bluuebunny/crossref_metadata_2025 huggingface dataset:
pH-Responsive Phase Separation Dynamics of Intrinsically Disordered Peptides
Authors: Nandy Manali , Ganar Ketan A. , Ippel Hans , Dijkgraaf Ingrid , Deshpande Siddharth
Published: January 2025

Liquid-liquid phase separation of biomolecules is crucial for maintaining the functional organization in biological systems. Intrinsically disordered proteins are particularly prone to form phase-separated condensates in response to various physicochemical triggers. While the effect of ionic strength and temperature on phase separation dynamics have been studied extensively, the influence of pH is less explored. Here, we study a model glycine-rich protein present in the tick bioadhesive, given its capability to undergo phase separation. After confirming its disordered nature through spectroscopy, we investigated its pH dependence and underlying molecular mechanisms. Our findings reveal that pH significantly influences the protein hydrophobicity via ionic residues, driving notable variations in the coacervation behavior (propensity, progression) and in shaping the material properties (viscosity, interfacial activity) of the formed condensates. Given the ubiquitous presence of disordered proteins in biology, this study provides valuable insights about the broad implications of the pH-dependent behavior of intrinsically disordered proteins.
Evolution of CYP71D as a driving force of the diversification of monoterpene indole alkaloid biosynthesis
Authors: Besseau Sébastien , Durand Mickael , Zamar Duchesse-Lacours , Lezin Enzo , Méteignier Louis-Valentin , Birer Williams Caroline , Dutilleul Christelle , Perrot Thomas , Lanoue Arnaud , Oudin Audrey , Papon Nicolas , Sun Chao , St-Pierre Benoit , Courdavault Vincent
Published: January 2025

Monoterpene indole alkaloids (MIAs) constitute a vast group of plant natural products synthesized within the Gentianales order. MIAs possess outstanding pharmacological properties that explain their wide use in the treatment of human diseases. These biological activities result from the complex structure of MIAs that originate from intricated biosynthetic pathways involving several enzyme families and notably cytochrome P450s. The early steps of MIA synthesis involve several P450s from the 71 clade, which catalyse the conversion of various reduced strictosidine aglycones into MIAs from the mavacurane, strychnane, akuammilane, sarpagane, and heteroyohimane groups. An extensive study of these P450 distribution in genomic resources reveals that they all belong to a single evolutionary lineage named GAS clade, restricted to the MIA producing Gentianales (Gelsemiaceae and Rauvolfioideae). A related but distinct P450 lineage (named sister GAS clade) was found in non-MIA producing Gentianales and species producing structurally distinct MIAs (Rubiaceae). Functional characterization of 36 members of the GAS clade revealed that these enzymes felt into four main groups of activity depending on substrate acceptance (ex: tetrahydroalstonine, geissoschizine, ajmalicine…) and the nature of the catalyzed reaction (aromatization, cyclisation). These characterizations also lead to the identification of a yohimbane aromatization activity for several of these P450s, increasing the number of MIA scaffolds associated with GAS activity to six. Lastly, the chronology of emergence of these GAS activities was assessed by using ancestral sequence reconstitution, establishing that the initial ancestor of the whole GAS clade exhibits a main alstonine synthase activity. Subsequent gene duplication events, combined with neofunctionalization, facilitated the progressive emergence of eight additional activities, variably distributed among the four GAS subgroups. This comprehensive enzyme characterization establishes the evolutionary trajectory of the GAS clade, demonstrating how its diversification has progressively shaped the chemical diversity of MIAs in Gentianales.
TERRA R-loops trigger a switch in telomere maintenance towards break-induced replication and PrimPol-dependent repair
Authors: In Suna , Renck Nunes Patricia , Valador Fernandes Rita , Lingner Joachim
Published: January 2025

TERRA long noncoding RNAs associate with telomeres post transcription through base-pairing with telomeric DNA forming R-loop structures. TERRA regulates telomere maintenance but its exact modes of action remain unknown. Here, we induce TERRA transcription and R-loop formation in telomerase-expressing cells and determine that TERRA R-loop formation requires non-redundant functions of the RAD51 DNA recombinase and its enhancer RAD51AP1. TERRA R-loops interfere with semiconservative DNA replication promoting telomere maintenance by a homology-directed repair (HDR) mechanism known as Break Induced Replication (BIR), which ensures telomere maintenance in ALT cancer cells. In addition, TERRA induced PrimPol-dependent repair, which can initiate DNA synthesis de novo downstream of replication obstacles. PrimPol acts in parallel to BIR for telomere maintenance of TERRA over-expressing cells promoting their survival. Similarly, we find that PrimPol depletion is synthetic lethal with BIR deficiency in U2OS ALT cancer cells. Therefore, in the absence of other ALT-typical telomeric chromatin changes, TERRA R-loops per se are sufficient to induce ALT-typical telomere repair mechanisms.
Astroglial deficiency for oligophrenin-1 contributes to intellectual disability
Authors: Cresto Noémie , Ezan Pascal , Pillet Laure-Elise , Mazaud David , Mailly Philippe , Bemelmans Alexis , Meziane Hamid , Selloum Mohammed , Sorg Tania , Marchi Nicola , Hérault Yann , Billuart Pierre , Rouach Nathalie
Published: January 2025

Neurodevelopmental disorders, including X-linked intellectual disability, autism spectrum disorder or schizophrenia, can result from the mutation of oligophrenin-1 (Ophn1), encoding a Rho-GTPase-activating protein.Ophn1regulates synaptic development and function, in part via cytoskeleton reorganization, and is expressed in both neurons and astrocytes. Despite the crucial role of astrocytes in synapse function, altered in neurodevelopmental disorders, and theirOphn1expression, the specific impact of astroglialOphn1deficiency on synaptic transmission and behavior remains unknown. Here, we show thatOphn1deficiency postnatally in hippocampal astrocytes impairs synaptic transmission, short-term plasticity and spatial working memory in adults. This involves an adenosine A1 receptor-dependent presynaptic mechanism associated with astroglial morphological rearrangements resulting in increased astroglial synapse coverage. The structural, functional and behavioral alterations induced by astroglialOphn1deficiency are rescued in adults by pharmacological inhibition of the RhoA/ROCK pathway. Our findings uncover an important role for astroglialOphn1deficiency in synaptic and behavioral dysfunctions, pointing to a novel cellular therapeutic target for neurodevelopmental disorders.
Dose-dependent sensitivity of human 3D chromatin to a heart disease-linked transcription factor
Authors: Grant Zoe L. , Kuang Shuzhen , Zhang Shu , Horrillo Abraham J. , Rao Kavitha S. , Kameswaran Vasumathi , Joubran Carine , Lau Pik Ki , Dong Keyi , Yang Bing , Bartosik Weronika M. , Zemke Nathan R. , Ren Bing , Kathiriya Irfan S. , Pollard Katherine S. , Bruneau Benoit G.
Published: January 2025

Dosage-sensitive transcription factors (TFs) underlie altered gene regulation in human developmental disorders, and cell-type specific gene regulation is linked to the reorganization of 3D chromatin during cellular differentiation. Here, we show dose-dependent regulation of chromatin organization by the congenital heart disease (CHD)- linked, lineage-restricted TF TBX5 in human cardiomyocyte differentiation. Genome organization, including compartments, topologically associated domains, and chromatin loops, are sensitive to reducedTBX5dosage in a human model of CHD, with variations in response across individual cells. Regions normally bound by TBX5 are especially sensitive, while co-occupancy with CTCF partially protects TBX5-bound TAD boundaries and loop anchors. These results highlight the importance of lineage-restricted TF dosage in cell-type specific 3D chromatin dynamics, suggesting a new mechanism for TF-dependent disease.
Endemic and invasion dynamics of wild tomato species on the Galápagos Islands, across two centuries of collection records
Authors: Kutza Alex D. , Hert Zoe L. , Moyle Leonie C.
Published: January 2025

We aggregated digitized herbarium and other collection records—spanning >225 years since 1795—to assess the biological, geographical, and historical factors shaping distributions of three wild tomato species on the Galápagos Islands, and to infer future threats to the two endemic species (Solanum cheesmaniaeandS. galapagense) and risks posed by their invasive congener (S. pimpinellifolium).

Combining >400 unique geolocated Galápagos records with bioclimate data and species distribution modelling, we quantified the geo-spatial distribution of each species, bracketed the historical timing and location of introductions of the invasive species, characterized species bioclimate envelopes, and projected suitable habitat overlap.

We infer that dispersal limitation and alternative selective histories shape current species distributions, and that anthropogenic change has and will continue to have different impacts on the two endemic species—closely associated with their different geographic and environmental distributions. We also identify plausible avenues for, and limits to, future invasive expansion.

These data vastly extend the temporal and spatial reach of our direct historical inferences, provide a critical complement to genomic analyses of contemporary Galápagos populations, and demonstrate that scientific collections are especially valuable for interpreting factors shaping species distributions on high-endemism islands with recent rapid environmental change.
Transgenic A53T mice have astrocytic α-synuclein aggregates in dopamine and striatal regions
Authors: Peat Cormac , Prasad Asheeta , Finkelstein David , Sue Caroline , Johnston Jennifer A. , Parish Clare L. , Thompson Lachlan , Kirik Deniz , Halliday Glenda M.
Published: January 2025

Parkinson’s disease is considered biologically a neuronal α-synuclein disease, largely ignoring the more widespread α-synuclein deposition that occurs in astrocytes. Recent single cell transcriptomics have identified early astrocytic differences in both Parkinson’s disease and mouse models with an increase in reactive astrocytes associated with proteostasis. To identify whether astrocytes accumulate α-synuclein before or after neurons, the present study histologically assessed astrocytes and α-synuclein accumulation in the M83 A53T transgenic mouse model of Parkinson’s disease prior to significant neuronal α-synuclein accumulation.

The brains of M83 A53T transgenic (n=5) and wild-type (n=4) mice were perfusion fixed and serial sections of the midbrain and striatum processed for multiplex labelling. Digital images were captured from standardised sampling regions and astrocyte quantitation performed using QuPath software. Multivariate linear region models with Turkey posthoc tests were used to evaluate the effects of genotype on regional astrocyte morphology and numbers.

The density of astrocytes within the substantia nigra pars compacta was approximately 30% greater compared with other sampled regions (P<0.005). Small aggregates of α-synuclein were observed in astrocytic processes, including in wild-type mice where a quarter of all astrocytes had an obvious α-synuclein aggregate. Compared to wild-type, A53T transgenic astrocytes had significantly enlarged somas (P<0.001) with more processes (P<0.001) consistent with a reactive phenotype. The expression of vascular endothelial growth factor A was present in analysed astrocytes, but not the synthesising enzyme for vitamin D CYP27B1. The A53T transgenic mice had more than double the numbers of astrocytes (P<0.001) and 2.5 times more astrocytes with α-synuclein aggregates compared to wild-type mice (P<0.001).

These data suggest that α-synuclein is normally cleared by astrocytes and that the substantia nigra pars compacta requires more astrocytic support than other midbrain dopaminergic regions or the striatum. This adds another vulnerability factor to those already known for the substantia nigra. In the A53T transgenic mouse model, astrocytes have an early upregulation of their clearance of α-synuclein aggregates. While speculative, a loss of this ability to take up α-synuclein in these regions may precipitate the selective neuronal degeneration and pathologies observed in Parkinson’s disease. As we move to a biological definition for this disease, understanding this early role astrocytes needs to be considered further.
Daily Experiences of Urinary and Fecal Incontinence in Young Adults with Spina Bifida: Preliminary Results from an Ecological Momentary Assessment Study
Authors: Hensel Devon J. , Young Audrey I. , Szymanski Konrad M.
Published: January 2025

Background

Urinary (UI) and fecal (FI) incontinence are prevalent secondary chronic conditions among young adults with spina bifida (YASB). UI and FI decrease daily functioning for YASB, but no research has prospectively examined characteristics of UI and FI among YASB. We used ecological momentary assessment (EMA) over 30 days to describe the prevalence, episode-specific characteristics and negativity associated with UI and FI among a cohort of YASB.

Method

Data were collected as part of a larger 30-day EMA study prospectively examining the daily prevalence and context of UI and FI in adults with SB. We drew an analytic sample of young adults (YASB) participants aged 18-27 years (N=23 [26.1% of all study-participants [N=88];). Participants completed an end- of-day EMA tracking the frequency, dry intervals, volume, activity avoidance, management, positive and negative mood, current UI (UIA) or FI (FIA) anxiety, past UIA and FIA and past number of UI or FI events.

Results

YASB contributed a 643 daily EMAs. Nearly 60% (370/643) of all daily entries was associated with a general report of incontinence (UI: 54.1% [348/643]; FI: 20.8% [134/643]). Prevalence, characteristics and negativity associated with UI and FI varied significantly from day-to-day. Higher UI frequency, shorter dry intervals, greater UI volume, needing management help, avoiding activities because of UI, higher past median UIA, higher negative mood and fewer past UI events were associated with higher daily UIA. Shorter FI dry intervals, higher past median FIA, higher negative mood and fewer past FI events were associated with higher daily FIA.

Discussion

Day-to-day experiences of UI and FI vary among adults with SB across multiple dimensions. Negativity about incontinence when it occurs varies not only based on individual- and episode-specific characteristics, but also on incontinence in the preceding days. Operationalizing these insights into potential clinical interventions warrants further investigation.

Discussion and Implications

Young people with SB (YASB) experience day-to-day differences in the characteristics of urinary (UI) and fecal (FI) incontinence (e.g. frequency, self-management) events and the way they felt (e.g. affect) about UI and FI. The unique relationship of these factors to UI and FI anxiety suggest novel potential points of intervention.
Estimating the burden of RSV- and influenza-associated hospitalizations, ICU admissions, and deaths across age and socioeconomic groups in New York State, 2005-2019
Authors: Xu Hanmeng , Pitzer Virginia E. , Warren Joshua L. , Shapiro Eugene D. , Weinberger Daniel M.
Published: January 2025

Background

Multiple prophylactic products are now available to protect against respiratory syncytial virus (RSV) in different age groups. Assessing the pre-intervention burden of RSV infections across various severity levels and risk groups is crucial, as it provides a baseline for evaluating the impact of these products.

Methods

We obtained monthly time series data on hospitalizations, intensive care unit (ICU) admissions, and deaths by age group, ZIP code, and cause for New York state from 2005 to 2019. Socioeconomic status (SES) of the ZIP codes was classified using supervised principal component analysis (PCA). We estimated the incidence of hospitalizations, ICU admissions, and deaths attributable to RSV and to influenza using hierarchical Bayesian regression models. Additionally, we assessed severity, defined by ICU admission and mortality risks, as well as recording fraction (i.e., percent of estimated virus-associated hospitalizations recorded as being due to the specific virus), stratified by age, SES, and over time.

Results

The estimated annual incidence of RSV-associated hospitalizations and ICU admissions were highest in infants under 1 in the low SES group (2,240 [95% credible interval (CrI): 2,200-2,290] hospitalizations and 330 [95% CrI: 320-350] ICU admissions per 100,000 person-years). The incidence of RSV-associated deaths was highest among adults ≥85 years old (61 [95% CrI: 49-74] per 100,000 person-years). In contrast to RSV, the burden of influenza was greatest in age groups ≥65 years. The risk of ICU admission varied by patients’ age and SES, and the mortality risk increased dramatically with age for both pathogens (RSV: 11.9% [95% CrI: 9.6-14.3%], influenza: 14.4% [95% CrI: 13.1-15.6%] among ≥85 year age group). Incidence varied by epidemic year and season, and we observed an increasing recording fraction of RSV among all age groups over the study period.

Conclusions

RSV and influenza contribute significantly to the burden of hospitalizations, ICU admissions, and deaths, particularly among infants and older adults. Although the recording fraction of RSV increased over the study period, it remains lower, particularly for adults. Our findings reveal a disparity in hospitalization burden by SES, particularly among younger age groups.
Qualitative Study of Acceptability, Benefits, and Feasibility of a Food-based Intervention among Participants and Stakeholders of the RATIONS Trial
Authors: Bandewar Sunita Sheel , Bhargava Madhavi , Pisal Hema , Sreekumar Sharanya , Bhan Anant , Meher Ajay , Bhargava Anurag
Published: January 2025

Background

A qualitative study was conducted during the Reducing Activation of Tuberculosis by Improvement of Nutritional Status (RATIONS) trial to explore the perceptions, experiences, and expectations of participants and stakeholders on the acceptability, benefits, and feasibility of the nutritional intervention.

Methodology

We recruited 58 individuals for in-depth interviews (IDI) and focus group discussions (FGDs) using referential sampling. These included patients with TB (PwTB), household contacts (HHCs), and stakeholders such as trial team members, government frontline workers (the Sahiyas), and National TB Elimination Program (NTEP) staff. All IDI and FGDs were audio-recorded, transcribed, and translated. The codes were generated using an inductive process and categorized manually into themes. Direct quotes were employed to describe the themes.

Results

The intervention was found to be acceptable in terms of cultural compatibility, quality, quantity, and duration; considered beneficial in helping tolerate the adverse effects of medications, gain of weight, improvement of health, and resuming work; and was considered life-saving by many during the COVID-19 pandemic. Other observations included food-sharing in the control arm, inability to regain pre-disease functional status despite weight gain, and preference for either in-kind support or preference for both cash and food support in-kind. The Sahiyas favored this food-based intervention because they observed reduced TB deaths, improved adherence, and better functional recovery. They expressed confidence in its feasibility and willingness to take responsibility for its implementation. The field staff found it challenging in the context of a trial due to the added responsibilities of rigorous data collection but found it important and gratifying. The NTEP staff considered it feasible, provided the necessary resources were provided. Many favored the extension of food support to the HHCs of PwTB.

Conclusions

The qualitative inquiry revealed that the food-based intervention for the PwTB and their HHCs was acceptable, feasible, and beneficial for the recipients and the NTEP. Participants suggested the extension of nutritional support in some areas, as well as enhanced cash support and nutritional support to patients with all forms of TB and their HHCs. Opinion on cash or support in kind was divided; many preferred food support over cash, but others expressed a requirement for both.
Enhancing national cholera surveillance using rapid diagnostic tests (RDTs): a mixed methods evaluation
Authors: Baumgartner ET , Williams KN , Rai E , Rosser EN , Marasini RP , Dahal S , Shakya A , Lynch J , Karki K , Bajracharya D , Sack DA , Debes AK
Published: January 2025

Background

Cholera rapid diagnostic tests (RDTs) can strengthen existing surveillance systems by offering a cost-effective screening method that improves understanding of cholera burden allowing for targeted prevention and control efforts. The RDT Implementation Strategy and Evaluation (RISE) project is the pilot study for Gavi’s innovative Diagnostic Procurement Platform which provides cholera RDTs to enhance national surveillance.

Methods

Implementation of cholera RDTs was evaluated following their distribution in 2023 to facilities within Nepal’s Early Warning and Reporting System (EWARS). Quantitative data was collected through EWARS surveillance reports, national-level and individual-level REDCap surveys from select facilities in Kathmandu. Key-informant interviews were also conducted in Kathmandu with personnel involved in cholera surveillance and response. Interviews were conducted using a semi-structured interview guide and analyzed according to inductively identified themes.

Results

Qualitative findings indicated generally positive perceptions of cholera RDTs, highlighting their speed and ease of use, and suitability for deployment in under-resourced areas by unskilled personnel. However, a lack of awareness of the RDTs, limited training, and concerns about the RDTs’ quality, availability, and costs were challenges raised consistently. Quantitative findings revealed underreporting of acute gastroenteritis (AGE) and cholera in EWARS and an underutilization of the cholera RDTs, with only 2.6% of reported AGE cases screened using an RDT.

Discussion

This field evaluation demonstrated that RDTs can have an important role in cholera surveillance but highlighted significant challenges with cholera lab capacity, reporting, and training. Both the qualitative and quantitative findings showed gaps in surveillance reporting, which were exacerbated by the complexity of adding RDTs without strong guidance as well as beliefs about the RDTs’ poor validity. These misconceptions and challenges need to be addressed at the local and national level to successfully scale-up cholera RDTs in Nepal and beyond.
Profiling of early-onset bladder cancer identifies key genomic alterations and potential targets
Authors: Magnani Christopher J. , D’Andrea Vincent D. , Qian Zhiyu , Ernandez John , Yim Kendrick , Kibel Adam S. , Chang Steven L. , Mossanen Matthew , Preston Mark A. , Feldman Adam S. , Bochner Bernard H. , Solit David B. , Pietzak Eugene J. , Mouw Kent W. , Carvalho Filipe L.F. , Clinton Timothy N.
Published: January 2025

Younger patients with bladder cancer typically have fewer environmental exposures or risk factors, suggesting molecular pathways implicated in early-onset disease differ from older patients. Dissecting the genomic profile of early-onset tumors may define targeted treatments for these young patients. We compared the frequency of somatic mutations in early-onset bladder cancer, defined as diagnosis before the age of 55 years old which encompasses about 1 in 10 diagnoses, in two cohorts: the Mass General Brigham Young Cystectomy Cohort (MGB-YCC, n=134 patients) and the Memorial Sloan-Kettering-IMPACT bladder cancer cohort (MSK-IMPACT, n=1271). Both MGB-YCC and MSK-IMPACT cohorts were predominantly male with younger patients less likely to smoke or have muscle-invasive disease. Genomic characterization in MGB-YCC demonstrated KMT2D mutations almost exclusively among the youngest patients (83% <45-years-old, p=0.008). MSK-IMPACT revealed a significant increase of FGFR3 mutations in younger patients (37% vs 23%, p<0.001). Altogether, our results find key somatic mutations likely drive early-onset bladder cancers, some of which may be targetable; this suggests potential benefit from genomic tumor profiling to guide personalized treatment.

Source of Funding

NCI K08CA282969-01A1 (FLC), BCAN Career Development Award (FLC), NCI 3P30CA006516-59W2 Early-Stage Surgeon-Scientist Program award (FLC).

Disclosures or conflicts

none
Personal care product use and risk of adult-onset asthma: findings from the Sister Study
Authors: Lim Jungeun , Chang Che-Jung , White Alexandra J. , Lo Shelton , Wang Hantao , Goodney Gabriel , Miao Rui , Barochia Amisha V. , Roger Véronique L. , Sandler Dale P. , Wong Jason Y.Y.
Published: January 2025

BACKGROUND

Personal care products (PCPs) contain endocrine-disrupting chemicals (EDCs) linked to hormonally-sensitive diseases. Population studies have found associations between prenatal EDC exposure and childhood asthma; however, few have investigated adult-onset asthma.

OBJECTIVES

We investigated the associations between commonly used PCPs and the risk of adult-onset asthma in a prospective cohort study of U.S. women.

METHODS

We analyzed 39,408 participants from the Sister Study (2003-2009). The participants self-reported their usage frequency of 41 PCPs in the 12-month period before baseline. Latent classes were used to identify groups with similar usage patterns (‘infrequent’, ‘moderate’, ‘frequent’) within types of products (‘beauty’, ‘everyday hair’, ‘hygiene’, and ‘skincare’). Multivariable Cox regression models were used to assess the associations between PCP use and incident adult-onset asthma.

RESULTS

Over an average 12.5-year follow-up, 1,774 incident asthma cases were identified. Compared to infrequent users, moderate (hazard ratio [HR]=1.21 (95% confidence interval (CI):1.07,1.37)) and frequent (HR=1.22 (95%CI:1.08,1.38)) users of beauty products had significantly higher asthma risk. Similar associations were observed for hygiene (moderate: HR=1.14 (95%CI:1.01,1.29) and frequent: HR=1.20 (95%CI:1.06,1.36)) and skincare products (moderate: HR=1.21 (95%CI:1.06,1.38) and frequent: HR=1.20 (95%CI:1.06,1.35)). Several individual everyday hair products (hair spray, hair styling gel/mousse, and pomade or hair grease) were positively associated with asthma risk, but associations were not detected for everyday hair latent classes.

DISCUSSION

Our findings suggest that PCP use potentially contributes to future risk of adult-onset asthma among women. These novel findings reinforce the need for regulation of PCPs and their components to reduce the burden of asthma.
Exploring the Association Between Urinary Incontinence and Depression Based on a Series of Large-Scale National Health Studies in Turkiye
Authors: Dasdelen Muhammed Furkan , Dasdelen Zehra Betul , Almas Furkan , Cokkececi Beyza , Laguna Pilar , de la Rosette Jean , Kocak Mehmet
Published: January 2025

Urinary incontinence (UI) and depression are prevalent conditions affecting millions globally and are significantly associated with various demographic, health, and socio-economic factors. This study examines the trends and associations of UI and depression over a 14-year period using nationwide data. We analyzed data from the Turkish Health Studies Surveys conducted in seven years between 2008 and 2022, including 125,279 participants aged 15 and older, excluding those with incomplete key health data. Variables included chronic conditions, BMI, depression severity (assessed by PHQ-8), socio-economic status, and lifestyle factors. Univariable and multivariable logistic regression models were used to investigate associations between UI and various risk factors over time. The prevalence of UI and depression fluctuated over the 14-years, with a significant increase observed in 2014. Multivariate analysis confirmed a strong and consistent association between UI and depression across genders and age groups, even after adjusting for confounders. Higher depression severity increased the odds of experiencing UI. Age, multiple comorbidities, higher BMI, and lower socio-economic status were associated with an increased likelihood of UI. Obesity was a significant risk factor for UI in females but not in males. Urban living and higher education levels were inversely associated with UI. The simultaneous rise in UI and depression in 2014 may be linked to socio-economic changes during that period. The findings suggest a robust link between UI and depression, influenced by a complex interplay of health, demographic, and socio-economic factors, needing prospective studies to further investigate the causal pathway of these associations.
Unveiling Alcohol Bias and Impaired Inhibitory Control in Young Binge Drinkers: Insights from the Alcohol Hayling Task
Authors: Carbia Carina , Almeida-Antunes Natália , Vasconcelos Margarida , López-Caneda Eduardo
Published: January 2025

Craving and alcohol-related bias play a central role in addiction development. Previous research suggests that individuals with alcohol misuse exhibit heightened alcohol bias and deficits in inhibitory control, contributing to increased craving and sustained alcohol consumption. However, this relationship remains poorly understood in young binge drinkers, particularly regarding a specific form of alcohol bias known as semantic alcohol bias (heightened automatic accessibility of alcohol-related concepts), which may influence craving and drinking behavior. The present study is aimed at addressing this gap. A total of 81 college students (41 Binge Drinkers and 40 Non/Low Drinkers). completed craving questionnaires and the Alcohol Hayling task, a sentence-completion paradigm designed to measure semantic alcohol bias and inhibitory control. Results revealed that young binge drinkers generated more alcohol-related words in drinking- context sentences, committed more errors (i.e., producing alcohol-related words when they should have generated unrelated words), and displayed slower response times when inhibiting alcohol-related responses. A positive correlation was observed between craving and the frequency of alcohol-related words. These findings suggest that young binge drinkers exhibit a semantic accessibility bias towards alcohol-related concepts and difficulties inhibiting alcohol-related content. This study highlights the role of alcohol- related semantic networks in craving states, providing new insights into how alcohol biases may contribute to binge drinking behaviors among youth.
Novel tools for comparing the architecture of psychopathology between neurogenetic disorders: An application to X- vs. Y-chromosome aneuploidy effects in males
Authors: Larsen Isabella G. , Liu Siyuan , Schaffer Lukas , Rau Srishti , Ajumobi Tiffany , Mahony Bridget W. , Warling Allysa , Whitman Ethan T. , Nadig Ajay , McDermott Cassidy , Xenophontos Anastasia , Wilson Kathleen , Clasen Liv S. , Torres Erin N. , Blumenthal Jonathan D. , Bassett Dani S. , Raznahan Armin
Published: January 2025

Background

Psychiatric symptoms are typically highly inter-correlated at the group level. Collectively, these correlations define the architecture of psychopathology—informing taxonomic and mechanistic models in psychiatry. However, to date, it remains unclear if this architecture differs between etiologically distinct subgroups, despite the core relevance of this understanding for personalized medicine. Here, we introduce a new analytic pipeline to probe group differences in the psychopathology architecture—demonstrated through comparison of two distinct neurogenetic disorders.

Methods

We use a large questionnaire battery in 300 individuals aged 5-25 years (n= 102 XXY/KS,n= 64 XYY,n= 134 age-matched XY) to characterize the structure of correlations among 53 diverse measures of psychopathology in XXY/KS and XYY syndrome—enabling us to compare the effects of X- vs. Y-chromosome dosage on the architecture of psychopathology at multiple, distinctly informative levels.

Results

Behavior correlation matrices describe the architecture of psychopathology in each syndrome. Comparison of matrix row averages reveals that autism-related features and externalizing symptoms are most differentially coupled to other aspects of psychopathology in XXY/KS vs. XYY. Clustering the difference between matrices captures coordinated group differences in pairwise coupling between measures of psychopathology: XXY/KS increases coherence among externalizing, internalizing, and autism-related features, while XYY syndrome shows greater coherence in dissociality and early neurodevelopmental impairment.

Conclusions

These methods offer new insights into X- and Y-chromosome dosage effects on behavior, and our shared code can now be applied to other clinical groups of interest—helping to hone mechanistic models and inform the tailoring of care.
Machine learning for estimating and comparing clinical rules for treating diarrheal illness with antibiotics
Authors: Codi Allison , Kim Sara , McQuade Elizabeth Rogawski , Benkeser David ,   the AntiBiotics for Children with severe Diarrhea (ABCD) Study Group
Published: January 2025

Acute diarrheal disease is one of the leading causes of death in children under age 5, disproportionately impacting children in low-resource settings. Many of these cases are caused by bacteria and therefore could respond to antibiotic treatment; however, the benefits of widely prescribing antibiotics must be weighed against the risks for the emergence of microbial resistance. These challenges present the opportunity for developing individualized treatment guidelines for diarrheal disease. In this study, we utilize a framework for the creation and evaluation of individualized treatment rules that leverage diagnostic and other clinical information to recommend antibiotic treatment to children with watery diarrhea. In contrast to many applications of pipelines for creating and evaluating treatment rules, we (i) explicitly consider creating rules that limit the proportion of children treated under a rule, to limit risks for overtreatment and the emergence of microbial resistance and (ii) propose methods to compare the performance of rules based on different sets of input covariates, which allows for quantification of the impact of measuring additional diagnostic biomarkers in clinical settings. We use a nested cross validation procedure that makes use of ensemble machine learning and doubly-robust estimation approach to derive, evaluate, and compare rules. We demonstrate that our proposed method yields appropriate inference in a realistic simulation study and apply our method to a real-data analysis of the AntiBiotics for Children with severe Diarrhea (ABCD) trial.
Competing signaling pathways controls electrotaxis
Authors: Kulkarni S. , Tebar F. , Rentero C. , Zhao M. , Sáez P.
Published: January 2025

Understanding how cells migrate following exogenous cues is one of the most fundamental questions for biology, medicine, and bioengineering. Growing evidence shows that electrotaxis, the directed cell migration toward electric potential gradients, represents a precise and programmable method to control cell migration. Most data suggest that the polarization of membrane components and the following downstream signaling are central to electrotaxis. Unfortunately, how these multiple mechanisms coordinate with the motile machinery of the cell to respond to an electric field is still poorly understood. Here, we develop a mechanistic model that explains and recapitulate electrotaxis across different cell types. Using the zebrafish proteome, we identify membrane proteins directly related to migration signaling pathways that polarize anodally and cathodally. Further, we show that simultaneous and asymmetric distribution of charged membrane receptors towards the anode and the cathode establishes multiple cooperative and competing stimuli for downstream signaling pathways. The resulting polarization of signals controls the actomyosin network dynamics, directing the anodal and cathodal migration of the cell. Our theoretical framework rationalizes the physical processes that determine electrotaxis across cell types and provides a physical framework to test multiple electrotactic pathways. These results together show us how to control cell migration to, e.g., enhance, cancel, or switch directed cell migration, which opens up new avenues not only to promote tissue regeneration or arrest tumor progression but also to design better biomimetic-engineered tissue constructs.
Absolute measurement of fast and slow neuronal signals with fluorescence lifetime photometry at high temporal resolution
Authors: Lodder Bart , Kamath Tarun , Savenco Ecaterina , Röring Berend , Siegel Michelle , Chouinard Julie , Lee Suk Joon , Zagoren Caroline , Rosen Paul , Adan Roger , Tian Lin , Sabatini Bernardo L.
Published: January 2025

The concentrations of extracellular and intracellular signaling molecules, such as dopamine and cAMP, change over both fast and slow timescales and impact downstream pathways in a cell-type specific manner. Fluorescence sensors currently used to monitor such signalsin vivoare typically optimized to detect fast, relative changes in concentration of the target molecule. They are less well suited to detect slowly-changing signals and rarely provide absolute measurements of either fast and slow signaling components. Here, we developed a system for fluorescence lifetime photometry at high temporal resolution (FLIPR) that utilizes frequency-domain analog processing to measure the absolute fluorescence lifetime of genetically-encoded sensors at high speed but with long-term stability and picosecond precision in freely moving mice. We applied FLIPR to investigate dopamine signaling in two functionally distinct regions in the striatum, the nucleus accumbens core (NAC) and the tail of striatum (TOS). We observed higher tonic dopamine levels at baseline in the TOS compared to the NAC and detected differential and dynamic responses in phasic and tonic dopamine to appetitive and aversive stimuli. Thus, FLIPR enables simple monitoring of fast and slow time-scale neuronal signaling in absolute units, revealing previously unappreciated spatial and temporal variation even in well-studied signaling systems.
Common symbiotic signalling pathway not essential for formation of functional mutualisms with endophytic fungi
Authors: Williams Alex , Sinanaj Besiana , Rodriguez-Morelos Victor , Prout James , Howard Nathan , Durant Emily , Pressel Silvia , Field Katie J.
Published: January 2025

Most plants form mutualistic symbioses with soil fungi, including arbuscular mycorrhizal (AM) fungi. These fungi usually transfer soil nutrients to plants and assimilate carbon from host plant photosynthesis. Recently, Mucoromycotina ‘fine root endophytes’ (MFRE) were identified as nutritionally mutualistic and widespread fungal symbionts of plants, establishing MFRE as a new class of mycorrhizal fungi. However, the regulatory mechanisms for MFRE symbioses are completely unknown. Other symbionts, like AM fungi, use the ‘Common Symbiotic Signalling Pathway’ (CSSP) to establish symbiosis. To explore whether MFRE interactions also involve this pathway, we cultured MFRE with CSSP mutants ofMedicago truncatulawhich show impaired AM symbioses and tracked carbon and nutrient transfers using isotope tracers. Results show no differences in root colonization or nutrient exchange, suggesting MFRE symbioses are regulated by different molecular mechanisms. This finding highlights the unique nature of MFRE symbiosis, broadening our understanding of diverse fungal symbioses and their evolutionary significance.
Host-specific microbiome and genomic signatures in Bifidobacterium reveal co-evolutionary and functional adaptations across diverse animal hosts
Authors: Kujawska Magdalena , Seki David , Chalklen Lisa , Malsom Jennifer , Goatcher Sara , Christoforou Ioulios , Mitra Suparna , Crouch Lucy , Hall Lindsay J
Published: January 2025

Animal hosts harbour divergent microbiota, including various Bifidobacterium species and strains, yet their evolutionary relationships, and functional adaptions remain understudied. By integrating taxonomic, genomic and predicted functional annotations, we uncover how Bifidobacterium adapts to host-specific environments, shaped by vertical transmission, dietary influences, and host phylogeny. Our findings reveal that host phylogeny is a major determinant of gut microbiota composition. Distinct microbial networks in mammalian and avian hosts reflect evolutionary adaptations to dietary niches, such as carnivory, and ecological pressures. At a strain-resolved level, we identify strong co-phylogenetic associations between Bifidobacterium strains and their hosts, driven by vertical transmission and dietary selection, underscoring the intricate co-evolutionary dynamics between these microbes and their hosts. Functional analyses highlight striking host-specific metabolic adaptations in Bifidobacterium, particularly in carbohydrate metabolism and oxidative stress responses. In mammals, we observe an enrichment of glycoside hydrolases (GH) tailored to complex carbohydrate-rich diets, including multi-domain GH13_28 α-amylases featuring diverse carbohydrate-binding modules (CBM25, CBM26, and the novel CBM74). These adaptations emphasise the ecological flexibility of Bifidobacterium in breaking down alpha-linked glucose polysaccharides, such as resistant starch. Together, our study provides new insights into the evolutionary trajectories and ecological plasticity of Bifidobacterium, revealing how host phylogeny and dietary ecology drive microbial diversity and function. These findings deepen our understanding of host-microbe co-evolution and the critical role of microbiota in shaping animal health and adaptation.
Monoamine-induced diacylglycerol signaling rapidly accumulates Unc13 in nanoclusters for fast presynaptic potentiation
Authors: Blaum Natalie , Ghelani Tina , Götz Torsten , Chronister Keagan S. , Bengochea Mercedes , Christensen Christian F. , Moulin Thiago C. , Ceresnova Livia , Kern Hanna , Thomas Ulrich , Heine Martin , Sigrist Stephan J. , Walter Alexander M.
Published: January 2025

Neuromodulators control mood, arousal, and behavior by inducing synaptic plasticity via G-protein coupled receptors. Long-term potentiation of presynaptic neurotransmitter release requires structural changes, but how fast potentiation is achieved within minutes remains enigmatic. Using theDrosophila melanogasterneuromuscular junction, we show that on the timescale of one minute, octopamine, the invertebrate analog of nor-epinephrine, rapidly potentiates evoked neurotransmitter release by a G protein coupled pathway involving presynaptic OAMB receptors and phospholipase C. No changes of presynaptic calcium influx were seen, but confocal signals of the release factor Unc13A and the scaffolding protein Bruchpilot increased within one minute of octopamine treatment. On the same timescale, live, single-molecule imaging of endogenously tagged Unc13 revealed its instantly reduced motility and its increased concentration in synaptic nanoclusters with potentiation. Presynaptic knockdown of Unc13A fully blocked fast potentiation and removal of its N-terminal localization sequence delocalized the protein fragment to the cytosol, but it was rapidly recruited to the plasma membrane by DAG analog phorbol esters and octopamine, pointing to a role in C-terminal domains. Point mutation of endogenous Unc13 disrupting diacylglycerol-binding to its C1 domain blocked plasticity-induced nanoscopic enrichment and synaptic potentiation. The mutation increased basal neurotransmission but reduced Unc13 levels, revealing a gain of function and potential homeostatic compensation. The mutation also blocked phorbol ester-induced potentiation, decreased the calcium-sensitivity of neurotransmission and caused short-term synaptic depression. At the organismal level, the mutation reduced locomotion and survival while enhancing reproduction. Thus, the Unc13 C1 domain mediates acute subsynaptic compaction of Unc13 under monoamine-induced potentiation and influences short-term plasticity, locomotion, reproduction, and survival.
How Intrinsic Neural Timescales Relate To Event-Related Activity – Key Role For Intracolumnar Connections
Authors: Çatal Yasir , Wolman Angelika , Buccellato Andrea , Keskin Kaan , Northoff Georg
Published: January 2025

The relationship of the brain’s intrinsic neural timescales (INTs) during the resting state with event-related activity in response to external stimuli remains poorly understood. Here, we bridge this gap by combining computational modeling with magnetoencephalography (MEG) data to investigate the relation of intrinsic neuronal timescales (INT) with task-related activity, e.g., event-related fields (ERFs). Using the Jansen-Rit model, we first show that intracolumnar (and thus intra-regional) excitatory and inhibitory connections (rather than inter-regional feedback, feedforward and lateral connections between the columns of different regions) strongly influence both resting state INTs and task-related ERFs. Secondly, our results demonstrate a positive relationship between the magnitude of event-related fields (mERFs) and INTs, observed in both model simulations and empirical MEG data collected during an emotional face recognition task. Thirdly, modeling shows that the positive relationship of mERF and INT depends on intracolumnar connections through observing that the correlation between them disappears for fixed values of intracolumnar connections. Together, these findings highlight the importance of intracolumnar connections as a shared biological mechanism underlying both the resting-state’s INTs and the task-state’s event-related activity including their interplay.
Respiration facilitates behaviour during multisensory integration
Authors: Saltafossi Martina , Zaccaro Andrea , Kluger Daniel S. , Perrucci Mauro Gianni , Ferri Francesca , Costantini Marcello
Published: January 2025

The brain processes information from the external environment alongside signals generated by the body. Among bodily rhythms, respiration emerges as a key modulator of sensory processing. Multisensory integration, the non-linear combination of information from multiple senses to reduce environmental uncertainty, may be influenced by respiratory dynamics. This study investigated how respiration modulates reaction times and multisensory integration in a simple detection task. Forty healthy participants were presented with unimodal (Auditory, Visual, Tactile) and bimodal (Audio-Tactile, Audio-Visual, Visuo-Tactile) stimuli while their respiratory activity was recorded. Results revealed that reaction times systematically varied with respiration, with faster responses during peak inspiration and early expiration but slower responses during the expiration-to-inspiration transition. Applying the race model inequality approach to quantify multisensory integration, we found that Audio-Tactile and Audio-Visual stimuli exhibited the highest integration during the expiration-to-inspiration phase. These findings conceivably reflect respiration phase-locked changes in cortical excitability which in turn, orchestrates multisensory integration. Interestingly, participants also tended to adapt their respiratory cycles, aligning response onsets preferentially with early expiration. This suggests that, rather than a mere bottom-up mechanism, respiration is actively adjusted to maximise the signal-to-noise balance between interoceptive and exteroceptive signals.