bluuebunny/crossref_metadata_2025 huggingface dataset:
Early resident NK cell response to local HIV infection in lymphoid tissue
Authors: Perea David , Gonzalez Alba , Sanchez-Gaona Nerea , Pumarola Felix , Ortiz Nuria , Llano Ines , Lorente Juan , Falco Vicenc , Genesca Meritxell , Buzon Maria J
Published: February 2025

Natural killer (NK) cells are critical mediators of antiviral immunity, yet their role in lymphoid tissues, key reservoirs of HIV persistence, remains poorly defined. Here, we uncover a distinct cytotoxic signature of tonsil-resident NK cells essential for targeting HIV-infected CD4⁺ T cells. Using a human tonsillar model of HIV infection and extracellular matrix-based functional assays, we identify a subset of NK cells co-expressing CD69, CD49a, CD103, and the adaptive marker NKG2C as potent effectors against autologous HIV-infected tissue CD4⁺ T cells. Both CD16⁺ and CD16⁻ NK subsets exhibited cytotoxic antiviral activity. However, HIV infection induced profound functional alterations in these NK cells, including dysregulated expression of CD9, TRAF2, ITGA1, suggesting disrupted activation, signaling, and tissue residency. Functional assays corroborated a significant impairment in the cytotoxic capacity, indicating HIV-driven NK cell dysfunction. Intriguingly, a subset of immature CD16⁻CD69⁺ NK cells underwent functional reprogramming, transitioning into a migration-competent, and metabolically primed state, driven by the upregulation of NUMAI, LCP1, SLC38A1, MT-ND2, NUMA1, MYH9, and CD44. Functional assays confirmed this transition, revealing changes in the expression of immune checkpoint receptors and a gain of cytotoxic function in these reprogrammed cells. These findings advance our understanding of NK cell biology in HIV infection and highlight novel avenues for NK-cell-based therapeutic strategies.
A foundation model for protein-ligand affinity prediction through jointly optimizing virtual screening and hit-to-lead optimization
Authors: Feng Bin , Liu Zijing , Yang Mingjun , Zou Junjie , Cao He , Li Yu , Zhang Lei , Wang Sheng
Published: February 2025

Protein-ligand binding affinity plays an important role in drug discovery, especially during virtual screening and hit-to-lead optimization. Computational chemistry and machine learning methods have been developed to investigate these tasks. Despite the encouraging performance, virtual screening and hit-to-lead optimization are often studied separately by existing methods, partially because they are performed sequentially in the existing drug discovery pipeline, thereby overlooking their interdependency and complementarity. To address this problem, we propose LigUnity, a foundation model for protein-ligand binding prediction by jointly optimizing virtual screening and hit-to-lead optimization. In particular, LigUnity learns coarse-grained active/inactive distinction for virtual screening, and fine-grained pocket-specific ligand preference for hit-to-lead optimization. We demonstrate the effectiveness and versatility of LigUnity on eight benchmarks across both tasks. In virtual screening, LigUnity outperforms 24 competing methods with more than 50% improvement on the DUD-E and Dekois 2.0 benchmarks, and shows robust generalization to novel proteins. In hit-to-lead optimization, LigUnity achieves the best performance on split-by-time, split-by-scaffold, and split-by-unit settings, further demonstrating its potential as a cost-effective alternative to free energy perturbation (FEP) calculations. We further showcase how LigUnity can be employed in an active learning framework to efficiently identify active ligands for TYK2, a therapeutic target for autoimmune diseases, yielding over 40% improved prediction performance. Collectively, these comprehensive results establish LigUnity as a versatile foundation model for both virtual screening and hit-to-lead optimization, offering broad applicability across the drug discovery pipeline through accurate protein-ligand affinity predictions.
Systematic engineering of synthetic serine cycles in Pseudomonas putida uncovers emergent topologies for methanol assimilation
Authors: Puiggené Òscar , Muñoz-Triviño Jaime , Civil-Ferrer Laura , Gille Line , Schulz-Mirbach Helena , Bergen Daniel , Erb Tobias J. , Ebert Birgitta E. , Nikel Pablo I.
Published: February 2025

The urgent need for a circular carbon economy has driven research into sustainable substrates, including one-carbon (C1) compounds. The non-pathogenic soil bacteriumPseudomonas putidais a promising host for exploring synthetic methylotrophy due to its versatile metabolism. In this work, we implemented synthetic serine cycle variants inP. putidafor methanol assimilation combining modular engineering and growth-coupled selection, whereby methanol assimilation supported biosynthesis of the essential amino acid serine. The serine cycle forms acetyl-coenzyme A from C1molecules without carbon loss but has bottlenecks that hinder engineering efforts. We adopted three synthetic variants (serine-threonine cycle, homoserine cycle, and modified serine cycle) that yield serine in a methanol-dependent fashion to overcome these challenges. By dividing these metabolic designs into functional modules, we systematically compared their performance for implementationin vivo. Additionally, we harnessed native pyrroloquinoline quinone-dependent dehydrogenases for engineering methylotrophy. Recursive rewiring of synthetic and native activities revealed novel metabolic topologies for methanol utilization, termed enhanced serine-threonine cycle, providing a blueprint for engineering C1assimilation in non-model heterotrophic bacteria.

GRAPHICAL ABSTRACT
A Case for Automated Segmentation of MRI Data in Milder Neurodegenerative Diseases
Authors: Lewis Connor J. , Johnston Jean M. , D’Souza Precilla , Kolstad Josephine , Zoppo Christopher , Vardar Zeynep , Kühn Anna Luisa , Peker Ahmet , Rentiya Zubir S. , Gahl William A. , Shazeeb Mohammed Salman , Tifft Cynthia J. , Acosta Maria T.
Published: February 2025

Background

Volumetric analysis and segmentation of magnetic resonance imaging (MRI) data is an important tool for evaluating neurological disease progression and neurodevelopment. Fully automated segmentation pipelines offer faster and more reproducible results. However, since these analysis pipelines were trained on or run based on atlases consisting of neurotypical controls, it is important to evaluate how accurate these methods are for neurodegenerative diseases. In this study, we compared 5 fully automated segmentation pipelines including FSL, Freesurfer, volBrain, SPM12, and SimNIBS with a manual segmentation process in GM1 gangliosidosis patients and neurotypical controls.

Methods

We analyzed 45 MRI scans from 16 juvenile GM1 gangliosidosis patients, 11 MRI scans from 8 late-infantile GM1 gangliosidosis patients, and 19 MRI scans from 11 neurotypical controls. We compared results for 7 brain structures including volumes of the total brain, bilateral thalamus, ventricles, bilateral caudate nucleus, bilateral lentiform nucleus, corpus callosum, and cerebellum.

Results

We found volBrain’svol2Brainpipeline to have the strongest correlations with the manual segmentation process for the whole brain, ventricles, and thalamus. We also found Freesurfer’srecon-allpipeline to have the strongest correlations with the manual segmentation process for the caudate nucleus. For the cerebellum, we found a combination of volBrain’svol2Brainand SimNIBS’headrecoto have the strongest correlations depending on the cohort. For the lentiform nucleus, we found a combination ofrecon-alland FSL’sFIRSTto give the strongest correlations depending on the cohort. Lastly, we found segmentation of the corpus callosum to be highly variable.

Conclusion

Previous studies have considered automated segmentation techniques to be unreliable, particularly in neurodegenerative diseases. However, in our study we produced results comparable to those obtained with a manual segmentation process. While manual segmentation processes conducted by neuroradiologists remain the gold standard, we present evidence to the capabilities and advantages of using an automated process including the ability to segment white matter throughout the brain or analyze large datasets, which pose feasibility issues to fully manual processes. Future investigations should consider the use of artificial intelligence-based segmentation pipelines to determine their accuracy in GM1 gangliosidosis, lysosomal storage disorders, and other neurodegenerative diseases.
Health of first- and second-generation immigrant children in England and Wales: serial, cross-sectional study using linked Census and birth registration data
Authors: Hardelid Pia , Yu Senhao , Stockton Jemima , Langella Rebecca , Lewis Kate
Published: February 2025

Introduction

There is limited research on the health outcomes of children who have migrated, or whose parents have migrated, to the UK.

Methods

We used linked birth registration and Census data from the 1991, 2001 and 2011 waves of the Longitudinal Study, covering 1% of the England and Wales population. We derived the prevalence of self-or-caregiver reported limiting long-term illness (2001, 2011 Censuses) and poor health (1991, 2001, 2011 Censuses) among household members <18 years old. We defined immigration background using child and parent country of birth. Logistic regression models assessed the association between immigration background and health outcomes.

Results

The percentage of children who were first-or second-generation immigrants increased from 16.6% (20120/121109) in 1991 to 24.7% (28965/117116) in 2011. We found no evidence of an association between immigration background and health outcomes in 1991. In 2011, children born outside the UK were less likely to report a limiting long-term illness (odds ratio 0.67; 95% confidence interval 0.58, 0.76) compared to average. Also in 2011, children born in the UK to UK-born parents or non-UK-born fathers/UK-born mothers had higher odds of reporting long-term illness compared to average (1.25; 1.17, 1.32 and 1.21; 1.08, 1.36, respectively). In both 2001 and 2011, children born in the UK to non-UK-born parents had the highest odds of reporting poor health.

Conclusion

Whilst immigrant children with a first-generation immigrant background are less likely to live with limiting long-term illness, evidence-based National Health Service guidelines for supporting second-generation immigrant children are needed.

What is already known on this topic

Studies of adults have identified a ‘healthy migrant effect’, where immigrants have lower mortality rates than the host population.

It is not clear if this applies to children or to non-mortality outcomes.

What this study adds

There was no association between children’s immigration background and prevalence of long-term illness before 2011, or poor health before 2001.

First generation immigrant children had lower prevalence of limiting long-term illness, and similar prevalence of poor health to non-immigrant children.

Children born in the UK to UK-born parents or second-generation immigrant children via the father had higher prevalence of long-term illness, and UK-born children whose parents were both born abroad had higher prevalence of poor health.

How this study might affect research, practice or policy

The National Health Service should develop evidence-based guidelines for how health services can support second generation immigrant children.
Structural basis for lipid transport at membrane contact sites by the Ist2/Osh6 complex
Authors: Arndt Melanie , Schweri Angela , Dutzler Raimund
Published: February 2025

Membrane contact sites (MCS) are hubs for inter-organellar lipid transport within eukaryotic cells. As one of the principal tethers bridging the ER and the plasma membrane inSaccharomyces cerevisiae, the protein Ist2 plays a major role during lipid transport between both compartments. Here, we present a comprehensive investigation elucidating structural and mechanistic properties of Ist2 and its interaction with the soluble lipid transport protein Osh6. The ER-embedded transmembrane domain of Ist2 is homologous to the TMEM16 family and acts as constitutively active lipid scramblase. The extended C-terminus binds to the plasma membrane and the PS/PI4P exchanger Osh6. Through cellular growth assays, biochemical and structural studies, we have elucidated the interaction between both proteins and provide evidence that Osh6 remains associated with Ist2 during lipid shuttling between membranes. These results highlight the role of the Ist2/Osh6 complex in lipid trafficking and offer new insights into the relevance of scramblases at MCSs.
Persistent articular infection and host reactive response contribute toBrucella-induced spondyloarthritis in SKG mice
Authors: Harms Jerome S. , Lasarev Michael , Warner Thomas , Costa Oliveira Sergio , Smith Judith A.
Published: February 2025

Brucellosis, one of the most prevalent zoonotic diseases worldwide, often results in osteoarticular complications including large joint and axial arthritis mimicking spondyloarthritis. To model this chronic manifestation, we infected autoimmunity-prone SKG mice containing a mutation in the T-cell adaptor ZAP-70 withBrucellaspecies.B. melitensisinfection resulted in a fully penetrant, readily scoreable disease involving large joint wrist and foot arthritis, peri-ocular inflammation, and less frequent scaly paw rash. Infection withB. abortusresulted in delayed arthritis onset, andB. neotomaerevealed sex differences, with more severe disease and a dose response in females. Heat-killedBrucelladid not induce arthritis, evincing a requirement for viable infection. Across species, splenic CFU correlated well with final clinical score at 12 weeks (ρ=0.79 and p<0.001).In vivoimaging using luminescentB. neotomaerevealed rapid colonization of the paws by one-week post-infection, more than a month prior to arthritis onset. Paw luminescence levels decreased after 2 weeks and then remained relatively static, even as clinical scores increased. Thus, the degree of arthritis did not strictly correlate with degree of paw infection but suggested an additional reactive component. Further, in examining aBrucellaΔtcpBmutant lacking a Type IV secretion system-dependent mediator, mice displayed an intermediate phenotype without significant differences in splenic CFU. Together these data suggestBrucellainduced spondyloarthritis reflects both persistent colonization as well as excess host reactivity. Moreover, the sensitivity of the SKG model to different species and mutants will provide new opportunities for dissecting correlates ofBrucellavirulence and host immunity.

Importance

Brucellosis, a bacterial infection acquired from herd animals, remains one of the most common zoonotic diseases worldwide. Chronic infection often results in spondyloarthritis-like complications. Investigation into pathogenesis has been limited by the lack of overt disease in standard lab mice. We addressed this issue using spondyloarthritis-susceptible SKG mice. Upon infection withB. melitensis, SKG mice develop robust, fully penetrant large joint arthritis. Arthritis development required viable bacteria. Moreover, studies of colonization, gene expression and anatomic distribution using bioluminescent bacteria revealed active persistent infection in the mouse paws. However, peak paw infection occurred much earlier than arthritis onset, suggesting an added immune reactive component. Disease onset, severity and manifestations varied upon infection with differentBrucellaspecies and mutants. Together these results suggest this new model will be very useful to the scientific community for determining correlates of bacterial virulence leading to clinical disease.
Estimates of underlying health biases in SARS-CoV-2 vaccination recipients: a nationwide study in previously-infected adults
Authors: Riedmann Uwe , Chalupka Alena , Richter Lukas , Werber Dirk , Sprenger Martin , Willeit Peter , Rijksen Marc , Lodron Julia , Høeg Tracy Beth , Ioannidis John PA , Pilz Stefan
Published: February 2025

Background

Observational studies may over- or under-estimate SARS-CoV-2 vaccine effectiveness (VE) depending on whether healthier (i.e. healthy vaccine effect (HVE)) or more ill individuals are preferentially vaccinated. To evaluate this issue, we compared non-COVID-19, all-cause, cancer and COVID-19 mortality in vaccinated versus unvaccinated individuals.

Methods

This is a nationwide retrospective observational study in the entire adult population in Austria with previously documented SARS-CoV-2 infection with a follow-up from 2021 to 2023. Cox regression analyses were used to calculate hazard ratios (HRs) according to the number of SARS-CoV-2 vaccinations. We also performed matched analyses, where on each day, newly vaccinated individuals were matched with unvaccinated individuals based on age, sex and nursing home residency.

Results

Overall, 4,324,485 individuals (median age (IQR): 46 (33-59) years; 52.56% female) were eligible and 2.23 non-COVID-19 deaths occurred per 100,000 person days. Group differences in non-COVID-19 mortality risk were most prominent in the early periods (e.g., in Q4 2021, adjusted HRs (95% CI) in vaccinated versus unvaccinated were 0.69 (0.59 - 0.81), 0.65 (0.58 - 0.74), and 0.56 (0.48 - 0.66) for 1-, 2-, and 3-vaccinations, respectively) and decreased thereafter. Matched analyses for the first two weeks after vaccination showed HRs below 0.5 for vaccinated versus unvaccinated individuals irrespective of vaccination numbers. Similar findings were retrieved for non-COVID-19, all-cause, and cancer deaths. Overall, COVID-19 deaths were significantly reduced in vaccinated individuals.

Conclusions

HVE for SARS-CoV-2 vaccines was strong early after vaccination and diminished over time. HVE should be considered when estimating VE.
Diabetes impact on nigrostriatal vulnerability in Parkinson’s Disease
Authors: Galli Alice , Zatti Cinzia , Lupini Alessandro , Caminiti Silvia Paola , Rizzardi Andrea , Lucchini Silvia , Bertagna Francesco , Paghera Barbara , Outeiro Tiago Fleming , Perani Daniela , Padovani Alessandro , Pilotto Andrea
Published: February 2025

Mechanisms underlying the role of diabetes mellitus (DM) as modulator of severity in Parkinson’s Disease (PD) remain unclear. Aim of this study was to investigate the impact of DM on nigrostriatal dopaminergic vulnerability considering two independent cohorts of drug-naïve PD patients (PPMI and DNA studies). Patients with and without DM were first compared and then matched for age, sex, symptoms severity. Differences in123I-FP-CIT binding and molecular connectivity alterations were tested in PD with and without DM within the nigrostriatal pathway. 269 drug-naïve patients were enrolled (PPMI, n=174; DNA, n=95). In both cohorts, patients with DM were older, predominantly male, and exhibited worse non-motor and cognitive symptoms. After severity-matching, patients with DM were found to exhibit more preserved dopamine binding in striatal regions compared to those without DM, together with a lower neural reserve. Patients with DM showed significant dopaminergic connectivity alterations (20%), primarily due to a loss of connectivity (98%). In contrast, patients without DM had more widespread connectivity changes (33%), characterized by both loss (84%) and gained connections (16%). These findings suggest that diabetes directly affects the nigrostriatal network, resulting in less deficits despite similar disease severity, perhaps decreasing the effect of reserve on dopaminergic neurons loss.
Common Genetic Variants Modify Disease Risk and Clinical Presentation in Monogenic Diabetes
Authors: Leech Jacques Murray , Beaumont Robin N , Arni Ankit M , Chundru V. Kartik , Sharp Luke N , Colclough Kevin , Hattersley Andrew T , Weedon Michael N , Patel Kashyap A
Published: February 2025

The contribution of polygenic background in young onset monogenic disorders needs further exploration. Understanding this will provide new biological insights and may improve risk prediction of monogenic disease. Here we investigated the role of polygenic background in MODY—a common monogenic disorder with an age-dependent onset.We found strong enrichment of type 2 diabetes (T2D) polygenic risk, but not type 1 diabetes risk, in genetically confirmed MODY cases. This T2D polygenic burden, primarily through beta-cell dysfunction pathways, was strongly associated with earlier age of diagnosis and increased diabetes severity. Common genetic variants collectively accounted for 24% (p<0.0001) of the phenotypic variability. Using a large population cohort, we demonstrated that T2D polygenic burden substantially modifies diabetes onset in individuals with pathogenic variants, with diabetes risk ranging from 11% to 81%. Finally, we show that individuals with MODY-like phenotypes without a causal variant had elevated polygenic burden for T2D and related traits representing potential polygenic phenocopies. These findings reveal substantial influence of common genetic variation in shaping the clinical presentation of early-onset monogenic disorders. Incorporating these may improve risk estimates for individuals carrying pathogenic monogenic variants.
Analyzing concordance between MUAC, MUACZ, and WHZ in diagnosing acute malnutrition among children under 5 in Somalia
Authors: Garretson Sydney , Walton Shelley , Alier Kemish Kenneth , Grounds Samantha , Khattak Qundeel , Mohamoud Said Aden , Arays Abdullahi , Mohamud Farhan Mohamed , Mohamoud Abdullahi Muse , Mahdi Adan , Omer Meftuh , Mahat Mohamed Billow , Loddo Fabrizio , Tripaldi Marina , Akseer Nadia
Published: February 2025

Background

Acute malnutrition, also known as wasting, affected an estimated 45 million children under 5 (CU5) globally in 2023. Wasting is measured using a child’s mid upper arm circumference (MUAC), weight-for-height z-score (WHZ), or nutritional edema. In low-resource contexts, MUAC is often the only measurement used to regularly screen for malnutrition, but recent research suggests MUAC alone fails to diagnose 25%-80% of WHZ-wasted children. MUACZ, an age-adjusted MUAC z-score, may identify additional cases missed by MUAC alone.

Methods

This was a secondary analysis of 1,408 CU5 enrolled in a cluster-randomized controlled trial in two high-wasting regions of Somalia. This analysis explored wasting prevalences, concordance between indicator pairs, linear regression modelling, and ROC analysis using WHZ as a gold standard to examine alternative MUAC and MUACZ thresholds.

Results

Wasting prevalence was 1.5% by MUAC, 8.5% by MUACZ, and 14.8% by WHZ. MUAC alone failed to identify 94% of WHZ-wasted children. There was slight concordance between MUAC and WHZ (κ=0.089) and fair concordance between MUACZ and WHZ (κ=0.385). Linear regression indicated that MUAC, age, sex, and stunting were all statistically significant variables for estimating child WHZ. Using WHZ as a gold standard, a MUAC of 13.7cm and MUACZ of –0.9 SD both accurately diagnosed >82% of wasted children ages 9-23 months. A MUAC of 14.4cm and MUACZ of −1 SD both accurately diagnosed >76% of wasted children ages 24-59 months.

Conclusion

Poor concordance between MUAC and WHZ should prompt review of wasting measurement guidelines for this population. Stratified analyses and regression modelling showed increased MUAC with age among CU5. MUACZ or age-specific MUAC thresholds may identify more truly wasted children, improving coverage of treatment interventions. Policymakers should examine how adapting screening guidelines impacts health facilities and treatment availability. Future studies should consider long-term outcomes and mortality associated with increased thresholds of MUAC and MUACZ.

Registration

The cluster-RCT is registered at ClinicalTrials.gov, ID:NCT06642012.
Oropouche virus importation in Southern Brazil and emerging concern calling for enhanced public health surveillance
Authors: dos Santos Franciellen Machado , de Melo Elverson Soares , de Lima Gustavo Barbosa , da Silva Alexandre Freitas , Santos Paiva Marcelo Henrique , Acioli-Santos Bartolomeu , Lins de Moraes Clarice Neuenschwander , Ruivo Amanda Pellenz , Gregianini Tatiana Schäffer , Bauermann Milena , Bermann Thales , Lagranha Valeska Lizzi , Baethgen Ludmila Fiorenzano , Godinho Fernanda , da Luz Wallau Gabriel , Gorini da Veiga Ana Beatriz , Salvato Richard Steiner
Published: February 2025

Oropouche virus, an arthropod-borne virus transmitted byCulicoides paraensis, is an endemic arbovirus that mostly circulates in the Amazon basin. However, between 2022 and 2024, it reemerged as a more widespread public health concern in South America. We conducted a pooled-sample molecular surveillance to understand the true prevalence of Oropouche fever in Brazil’s southernmost state. Over 18 months, we analyzed 4,060 samples to monitor the virus emergence in the Rio Grande do Sul state. We detected the first human case of Oropouche virus in the state, and our phylogenetic reconstruction indicated a travel-related introduction from Amazon region into Rio Grande do Sul. Despite the absence of local transmission, the invasion ofCulicoides paraensisand enzootic circulation of the Oropouche virus in Rio Grande do Sul highlight the risk of Oropouche fever outbreaks in the region. We demonstrated that pooled-sample surveillance effectively monitors virus introduction during periods of low endemic circulation, serving as an essential active surveillance tool for the timely detection of virus emergence and enhancing public health preparedness. The multiple introductions of distinct Oropouche virus lineages into southern Brazil underscore the importance of genomic surveillance and public health strategies to monitor and mitigate arbovirus spread in the region.
Novel Digital Gastric Alimetry® Symptom Scales for Use in Gastroduodenal Disorders and Validation against Rome IV Criteria
Authors: Gharibans Armen A. , Huang I-Hsuan , Varghese Chris , Schamberg Gabriel , Taherian Sarvnaz , Dachs Nicky , Law Mikaela , Calder Stefan , Andrews Christopher N. , Tack Jan , O’Grady Greg
Published: February 2025

Background

Patients with chronic gastroduodenal disorders present with overlapping symptoms. Guidelines emphasize symptom-based criteria, but clinical evaluations are inconsistent due to non-standardized assessments and recall bias. Gastric Alimetry® is a non-invasive test of gastric function enabling real-time symptom evaluation via a standardized app.

Methods

Participants meeting Rome IV criteria for functional dyspepsia (FD) and/or chronic nausea and vomiting syndrome (CNVS) underwent a Gastric Alimetry test, including a meal challenge, with symptoms recorded every 15 minutes in the app. Based on time-of-test symptoms, four novel scores were developed: nausea/vomiting, postprandial distress, epigastric pain, and burning/reflux. Group differences were analyzed using pairwise t-tests, and Rome IV classifications were predicted via logistic regression. Remote moderated usability testing assessed score acceptability.

Key Results

Among 109 participants (79% female, 18-80 yrs), 54 met criteria for CNVS with/without FD, 41 for postprandial distress syndrome (PDS) only, and 14 for epigastric pain syndrome (EPS) with/without PDS. Symptom scores aligned with Rome IV classifications (p<.05 for CNVS and EPS). Logistic regression showed good discrimination for CNVS (AUC=0.85) and EPS (AUC=0.80), and moderate discrimination for PDS (AUC=0.68). Usability testing confirmed clinical utility and ease of use.

Conclusions & Inferences

Gastric Alimetry symptom scores align with Rome IV classifications, with real-time patient-reported snapshots accurately reflecting chronic symptom burden. These scores provide a clinically applicable diagnostic tool alongside simultaneous physiological gastric function assessments.

Key Points

Four novel Gastric Alimetry symptom scores summarize the relative severity of symptoms in subgroups aligned with Rome IV classifications.

The proposed time-of-test symptom scores showed moderate-to-good ability to predict diagnoses made using the Rome IV criteria.

Usability testing with eight clinicians showed that the scores provided an easy-to-use and clinically useful tool to complement diagnosis of gastroduodenal disorders.
SBDH-Reader: an LLM-powered method for extracting social and behavioral determinants of health from medical notes
Authors: Gu Zifan , He Lesi , Naeem Awais , Chan Pui Man , Mohamed Asim , Khalil Hafsa , Guo Yujia , Shi Wenqi , Dupre Matthew E. , Xiao Guanghua , Peterson Eric D. , Xie Yang , Navar Ann Marie , Yang Donghan M.
Published: February 2025

Introduction

Social and behavioral determinants of health (SBDH) are increasingly recognized as essential for prognostication and informing targeted interventions. While medical notes contain rich SBDH details, these are unstructured and conventional extraction methods tend to be labor intensive, inaccurate, and/or unscalable. The emergence of large language models (LLMs) presents an opportunity to develop more effective approaches for extracting SBDH data.

Materials and Methods

We developed the SBDH-Reader, an LLM-powered method to extract structured SBDH data from full-length medical notes through prompt engineering. Six SBDH categories were queried including: employment, housing, marital relationship, and substance use including alcohol, tobacco, and drug use. The development dataset included 7,225 notes from 6,382 patients in the MIMIC-III database. The method was then independently tested on 971 notes from 437 patients at UT Southwestern Medical Center (UTSW). We evaluated SBDH-Reader’s performance using precision, recall, F1, and confusion matrix.

Results

When tested on the UTSW validation set, the GPT-4o-based SBDH-Reader achieved a macro-average F1 ranging from 0.85 to 0.98 across six SBDH categories. For clinically relevant adverse attributes, F1 ranged from 0.94 (employment) to 0.99 (tobacco use). When extracting any adverse attributes across all SBDH categories, the SBDH-Reader achieved an F1 of 0.96, recall of 0.97, and precision of 0.96 in this independent validation set.

Conclusion

A general-purpose LLM can accurately extract structured SBDH data through effective prompt engineering. The SBDH-Reader has the potential to serve as a scalable and effective method for collecting real-time, patient-level SBDH data to support clinical research and care.
Distinct cis-acting elements mediate co-localization of mRNAs encoding for co-translational interactors in cytoplasmic clusters
Authors: Shade Qamar , Estrada Marianna , Kramer Guenter , Bukau Bernd , Shiber Ayala
Published: February 2025

Many newly synthesized proteins assemble co-translationally, providing a vital mechanism to prevent subunit misfolding in the crowded cytoplasm. Initial evidence indicates that the spatial organization of mRNAs aids this assembly, but it is unclear how these mRNAs are organized and how common this mechanism is. We used single-molecule Fluorescence in situ Hybridization to examine the spatial organization of mRNAs encoding subunits of various cytosolic complexes involved in critical cellular functions, such as fatty acid synthesis, glycolysis, translation and amino acid biosynthesis. We found that mRNAs of the same protein complex often co-localize in specific cytoplasmic clusters. Additionally, we observed that the mRNAs encoding enzymes of biosynthetic pathways are organized in cytosolic clusters. Focusing on mRNAs encoding fatty acid synthase complex subunits, we discovered that non-coding cis-elements significantly influence mRNA localization in an additive manner. Inhibiting mRNA co-localization impaired growth when complex activity was essential, highlighting the importance of mRNA spatial organization for cellular survival. Transiently disrupting mRNA translation also affected clustering, indicating that both the nascent chains and mRNA sequence targeting cues are important for spatial organization. In summary, we provide evidence that mRNA co-localization in cytoplasmic foci is coordinated by complementary mechanisms crucial for co-translational assembly, allowing efficient regulation of protein complex formation and entire pathways.
Rhythmic modulation of dorsal hippocampus across distinct behavioral timescales during spatial set-shifting
Authors: Bottoms Maeve , Miles Jesse T. , Mizumori Sheri J.Y.
Published: February 2025

Previous work has shown frequency-specific modulation of dorsal hippocampus (dHPC) neural activity during simple behavioral tasks, suggesting shifts in neural population activity throughout different task phases and animal behaviors. Relatively little is known about task-relevant orchestrated shifts in theta, beta, and gamma rhythms across multiple behavioral timescales during a complex task that requires repeated adaptation of behavioral strategies based on changing reward contingencies. To address this gap in knowledge, we used a spatial set-shifting task to determine whether dHPC plays a specific role in strategy switching. The task requires rats to use two spatial strategies on an elevated plus maze: 1) alternating between East and West reward locations or 2) always going to the same reward location (e.g., only East or only West). Across specific timescales (session-based alignments, comparisons of trial types, within trial epochs), dHPC associated differentially with all three temporal categories. Across a session, we observed a decrease in theta and beta power before, and an increase in theta power after, the target strategy changed. Beta power was increased around the point at which rats learn the current rule. Comparing trial types, on trials before a rat learned the correct strategy, beta power increased. Within a single trial, after an incorrect (but not correct) choice, beta and gamma power increased while the rat returned to start a new trial. If gamma (but not beta) power was high during this return, the rat was more likely to make a correct choice on the next trial. On the other hand, low gamma power during the return was associated with incorrect trials. Rhythmic activity in dHPC, therefore, appears to track task demands, with the strength of each rhythmic frequency differentially associating with specific behaviors across three distinct timescales.
Bayesian Integration in Sense of Agency: Understanding Self-attribution and Individual Differences
Authors: Chang Acer Chan-Yu , Wen Wen
Published: February 2025

This study developed a Bayesian integration model to explore individual differences in the sense of agency, particularly when multiple sensory cues influence action perception. Behavioral results showed that individuals consistently integrate sensory cues in agency judgments, though cue weighting varies significantly across individuals. The estimated parameters of our model successfully captured these differences, reflecting individual sensitivities and criteria for agency. Higher sensitivity to sensory inputs was associated with lower variance in the likelihood distribution under the assumption of control. Our model provides critical insights into the mechanisms of the sense of agency and its variability, highlighting the model’s potential for understanding both typical and disordered agency experiences.
Cost-Effectiveness Analysis of Statins, Berberine, and Their Combined Use for Primary Prevention of Cardiovascular Disease
Authors: Xia Yuanqing , Leung Kathy , Zhao Jie V.
Published: February 2025

Background

Statins are the cornerstone treatment for the primary prevention of cardiovascular disease (CVD), but intolerance and side effects can hinder adherence. Berberine, with promising lipid-lowering effects and good tolerance, presents a potential alternative for statin-intolerant patients.

Aim

To estimate and compare the cost-effectiveness of statins, berberine, and their combined use for primary CVD prevention.

Methods

The Scottish CVD Policy Model was used to predict long-term health and cost outcomes in Scottish adults aged 40 years or older without pre-existing CVD. Intervention and cost inputs were sourced from published literature and health service cost data. The primary outcome measure was the lifetime incremental cost-effectiveness ratio (ICER), evaluated as cost per quality-adjusted life year (QALY) gained. The intervention strategies of no intervention, atorvastatin 20 mg per day (“statins”), berberine 1000 mg per day (“berberine”), simvastatin 20 mg plus berberine 1500 mg per day (“combined intervention 1”) and simvastatin 20 mg plus berberine 900 mg per day (“combined intervention 2”) were analyzed for individuals with ASSIGN risk scores ≥20% and ≥10%.

Results

All intervention strategies were cost-effective (statins: ICER £1,260.7/QALY, 95%CI: £- 2,528.6/QALY ∼ £2,305.5/QALY; berberine: ICER £6,192.4/QALY, 95%CI: £4,655.7/QALY ∼ £11,387.0/QALY; combined intervention 1: ICER £5,506.5/QALY, 95%CI: £4,506.8/QALY ∼ £10,732.0/QALY; combined intervention 2: ICER £3,846.4/QALY, 95%CI: £3,107.0/QALY ∼ £5,270.1/QALY), compared to no intervention, at the threshold of ICER of £20,000 per QALY. Compared to statins, berberine was less cost-effective, but the combined interventions remained cost-effective (£10,198.6/QALY [95%CI: £6,740.4/QALY ∼ £58,473.3/QALY]; £6,362.8/QALY [95%CI: £5,187.7/QALY ∼ £12,499.2/QALY]) at the threshold of £20,000/QALY. Notably, when using drug costs from China (reflecting lower berberine prices), berberine and the combined interventions were preferable to statins alone.

Conclusions

Statins, berberine, and combined interventions are all cost-effective options for primary CVD prevention. Berberine could be considered a valuable alternative or complementary therapy, particularly if its price decreases below that of statins.
Food Insecurity and Food Practices among Child Care Workers During COVID-19
Authors: Dynia Jaclyn M. , Koury Abel J. , Bates Randi A.
Published: February 2025

During the COVID-19 pandemic, food insecurity skyrocketed among U.S. households. In particular, child care workers may have been severely affected, with 33% reporting food insecurity (RAPID-EC, 2021). Using nationally representative data from December 2020, roughly one year into the COVID-19 pandemic, we conducted a detailed examination of food insecurity and practices among U.S. child care workers. We found that child care workers experienced triple the rates of food insecurity compared to the general population (33.3% versus 10.2%), with 20% reporting high/very high food insecurity. To cope with food insecurity, child care workers were more likely to use individual-level strategies (e.g., stretching food budgets) than participating in local or federal programs. After accounting for demographic characteristics, higher-income households had lower odds of experiencing food insecurity, suggesting that increasing wages for child care workers, especially during periods of economic turmoil, could prevent food insecurity among this vital workforce.
Contralateral spread of unilateral tremor in Parkinson’s Disease
Authors: Pasquini Jacopo , Pavese Nicola , Ceravolo Roberto , Helmich Rick C. , Deuschl Günther
Published: February 2025

Background

Parkinsonian tremor usually starts unilaterally. The mid-term prognosis of this lateralized tremor is unknown, as is the development of tremor in the contralateral arm.

Objective

To investigate the emergence of contralateral tremor in the Parkinson-Progression-Marker-Initiative database, with data available for 7 years.

Methods

Tremor Amenable for surgery (TAS) was defined as any rest, postural or kinetic tremor with amplitude >1 cm (MDS-UPDRS score ≥2) as this criterion is commonly accepted for inclusion in surgical studies. Tremor was analyzed by side mainly in the off-medication state.

Results

At baseline, 348 (87.7%) of the 397 patients with Parkinson’s disease had tremor at least on one side of the body. 183 (46%) had only mild tremors but 165 (41.6%) had TAS. 159 patients (40.1%) had lateralized TAS and 6 (1.6%) had bilateral TAS. Among patients with unilateral TAS, 40 patients (25.8%) developed contralateral TAS at 3 years, 49 patients (30.8%) at 5 years, and 61 patients (39%) at 7 years. The side more affected by tremor was also more affected by other cardinal symptoms. In 159 patients with initially unilateral TAS, tremor severity did not increase on the tremor-dominant side over the 7-year period. However, there was an increase in tremor on the contralateral side. This was associated with a clear increase in bradykinesia and rigidity on both sides.

Conclusion

The study findings may prove beneficial in counselling patients with TAS, and may also provide an explanation as to why the worsening of tremor is not correlated with overall disease progression.
Two matings lead to more copulatory wounding than a single mating in femaleDrosophila melanogaster
Authors: Subasi Bengisu S. , Finsterbusch Anika L. , Büge Martha , Armitage Sophie A.O.
Published: February 2025

Copulation can result in males inflicting wounds to the female genitalia, so-called traumatic mating. Such wounds are potentially costly as they could be entry points for infections, and they have been associated with a shorter lifespan in an insect species. In many species of insects, females mate with more than one male, which leads to the question of whether the number of matings affects the amount of genital damage that females suffer from those matings. Here we test whether copulation frequency affects the number or size of genital wounds inDrosophila melanogaster. Females who mated twice had more genital wounds and a larger total area of wounding, compared to females who mated once. However, females who refused to mate a second time had a similar area of wounding as females who mated twice. We found that wounds to the ventral abdomen also increased with increased mating frequency. Our results support the idea that polyandry can incur an under-appreciated cost in terms of increased female copulatory wounding. Investigating genital and abdominal wounds is crucial to a better understanding of the consequences of sexual conflict and the selective pressures shaping mating behaviour.
Teach your microscope how to print: Low-cost and rapid-iteration microfabrication for biology
Authors: Hinderling Lucien , Hadorn Remo , Kwasny Moritz , Frei Joël , Grädel Benjamin , Psalmon Sacha , Blum Yannick , Berthoz Rémi , Landolt Alex , Towbin Benjamin D. , Riveline Daniel , Pertz Olivier
Published: February 2025

The application of traditional microfabrication techniques to biological research is hindered by their reliance on clean rooms, expensive or toxic materials, and slow iteration cycles. We present an accessible microfabrication workflow that addresses these challenges by integrating consumer 3D printing techniques and repurposing standard fluorescence microscopes equipped with DMDs for maskless photolithography. Our method achieves micrometer-scale precision across centimeter-sized areas without clean room infrastructure, using affordable and readily available consumables. We demonstrate the versatility of this approach through four biological applications: inducing cytoskeletal protrusions via 1 μm-resolution surface topographies; micropatterning to standardize cell and tissue morphology; fabricating multilayer microfluidic devices for confined cell migration studies; imprinting agar chambers for long-time tracking ofC. elegans. Our protocol drastically reduces material costs compared to conventional methods and enables design-to-device turnaround within a day. By leveraging open-source microscope control software and existing lab equipment, our workflow lowers the entry barrier to micro-fabrication, enabling labs to prototype custom solutions for diverse experimental needs while maintaining compatibility with soft lithography and downstream biological assays.
Short-term monocular deprivation in adult humans: a meta-analysis and new perspectives
Authors: Steinwurzel Cecilia , Pennella Giacomo , Binda Paola
Published: February 2025

Starting from the early 2010s [1, 2], several studies have shown that a short period of monocular deprivation in adult volunteers transiently shifts ocular dominance in favor of the deprived eye. We compiled a meta-analysis of 73 such studies that measured the effects of monocular deprivation and related manipulations, using a diverse set of techniques [1-73]. The ocular dominance shift elicited by monocular deprivation was comparable across studies where deprivation was achieved with an opaque or translucent patch and irrespectively of whether the dominant or non-dominant eye was deprived. Effects were larger and longer lasting after longer periods of deprivation. Qualitatively similar effects were produced by monocular manipulations that did not reduce the strength of the stimulus: filtering or distorting the image in one eye, suppressing it from awareness or merely making it task irrelevant. We discuss the available evidence in the light of current models and a new perspective inspired by predictive coding.
Cholesterol taste avoidance inDrosophila melanogaster
Authors: Pradhan Roshani Nhuchhen , Montell Craig , Lee Youngseok
Published: February 2025

The question as to whether animals taste cholesterol taste is not resolved. This study investigates whether the fruit fly,Drosophila melanogaster, is capable of detecting cholesterol through their gustatory system. We found that flies are indifferent to low levels of cholesterol and avoid higher levels. The avoidance is mediated by gustatory receptor neurons (GRNs), demonstrating that flies can taste cholesterol. The cholesterol responsive GRNs comprise a subset that also respond to bitter substances. Cholesterol detection depends on five ionotropic receptor (IR) family members, and disrupting any of these genes impairs the flies’ ability to avoid cholesterol. Ectopic expressions of these IRs in GRNs reveals two classes of cholesterol receptors, each with three shared IRs and one unique subunit. Additionally, expressing cholesterol receptors in sugar-responsive GRNs confers attraction to cholesterol. This study reveals that flies can taste cholesterol, and that the detection depends on IRs in GRNs.
Cerebellar and Subcortical Contributions to Working Memory Manipulation
Authors: Tan Joshua Bradley Chan , Orlando Isabella F , Whyte Christopher , Bryant Annie G , Munn Brandon R , Baracchini Giulia , King Maedbh , O'Callaghan Claire , Müller Eli J , Shine James M
Published: February 2025

Working memory enables us to temporarily store and manipulate information, a crucial function for problem-solving. However, most working memory models emphasize cortical interactions ignoring contributions from subcortical and cerebellar regions. Given the dense connectivity between the cerebellum, subcortex, and cortex, we hypothesize that these regions provide unique contributions during working memory manipulation. We tested this hypothesis using functional Magnetic Resonance Imaging (fMRI) to measure blood oxygen-level dependent (BOLD) activity during a mental rotation task, where participants judged whether rotated pairs of three-dimensional stimuli were identical. Our results revealed a distributed network spanning the cortex, subcortex, and cerebellum that differentiates rotated from non-rotated stimuli and correct from incorrect responses. BOLD recruitment in these regions increased with larger angles of rotation. We observed delayed responses in premotor, subcortical, and cerebellar regions during incorrect trials. These findings suggest that cerebellar and subcortical regions support working memory manipulation, highlighting a broader mechanism by which distributed brain regions interact to coordinate higher cognitive functions.