bluuebunny/crossref_metadata_2025 huggingface dataset:
Development and first-in-human CAR T therapy against the pathognomonic MiT fusion driven protein GPNMB
Authors: Zemp Franz J , Breckenridge Zackariah , Song Hyojin , Gill Gurveer S. , Liu Hongrui , Suh Yeon , Guignard Louisa , Pyczek Joanna , John Cini , Mah Laura K. , Rajwani Jahanara , Louie Taye , Ellestad Kristofer K. , Evseev Danyel , Turk Madison , Benaoudia Sacha , Alex Jonathan , Naumenko Victor , Manoharan Varsha Thoppey , Mehrabadi Mobina Kazemi , Smith Harmony A. , Gilbert Geneece N.Y. , Narta Kiran , Gilmour Aaron , Verhey Ted B. , Todesco Hayley M. , Osz Katalin , Ahn Bo-Young , Bogossian Ana , Anderson Colleen , Bismar Tarek A. , Heng Daniel Y.C. , Lawson Keith , Lineham Marston , Pedersen Haley , Gordon Paul , McIntyre John B. , MacGregor John , Brodeur-Robb Kathy , Difranscesco Lisa M. , Ogilvie Travis , Schoffski Patrick , Wozniak Agnieszka , Holt Robert A. , Bell John , Senger Donna , Lewis Victor , Monument Michael , Potts Kyle , Trpkov Kiril , Hay Kevin , Quizi Jennifer , Chan Jennifer , Saleh Ramy , Henning Jan Willem , Prokopishyn Nicole , Morrissy A. Sorana , Shafey Mona , Mahoney Douglas J.
Published: February 2025

CAR T therapy for solid tumors is limited by a lack of safe and uniformly expressed cell-surface targets. Here, we identify the MiT fusion-driven protein GPNMB as being highly, homogeneously, and stably expressed in primary and relapsed translocation-positive alveolar soft part sarcoma (ASPS) and renal cell carcinoma (tRCC). We developed a GPNMB-targeting CAR T therapy called GCAR1 that shows activity against patient-matched cells, organoids and xenograft models. First-in-human treatment of a patient with metastatic ASPS was well tolerated and generated stable disease until 6 months, with many non-target lesions resolving post-treatment. A polyclonal population of GCAR1 cells expanded in blood and were detectable until 6 months. Spatial transcriptomics revealed multiple immunosuppressive niches in proximity to T cells infiltrating a treatment-resistant lesion, and PDL1 blockade showed synergy with GCAR1 in a xenograft model. Our data provide clinical evidence for treating solid tumors with CAR T cells targeting a surface protein driven by an oncogenic gene fusion.
Transmission ofStaphylococcus aureusin the neonatal intensive care unit predicts invasive infection
Authors: She Qianxuan , Srinivasan Lakshmi , Theiller Erin , Galis Bianca E. , Napper T’Nia , Feder Andries , Arvanitis Alex , Jones Steven M. , Hayes Ericka , Puopolo Karen M. , Baldassano Robert N. , David Michael Z. , Coffin Susan E. , Gibbs Kathleen A. , Smith Kenneth , Harris Rebecca M. , Zackular Joseph P. , Moustafa Ahmed M. , Planet Paul J.
Published: February 2025

Background

Staphylococcus aureusis a leading cause of healthcare-associated infection and is one of the most common pathogens causing serious invasive infection in the neonatal intensive care unit (NICU). Asymptomatic colonization byS. aureuspresents a significant risk for subsequent infection of the colonized infant and for patient-to-patient transmission. Transmission of more virulentS. aureusstrains in the NICU could increase infection risk in this vulnerable population.

Methods

We performed a three-year, unit-wide screening forS. aureusin the Children’s Hospital of Philadelphia (CHOP) NICU, with whole genome sequencing (WGS) of 1,670 isolates from patient colonization surveillance, blood cultures from both NICU and non-NICU patients, and environmental surfaces. We used comparative genomic epidemiological approaches to investigate the transmission dynamics ofS. aureusin the NICU setting.

Findings

Our analyses revealed 490 unique strains with multiple, highly related, clones among NICUS. aureusgenomes. We identified sixty-nine transmission clusters, of which 87% (60/69) were methicillin susceptibleS. aureus(MSSA), and 28% (19/69) included isolates from both colonizing sites and bacteremia. The largest invasive cluster persisted over 2 years, involved 30 infants, and caused 4 cases of bacteremia. Spatial and temporal epidemiological links were found in 88% of clusters, and suggest that shared spaces served as the predominant means of transmission in the NICU setting. NICU environmental surveillance revealedS. aureuson surfaces; 3 of these isolates were also identified in colonizing and invasive clusters, suggesting potential environmental reservoirs. Remarkably, transmission clusters with both colonizing and invasive isolates were associated with higher rates of transmission, suggesting that specific transmission clusters pose a significantly higher risk for invasive infections in the NICU.

Interpretations

Genomic temporal-spatial epidemiologic analyses revealed high levels ofS. aureustransmission in the NICU with multiple transmission clusters that persisted over long periods of time. Our findings demonstrate a strong association amongst colonization, transmission, and the development of invasive infections, underscoring the importance of targeted measures to preventS. aureusinfections in the NICU setting.

Funding

This work was supported by the Center for Microbial Medicine, Microbial Archive and Cryocollection and the Research Institute (CLABSI Innovation and OMICS Initiative) at CHOP.
Characterization of p53 p.T253I as a pathogenic mutation underlying Li-Fraumeni Syndrome
Authors: Holcomb Nathaniel Charles , Harrington Amanda A , Pu Hong A , Halilovic Berina August , Shelman Nathan A , Zhang Shulin A , Sears Catherine A , Armstrong Terra A , Shelton Brent A , Corum Lauren A , D'Orazio John August
Published: February 2025

We identified a germline TP53 c.758C>T (p.T253I) mutation in the TP53 tumor suppressor gene in a pediatric adrenocortical carcinoma (ACC) patient. Characteristic to pathogenic p53 mutations, we observed upregulation of total p53 protein levels in the patient’s ACC and concurrent suppression of the wild-type (WT) TP53 allele. As ACC can be associated with Li-Fraumeni Syndrome (LFS) and the mutation has not yet been linked to LFS, we sought to characterize the functionality of the T253I mutation. We acquired p53-/- HEK293 cells and stably transduced them with GFP-tagged wild type (T253) or T253I p53 as well as two established pathogenic p53 mutants (C176Y and R213X). Compared to p53 WT, levels of T253I p53 increased while MDM2 levels decreased, suggesting a loss of MDM2-mediated regulation of T253I p53. Additionally, T253I showed a reduction in DNA damage responsive events, diminished DNA binding capabilities, and blunted transactivation capacity. These experimental data lead us to conclude that T253I represents a pathologic variant in TP53 that may predispose to LFS-associated tumors.
Protein-based tools for the detection and characterisation of Oropouche virus infection
Authors: Merchant Monique K. , de Paula Souza Juliano , Abdelkarim Sahar , Chakraborty Shrestha , Nasser Tufi A. , Gutierrez Manchay Kristel I. , de Melo Jorge Daniel M. , Alves do Nascimento Valdinete , Sun Yuxian , Caroe Eve R. , Eyssen Lauren E.A. , Rudd Jared S. , Ribeiro Piauilino Isa C. , Damasceno Pinto Sergio , Pereira da Silva Matheus H. , Rocha do Nasciemento Felipe , Gomes Naveca Filipe , Proenca Modena Jose L. , daSilva Luis L.P. , Pinto de Figueiredo Regina M. , Owens Raymond J. , Arruda Eurico , Graham Stephen C.
Published: February 2025

Oropouche fever is a neglected tropical viral disease endemic to Latin America and the Caribbean. Oropouche fever is caused by Oropouche virus (OROV), an orthobunyavirus with a tri-segmented (-)ssRNA genome. A recent epidemic caused by a novel reassortant has seen the first recorded deaths from OROV infection and reports of vertical transmission, affecting individuals across a dramatically expanded geographical range. Despite its importance as an emerging pathogen, research into OROV infection is hampered by paucity of available tools for serology and molecular virology. We have purified high-quality recombinant OROV nucleoprotein and the spike region of the viral surface glycoprotein Gc. We have used these antigens in indirect ELISA to detect seroconversion following experimental infection of animals, confirming their antigenic authenticity. These antigens stimulate the production of high neutralizing antibody titres in animals, highlighting their promise as immunogens for vaccination. We generated nanobodies that recognize both recombinant and infection-derived OROV antigens and developed a sandwich ELISA assay that can detect OROV antigens in human clinical serum samples with high efficiency. We have also shown that recombinant nanobodies directed against OROV Gc spike can potently neutralise infection by both historical OROV strains and the newly emerged reassortant. These protein-based reagents will accelerate OROV research and highlight the utility of protein-based tools for future OROV vaccines and point-of-care diagnostic devices.
Genotype-First Assessment of Presentation and Penetrance of Neurofibromatosis Type 1, Autosomal Dominant Polycystic Kidney Disease, and Marfan Syndrome Within the All of Us Research Program Cohort
Authors: Felker Stephanie A , Korf Bruce , Barsh Greg S
Published: February 2025

Purpose Phenotype-based ascertainment of probands in studies of Mendelian disorders may exclude individuals with mild phenotypes or that lack health care access. We explore this premise in All of Us Research Program participants with pathogenic variation causal for three Mendelian conditions: autosomal dominant polycystic kidney disease (ADPKD), Marfan syndrome, and neurofibromatosis type 1 (NF1). Methods We identified All of Us Research Program participants with putatively pathogenic variation in NF1, FBN1, PKD1, and PKD2. Concept terms were extracted from electronic health records to assess participant diagnosis and phenotype. Variant annotation and participant surveys were evaluated to identify biological and social factors differentiating diagnosed and undiagnosed individuals. Results Large proportions of individuals with pathogenic variation in NF1, FBN1, or PKD1/PKD2 lack the associated diagnosis of NF1 (47%), Marfan syndrome (58%), or ADPKD (51%), respectively. Pathogenic variants in diagnosed individuals have greater inferred deleteriousness for NF1 and ADPKD, and undiagnosed individuals had less severe phenotypes compared to diagnosed individuals for all three conditions. Conclusion A genotype-first ascertainment of individuals in genomic research allows for a more comprehensive assessment of Mendelian disease and removes biases that confound our understanding of the penetrance and presentation of these conditions.
PREVALENCE, PATTERN, AND CORRELATES OF DEPRESSION AMONG DRUG-SUSCEPTIBLE TUBERCULOSIS PATIENT ENROLLEES IN OGBOMOSO, OYO STATE: A CROSS-SECTIONAL STUDY
Authors: olarewaju sunday olakunle , Adeyemo Sunday Charles , Kayode Ayomide Timilehin , Ayinmodu Janet Oluwaseyi , Oladeji Olushina Ololade , Odedele John Temitayo , Olaniyan Doyin Victoria , Oyedeji Oluwatoba Jeremiah , Abdulsalam Zainab Adedamola , Olabode Eniola Dorcas , Ajayi Ayodele Raphael
Published: February 2025

Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis is still one of the leading public health problems, despite advances in the effort to reduce its incidence, morbidity, and mortality. Studies have shown that the prevalence of depression correlated with the severity and duration of tuberculosis. Therefore this study aims to find out the prevalence and pattern of depression among drug-susceptible TB patients to improve treatment outcomes and thereby reduce morbidity and mortality from the disease. The study was a cross-sectional hospital-based survey. Sample size of 333 respondents was calculated using Leslie Fischer's formula (n= z2pq /d2). A multistage sampling technique was used to select respondents. Data was collected using a pre-tested semi-structured questionnaire and analyzed using Statistical Package for Social Sciences (SPSS) version 20. Descriptive analysis was done or all variables. Bivariate and multivariate analysis was done using chi-square and binomial regression respectively. The level of significance is set with a p-value less than 0.05. More than half of the respondents (186, 55.9%) of the respondents were depressed. The majority (122, 65.5%) of respondents had mild depression, 46 (24.7%) had moderate depression while 18(9.7%) had moderately severe depression. Sex, marital status, level of education and average monthly income were significantly associated with depression status at bivariate level. Multivariate analysis revealed that respondents with no formal education were 6 times less likely to develop depression (AOR = 0.175, P = 0.001). Respondents with Primary level of education were 2 times less likely to develop depression (AOR = 0.427, P = 0.023). Respondents with Secondary level of education were 3 times less likely to develop depression compared to Tertiary level of education. Respondents living with HIV were 35 times more likely to develop depression (AOR = 35.303, P = 0.017) compared to those who were HIV negative.
Process Evaluation for the Delivery of a Water, Sanitation and Hygiene Mobile Health Program: Randomized Controlled Trial of the PICHA7 Mobile Health Program
Authors: Sanvura Presence , Endres Kelly , Bisimwa Jean-Claude , Perin Jamie , Cikomola Cirhuza , Bengehya Justin , Maheshe Ghislain , Mwishingo Alain , Bisimwa Lucien , Williams Camille , George Christine Marie
Published: February 2025

Background: In the Democratic Republic of the Congo (DRC) there are over 85 million diarrhea episodes annually. Effective and scalable water, sanitation, and hygiene (WASH) interventions are urgently needed to reduce diarrheal diseases in the DRC. Mobile health (mHealth) reminders on public health information have been shown to reduce disease morbidity and increase health-protective behaviors. Therefore, WASH mHealth programs present a promising approach to improve WASH behaviors. The Preventative-Intervention-for-Cholera-for-7-days (PICHA7) program is a targeted WASH intervention using a combination of mHealth and in-person visits delivered to diarrhea patient households in DRC to reduce diarrheal diseases. Methods: During the randomized controlled trial (RCT) of PICHA7, 1196 participants received weekly voice, interactive voice response (IVR) quiz, and text messages from the PICHA7 mHealth program over the 12-month program period. Outcome indicators included % of unique text, voice, and IVR messages received (fidelity) and % of unique messages fully listened to (dose) assessed using the engageSPARK mobile message platform, and program reach to households assessed through monthly follow-up visits. Results: Overall, 84% of program households received unique text messages and 90% of unique voice and IVR messages were answered. Program households reported receiving a PICHA7 mHealth message in the past two weeks at 72% of surveillance visits (844/1177). Seventy-four percent (309/418) of participants reported sharing a PICHA7 mHealth message with another person at least once during the study period. Conclusion: These findings show high fidelity, dose, and reach of mobile message delivery in the PICHA7 mHealth program. This study demonstrates the feasibility of delivering the PICHA7 mHealth program in eastern DRC and provides important insights for delivering WASH mHealth programing in low- and middle-income countries globally.
SEEDNet: Covariate-free multi-country settlement-level epidemiological estimates datasets for network analysis
Authors: Darooneh Amir Hossein , Kortenaar Jean-Luc , Goulart Céline M. , McLaughlin Katie , Cornelius Sean P. , Bassani Diego G.
Published: February 2025

The study of population health through network science holds high promise, but data sources that allow complete representation of populations are limited in low-and middle-income countries. Large national health surveys designed to gather nationally representative health and development data are promising data sources but are not designed to produce small-area estimates of health indicators. Methods for producing these from national surveys tend to rely on varied covariate data sources and are computationally demanding, limiting their use for network representations of populations. To reduce the sources of measurement error and allow efficient multi-country representation of populations as networks of human settlements here, we present SEEDNet (Settlement-level Epidemiological Estimates Datasets for Network Analysis)1, a data library of multi-country representations of population health across human settlements. Our covariate-free method uses georeferenced national surveys to produce SAEs of health indicators through local inverse-distance weighted interpolation and includes an algorithm for the comprehensive identification of population settlements of all sizes across the globe. Our estimates are cross-validated against those obtained using a Bayesian Geostatistical Model. The method is fully automated, requiring a single standard georeferenced survey data source for mapping populations, eliminating the need for indicator or country-specific covariate selection by investigators. Computational efficiency is achieved by restricting computation to human-occupied areas and by adopting a logical aggregation of estimates into the complete range of settlement sizes. Standardized georeferenced settlement-level datasets for 15 indicators and 10 countries were validated in this paper, as well as the novel method to identify settlements. SEEDNet1is a specialized library of nodes that can serve as a basis for network representations of population health in low-and middle-income countries.
Characterizing the Short- and Long-Term Temporal Dynamics of Antibody Responses to Influenza Vaccination
Authors: Lane Aaron , Quach Huy Q. , Ovsyannikova Inna G. , Kennedy Richard B. , Ross Ted M. , Einav Tal
Published: February 2025

Most influenza vaccine studies evaluate acute antibody responses 1 month post-vaccination, leaving long-term immunity poorly understood. Here, we performed a combined analysis of 14 large-scale vaccine studies and conducted two new studies mapping antibody responses in high resolution from their inception out to 1 year post-vaccination. Vaccine antibody responses were classified as weak (<4x fold-change at 1 month and 1 year), transient (≥4x at 1 month, <4x at 1 year), or durable (≥4x at 1 month and 1 year). Surprisingly, >50% of vaccine recipients were weak across seasons, age groups, sexes, pre-vaccination titers, and high or standard vaccine doses. Peak fold-change at 1 month post-vaccination was strongly associated with the long-term response, with most transient responders achieving a maximum fold-change of 4x, while most durable responders reached ≥16x, with both groups maintaining these titers for 2 months (10-75 days post-vaccination). Using the weak, transient, and durable trajectories, a single time point early in the response (days 7-8 or 21) predicted an individual's response out to 1 year post-vaccination. These results demonstrate that influenza vaccine responses range from little-to-no response to eliciting strong-and-durable immunity, highlighting the stark heterogeneity that is consistently seen across influenza seasons.
Accuracy of pattern-based dementia diagnostic protocols: Using longitudinal data to infer etiology of Alzheimer's disease and related dementia as compared to stroke or normal aging
Authors: Clouston Sean , Hanes Douglas W. , Danesh Yazdi Mahdieh
Published: February 2025

Introduction: The goal of this study was to compare accuracy for pattern-recognition protocols to prospectively identify dementia due to Alzheimer's disease and related dementias (ADRD) or stroke. Methods We used data from cognitively unimpaired respondents who completed at least 5 cognitive assessments during waves 3-12 of the Health and Retirement Study (HRS), a longitudinal study of older US residents. Participants were assessed at wave 12 (in 2019) for cognitive status. Patterns of participants' cognitive decline were analyzed to differentially identify ADRD and stroke and were compared against self-reported and objective diagnoses of amnestic, executive, and multidomain mild cognitive impairment (MCI) and ADRD. We reported sensitivity/specificity to detect new-onset dementia at the final wave of observation. Results: After applying inclusion/exclusion criteria, 43 (1.69%) of cognitively unimpaired participants developed dementia, while 165 (6.49%) developed amnestic MCI. Patterns of cognitive decline consistent with ADRD affected 372 (14.6%) of respondents, while patterns of cognitive decline consistent with stroke were evident in 917 (36.1%) participants. ADRD-consistent cognitive declines were evident in 75.8% and 76.7% cases of amnestic MCI and dementia, respectively, though only 24.5% reported receiving a clinical diagnosis of dementia. Sensitivity/Specificity of ADRD was 94.3%/87.0% when detecting dementia without stroke. Discussion: This study implies that we can reliably use longitudinal patterns of cognitive decline to differentially diagnose ADRD from Stroke in most participants with dementia.
Enhancing Brain Age Estimation Under Uncertainty: A Spectral-normalized Neural Gaussian Process Approach Utilizing 2.5D Slicing
Authors: Linli Zeqiang , Liang Xingcheng , Zhang Zhenhua , Hu Kang , Guo Shuixia
Published: February 2025

Brain age gap, the difference between estimated brain age and chronological age via magnetic resonance imaging, has emerged as a pivotal biomarker in the detection of brain abnormalities. While deep learning is accurate in estimating brain age, the absence of uncertainty estimation may pose risks in clinical use. Moreover, current 3D brain age models are intricate, and using 2D slices hinders comprehensive dimensional data integration. Here, we introduced Spectral-normalized Neural Gaussian Process (SNGP) accompanied by 2.5D slice approach for seamless uncertainty integration in a single network with low computational expenses, and extra dimensional data integration without added model complexity. Subsequently, we compared different deep learning methods for estimating brain age uncertainty via the Pearson correlation coefficient, a metric that helps circumvent systematic underestimation of uncertainty during training. SNGP shows excellent uncertainty estimation and generalization on a dataset of 11 public datasets (N=6327), with competitive predictive performance (MAE=2.95). Besides, SNGP demonstrates superior generalization performance (MAE=3.47) on an independent validation set (N=301). Additionally, we conducted five controlled experiments to validate our method. Firstly, uncertainty adjustment in brain age estimation improved the detection of accelerated brain aging in adolescents with ADHD, with a 38% increase in effect size after adjustment. Secondly, the SNGP model exhibited OOD detection capabilities, showing significant differences in uncertainty across Asian and non-Asian datasets. Thirdly, the performance of DenseNet as a backbone for SNGP was slightly better than ResNeXt, attributed to DenseNet’s feature reuse capability, with robust generalization on an independent validation set. Fourthly, site effect harmonization led to a decline in model performance, consistent with previous studies. Finally, the 2.5D slice approach significantly outperformed 2D methods, improving model performance without increasing network complexity. In conclusion, we present a cost-effective method for estimating brain age with uncertainty, utilizing 2.5D slicing for enhanced performance, showcasing promise for clinical applications.
Impact of washout duration to account for left truncation in register-based epidemiological studies: a case study on estimating the risk of mental disorders
Authors: Plana-Ripoll Oleguer , Momen Natalie C. , Gallego-Alabanda Didac , Chen Danni , Hansen Stefan Nygaard , Gomez Melis Guadalupe , Pedersen Carsten Bocker , Agerbo Esben
Published: February 2025

Background Washout periods can identify and exclude prevalent cases from analyses based on administrative registers with left truncation, but the impact of washout duration on estimates is unknown. We estimated risks of clinically-diagnosed mental disorders according to different washout period durations. Methods Population-based cohort including all 6,478,162 individuals aged 1-80 years living in Denmark in 2010-2021. Using hospital contacts in 2010-2021, we estimated age-specific incidence rates and cumulative incidence of mental disorders according to different washout period durations (0, 1, 2, 5, 15, and 41 years) based on hospital contacts prior to 2010. Results Without a washout period, the lifetime cumulative incidence of any mental disorder was 49.4% (95% CI: 49.2%-49.5%) for females and 45.1% (95% CI: 45.0%-45.2%) for males. For each increase in the duration of the washout period to identify and exclude prevalent cases, estimates decreased, reaching a lifetime incidence of 40.3% (95% CI: 40.1%-40.4%) for females and 36.6% (95% CI: 36.5%-36.8%) for males when using all available data (41 years of washout). Without a washout period, estimates for specific mental disorder types were up to 60% higher than those obtained with the maximum washout period, but the bias in absolute terms depended on the underlying risks. Conclusions Our study is the first to quantify the potential biases related to prevalent cases being incorrectly considered as incident cases. While including all cases identifiable in a register may decrease uncertainty, the inclusion of prevalent cases as being at risk may lead to substantially overestimated measures. We highlight the need for caution when using data sources in which there is left truncation, like administrative registers and electronic healthcare databases.
TEAD inhibition alters the lung immune microenvironment and attenuates metastasis.
Authors: Sharif Ghada M , Rahhal Raneen , Schmidt Marcel O , Moussa Maha , Asemi Tina , Battina Rohith , Kiliti Amber , Riegel Anna T , Wellstein Anton
Published: February 2025

The Hippo pathway signaling mediated through YAP/TAZ, and the transcription factor TEAD is known to be involved in primary tumor progression. Here we report that novel TEAD inhibitors (iTEAD) currently in clinical trials, cause a significant reduction in the outgrowth of lung metastases from triple negative breast cancer (TNBC) models mediated predominantly through changes in stromal immune signaling. TEAD inhibition did not affect the proliferation of TNBC cancer cells in vitro or the growth of the primary tumor in vivo. In normal mice that were treated with iTEAD in the absence of tumors, the lungs showed a decrease in pro-tumor inflammatory pathways. However, the IL12 signaling pathway was enhanced and its production from isolated lung tissue resident macrophages, but not bone marrow derived macrophages, was elevated. In syngeneic TNBC mouse models, inhibition of TEAD suppressed pro-tumor inflammation and the M2-like macrophage phenotype in lung tissues, and increased the infiltration of CD8+ T cells into the lung as well as Th1 CD4+ T cells, restoring an immune responsive microenvironment. iTEAD-treated T cells showed enhanced cytotoxicity and degranulation when co-cultured with cancer cells via increased IL-2 activity. Furthermore, TEAD inhibition or knockdown, enhanced T-cell macrophage crosstalk and anti-tumor activity in 3D tumorspheres which was reversed by IL12 neutralizing antibodies. Our data supports a multifaceted model of TEAD inhibition on the innate and adaptive immune cells as they respond to tumor cell signals and reveals an important stromal phenotype by which TEAD inhibitors could reverse immune suppression and eliminate seeded metastases in the lungs.
Co-optation of Transcription Factors Drives Evolution of Quantitative Disease Resistance Against a Necrotrophic Pathogen.
Authors: Einspanier Severin , Tominello-Ramirez Christopher , Delplace Florent , Stam Remco
Published: February 2025

Wild relatives of crop species possess diverse levels of quantitative disease resistance (QDR) to biotic stresses, yet the genomic and regulatory mechanisms underlying these differences are poorly understood. In particular, how QDR against a generalist necrotrophic pathogen evolved and whether it is driven by conserved or species-specific regulatory networks remains unclear. Here, we examined the transcriptomic responses of five diverse wild tomato species that span a gradient of QDR. We initially hypothesised that conserved regulatory modules might control QDR. Instead, we use differential gene expression analysis and weighted gene co-expression network analysis (WGCNA) to find that species-specific regulatory features, encompassing both infection-induced and constitutively expressed genes, predominantly shape QDR levels. Although we identified an ethylene response factor among candidate genes for QDR-regulation, it did not fully account for the phenotypic variation. To further dissect the evolutionary basis of these regulatory patterns, we performed phylotranscriptomic analyses on gene regulatory networks. Notably, our findings reveal that the conserved NAC transcription factor 29 is pivotal in developing disease resistance only in S. pennellii. The differential regulation and altered downstream signalling pathways of NAC29 provide evidence for its co-option in the resistance mechanisms of S. pennellii. This finding highlights the species-specific rewiring of gene regulatory networks by repurposing a conserved regulatory element to enhance resistance against pathogens effectively. These results offer new insights into the evolutionary and regulatory complexity underlying QDR and emphasise the significance of species-specific gene regulation in shaping resistance against a cosmopolitan necrotrophic pathogen.
Rainwash eDNA to monitor tropical rainforest biodiversity
Authors: Zinger Lucie , Benoiston Anne-Sophie , Cuenot Yves , Leroy Celine , Louisanna Eliane , Moreau Lucie , Petitclerc Frederic , Piatscheck Finn , Orivel Jerome , Richard-Hansen Cecile , Hansen-Chaffard Lou , Troispoux Valerie , Boyer Frederic , Chave Jerome , Decaens Thibaud , Fouquet Antoine , Pansu Johan , Raynaud Jeremy , Rougerie Rodolphe , Sire Lucas , Schimann Heidy , Taberlet Pierre , Iribar Amaia
Published: February 2025

Tropical rainforests are vital for global biogeochemical cycles and human well-being and shelter a tremendous, unique, yet underexplored reservoir of biodiversity. With the increasing pressures they face, including deforestation, biological invasions, and climate change, improving methods to monitor their biodiversity is now a pressing societal demand. In recent years, the amplification and sequencing of taxonomically-informative DNA fragments from environmental samples (i.e. eDNA) has revolutionised biomonitoring. Soil, invertebrates bulk, marine and freshwater, or even air, are commonly sampled environmental matrices for such purposes, but present several caveats for the sampling of terrestrial aboveground biodiversity. Here, we explore the potential of DNA contained in rainwash water collected below the forest canopy. We show that it contains not only DNA from invertebrates, but also from the many plants and vertebrates that thrive in the forest canopy. By sampling rainwash eDNA in two 1ha-plots from a tree plantation, and an old-growth Amazonian forest, we detected 170 plant taxa, mainly trees, 72 vertebrate taxa mainly consisting of mammals, birds, and amphibians, and 313 insect taxa including mosquitoes, ants, beetles, etc. The taxonomic composition retrieved in these two plots reflected their different disturbance status. Rainwash eDNA can be efficiently collected passively and persists over ten days while providing a local picture of the diversity. These criteria are compatible with field and environmental management constraints, making the approach promising for an efficient, cost-effective large-scale biomonitoring of tropical rainforest, and more generally all forest canopies.
Copper supplementation mitigates Parkinson-like wild-type SOD1 pathology and nigrostriatal degeneration in a novel mouse model
Authors: Rowlands Benjamin D , Trist Benjamin G , Karozis Conor , Schaffer Greta , Mor David , Harwood Richard , Rosolen Sarah A , Cottam Veronica , Persson-Carboni Freyja , Richardson Miriam , Li Anne A , Gotsbacher Michael P , Abdeen Amr H , Codd Rachel , Double Kay L
Published: February 2025

Wild-type superoxide dismutase 1 (disSOD1) protein misfolding and deposition is implicated in the death of substantia nigra (SN) dopamine neurons in Parkinson disease. Regionally reduced copper availability, and subsequent reduced copper binding to SOD1, is a key factor driving the development of this pathology, suggesting brain copper supplementation may constitute an effective means of preventing its formation. We evaluated the potential of the blood-brain-barrier-permeable copper delivery drug, CuATSM, to attenuate the misfolding and deposition of wild-type disSOD1, and associated neuron death, in a novel mouse model that expresses this pathology. Using proteomic and elemental mass spectrometry, together with biochemical and histological workflows, we demonstrated copper supplementation corrects altered post-translational modifications on soluble SOD1 and improves the enzymatic activity of the protein in the brains of these animals. These changes were associated with a significant reduction in disSOD1 pathology and preservation of dopamine neurons in the SN, which were highly correlated with tissue copper levels. These data position wild-type disSOD1 pathology as a novel drug target for Parkinson disease and suggest that brain copper supplementation may constitute an effective means of slowing SN dopamine neuron death in this disorder.
Focus-Tunable Two-Photon Fiberscope Enabling in vivo Imaging at Selected Depths
Authors: Liu Yuehan , Huang Jiayun Laurie , Li Xingde
Published: February 2025

Miniaturized two-photon imaging devices enable real-time in vivo and in situ imaging at subcellular resolution, highly valuable for clinical applications and basic research (such as neuroscience). However, achieving high-quality volumetric imaging at varying depths remains challenging. In this study, we demonstrated a 2P fiberscope capable of three-dimensional imaging over a cylindrical volume of a 350 μm diameter and a 400 μm depth. Depth scanning was achieved by incorporating a miniature electrowetting-based varioptic lens (VL) into a two-dimensional scanning 2P fiberscope, whose focus was tuned by modulating the VL drive voltage. The performance of the fiberscope was first characterized using phantoms and then demonstrated by ex vivo imaging of fluorescently stained convallaria and GFP mouse brain sections, as well as in vivo dynamic GCaMP-based calcium imaging of cortical neurons in an awake mouse.
Soluble immune checkpoints are dysregulated in patients with sickle cell disease and correlate with inflammatory mediators, autoantibodies, immune cell profiles, and clinical outcomes
Authors: Li Wei , Pucka Andrew Q , Houran Lina , Huang Xiaoqing , Debats Candice , Reyes Brandon , O'Brien Andrew RW , Yu Qigui , Wang Ying
Published: February 2025

Background: Sickle cell disease (SCD) is a chronic condition characterized by inflammation, immune dysregulation, and debilitating pain. Aim: This study investigates soluble immune checkpoints (sICPs) and their associations with inflammatory mediators, immune cell profiles, autoantibodies, and clinical outcomes in SCD. Method: Peripheral blood samples from 50 SCD patients and 40 demographic-matched healthy controls (HCs) were analyzed for 37 sICPs, 80 inflammatory mediators, and 18 autoantibodies using multiplex assays, alongside immune cell profiles via flow cytometry. Pain and quality of life (QoL) were assessed through patient-reported outcome measures (PROMs). Results: Twenty-three sICPs, including arginase-1, BTLA, CD27, CD28, CD47, CD80, CD96, CD134, CD137, CD152, GITR, HVEM, IDO, LAG-3, MICA, MICB, Nectin-2, PD-1, Siglec-7, Siglec-9, TIM-3, TIMD-4, and VISTA, were significantly elevated in SCD patients compared to HCs. These sICPs correlated with multiple proinflammatory mediators (e.g., IL-18), autoantibodies (e.g., MPO), and immune cell activation markers (e.g., CD38/HLA-DR on CD8 T cells). Notably, CD28, CD152, HVEM, and VISTA were strongly associated with systemic inflammation and immune cell activation, while BTLA, LAG-3, PD-1, and CD80 correlated with pain and anxiety scores and QoL. Conclusion: This study highlights complex interactions between sICPs, immune activation, inflammation, and clinical outcomes in SCD, underscoring their potential as biomarkers or therapeutic targets to alleviate inflammation and improve QoL in this challenging clinical population.
Accessibility and perceived quality of GP care for socioeconomically disadvantaged patients: a qualitative patient-centered interview study
Authors: Bijl Hannah A. , Zwinkels Dionne N. , van Linschoten Reinier C.A.
Published: February 2025

Introduction Patients with lower socioeconomic status (SES) in the Netherlands may face significant barriers to accessing and receiving general practitioner (GP) care. Factors such as lower health literacy, economic disadvantage, and cultural diversity contribute to these challenges, often leading to lower satisfaction and reduced access. This study investigates how patients with low SES perceive the accessibility and quality of GP care, with the goal of identifying ways to improve care for this vulnerable group. Methods This qualitative study used in-depth semi-structured interviews to explore how patients with low SES experience the accessibility and perceived quality of GP care. Data were analyzed using thematic analysis. Results A total of 16 patients were interviewed. Key themes emerged regarding accessibility and perceived quality of care. Patients highly valued quick access to appointments and multiple contact options. Digital healthcare tools were appreciated for their convenience, especially among younger and more educated patients. However, face-to-face interactions were universally preferred for serious health concerns. Effective communication and empathic care turned out to be crucial factors in shaping patient satisfaction. Lastly, the importance of continuity of care was emphasized, especially by patients with chronic conditions, who valued building strong rapports with their GP. Conclusion Our study found that quick access, multiple contact options, and clear communication are key drivers of patient satisfaction with GP care for patients with low SES. Emphasizing communication quality and empathetic care can significantly improve the perceived quality and accessibility of healthcare for vulnerable populations.
A Genomic Analysis of Usher Syndrome: Population-Scale Prevalence and Therapeutic Targets
Authors: Redfield Shelby E. , Mauriac Stephanie A. , Géléoc Gwenaëlle S. , Shearer A. Eliot
Published: February 2025

Usher syndrome (USH), the most common form of deaf-blindness, displays extensive genetic, allelic, and phenotypic heterogeneity. The dual sensory impairment associated with this disorder makes Usher syndrome an important target for gene therapy, with dozens of published preclinical studies targeting multiple USH genes and using multiple gene therapy strategies. Nine genes have been conclusively linked to Usher syndrome; however, data on prevalence and contribution of specific genetic variants is lacking. Such information is essential to choosing a favorable target gene or therapeutic approach during clinical trial design. Here, we used large genomic databases to systematically evaluate the genomics of Usher syndrome. We ascertained pathogenic USH variants from three clinical databases and determined the occurrence of these pathogenic USH variants within: (1) a publicly available dataset including worldwide populations (GnomAD), (2) a cohort of 3,888 children without hearing loss, and (3) 637 children with hearing loss. Results show significant variability in the frequency of USH variants by gene and genetic ancestry. 1% of control subjects carry a pathogenic USH variant. Pathogenic variants inUSH2Aare the most prevalent, at 1 in 150 individuals (0.0062). Calculated general population prevalence for all USH subtypes is 1 in ∼29,000, indicating that 30,405 individuals in the United States and 721,769 individuals worldwide are affected. We estimate that 324 babies in the United States and 12,090 worldwide are born with Usher syndrome each year. We identify key targets for genetic therapy based on population-level prevalence including a focus on alternatives to gene replacement therapies, specifically forUSH2A.
Clinical patterns in a neuroimaging-based predictive model of self-reported dissociation
Authors: Purcell Juliann B , Ren Boyu , Palermo Cori A , Bair Zoe A , Marr Mollie C , Modell Rebecca L , Pan Xi , Robinson Matthew A , Shanahan Meghan E , Swee Michaela B , Kaufman Milissa L , Lebois Lauren A. M.
Published: February 2025

Objective: Assessment of trauma-related dissociation has been historically challenging given its subjective nature and the lack of provider education around this topic. Recent work identified a promising neural biomarker of trauma-related dissociation, representing a significant step toward improved assessment and identification of dissociation. However, it is necessary to better understand clinical factors that may be associated with this biomarker. Method: Participants were 65 women with histories of childhood maltreatment, posttraumatic stress disorder (PTSD), and varying levels of dissociation (e.g., co-occurring dissociative identity disorder, DID). Data were drawn from a previously published work that identified a model predicting Multidimensional Inventory of Dissociation severe pathological dissociation scores on the basis of neural functional connectivity. Here, we conducted a k-means cluster analysis to explore patterns in results of the prediction model. We then investigated differences among the clusters in a range of clinically-relevant variables. Results: The clustering analysis identified four distinct groups. The functional connectivity model best predicted those at the low (cluster 1, 82% PTSD) and high (cluster 3, 86% DID) ends of the self-reported dissociation scale. Cluster 2 also largely included participants with DID (67%), but the predictive model was less accurate for these individuals. Follow up analyses revealed that DID participants in cluster 2 reported lower levels of self-state intrusions, a type of DID-specific dissociation, compared to those in cluster 3. Conclusions: The predictive performance of the functional connectivity biomarker is linked to DID-specific dissociation. This suggests that in the future functional connectivity signatures may improve accurate assessment of DID.
Can PowerPoint Save Lives? Assessment of Equity and Reach of Traditional Dissemination Channels in Geriatric Trauma Education - A Mixed-Methods Study using Digital Analytics
Authors: Moreno Ashley N. , Knight Ariel W. , Nelson Adam , Anderson Jessica , Kwak Min Ji , Reinhart Linda , Bongiovanni Tasce , Barsan Ilinca , Buck Caroline , Bandera Victoria , Adams Sasha D. , Joseph Bellal , Stein Deborah M. , Holmes Holly M. , Lewis Richard , Lagrone Lacey
Published: February 2025

ABSTRACT Background: Creation of resources for evidence-based clinical guidance does not necessarily improve patient outcomes without deliberate dissemination and implementation. We sought to better understand the effectiveness of pre-recorded didactics in improving knowledge as well as the reach of various information dissemination strategies. Methods: A mixed-methods study was conducted amongst all United States trauma care clinicians from March to August 2023. A 30-minute didactic video on anticoagulant management in geriatric traumatic brain injury (TBI), along with pre-and post-video knowledge surveys, was circulated via email, web, and social media accounts affiliated with 7 professional trauma societies as well as state and regional health departments. Digital analytics were captured, and descriptive and regression analyses conducted. Results: The didactic video was viewed 1,407 times on YouTube with a mean view time of 7 minutes. A total of 311 participants responded to the survey. Most were registered nurses (RNs) from urban, non-academic institutions with 11+ years of clinical experience. Only 16.1% of respondents correctly answered all pre-video knowledge questions (n=48/298); this increased to 51.6% post-video (n=94/182). Surgeons and advanced practice providers (APPs) (r=0.148, p<0.05), male respondents (r=0.131, p<0.05), and clinicians at higher-level trauma centers (r=-0.140, p<0.05) answered more pre-video questions correctly. With regard to general knowledge acquisition practices, surgeons and APPs were more likely than RNs to report primary use of literature (r=0.134, p<0.05) and point-of-care medical information (r=0.133, p<0.05). Conclusion: Viewing a recorded didactic was associated with improved knowledge of anticoagulation management in geriatric TBI. Trauma society-sponsored email is an effective means of information dissemination to urban, Level I/II trauma centers, but still fails to reach many rural and Level III/IV trauma centers. Given the low rate of correct pre-video answers and increase after viewing, further study is needed to better understand end-user needs to optimize dissemination and implementation of up-to-date clinical guidance.
Genomic basis of adaptation to serpentine soil in two Alyssum species shows convergence with Arabidopsis across 20 million years of divergence
Authors: Celestini Sonia , Duchoslav Milos , Nezamivand-Chegini Mahnaz , Gerchen Jorn , Sramkova Gabriela , Wijfjes Raul , Krejcova Anna , Kuzmanovic Nevena , Spaniel Stanislav , Schneeberger Korbinian , Yant Levi , Kolar Filip
Published: February 2025

Background and Aims Serpentine outcrops, characterized by low nutrient availability, high heavy metal concentrations, propensity to drought, and island-like distributions, offer valuable systems to study parallelisms in repeated adaptation to extreme environments. While shared phenotypic manifestation of adaptation to serpentine environments has been investigated in many species, it is still unclear whether there may be a common genetic basis underlying such responses. Here we assess local adaptation to serpentine soil and infer the parallel genetic signatures of local adaptation to serpentine environments in two thus far unexplored closely related species, Alyssum gmelinii and Alyssum spruneri (Brassicaceae). Then we measure gene- and function-level convergence with the previously explored Arabidopsis arenosa, to reveal candidate shared adaptive strategies within Brassicaceae. Methods We tested for adaptation using a reciprocal substrate-transplant experiment in A. gmelinii. Then, after assembling a reference genome, we generated population-level sequencing data of four population pairs and performed genome scans for directional selection to infer serpentine adaptive candidate genes in Alyssum. Finally, we compared candidate gene lists with those inferred in similar experiments in Arabidopsis arenosa and used protein-protein interaction networks to discern functional convergence in serpentine adaptation. Key Results Independent colonization of serpentine environments by Alyssum populations is associated with footprints of selection on genes related to ion transport and homeostasis, nutrient and water uptake, and life-history traits related to germination and reproduction. Reciprocal transplant experiments demonstrated that adapted plants germinate sooner and exhibit better growth in serpentine conditions while excluding heavy metals and increasing Ca uptake in their tissues. Finally, a significant fraction of such genes and molecular pathways is shared with Arabidopsis arenosa. Conclusions We show that genetic adaptation to the multi-factorial challenge imposed by serpentine environments involves key pathways that are shared not only between closely related species, but also between Brassicaceae tribes of ~20 Mya divergence.