bluuebunny/crossref_metadata_2025 huggingface dataset:
Socioeconomic Disparities in the Progression of GERD and Barrett’s Esophagus to Esophageal Adenocarcinoma
Authors: Sarici Inanc S. , Eriksson Sven E. , Chaudhry Naveed , Zheng Ping , Chalikonda Sricharan , Bartlett David L. , Ayazi Shahin
Published: February 2025

Objective:

To assess the impact of socioeconomic and other factors on progression from gastroesophageal reflux disease (GERD) and Barrett’s esophagus (BE) to esophageal adenocarcinoma (EAC).

Summary Background Data:

Socioeconomic status (SES) influences outcomes in EAC, but its role in the progression from GERD and BE to EAC is not well-defined. Risk of progression may be influenced by access and engagement with endoscopic screening and surveillance, healthcare utilization, health literacy and other competing social determinants of health that vary with SES.

Methods:

Patients diagnosed with GERD between 2015 and 2023 across a regional network of 14 hospitals and >300 clinics were reviewed for BE and EAC. U.S. Census data on wealth, income, education and occupation were used to categorize patients into low, middle, and high SES groups. Univariate and multivariable analyses were conducted to evaluate the influence of demographic, clinical, and SES factors on progression to EAC from GERD and BE.

Results:

Among 162,542 GERD patients, 7,604 (4.70%) developed BE and 331 (0.20%) progressed to EAC. Unemployment, disability, lack of college education, and high school non-graduation were associated with progression to EAC (all P<0.0001). Independent predictors of disease progression included established demographic and clinical factors (all P<0.0001), lack of private insurance (OR:1.4, P<0.0001), and low SES (OR:1.6, P<0.0001). For BE to EAC progression, predictors were similar, including lack of private insurance (OR:2.0, P=0.015) and low SES (OR:2.0, P=0.028). Patients with low SES were less frequently endoscopically evaluated (4 per 1,000 vs. 10 per 1,000, P<0.0001) or diagnosed with BE (4 per 1,000 vs. 50 per 1,000, P<0.0001). They were also more likely to be diagnosed with early-onset EAC (13 per 1,000 vs. 5 per 1,000, P=0.0138) and metastatic EAC (77.4% vs. 53.1%, P=0.001). Among patients with BE, those with low SES had a higher rate of progression to EAC (1.77% vs. 0.95%, P=0.026).

Conclusion:

Low SES is associated with increased progression to EAC, with higher rates of early-onset and metastatic disease at diagnosis. Disparities in access to endoscopic screening and surveillance play a significant role, compounded by socioeconomic barriers such as limited healthcare engagement and competing social priorities. Integrating SES into risk stratification models alongside clinical factors is essential for improving early detection and reducing the burden of advanced disease.
Closer to home: Managing more than three rib fractures at level IV trauma centers
Authors: Lizak Adam , Allsbrook Anthony , Wilde-Onia Rebecca , Robins Lisa , Boyer Rebecca , Cipolla James , Thomas Peter , Castillo Roberto , Braverman Maxwell A.
Published: February 2025

INTRODUCTION

Rib fractures remain a significant source of trauma admissions. In 2020, the Pennsylvania Trauma System Foundation standards changed to allow patients with more than three rib fractures to be admitted to level IV centers. The primary aim of this study was to evaluate outcomes of patients with more than three uncomplicated rib fractures admitted to level IV trauma centers.

METHODS

Our network database was queried for patients with isolated uncomplicated rib fractures between 2018 and 2022. Patients were stratified based on evaluation before or after the change in standards. Patients evaluated at level IV centers were compared for demographics, injury characteristics, transfer rate, and outcomes. Finally, 1:1 propensity score matching was used to create a matched group of patients with more than three rib fractures to assess outcomes based on admission to level IV versus level I/II centers.

RESULTS

A total of 1,070 patients with isolated rib fractures were admitted over the study period. Level IV centers evaluated 360 patients with 132 (36.6%) and 228 (63.3%) in the pre- and poststandard change periods. There was a significant reduction in transfers for isolated rib fractures (56% vs. 21% p < 0.01). Compared with patients with three or less rib fractures, those with more than three fractures had similar hospital length of stay (median [interquartile range (IQR)], 3 [2–5] vs. 2 [1–4]; p = 0.29) and mortality (0% vs. 2.3%, p = 0.22). After propensity match, there was no difference in age (median [IQR], 71 [60–81] vs. 73 [65–85]; p = 0.24), injury characteristics, hospital length of stay (median [IQR], 2.5 [2–5] vs. 2 [1–4]; p = 0.37), and mortality (1.7% vs. 0%, p = 0.30).

CONCLUSION

Change in state admission standards allowed for a reduction in transfer of patients with more than three isolated rib fractures. In a group of matched patients with more than three rib fractures, level IV centers had similar outcomes to level I or II centers.

LEVEL OF EVIDENCE

Clinical Research, Retrospective Study; Level III.
A rare case of Aerococcus urinae native valve endocarditis
Authors: Goes Sofie Eva , Callebaut Kim , Pierard Denis , Wybo Ingrid , De Geyter Deborah , Muyldermans Astrid , Geers Jolien , Kerselaers Laura , Demuyser Thomas
Published: February 2025

Background

Aerococcus urinae, was initially considered a commensal of the urinary tract, but there is now increasing evidence for its involvement in urinary tract and systemic infections. A. urinae endocarditis has a non-negligible  mortality rate and occurs mainly in patients with underlying conditions or presence of extraneous material.

Case presentation

This report handles the case of a 65 year old male with cardiac antecedents, who was admitted to the cardiology department after a syncope of unknown origin and diagnosed with severe mixed aortic valve disease and mitral valve sclerosis through the means of a transesophageal echocardiography (TEE). During hospitalisation, the patient progressively deteriorated with the development of shortness of breath and an inflammatory syndrome. Both the urine and blood cultures showed growth of A. urinae. Treatment with piperacillin/tazobactam was started empirically. Repeated TEE showed evidence for endocarditis with vegetation and perforation of the mitral valve that required an emergency surgery with mitral valve repair. After surgery, gentamicin and penicillin G were administered for 48 hours, followed by combined ceftriaxone/penicillin G treatment for 6 weeks. At first, flucloxacillin was also associated as the culture of the valve was negative. Finally, 16S rRNA polymerase chain reaction (PCR) on the valve tissue, confirmed the A. urinae endocarditis.

Conclusion

A. urinae is an underestimated cause of serious infections such as endocarditis. Urinary tract infections mainly in older men can be an entry point for this type of invasive infection.
Bridging mental health, cognition and the brain in mild traumatic brain injury: A multilayer network analysis of the TRACK-TBI study
Authors: Domínguez D. Juan F. , Singh Mervyn , Firman-Sadler Lyndon , Guarnera Jade , Simpson-Kent Ivan L. , Imms Phoebe , Irimia Andrei , Caeyenberghs Karen ,   TRACK-TBI Investigators
Published: February 2025

Background

Mild traumatic brain injury (mTBI) patients suffer from several mental health symptoms (e.g., anxiety, depressive symptoms) and cognitive deficits (e.g., attentional deficits, slowed processing speed). However, symptoms in TBI are largely investigated in isolation, using univariate approaches, ignoring the interactions between symptoms and the underlying large-scale brain networks. We constructed the first multilayer network in mTBI to examine the relationships between networks of cognition, mental health and structural brain measures and to identify key variables bridging relationships across these networks.

Methods

Chronic phase cross-sectional data (6-month follow-up) from 457 mTBI patients was extracted from the TRACK-TBI Longitudinal study. We selected four variables from self-report mental health questionnaires (affective layer), eight cognitive test scores from the NIH toolbox (cognitive layer), and grey matter volumes from eight brain regions of the central executive and salience networks from anatomical MRI scans (brain layer). We used a multilayer network approach to examine the relationships (edges) between all variables (nodes) across layers. We then used the bridge strength centrality metric to identify nodes that ‘bridge’ the affective, cognitive, and brain layers.

Results

Insomnia severity, immediate verbal memory, somatisation and processing speed nodes exceeded ana priori80th percentile threshold on the bridge strength scores and can therefore be regarded as key nodes bridging relationships across affective, cognitive and brain layers.

Conclusions

The bridging nodes identified in our multilayer network analyses suggest targets for future studies to develop more customized, efficient, and efficacious treatments to alleviate mental health symptoms and cognitive deficits in mTBI patients.
Deep Learning based deconvolution methods: a systematic review
Authors: Redondo Alba Lomas , Sánchez Velázquez Jose M. , García Tejedor Álvaro J. , Sánchez–Arévalo Víctor Javier
Published: February 2025

Within this systematic review we examine the role of Artificial Intelligence (AI) and Deep Learning (DL) in the development of cellular deconvolution tools, with an special focus on their application to the analysis of transcriptomics data from RNA sequencing. We emphasize the critical importance of high–quality reference profiles for enhancing the accuracy of the discussed deconvolution methods, which is essential to determine cellular compositions in complex biological samples. To ensure the robustness of our work, we have applied a rigorous selection process following the Preferred Reporting Items for Systematic Reviews and Meta–Analysis (PRISMA) guidelines. Through the review process, we have identified several key research gaps, highlighting the necessity for standardized methodologies and the improvement of the interpretability of the models. Overall, we present a comprehensive, up to date overview of the different methodologies, datasets, and findings associated with DL–driven deconvolution tools, paving the way for future research and emphasizing the value of collaboration between computational and biological sciences.
Insights into the structure and modulation of human TWIK-2
Authors: Ma Qianqian , Hernandez Ciria C. , Navratna Vikas , Kumar Arvind , Lee Abraham , Mosalaganti Shyamal
Published: February 2025

TheTandem of pore domain in aWeak InwardRectifyingK+channel 2(TWIK-2; KCNK6) is a member of the Two-Pore Domain K+(K2P) channel family, which is associated with pulmonary hypertension, lung injury, and inflammation. The structure and regulatory mechanisms of TWIK-2 remain largely unknown. Here, we present the cryo-electron microscopy (cryo-EM) structure of human TWIK-2 at ∼3.7 Å and highlight its conserved and unique features. Using automated whole-cell patch clamp recordings, we demonstrate that gating in TWIK-2 is voltage-dependent and insensitive to changes in the extracellular pH. We identify key residues that influence TWIK-2 activity by employing structure and sequence-guided site-directed mutagenesis and provide insights into the possible mechanism of TWIK-2 regulation. Additionally, we demonstrate the application of high-throughput automated whole-cell patch clamp platforms to screen small molecule modulators of TWIK-2. Our work serves as a foundation for designing high-throughput small molecule screening campaigns to identify specific high-affinity TWIK-2 modulators, including promising new anti-inflammatory therapeutics.
Time-series RNA metabarcoding of the activePopulus tremuloidesroot microbiome reveals hidden temporal dynamics and dormant core members
Authors: Nash Jake , Tremble Keaton , Schadt Christopher , Cregger Melissa A. , Bryan Corbin , Vilgalys Rytas
Published: February 2025

Dormancy is a key life history stage of many microbes that involves existence in a metabolically inactive state. Although dormant taxa may contribute little to community function, most microbial metabarcoding community surveys of microbial systems target DNA which captures dormant and dead taxa in addition to the active and living fraction of the community. RNA metabarcoding offers the potential to delineate the active fraction of microbial communities. Transitions between dormancy and activity may also serve as a rapid response mechanism for communities for communities to alter their function faster than turnover in community composition. Additionally, a focus on active microbiomes may provide further insight into which taxa should be prioritized as part of the core microbiome. We used DNA and RNA metabarcoding in samples collected as a time-series of the quaking aspen (Populus tremuloides) root microbiome across a natural environmental gradient to identify the degree of spatiotemporal dynamism in active and total microbial communities and to document the extent of dormancy in the core microbiome. We found that active bacterial and fungal communities were more temporally dynamic than total communities, while total communities exhibited a stronger response to spatial variability in site conditions. Additionally, we found that core microbiome members are frequently inactive, resulting in a reduced active core microbiome. This study stresses the need to focus on turnover in the active microbial community to detect variation in microbial communities in time-series and to use microbial activity levels as a key determinant of core microbiome membership.
Missense mutations in intrinsically disordered protein regions link pathogenicity and phase separation
Authors: Kipp Oliver L. , Lewis Karen A. , Hough Loren E. , Whitten Steven T.
Published: February 2025

The impact of missense genetic variations on protein function is often enigmatic, especially for mutations that map to intrinsically disordered regions (IDRs). Given the functional importance of phase separation of IDRs, it has been proposed that mutations that modulate phase separation might preferentially lead to disease. To examine this idea, we used the robust predictability of phase-separating (PS) IDRs and annotation of disease-associated proteins and mutations to map the correlation between disease and phase separation. Consistent with previous work linking phase separation to cancer and autism spectrum disorder, we find a higher prevalence of predicted phase separation behavior in disease-associated proteins than typical for human proteins. We map the prevalence of phase separation across a wide range of diseases, finding that most, but not all, show an enrichment of phase separation in the proteins associated with them. Strikingly, the frequency of pathogenic mutations in predicted PS IDRs was elevated three-fold relative to IDRs not predicted to phase separate. Substitutions involving arginine and the aromatic types were among the most pathogenic for PS IDRs, while substitutions involving serine, threonine, and alanine the most benign. We applied these trends to mutations of uncertain clinical significance and predict that half found in PS IDRs are likely pathogenic. We find that phosphorylation sites were enriched in PS IDRs when compared to other protein regions, though mutations at such sites were mostly benign. Pathogenicity was highest for mutations in predicted PS IDRs when also found in a short linear motif, known mediators of protein-protein interactions.
Data retention in awake infant fMRI: Lessons from more than 750 scanning sessions
Authors: Behm Lillian , Yates Tristan S. , Trach Juliana E. , Choi Dawoon , Du Haoyu , Osumah Camille , Deen Ben , Kosakowski Heather L. , Chen Emily M. , Kamps Frederik S. , Olson Halie A. , Ellis Cameron T. , Saxe Rebecca , Turk-Browne Nicholas B.
Published: February 2025

Functional magnetic resonance imaging (fMRI) in awake infants has the potential to reveal how the early developing brain gives rise to cognition and behavior. However, awake infant fMRI poses significant methodological challenges that have hampered wider adoption. The present work takes stock after the collection of a substantial amount of awake infant fMRI data across multiple studies from two labs at different institutions. We leveraged these data to glean insights on participant recruitment, experimental design, and data acquisition that could be useful to consider for future studies. Across 766 awake infant fMRI sessions, we explored the factors that influenced how much usable data were obtained per session (average of 9 minutes). The age of an infant predicted whether they would successfully enter the scanner (younger was more likely) and, if they did enter, the number of minutes of functional data retained after preprocessing. The amount of functional data retained was also influenced by assigned sex (female more), experimental paradigm (movies better than blocks and events), and stimulus content (social better than abstract). In addition, we assessed the value of attempting to collect multiple experiments per session, an approach that yielded more than one usable experiment averaging across all sessions (including those with no data). Although any given scan is unpredictable, these findings support the feasibility of awake infant fMRI and suggest practices to optimize future research.
Early onset memory deficit of WMI rats compared to their nearly isogenic WLIs is reversed by enriched environment in females
Authors: Ji Michelle T. , Przybyl Katherine J. , Harter Aspen M. , Nemesh Mariya , Jenz Sophia , Yamazaki Anna , Kim Chris , Mulligan Megan K. , Chen Hao , Redei Eva E.
Published: February 2025

We tested the hypothesis that environmental enrichment (EE) can attenuate early-onset cognitive decline in a stress-hyperresponsive rat strain. The novel genetic model, the Wistar Kyoto More Immobile (WMI) inbred rat strain demonstrates increased stress reactivity and enhanced depression-like behavior compared to its nearly isogenic control, the Wistar Kyoto Less Immobile strain (WLI). Middle-aged (12 months) WMI females exhibited diminished fear, and spatial memory in the contextual fear conditioning and Morris Water Maze paradigms, respectively, compared to young animals (6 months) of both strains and to middle-aged WLIs. Middle-aged WMI males showed a lesser age-induced deficit. EE from six to 12 months of age reversed these memory deficits in middle-aged WMI females and attenuated them in WMI males. Plasma levels of estradiol followed the same pattern as memory in WMI females following EE. RNA sequencing from female hippocampi revealed significant strain, age, and enrichment-induced differentially expressed genes. Among these, solute carrier family 35, member A4 (Slc35a4) and potassium inwardly rectifying channel, subfamily J, member 2 (Kcnj2) were confirmed to show hippocampal expression changes parallel to that of memory in the WMI. These genes have critical roles in the integrated stress response, cellular metabolism, and the effects of stress on neurovascular coupling, respectively. Pathway analyses revealed the involvement of oxidative phosphorylation and mitochondrial dysfunction in the hippocampal processes of aging and EE-induced reversal. These findings underscore the critical involvement of molecular stress responses in early-onset memory decline and suggest potential therapeutic targets for age-related cognitive impairment.

Highlights

Heightened innate stress response and depression leads to early onset memory decline

Enriched environment reverses memory decline of middle-aged females

Enriched environment also reverses declining estrogen levels of middle-aged females

Mitochondrial dysfunction may underly mid-life cognitive and molecular changes
Mathematical modelling predicts novel mechanisms of stream confinement from Trail/Colec12/Dan in the collective migration of cranial neural crest cells
Authors: Johnson Samuel W.S. , Kulesa Paul M. , Baker Ruth E. , Maini Philip K.
Published: February 2025

Background

In vertebrate embryogenesis, cranial neural crest cells (CNCCs) migrate along discrete pathways. Analyses in the chick have identified key molecular candidates for the confinement of CNCC migration to stereotypical pathways as Colec12, Trail, and Dan. The effects of these factors on CNCCsin vitroare known, but how they confine migration to discrete streamsin vivoremains poorly-understood. Here, we propose and test several hypothetical mechanisms by which these factors confine cell streams and maintain coherent migration, simulating an expanded agent-based model for collective CNCC migration.

Results

Model simulations suggest that Trail enhances adhesion between CNCCs, facilitating movement towards stereotypical migratory pathways, whereas Colec12 confines CNCCs by inducing longer, branched filopodia that facilitate movement down Colec12 gradients and re-connections with streams. Moreover, we find that Trail and Colec12 facilitate the exchange of CNCCs and formation of CNCC-bridges between adjacent streams that are observedin vivobut poorly-understood mechanistically. Finally, we predict that Dan increases the coherence of streams by preferentially modulating the speed of CNCCs at the leading edge of collectives to prevent escape.

Conclusions

Our work highlights the importance of Trail, Colec12, and Dan in CNCC migration and predicts novel mechanisms for the confinement of CNCCs to stereotypical pathwaysin vivo.
Episodic pain in Fabry disease is mediated by a heat shock protein-TRPA1 axis
Authors: Enders Jonathan D , Prodoehl Eve K , Penn Signe M , Sriram Anvitha , Stucky Cheryl L
Published: February 2025

Two-thirds of patients with Fabry disease suffer debilitating pain attacks triggered by exercise, fever, and exposure to environmental heat. These patients face endure even greater risk of heat-related episodic pain in the face of global climate change. Almost nothing is known about the biological mechanisms underlying heat-induced pain crises in Fabry disease, and there is no preclinical model available for to study Fabry crises. Here, we established the first model of heat-induced pain attacks in Fabry disease by exposing transgenic Fabry rats to environmental heat. Heat exposure precipitated robust mechanical hypersensitivity, closely matching temporal features reported by patients with Fabry disease. At the cellular level, heat exposure sensitized Fabry dorsal root ganglia (DRG) neurons to agonists for transient receptor potential cation channel A1 (TRPA1), but not TRPV1. The heat shock response, which normally confers heat-resilience, was impaired in Fabry disease, and we demonstrated that heat shock proteins (HSP70 and HSP90) regulate TRPA1. Strikingly, pharmacologically inhibiting HSP90 completely prevented cellular and behavioral sensitization by environmental heat in Fabry disease. Together, this work establishes the first model of episodic pain in Fabry disease, implicates the heat shock response in heat-evoked pain episodes, and identifies a novel heat shock protein-TRPA1 regulatory axis.

Abstract Figure
Proteomic profiling of plasma extracellular vesicles identifies signatures of innate immunity, coagulation, and endothelial activation in septic patients
Authors: Park Chanhee , Ryu Taekyung , Mohamed-Hinds Rashida , Kim Kyungdo , Kim Jin Hyeok , Zou Lin , Williams Brittney , Na Chan Hyun , Chao Wei
Published: February 2025

Plasma extracellular vesicles (EVs) are cell-derived lipid particles and reportedly play a role in sepsis pathogenesis. This study aimed to identify EV cargo proteins in septic patients and explore their association with key sepsis pathophysiology. Plasma EVs were subjected to Tandem Mass Tag (TMT)-based quantitative proteomic analysis. We identified 522 differentially expressed (DE) EV proteins in septic patients (n=15) compared to the healthy controls (n=10). The KEGG analysis of the DE proteins revealed multiple functional pathways linked to sepsis,e.g.,complement/coagulation, platelet activation, phagosome, inflammation, and neutrophil extracellular trap formation. Weighted Gene Coexpression Network Analysis of 1,642 EV proteins identified nine unique protein modules, some of which were highly correlated with the sepsis diagnosis and diverse plasma markers, including organ injury, inflammation, coagulopathy, and endothelial activation. Cell type-specific enrichment analysis revealed the cellular origins of EVs, including immune and epithelial cells, neurons, and glial cells. Thus, the current study discovered complex proteomic signatures in plasma EVs that are closely associated with key pathophysiological responses in sepsis. These findings support the importance of EV cargo proteins in the patients’ immune responses, coagulation, and endothelial activation and lay the foundation for future mechanistic study of plasma EVs in sepsis pathogenesis.
Precision Estimates of Longitudinal Brain Aging Capture Unexpected Individual Differences in One Year
Authors: Elliott Maxwell L. , Du Jingnan , Nielsen Jared A. , Hanford Lindsay C. , Kivisäkk Pia , Arnold Steven E. , Dickerson Bradford C. , Mair Ross W. , Eldaief Mark C. , Buckner Randy L.
Published: February 2025

Individual differences in human brain aging are difficult to estimate over short intervals because of measurement error. Using a cluster scanning approach that reduces error by densely repeating rapid structural scans, we measured brain aging in individuals in one year. Expected differences between young and older individuals were evident, as were differences between cognitively unimpaired and impaired individuals. Each person’s brain change trajectory was compared to modeled expectations from a large cohort of age-matched UK Biobank participants. Cognitively unimpaired older individuals variably revealed relative brain maintenance, unexpectedly rapid change, and asymmetrical change. These atypical brain aging trajectories were found across structures and verified in independent within-individual test and retest data. Precision estimates of brain change are possible over short intervals and reveal marked variability including among cognitively unimpaired individuals.
Trajectories of Heart Failure with Reduced Ejection Fraction: Insights from EHR Data on Recovery and Transitions
Authors: Do Duy , Murugiah Karthik , Sawano Mitsuaki , Cartwright Brianna M. Goodwin , Rodriguez Patricia J. , Gratzl Samuel , Baker Charlotte , Curtis Lesley H. , Stucky Nicholas L
Published: February 2025

What is the clinical question being addressed?

Heart failure with reduced ejection fraction (HFrEF) is a leading cause of morbidity and mortality, with guideline-directed medical therapy (GDMT) shown to improve left ventricular ejection fraction (LVEF) and clinical outcomes. However, contemporary real-world trajectories of LVEF changes following an initial transthoracic echocardiography (TTE) diagnosis of HFrEF and how these changes relate to patient characteristics, GDMT use, and outcomes are not well described.

What is the main finding?

Repeat LVEF assessment occurred in only one-third of patients with HFrEF within one year of the initial TTE. Among those with repeat imaging, 23.9% remained in HFrEF, 18.6% improved to heart failure with mid-range ejection fraction (HFmrEF), and 57.5% improved to heart failure with recovered ejection fraction (HFrecEF). Patients transitioning to HFmrEF or HFrecEF were more likely to be female, White, have a higher baseline LVEF, and fewer cardiovascular comorbidities. GDMT use was low across all LVEF transition categories, highlighting significant opportunities to improve heart failure outcomes.
GLOWORM-META: Modelling gastrointestinal nematode metapopulation dynamics to inform cattle biosecurity research
Authors: Ingle Olivia K. , Melville Lynsey A. , Beechener Sam , Hardy Claire , Howell Alison , Hobbs Neil P. , Mahon Niamh , Morgan Eric R. , Bartley David , Vineer Hannah Rose
Published: February 2025

Gastrointestinal nematode (GIN) parasite infections in grazing livestock cause significant disease, and are responsible for estimated annual losses of over €1.8 billion in Europe alone. The management of GINs in cattle is threatened by anthelmintic drug resistance (AR). Immediate action is needed to slow the progression of AR in cattle GINs and avoid the increasingly common scenario of multiple drug resistance seen in sheep. Although AR can arise independently on multiple farms, it may also be spread between holdings via purchased cattle. Therefore, effective biosecurity measures on cattle enterprises could help to reduce the risk of establishment of AR populations. A metapopulation model was developed and validated for two GIN species infecting cattle,Ostertagia ostertagiandCooperia oncophora, incorporating the full parasite life cycle, weather- and immunity-dependent parasite life history traits and multiple pasture sub-populations. This allowed for complex grazing management strategies and weather influences to be simulated. The models successfully replicated the seasonal patterns and intensity of infections reported in multiple published longitudinal datasets. Global sensitivity analysis against four Quantities of Interest (QoIs) related to factors affecting the safety of the resident herd and of the purchased animals was used to quantify the influence of candidate biosecurity measures. The duration of quarantine, the date of purchase (weather/seasonal influences) and the intensity of infection on the day of purchase strongly influenced the QoIs. The outcomes for the UK were not significantly influenced by the geographic location of the purchasing farm, suggesting that the influence of weather patterns on GIN populations outweighs that of regional climate differences, and thus regional variations to GIN biosecurity recommendations are not warranted without alternative evidence to support this. The model presented here is the first full lifecycle GIN metapopulation model forO. ostertagiandC. oncophora, validated against longitudinal field data, and can be broadly used to evaluate the relative efficacy of a range of cattle GIN management strategies, as demonstrated here. These findings offer valuable insights to focus initial biosecurity recommendations for cattle enterprises, and are being used to direct qualitative and quantitative research to refine recommendations.

Highlights

A metapopulation model for cattle GINs was developed

The model includes weather-dependence and complex grazing

The model replicated seasonal infection patterns from multiple datasets

Sensitivity analysis explored influential biosecurity measures

The influence of weather outweighed that of geographic location (climate)

Initial recommendations for biosecurity and further research are made
Coding of the basic components of subjective value in primate dopamine neurons: subjectively weighted reward amount and probability
Authors: Ferrari-Toniolo Simone , Seak Leo Chi U , Schultz Wolfram
Published: February 2025

Behavioral choices of uncertain rewards suggest that agents construct subjective reward value by combining the basic value components of utility and weighted probability. Despite the general acceptance of this evaluation mechanism for explaining economic choice, knowledge about its neuronal implementation is fractionated and remains essentially unknown. We investigated in monkeys whether reward signals in dopamine neurons might represent subjective reward value based on these two fundamental value components. Despite some heterogeneity across individual neurons, the dopamine population signal reliably represented the axiomatically defined integration of utility and weighted probability into subjective value in a way that closely matched the animal-specific choice behavior. In particular, we identified a crucial contribution of subjectively weighted probability to the dopamine signal of subjective reward value. These data demonstrate a neuronal implementation of subjective value constructed from the two most basic subjective reward components.

Preprint Server

An earlier version of this manuscript has been uploaded to bioRxiv in February 2025 (CC-BY).
Caspase-dependent ablation of indirect medium spiny neurons projecting to external globus pallidus promotes compulsive ethanol-seeking and drinking behaviors
Authors: Haroon Humza , Baker Matthew , Choi Doo-Sup
Published: February 2025

The dorsomedial striatum (DMS) is primarily recognized for regulating goal-directed reward-seeking behaviors, while the dorsolateral striatum (DLS) is predominantly associated with movement and habitual behaviors. In this study, we sought to investigate two pathways, direct medium spiny neuron (dMSN) and indirect medium spiny neuron (iMSN) in the two dorsal striatal subregions (DMS and DLS) in ethanol-seeking and drinking behaviors. Here, we selectively ablated iMSNDMS→GPeand iMSNDLS→GPeand trained mice to exhibit goal-directed and habitual reward-seeking behaviors using random ratio (RR) and random interval (RI) operant conditioning, respectively. We found that partial ablation of iMSNDLS→GPeexhibited increased resilience to bitter-tasting ethanol solution when subjected to quinine adulterated reward in operant conditioning paradigms, suggesting compulsive-like seeking behavior. Consistently, in a separate cohort of mice, we found that the iMSNDLS→GPeablated mice show higher preference and consumption of quinine adulterated ethanol solution than control mice in two-bottle choice continuous access drinking, with increasing quinine concentration and exhibit more compulsive-like behavior. On the other hand, ablation of iMSNDMS→GPeresulted in insensitivity to satiety-based reward devaluation in RR-trained mice, consistent with a shift toward habitual behavior but no change in compulsive ethanol-seeking and drinking behavior. Together, our findings demonstrate that DLS iMSN function is essential in inhibiting compulsive-like behavior.
Satiety, TAX-4, and OSM-9 Tune the Attraction ofC. elegansNematodes to Microbial Fermentation Products
Authors: Logan-Garbisch Theresa , Fryer Emily , Seyahi Lara Selin , Rogel-Hernandez Lucero , Rhee Seung Y. , Goodman Miriam B.
Published: February 2025

Animals are sensitive to selective pressures associated with nutrient acquisition, underscoring the evolutionary significance of chemosensation in foraging and its intersection with satiety. For the model nematodeCaenorhabditis elegans, isoamyl alcohol (3-methyl-1-butanol) and 2-methyl-1-butanol are produced by microbial fermentation and present in bacterial food sources collected from the natural environments. Both compounds, which are structural isomers of one another, elicit strong attraction in laboratory settings. Using laboratory chemotaxis assays, we show that starvation attenuates attraction to both compounds. Well-fedC. elegansis largely insensitive to the biosynthetic precursors of both alcohols, with the exception of 4-methyl-2-oxovaleric acid, which is a mild repellent.C. eleganschemosensation relies on expression oftax-4cyclic nucleotide-gated (CNG) andosm-9transient receptor potential, vanilloid (TRPV) ion channels and animals lacking both genes are taste- and smell-blind. Animals lackingtax-4fail to attract isoamyl alcohol and 2-methyl-1-butanol and those lackingosm-9exhibit stronger attraction than the wild-type. Starvation not only attenuates attraction, but also enhances repulsion to 4-methyl-2-oxovaleric acid and uncovers repulsion intax-4mutants absent in their well-fed counterparts. Collectively, these findings implicate satiety in regulating response strength,tax-4-dependent chemotaxis in attraction to isoamyl alcohol and 2-methyl-1-butanol, andosm-9-dependent chemotaxis in suppressing responses to biosynthetic precursors.
Context-Dependent and Gene-Specific Role of Chromatin Architecture Mediated by Histone Modifiers and Loop-extrusion Machinery
Authors: Tastemel Melodi , Jussila Adam , Saravanan Bharath , Huang Hui , Xie Yang , Zhu Quan , Jiang Yifan , Armand Ethan , Ren Bing
Published: February 2025

Loop-extrusion machinery, comprising the cohesin complex and CCCTC-binding factor CTCF, organizes the interphase chromosomes into topologically associating domains (TADs) and loops, but acute depletion of components of this machinery results in variable transcriptional changes in different cell types, highlighting the complex relationship between chromatin organization and gene regulation. Here, we systematically investigated the role of 3D genome architecture in gene regulation in mouse embryonic stem cells under various perturbation conditions. We found that acute depletion of cohesin or CTCF disrupts the formation of TADs, but affects gene regulation in a gene-specific and context-dependent manner. Furthermore, the loop extrusion machinery was dispensable for transcription from most genes in steady state, consistent with prior results, but became critical for a large number of genes during transition of cellular states. Through a genome-wide CRISPR screen, we uncovered multiple factors that can modulate the role of loop extrusion machinery in gene regulation in a gene-specific manner. Among them were the MORF acetyltransferase complex members (Kat6b, Ing5, Brpf1), which could antagonize the transcriptional insulation mediated by CTCF and cohesin complex at developmental genes. Interestingly, inhibition of Kat6b partially rescues the insulator defects in cells lacking the cohesin loader Nipbl, mutations of which are responsible for the developmental disorder Cornelia de Lange syndrome. Taken together, our findings uncovered interplays between the loop extrusion machinery and histone modifying complex that underscore the context-dependent and gene-specific role of the 3D genome.
First Successful Targeted Mutagenesis Using CRISPR/Cas9 in Stably Transformed Grain Amaranth Tissue
Authors: Vollmer Susanne K , Stetter Markus G , Hensel Götz
Published: February 2025

Genome editing using CRISPR/Cas is a key technology for speeding up breeding for climate-resilient, high-yielding crops (Schebenet al., 2017). However, efficient targeted mutagenesis requires implementing stable transformation methods and establishing a CRISPR/Cas setup suitable for the species of interest (Shanet al., 2020). The availability of such methods is a significant bottleneck to advancing many promising, albeit under-researched, crops. Testing and establishing vectors for efficient application of CRISPR/Cas in non-model crops could boost research and breeding of new valuable crops (Ye and Fan, 2021).

We edited key pathway genes in the betalain biosynthesis pathway of grain amaranth, i.e.,A. hypochondriacus L., to prove how targeted mutagenesis can be implemented in an orphan crop using the CasCADE modular cloning system (Hoffie, 2022). Grain amaranth is a resilient C4dicot orphan crop with excellent nutritional composition. These properties make amaranth a well-suited candidate to be bred as a climate-resilient crop (Joshiet al., 2018). However, no efficient and reproducible protocol for successful application of CRISPR/Cas9 or stable transformation and regeneration, has been demonstrated inA. hypochondriacus(Castellanos-Arévaloet al., 2020).
Dynamic reconfiguration of brain coactivation states associated with active and lecture-based learning of university physics
Authors: Smith Donisha D. , Bartley Jessica E. , Peraza Julio A. , Bottenhorn Katherine L. , Nomi Jason S. , Uddin Lucina Q. , Riedel Michael C. , Salo Taylor , Laird Robert W. , Pruden Shannon M. , Sutherland Matthew T. , Brewe Eric , Laird Angela R.
Published: February 2025

Academic institutions are increasingly adopting active learning methods to enhance educational outcomes. Using functional magnetic resonance imaging (fMRI), we investigated neurobiological differences between active learning and traditional lecture-based approaches in university physics education. Undergraduate students enrolled in an introductory physics course underwent an fMRI session before and after a 15-week semester. Coactivation pattern (CAP) analysis was used to examine the temporal dynamics of brain states across different cognitive contexts, including physics conceptual reasoning, physics knowledge retrieval, and rest. CAP results identified seven distinct brain states, with contributions from frontoparietal, somatomotor, and visuospatial networks. Among active learning students, physics learning was associated with increased engagement of a somatomotor network, supporting an embodied cognition framework, while lecture-based students demonstrated stronger engagement of a visuospatial network, consistent with observational learning. These findings suggest significant neural restructuring over a semester of physics learning, with different instructional approaches preferentially modulating distinct patterns of brain dynamics.
Triosephosphate Isomerase as a Quantum Logic Gate: Could quantum decoherence be toxic?
Authors: Romanello Daniele , Romanello Andrea
Published: February 2025

This study presents the hypothesis that triosephosphate isomerase (TIM), a pivotal enzyme in glycolysis, functions as a quantum logic gate. Utilizing quantum mechanics, we model TIM’s catalytic conversion of dihydroxyacetone phosphate (DHAP) to glyceraldehyde-3-phosphate (G3P) as a quantum operation involving precise proton transfer. To explore the broader implications of this quantum behavior, we developed a quantum model to assess the impact of Sodium-glucose co-transporter 2 inhibitors (SGLT2i) on methylglyoxal formation, a toxic byproduct linked to advanced glycation end products (AGEs). Our model predicts that SGLT2i could reduce methylglyoxal by decreasing the likelihood of intermediate formation, providing a potential mechanism for their protective effects observed in clinical contexts, including vascular and renal protection in diabetes, nephropathy, and heart failure. By reframing TIM as a quantum logic gate, this study not only challenges traditional views of enzymatic function but also opens new avenues for quantum biology, offering profound implications for the future of metabolic disease research and drug development. Moreover considering methylglyoxal as a result of a quantum tunnel inefficiency, it’s possible to hypothesize a new “noxa patogena” explicating it’s action as quantum interference.
SARS-CoV-2 nucleocapsid uniquely disrupts chromatin over pathophysiologically relevant gene promoters
Authors: Benoit Jane M , Dennis Jonathan H
Published: February 2025

SARS-CoV-2, the causative agent of COVID-19, is a positive-sense, single-stranded RNA virus that causes a spectrum of disease severity, from asymptomatic infection to severe illness to long-term sequelae. Similar to other human coronaviruses, SARS-CoV-2 proteins modulate host genomic responses through epigenomic modifications, facilitating viral replication and immune evasion. While the nucleocapsid protein is well known for its role in RNA stability and immune modulation, its impact on host chromatin organization remains unclear. To investigate this, we generated stable human alveolar cell lines expressing nucleocapsid proteins from endemic and pandemic human coronaviruses. Our analysis revealed that nucleocapsid proteins from all tested coronaviruses induced changes in nucleosome positioning and occupancy at specific gene promoters involved in coagulation pathways, hormone signaling, and innate immune responses. Additionally, SARS-CoV-2-specific alterations were identified in genes dysregulated in severe infections, suggesting a direct role for epigenomic modifications in disease pathophysiology. We also observed extensive changes in nucleosome susceptibility to nuclease digestion in SARS-CoV and SARS-CoV-2 samples that were not observed in common cold cell lines. Promoters with altered sensitivity and resistance to nuclease were linked to innate immune, metabolic, olfactory, and signaling pathways known to be dysregulated in severe COVID-19 and post-acute sequelae (PASC). These findings demonstrate that nucleocapsid protein expression alters chromatin structure at specific loci, implicating viral proteins in host genome dysregulation. Furthermore, we identified both shared and unique chromatin targets of SARS-CoV-2 and common cold coronaviruses, highlighting pathways for further investigation and potential therapeutic intervention.

Importance

Host chromatin is known to be modulated by coronaviruses during infections. However, the role of the nucleocapsid protein in these alterations are unknown. Here, we show that nucleocapsids from seven human coronaviruses alter nucleosome distribution and susceptibility to enzymatic digestion over specific gene promoters in a human lung cell line. Nucleocapsids from SARS-CoV and SARS-CoV-2 have the most prominent effects which are seen over genes involved in immune responses, metabolism, hormone signaling, and other pathways that are known to be dysregulated in severe COVID-19 and post-acute sequelae of COVID-19.

Graphical abstract
Structured Gamma Spikes in Mouse Anterodorsal Thalamus
Authors: Liu Tao , Liu Jia
Published: February 2025

Gamma-frequency oscillations (∼30–160 Hz) are a hallmark of neuronal syn-chronization, yet the fine-scale temporal arrangement of spikes within individual gamma cycles remains poorly understood. Here, we examine head direction (HD) cells in the mouse anterodorsal thalamic nucleus (ADn)—a circuit distinguished by prominent high-gamma activity—to uncover the principles governing gamma coordination. We reveal two fundamental mechanisms: (i) a stable anatomical gradient in which neurons firing earlier in the gamma cycle exhibit longer anticipatory time intervals (ATIs), and (ii) a dynamic rate-phase shift whereby spike timing advances as the animal’s head aligns with a neuron’s preferred direction. Together, these results delineate a spatiotemporally structured framework for gamma synchronization, advancing our understanding of the functional roles and circuit mechanisms underlying gamma rhythms in local brain networks.
Knowledge Connector: Decision support system for multiomics-based precision oncology
Authors: Hübschmann Daniel , Kreutzfeldt Simon , Roth Benjamin , Glocker Katrin , Schoop Janine , Oeser Lena , Hausmann Steffen , Koch Christian , Uhrig Sebastian , Hüllein Jennifer , Hutter Barbara , Fröhlich Martina , Heilig Christoph E. , Teleanu Maria-Veronica , Lipka Daniel B. , Kerle Irina A. , Baude Annika , Beck Katja , Heining Christoph , Glimm Hanno , Ückert Frank , Knurr Alexander , Fröhling Stefan , Horak Peter
Published: February 2025

Precision cancer medicine aims to improve patient outcomes by providing individually tailored recommendations for clinical management based on the evaluation of biological disease profiles in multidisciplinary molecular tumor boards (MTBs). The quality of MTB decisions depends on the comprehensive, reliable, and reproducible interpretation of increasingly complex molecular data. We developed and implemented, as part of a multicenter precision oncology program, the Knowledge Connector (KC), a decision support system that integrates individual patients’ molecular and clinical data with world knowledge to generate and document MTB recommendations. The KC supports data curation, database integration, and discussion based on multiomics data and provides an interface for creating a cross-institutional knowledge base. Furthermore, it extracts relevant biomarker-drug associations and increases the efficacy of data interpretation in a clinically relevant manner by reducing reliance on external sources and optimizing inter-curator concordance. Our results demonstrate that the KC is a versatile tool that supports medical decision-making in MTBs, thus enabling the scalability of precision cancer medicine.