timing of developmental stages
Authors: Cannavò Sara , Paleni Chiara , Costarelli Alma , Valeri Maria Cristina , Cerri Martina , Saccomanno Antonietta , Gregis Veronica , Chini Zittelli Graziella , Dobrev Petre I. , Reale Lara , Kater Martin M. , Paolocci Francesco
Published: October 2024

Strategies for increasing the yield of rice, the staple food for more than half of the global population, are needed to keep pace with the expected worldwide population increase, and sustainably forefront the challenges posed by climate change. In Southern-East Asian countries, rice farming benefits from the use ofAzollaspp. for nitrogen supply. In virtue of the symbiosis with the nitrogen-fixing cyanobacteriumTrichormus azollae, Azollaspp. are ferns that release nitrogen into the environment upon decomposition of their biomass. However, if and to what extent actively growingAzollaplants impact on the development of co-cultivated rice plantlets remains to be understood. Here, we show that actively growingAzolla filiculoidesplants alter the architecture of the roots and accelerates the differentiation and proliferation of leaves and tillers in co-cultivated rice plants. These changes result from an intimate cross-talk between rice andA. filiculoides,in which hormones and other metabolites released by the fern in the growth medium trigger an alteration in the rice root transcriptome and the hormonal profiles of both roots and leaves. Overall, the present data let us argue that co-cultivation withA. filiculoidesmight prime rice plants to better deal with both abiotic and biotic stress.

Highlight

Azolla filiculoidesalters the root transcriptome and hormonal balance in both roots and leaves of co-cultivated rice plantlets, thereby interfering with the progression of their developmental programs
Bacterial Supplements Attenuate Pelvic Irradiation-Induced Brain Metabolic Disruptions via the Gut-Brain Axis: A Multi-Omics Investigation
Authors: Venkidesh Babu Santhi , Narasimhamurthy Rekha Koravadi , Vinay Chigateri M. , Murali Thokur Sreepathy , Mumbrekar Kamalesh Dattaram
Published: October 2024

Recent advancements in cancer treatments have increased patient survival rates but also led to treatment-related side effects, negatively impacting the quality of life for cancer survivors. Research has highlighted the crucial role of gut microbiota in overall health, including cognition and neurodegenerative disorders. Cancer patients receiving pelvic radiation often experience gut dysbiosis and this may induce changes in brain through the bi-directional connection between the gut microbiota and the brain, known as the microbiota-gut-brain axis. Bacterial supplements intended to enhance health, whether consumed orally or applied topically. However, the mechanism of bacterial supplements to mitigate pelvic radiation-induced metabolomic alterations is not understood. To investigate this, we employed a multi-omics approach to elucidate how these supplements might mitigate radiation-induced metabolomic changes in the rat brain. A single 6 Gy dose of pelvic radiation was administered to 3–4-month-old Sprague Dawley rats and formulated bacterial supplements were given accordingly. Faecal bacterial sequencing and brain metabolomics performed to identify the changes in the gut microbiota and brain metabolomic analysis to check the altered brain metabolites post pelvic radiation. High-throughput 16S rRNA sequencing revealed significant shifts in bacterial composition, with reduced diversity in the radiation group compared to controls, which was restored in the supplementation groups. Notably, the dominant genera in the radiation group includedMethanobrevibacter, whileParasutterellaandBrachyspirawere prevalent in the supplementation cohorts. Untargeted metabolomic analysis identified 2,554 annotated metabolites, with 56 showing significant differences across groups. Principal Component Analysis demonstrated distinct metabolomic profiles between irradiated and control groups, with specific metabolomic pathways like retinol and glycerophospholipid metabolism altered by irradiation. Bacterial supplementation significantly attenuated these metabolomic disruptions. Therefore, bacterial supplementation could be a promising approach to addressing radiation-induced metabolomic reprogramming in the brains through gut dysbiosis in patients undergoing pelvic radiotherapy, enhancing overall well-being.
Mitochondrial reactive oxygen species cause arrhythmias in hypertrophic cardiomyopathy
Authors: Kohlhaas Michael , Sequeira Vasco , Parikh Shan , Dietl Alexander , Richter Olga , Bay Johannes , Bertero Edoardo , Schwemmlein Julia , Tian Qinghai , Friedrich Felix W. , Flenner Frederik , Nickel Alexander G. , Alscher Felix , Nanadikar Maithily S. , Venkataraman Raghav , Baudenbacher Franz J. , Kappl Reinhard , Johnson Victoria , Roma Leticia Prates , Kasakow Andrej , Hohl Mathias , Laufs Ulrich , Hoth Markus , Katschinski Dörthe M. , Böhm Michael , Lipp Peter , Carrier Lucie , Eschenhagen Thomas , Knollmann Björn C. , Maack Christoph
Published: October 2024

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease and caused by genetic variants that often increase sarcomeric Ca2+sensitivity. While Ca2+sensitization explains diastolic dysfunction, the genesis of ventricular arrhythmias is unresolved. Here, we show that HCM mutations or pharmacological interventions that increase myofilament Ca2+sensitivity generate bioenergetic mismatch and oxidative stress during β-adrenergic stimulation which provide a trigger and a substrate for arrhythmias. For any given sarcomere shortening that produces work and consumes ATP, less Ca2+stimulates the Krebs cycle to maintain mitochondrial NADH. This reverses the mitochondrial transhydrogenase to regenerate NADH from NADPH, supporting ATP production at the cost of NADPH-dependent antioxidative capacity. The ensuing overflow of reactive oxygen species (ROS) from mitochondria and glutathione oxidation induce spontaneous Ca2+release from the sarcoplasmic reticulum and Ca2+waves, well-defined triggers of arrhythmias. Furthermore, transhydrogenase-dependent ROS formation slows electrical conduction during β-adrenergic stimulationin vivo, providing a substrate for arrhythmias. Chronic treatment with a mitochondrially-targeted ROS scavenger abolishes the arrhythmic burden during β-adrenergic stimulation in HCM micein vivo,while inducing mitochondrial ROS with a redox cycler is sufficient to induce arrhythmias in wild-type animals. These findings may lead to new strategies to prevent sudden cardiac death in patients with HCM.
Pharmacological enhancement of slow-wave activity improves cognition and reduces amyloidosis at an early stage in a mouse model of Alzheimer’s disease
Authors: Kollarik Sedef , Bimbiryte Dorita , Sethi Aakriti , Dias Inês , Moreira Carlos G. , Noain Daniela
Published: October 2024

Improving sleep in murine Alzheimer’s disease (AD) is associated with reduced brain amyloidosis. However, the window of opportunity for successful sleep-targeted interventions regarding reduction of pathological hallmarks and related cognitive performance remains poorly characterized. Here, we enhanced slow-wave activity (SWA) during sleep via sodium oxybate (SO) oral administration for 2 weeks at early (6 months old) or moderately late (11 months old) disease stages in Tg2576 mice, and evaluated resulting neuropathology and behavioral performance. We observed that cognitive performance of 6 months old Tg2576 mice significantly improved upon SO treatment, whereas no change was observed in 11 months old mice. Histochemical assessment of amyloid plaques demonstrated that SO-treated 11 months old Tg2576 mice had significantly less plaque burden than placebo-treated ones, whereas ELISA of insoluble protein fractions from 6 months old Tg2576 mice’ brains indicated lower Aβ-42/Aβ-40 ratio in SO-treated group vs. placebo-treated controls. Altogether, our results suggest that SWA-dependent reduction of brain amyloidosis leads to alleviated behavioral impairment in Tg2576 mice only if administered early in the disease course, potentially highlighting the key importance of early sleep-based interventions in clinical cohorts.

Significance statement

A staggering amount of people worldwide live with AD. Despite extensive efforts from academy and industry, no cure is available to date. Sleep may be a modifiable factor involved in onset, progression and potentially also treatment of AD. However, knowledge regarding important aspects of sleep-targeted treatments is missing, e.g. adequate window of opportunity for their efficacious application, their minimal duration or their effect onto both pathology and cognition. We found that pharmacologically enhanced sleep depth is associated with reduced amyloid neuropathology in AD mice brains at both early- and moderately advanced-stage disease. However, only early-stage disease mice significantly benefited from sleep-enhancing treatment. Our results strongly encourage further mechanistic research and the launch of larger scale preclinical investigations in early AD populations.
Dysfunctional LHX6 pallido-subthalamic projections mediate epileptic events in a mouse model of Leigh Syndrome
Authors: Sánchez-Benito Laura , Compte Joan , Vila Miquel , Sanz Elisenda , Quintana Albert
Published: October 2024

Deficits in the mitochondrial energy-generating machinery cause mitochondrial disease (MD), a group of untreatable and usually fatal disorders. Among many severe symptoms, refractory epileptic events are a common neurological presentation of MD. However, the neuronal substrates and circuits for MD-induced epilepsy remain unclear. Here, using mouse models of mitochondrial epilepsy that lack mitochondrial complex I subunit NDUFS4 in a constitutive or conditional manner, we demonstrate that mitochondrial dysfunction leads to a reduction in the number of GABAergic neurons in the rostral external globus pallidus (GPe) and identify a specific affectation of pallidalLhx6-expressing inhibitory neurons. Our findings further reveal that viral vector-mediatedNdufs4re-expression in the GPe effectively prevents seizures and improves the survival in the models. Additionally, we highlight the subthalamic nucleus (STN) as a critical structure in the neural circuit involved in mitochondrial epilepsy, as its inhibition effectively reduces epileptic events. Thus, we have identified a novel role for pallido-subthalamic projections in the development of epilepsy in the context of mitochondrial dysfunction. Our results suggest STN inhibition as a potential therapeutic intervention for refractory epilepsy in patients with MD providing new leads in the quest to identify novel and effective treatments.
Metabolic growth mechanisms and theoretical growth potential of global woody plant communities
Authors: Shu Shumiao , Tang Xiaolu , Kontsevich George , Wang Xiaodan , Zhu Wanze , Zhao Yangyi , Wang Wenzhi , Zhao Xiaoxiang , Hu Zhaoyong
Published: October 2024

Predicting the growth and maximum biomass (Mmax) of woody plant communities (WPC) is challenging due to the complexity and variability of tree growth. While Metabolic Scaling Theory (MST) offers a promising concept, its current theoretical framework is still insufficient. Here, we applied MST principles and our previous findings to propose an iterative growth model for forest growth (IGMF). This model and its extension show that WPC growth, net primary productivity and other carbon budgets - such as total primary productivity, autotrophic respiration, organ turnover biomass and non-structural carbohydrates - can be expressed as functions of current biomass, maintenance respiration rate per unit biomass and stand age orMmax. These functions are globally convergent, allowing us to estimate the current (2018-2020) globalMmaxat 1451 ± 26 Pg based on the current state of WPCs alone, with a growth potential of 518 Pg, 83% of which is attributable to shrublands. By the end of the century, climate change is projected to reduce the totalMmaxby 266 Pg, mainly in species-rich evergreen broadleaf forests. Further analysis indicates that species richness increases the climate sensitivity ofMmax, while soil organic and moisture affects the direction of this response. Our findings reveal WPC growth kinetics and show a shift in the main contributor to terrestrial carbon sequestration from forests to shrublands.

Significance Statement

This study introduces a new theoretical model for understanding and predicting the growth and carbon budgets of woody plant communities (WPCs), which applies to diverse WPCs globally and reveals their convergent metabolic growth patterns.

We predict future changes in the maximum biomass of woody plant communities and find a significant decline in evergreen broadleaf forests, where sensitivity and response to climate change are influenced by current species richness and soil conditions.
Mechanism of DNA entrapment by the MukBEF SMC complex and its inhibition by a viral DNA mimic
Authors: Bürmann Frank , Clifton Bryony , Koekemoer Sophie , Wilkinson Oliver J. , Kimanius Dari , Dillingham Mark S. , Löwe Jan
Published: October 2024

Ring-like structural maintenance of chromosomes (SMC) complexes are crucial for genome organization and operate through mechanisms of DNA entrapment and loop extrusion. Here, we explore the DNA loading process of the bacterial SMC complex MukBEF. Using electron cryomicroscopy (cryo-EM), we demonstrate that ATP binding opens one of MukBEF’s three potential DNA entry gates, exposing a DNA capture site that positions DNA at the open neck gate. We discover that the gp5.9 protein of bacteriophage T7 blocks this capture site by DNA mimicry, thereby preventing DNA loading and inactivating MukBEF. We propose a comprehensive and unidirectional loading mechanism in which DNA is first captured at the complex’s periphery and then ingested through the DNA entry gate, powered by a single cycle of ATP hydrolysis. These findings illuminate a fundamental aspect of how ubiquitous DNA organizers are primed for genome maintenance and demonstrate how this process can be disrupted by viruses.

Graphical abstract
Engineered Whole Lungs for Tissue Biology
Authors: Greaney Allison Marie , Raredon Micha Sam Brickman , Obata Tomohiro , Wang Juan , Adams Taylor , Schupp Jonas , Mizoguchi Satoshi , Edelstein Sophie , Yuan Yifan , Baevova Pavlina , Wang Nuoya , Engler Alex , Leiby Katherine , Tsuchiya Tomoshi , Homer Robert , Kaminski Naftali , Langer Robert , Niklason Laura E. , Medzhitov Ruslan
Published: October 2024

End-stage lung disease and lung cancer significantly contribute to global mortality, necessitating new research strategies for studying pulmonary biology. Here, we present an engineered whole-lung tissue model used to evaluate the effects of cellular communities on tissue organization and alveolar barrier function. Engineered lungs were grownex vivoon decellularized whole-lung matrices as structurally biomimetic, bioactive scaffolds. Histologic architecture of engineered lungs improved with the addition of alveolar macrophages, coming to resemble neonatal lung. Incorporating alveolar macrophages maximized the differentiation of native-like cellular communities, including alveolar type I-like epithelium, bronchioalveolar stem cells, microvascular endothelium, and pericytes. Cell-cell signaling in engineered lungs showed activation of developmental and inflammatory pathways, including WNT, Notch, and FGF signaling pathways. Engineered lungs containing alveolar macrophages showed a 668% improvement in measured alveolar barrier function. This work demonstrates the potential utility of engineered lung models for studying principles of tissue biology and pulmonary regeneration.
PertEval-scFM: Benchmarking Single-Cell Foundation Models for Perturbation Effect Prediction
Authors: Wenteler A. , Occhetta M. , Branson N. , Huebner M. , Curean V. , Dee W. T. , Connell W. T. , Hawkins-Hooker A. , Chung S. P. , Ektefaie Y. , Gallagher-Syed A. , Córdova C. M. V.
Published: October 2024

Abstract

In silicomodeling of transcriptional responses to perturbations is crucial for advancing our understanding of cellular processes and disease mechanisms. We present PertEval-scFM, a standardized framework designed to evaluate models for perturbation effect prediction. We apply PertEval-scFM to benchmark zero-shot single-cell foundation model (scFM) embeddings against simpler baseline models to assess whether these contextualized representations enhance perturbation effect prediction. Our results show that scFM embeddings do not provide consistent improvements over baseline models, especially under distribution shift. Additionally, all models struggle with predicting strong or atypical perturbation effects. Overall, this study provides a systematic evaluation of zero-shot scFM embeddings for perturbation effect prediction, highlighting the challenges of this task and revealing the limitations of current-generation scFMs. Our findings underscore the need for specialized models and high-quality datasets that capture a broader range of cellular states. Source code and documentation can be found at:https://github.com/aaronwtr/PertEval.
“Nanoscale biodegradable printing for designed tuneability of vaccine delivery kinetics”
Authors: Peeler David J , Sun Rujie , Kütahya Ceren , Peschke Patrick , Zhou Kun , Brachi Giulia , Yeow Jonathan , Rifaie-Graham Omar , Wojciechowski Jonathan P , Debets Thomas Fernandez , LaLone Vernon , Song Xin , Polra Krunal , Tregoning John S , Shattock Robin J , Stevens Molly M
Published: October 2024

Two photon polymerization (2PP) 3D printing enables top-down biomaterial synthesis with nanoscale spatial resolution forde novodesign of monodisperse injectable drug delivery systems. To address the limitations of current 2PP resins, we developed Spatiotemporal Controlled Release Inks of Biocompatible polyEsters (SCRIBE), a novel poly(lactic-co-glycolic acid)-triacrylate resin family with sub-micron resolution and tuneable hydrolysis. SCRIBE enables direct printing of hollow microparticles with tuneable chemistry and complex geometries inaccessible to molding techniques, which we use to engineer controlled protein releasein vitroandin vivo. We use SCRIBE microparticles to modulate antibody titers and class switching as a function of antigen release rate and extend these findings to enable a single-injection vaccine formulation with extended antibody induction kinetics. Demonstrating how the chemistry and CAD of 2PP-printed microparticles can be used to tune responses to biomacromolecule releasein vivoopens significant opportunities for a new generation of drug delivery vehicles.
Early Intervention with Low-Dose Sclerostin Antibody Therapy can Reduce Osteocyte-mediated Secondary Mineralization after initial bone loss in Ovariectomised Rats
Authors: Naqvi Syeda Masooma , Allison Hollie , O’Sullivan Laoura M. , Holdsworth Gill , Panadero-Perez Juan Alberto , Schiavi-Tritz Jessica , McNamara Laoise M.
Published: October 2024

Neutralizing antibodies targeting sclerostin (Scl-Ab) mitigate bone loss and promote bone formation, thereby reducing fracture risk in postmenopausal osteoporosis. Clinical use of Scl-Ab is indicated for postmenopausal women with severe osteoporosis who are at high risk of, or have a history of, fragility fractures, which can occur many years after menopause. However, in early stages of estrogen deficiency there is rapid bone loss, which abates thereafter, whereas in the longer-term changes in bone mineralization occur. This study seeks to investigate whether administering intermittent low-dose monthly sclerostin antibody during early estrogen deficiency could mitigate osteoclastogenesis but also prevent osteocyte-driven secondary mineralization, due to apoptosis, perilacunar remodelling and osteocyte mechanosensitivity. Female Wistar rats that had completed their breeding cycles underwent bilateral ovariectomy as a model of postmenopausal osteoporosis. After 3 weeks of bone loss, one group received monthly low-dose Scl-Ab injections (2 mg/kg/month) and a control group remained untreated. We report that early treatment with intermittent low-dose Scl-Ab mildly increased bone formation, reduced TRAP+ osteoclasts and suppressed catabolic and matrix degradation gene expression (Sost, Ctsk, Mmp9) compared to untreated rats. There was a decrease in the percentage of empty lacunae and MMP14+ osteocytes, along with decreased gene expression associated with osteocyte-mediated mineralization (DMP1, PHEX, OPN, ALP) and mechanotransduction (Vcl, integrins α5, αV, β1, CX43, Axin2, IFT88, Adcy6, Pkd1, and Cav1). Thus, we propose that early intervention with intermittent low-dose Scl-Ab therapy can promote surface bone formation but reduce osteocyte-mediated secondary mineralization after initial bone loss.
Allosteric regulation of BH3-in-groove interactions by tail anchors of BCL-xL complexes limits BH3 mimetic antagonism.
Authors: Maillet Laurent , Fetiveau Aurelie , Lalier Lisenn , Barille-Nion Sophie , Guette Catherine , Gautier Fabien , Teletchea Stephane , Juin Philippe Paul
Published: October 2024

BCL-xL exerts an essential cell survival function which relies on its hydrophobic groove binding to BH3 domain of BH3-only initiators and downstream BAX and BAK executioners. Combining resonance energy transfer assays and molecular dynamics simulations, we unravel that the C-terminal tail mediated subcellular membrane anchoring of BCL-xL selectively advantages binding to membrane-anchored PUMA initiator over BH3 mimetic ligands of the groove. This is due to the combined allosteric effect on BH3-in-groove binding of BCL-xL and PUMA tail anchors. Moreover, doubly anchored PUMA / BCL-xL complexes recruit endogenous BAX, which favors their antagonism by BH3 mimetics. BAX C-terminal tail anchor alone is sufficient to enhance BH3 mimetics induced death in cells expressing PUMA / BCL-xL. Thus, the survival function of BCL-xL is regulated by a complex interplay between its tail anchor and those of its interacting partners. This enables both resistance to pharmacological inhibitors and modulation by BAX, which functions as a crucial feedback disruptor of the BCL-xL network.
Reward processing in children with Affective Dysregulation
Authors: Aggensteiner Pascal-M , Giller Francisca , Holz Nathalie , Kaiser Anna , Igel Christine , Hohmann Sarah , Döpfner Manfred , Roessner Veit , Beste Christian , Banaschewski Tobias , Brandeis Daniel
Published: October 2024

Introduction

Affective dysregulation (AD) in children is characterized by irritability, anger, and frequent intense temper outbursts. Considerable evidence implies altered processing of frustration about missed rewards, but few studies investigated the preceding and thus potentially predictive reward anticipation and initial delivery processing in children with AD.

Methods

A total of 103 children aged 8 to 12 years (50 with AD and 53 without AD) were examined during a monetary reward anticipation task with event-related potential (ERP) components resolving reward anticipation (cue-CNV [Contingent Negative Variation]) and reward delivery phases (Reward Positivity and Feedback-Related Negativity). All components were analyzed by repeated measures ANOVA. Regression analyses also evaluated the associations between those ERP components and dimensional AD symptoms.

Results

Children with AD showed attenuated anticipatory reward processing compared to No-ADs. The CNV at fronto-central site (FCz) showed a significant group effect (No-AD>AD, p=0.017). Post-hoc test showed that this group difference was stronger for the cue monetary condition (monetary cue: p=.007, d=0.56, verbal cue: p=.901, d=0.16), and that only the No-AD group showed a significant difference between conditions (p<0.001). No significant effects were obtained for the delivery phase. Regression analysis showed that a reduced anticipatory CNV at FCz significantly explained AD symptoms, and that anger/irritability and anxiety/depressive symptoms predicted a reduced anticipatory CNV at FCz.

Conclusion

This neurophysiological characterization of reward anticipation and delivery in children with AD demonstrates altered neural activity in AD during anticipation of reward rather than following the delivery (or omission) of the reward itself. Our results highlight that altered reward anticipation in AD can occur outside frustration-prone tasks or settings, and underline the important role of both anger/irritability and anxiety/depressive symptoms in the pathophysiology of AD for atypical reward anticipation.
Trichomonas vaginalisextracellular vesicles suppress IFNε-mediated protection against host cell cytolysis
Authors: Kochanowsky Joshua A. , Betts Emma L. , Encinas Gabriel , Amoah Johnson , Mukherjee Sandip Kumar , Johnson Patricia J.
Published: October 2024

Trichomonas vaginalisis a commonly acquired sexually transmitted infection (STI) often found in symbiosis with the intracellular bacteriumMycoplasma hominis, an opportunistic pathogen of the female reproductive tract associated with bacterial vaginosis. How this symbiosis affects infection outcomes, and the host cell innate immune response is still poorly understood. Here we show thatT. vaginalisextracellular vesicles down-regulate a non-canonical type I interferon, interferon-epsilon, and suppress type I interferon responses. Transcriptomic analysis reveals that infection withT. vaginalisin symbiosis withM. hominisorM. hominisalone upregulates genes involved in the type I IFN response, but infection withT. vaginalisalone does not. Finally, we show that interferon-epsilon stimulation is protective againstT. vaginaliscytoadherence and cytolysis of host cells and increases the ability of neutrophils to kill the parasite. These studies provide insight into the innate immune response induced by a highly prevalent STI and its bacterial symbiont.