bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Digital Diagnostic Pathway for Heart Failure: an economic evaluation
Authors: Mcmeekin Nicola , Davies Andrew , Petrie Mark C , Campbell Ross T , Lowe David J , Murphy Clare L , Macklin Leeanne , Brooksbank Katriona , Wu Olivia 
Published: November 2024

AbstractEarly diagnosis of heart failure improves patient outcomes, however diagnosis is complex and often delayed. This study evaluates a digital pathway for heart failure diagnosis, showing it reduces time to diagnosis and treatment initiation, with an incremental cost of £5,700 per quality adjusted life-year (QALY) gained over a lifetime. The pathway is cost-effective for the UK National Health Service at £20,000 per QALY threshold, however data uncertainties remain.NPJ digital health 3000-4000 word limit plus abstract 70 words no sub-headings
A confounder debiasing method for RCT-like comparability enables Machine Learning-based personalization of survival benefit in living donor liver transplantation
Authors: Gangadhar Anirudh , Hasjim Bima J. , Zhao Xun , Sun Yingji , Chon Joseph , Sidhu Aman , Jaeckel Elmar , Selzner Nazia , Cattral Mark S. , Sayed Blayne A. , Brudno Michael , McIntosh Chris , Bhat Mamatha 
Published: November 2024

AbstractMany clinical questions in medicine cannot be answered through randomized controlled trials (RCTs) due to ethical or feasibility constraints. In such cases, observational data is often the only available resource for evaluating treatment effects. To address this challenge, we have developed Decision Path Similarity Matching (DPSM), a novel machine learning (ML)-based algorithm that simulates RCT-like conditions to debias observational data. In this study, we apply DPSM to the clinical question of living donor liver transplantation (LDLT) versus deceased donor liver transplantation (DDLT), helping to identify which patients benefit most from LDLT. DPSM leverages decision paths from a Random Forest classifier to perform accurate, one-to-one matching between LDLT and DDLT recipients, minimizing confounding while retaining interpretability. Using data from the Scientific Registry of Transplant Recipients (SRTR), including 4,473 LDLT and 68,108 DDLT patients transplanted between 2002 and 2023, we trained independent Random Survival Forest (RSF) models on the matched cohorts to predict post-transplant survival. DPSM successfully reduced confounding associations between the two groups as shown by a decrease in area under the receiver operating characteristic (AUROC) from 0.82 to 0.51. Subsequently, RSF (C-indexldlt=0.67, C-indexddlt=0.74) outperformed the traditional Cox model (C-indexldlt=0.57, C-indexddlt=0.65). The predicted 10-year mean survival gain was 10.3% (SD = 5.7%). In conclusion, DPSM provides an effective approach for creating RCT-like comparability from observational data, enabling personalized survival predictions. By leveraging real-world data where RCTs are impractical, this method offers clinicians a tool for transitioning from population-level evidence to more nuanced, personalization.
In situ pressure modulation measurements by video capillaroscopy reveal capillary stiffening and reduced reactivity with age
Authors: Forst Marcus L. , Rincon Gabriela , Levy Juliette H. , Cornfield David N , Quake Stephen R 
Published: November 2024

AbstractUnderstanding tissue degradation with age and disease requires a clear picture of capillary function, but the small size of capillaries makes them difficult to model, perturb, and image. To measure capillary reactivity and stiffness, we recorded videos of nailbed capillaries while applying increasing external pressure to the finger. Combining the velocities at each pressure into participant velocity distributions showed that participants aged fifty and over (n=19) had a significantly higher median velocity than participants under fifty (n=16), whereas the effects of sex and blood pressure were insignificant. Notably, the effects of age were independent of blood pressure, suggesting that this method probes a different aspect of vascular health. Calculating dissimilarity using the earth-mover’s distance between individual and population velocity distributions classified age groups above and below fifty with an AUC of 0.79±0.07. These findings show that pressure-applying video capillaroscopy can measure the effects of capillary stiffening with age and interrogate how individual capillaries respond to the slowing and stopping of blood flow—suggesting that this method could be used to diagnose and evaluate vascular diseases in the future.
Role of Arginine and its Metabolism in TGF-β-Induced Activation of Lung Fibroblasts
Authors: Hamanaka Robert B , Shin Kun Woo D , Atalay M Volkan , Cetin-Atalay Rengul , Shah Hardik , Houpy Szafran Jennifer C , Woods Parker S , Meliton Angelo Y , Shamaa Obada R , Tian Yufeng , Cho Takugo , Mutlu Gökhan M. 
Published: November 2024

AbstractArginine is a conditionally essential amino acid with known roles in protein production, nitric oxide synthesis, biosynthesis of proline and polyamines, and regulation of intracellular signaling pathways. Arginine biosynthesis and catabolism have been linked to TGF-β-induced activation of fibroblasts in the context of pulmonary fibrosis; however, a thorough study on the metabolic and signaling roles of arginine in the process of fibroblast activation has not been conducted. Here, we used metabolic dropouts and labeling strategies to determine how activated fibroblasts utilize arginine. We found that arginine limitation leads to activation of GCN2 while inhibiting TGF-β-induced mTORC1 activation and collagen protein production. Extracellular citrulline could rescue the effect of arginine deprivation in an ASS1-dependent manner. Using metabolic tracers of arginine and its precursors, we found little evidence of arginine synthesis or catabolism in lung fibroblasts treated with TGF-β. Extracellular ornithine or glutamine were the primary sources of ornithine and polyamines, not arginine. Our findings suggest that the major role for arginine in lung fibroblasts is for charging of arginyl-tRNAs and for promotion of mTOR signaling.Highlights-Arginine depletion inhibits TGF-β-induced transcription in human lung fibroblasts (HLFs).-Arginine is not significantly catabolized in HLFs either through NOS or ARG dependent pathways.-Extracellular glutamine and ornithine are the primary sources of polyamines in lung fibroblasts.-The primary role of arginine in lung fibroblasts is for signaling through mTOR and GNC2.
Evidences that host genetic background more than the environment shapes the microbiota of the snailBulinus truncatus, an intermediate host ofSchistosomaspecies
Authors: Jaquet Mathilde J. , Douchet Philippe , Toulza Eve , Lefevre Thierry , Senghor Bruno , Boissier Jérôme , Lepais Olivier , Chancerel Emilie , Gourbal Benjamin , Rey Olivier 
Published: November 2024

AbstractMicrobiota are increasingly recognized as key players in regulating host biological functions, influencing both the ecology and evolution of organisms. However, the factors shaping microbiota diversity and structure in natural environments remain underexplored, especially the relative importance of host genetics versus environmental factors. In this study, we address this gap using the freshwater snailBulinus truncatus, an intermediate host for some human and animalSchistosomaparasites, as a model species. We developed 31 new microsatellite markers to assess the population structure ofB. truncatusacross 9 sites in Senegal. We then applied metabarcoding to characterize the diversity and structure of individual snail bacterial microbiota and environmental communities associated with each sampling site using environmental DNA. We also used molecular diagnostics to determine trematode infection status ofB. truncatusindividuals. By integrating these data through multiple regression on distance matrices (MRM) analyses, we quantified the influence ofB. truncatuspopulation genetics, spatial distribution, environmental bacterial communities, and infection status on the snail’s microbiota structure. Our results show that the genetic structure ofB. truncatuspopulations, and to a lower extent geographic distribution, are the main factors explaining the snail’s microbiota compositions. Neither the environmental bacterial communities nor trematode infection status significantly contributed to microbiota structure. A portion of the variance in microbiota composition remains unexplained, suggesting that additional ecological or intrinsic factors might be involved. These findings provide new insights into the drivers of microbiota structure in natural populations and highlight the complexity of host-microbiota-environment interactions.Key-words:Bulinus truncatus, Microbiota, Spatial structure, Population genetics, Trematodes, Multiple regressions on distance matrices
Context-dependent NMDA receptor dysfunction predicts seizure treatment in mice with human GluN1 variant
Authors: Venkatesan Sridevi , Nazarkina Daria , Sullivan Megan T , Tan Yao-Fang , Qu Sarah , Ramsey Amy J. , Lambe Evelyn K. 
Published: November 2024

SummaryMutations in N-Methyl D-Aspartate receptors (NMDARs) cause epilepsy and profound cognitive impairment, though the underlying subunit-specific vulnerabilities remain unclear. We investigate the impact of a severe human variant in the lurcher motif of obligate GluN1 NMDAR subunit using transgenic mice, leveraging context-specific dysfunction to devise a surprising treatment. We show that the GluN1 Y647S variant significantly reduces current flow through isolated NMDARs in the mouse brain. However, this loss-of-function paradoxically extends NMDAR-dependent dendritic integration, causing prolonged circuit-wide excitation that promotes seizures. Mutant receptors fail to sufficiently engage opposing dendritic ion channels that normally prevent NMDAR overactivation. Boosting negative feedback restores normal dendritic integration and successfully treats seizuresin vivo,despite loss-of-function of isolated NMDARs. We demonstrate how seizures arise from loss-of-function NMDARs and target the interaction between a GluN1 variant’s receptor-level effects and its dendritic environment to treat them effectively.
Gene expression and DNA methylation changes in response to hypoxia in toxicant-adapted Atlantic killifish (Fundulus heteroclitus)
Authors: Aluru Neelakanteswar , Venkataraman Yaamini R. , Murray Christopher S. , DePascuale Veronica 
Published: November 2024

AbstractCoastal fish populations are threatened by multiple anthropogenic impacts, including the accumulation of industrial contaminants and the increasing frequency of hypoxia. Some populations of the Atlantic killifish (Fundulus heteroclitus), like those in New Bedford Harbor (NBH), Massachusetts, have evolved a resistance to dioxin-like polychlorinated biphenyls (PCBs) that may influence their ability to cope with secondary stressors. To address this question, we compared hepatic gene expression and DNA methylation patterns in response to mild or severe hypoxia in killifish from NBH and Scorton Creek (SC), a reference population from a relatively pristine environment. We hypothesized that NBH fish would show altered responses to hypoxia due to trade-offs linked to toxicant resistance. Our results revealed substantial differences between populations. SC fish demonstrated a dose-dependent changes in gene expression in response to hypoxia, while NBH fish exhibited a muted transcriptional response to severe hypoxia. Interestingly, NBH fish showed significant DNA methylation changes in response to hypoxia, while SC fish did not exhibit notable epigenetic alterations. These findings suggest that toxicant-adapted killifish may face trade-offs in their molecular response to environmental stress, potentially impacting their ability to survive severe hypoxia in coastal habitats. Further research is needed to elucidate the functional implications of these epigenetic modifications and their role in adaptive stress responses.Summary StatementThis study reveals how evolved resistance to toxicants in killifish may compromise their ability to respond to hypoxia, highlighting trade-offs that impact survival in stressed coastal environments.
Distinct intraspecific diversification dynamics in Neotropical montane versus lowland birds revealed by whole-genome comparative phylogeography
Authors: Wacker K. S. , Winger B. M. 
Published: November 2024

AbstractComparing phylogeographic patterns across different biogeographic regions can illuminate how different types of landscapes promote the formation of incipient species, providing insights into the evolutionary mechanisms underlying broadscale biodiversity gradients. The Neotropics are a global biodiversity hotspot, and the megadiverse Andes-Amazonia system has elevational gradients in both species richness and speciation rates. Here, we compare the phylogeographic dynamics of birds in the tropical Andes mountains versus the Amazonian lowlands using whole genomes from a congeneric set of colorful canopy frugivores (Tangaratanagers). We first show that Andean species have greater population structuring across their geographic ranges than Amazonian species. Next, we evaluated whether differences in geographic barrier efficacy and range size drive this elevated population-level divergence in the mountains. We find greater population differentiation and reduced gene flow across individual geographic barriers in the Andes. Furthermore, Andean species have consistently lower genetic diversity and smaller effective population sizes. Together, these results support a model of Neotropical diversification whereby incipient species form more readily in the mountains than the lowlands owing to more effective geographic barriers and smaller populations. These different phylogeographic processes across the Andes-Amazonia system carry implications for our understanding of the origin and maintenance of regional biodiversity gradients.
The C3-C3aR axis modulates trained immunity in alveolar macrophages
Authors: Earhart Alexander P. , Alburquerque Rafael Aponte , Starick Marick , Nallapu Aasritha , Garnica Lorena , Ozanturk Ayse Naz , Maurya Rahul Kumar , Wu Xiaobo , Haspel Jeffrey A. , Kulkarni Hrishikesh S. 
Published: November 2024

ABSTRACTComplement protein C3 is crucial for immune responses in mucosal sites such as the lung, where it aids in microbe elimination and enhances inflammation. While trained immunity – enhanced secondary responses of innate immune cells after prior exposure – is well-studied, the role of the complement system in trained immune responses remains unclear. We investigated the role of C3 in trained immunity and found thatin vivo, trained wild-type mice showed significantly elevated pro-inflammatory cytokines and increased C3a levels upon a second stimulus, whereas C3-deficient mice exhibited a blunted cytokine response and heightened evidence of lung injury.Ex vivo, C3-deficient alveolar macrophages (AMs) displayed reduced chemokine and cytokine output after training, which was restored by exogenous C3 but not by C3a. Inhibiting C3aR, both pharmacologically and with a genetic C3aR knockout, prevented this restoration, indicating the necessity of C3aR engagement. Mechanistically, trained WT AMs demonstrated enhanced glycolytic activity compared to C3-deficient AMs – a defect corrected by exogenous C3 in a C3aR-dependent manner. These findings reveal that C3 modulates trained immunity in AMs through C3aR signaling, affecting cytokine production and metabolic reprogramming, and highlight a novel role for C3 in trained immunity.
CancerFoundation: A single-cell RNA sequencing foundation model to decipher drug resistance in cancer
Authors: Theus Alexander , Barkmann Florian , Wissel David , Boeva Valentina 
Published: November 2024

AbstractWe present CancerFoundation, a novel single-cell RNA-seq foundation model (scFM) trained exclusively on malignant cells. Despite being trained on only one million total cells, a fraction of the data used by existing models, CancerFoundation outperforms other scFMs in key tasks such as zero-shot batch integration and drug response prediction. During training, we employ tissue and technologyaware oversampling and domain-invariant training to enhance performance on underrepresented cancer types and sequencing technologies. We propose survival prediction as a new downstream task to evaluate the generalizability of single-cell foundation models to bulk RNA data and their applicability to patient stratification. CancerFoundation demonstrates superior batch integration performance and shows significant improvements in predicting drug responses for both unseen cell lines and drugs. These results highlight the potential of focused, smaller foundation models in advancing drug discovery and our understanding of cancer biology. Our code is available here1.
Optical Interference for the Guidance of Cryogenic Focused Ion Beam Milling Beyond the Axial Diffraction Limit
Authors: Sica Anthony V. , Zaoralová Magda , Antolini Cali , Boltje Daan B. , Penzes Judit J. , Malmqvist Lilyana M. , Jensen Grant , Kaelber Jason T. , Dahlberg Peter 
Published: November 2024

AbstractUsing a tri-coincident cryogenic FIB-SEM-LM system, we identify an interferometric optical response that can be used for targeting lamella production to fluorescently labelled structures with accuracy beyond the diffraction limit. We demonstrate the approach using synthetic samples of fluorescent beads embedded in micron-scale droplets of water. We then apply the approach to capture virions inside host cells. Successful targeting is confirmed by cryogenic electron tomography revealing clusters of virions in intracellular vesicles.
IKAROS facilitates antigen escape in the face of CD19- and CD22-targeted therapies for B-cell acute lymphoblastic leukemia
Authors: Domizi Pablo , Sarno Jolanda , Jager Astraea , Merchant Milton , Pacheco Kaithlen Zen B , Yamada-Hunter Sean A. , Rotiroti Maria Caterina , Liu Yuxuan , Baskar Reema , Reynolds Warren D. , Sworder Brian J. , Sahaf Bita , Bendall Sean C. , Mullighan Charles G. , Alizadeh Ash A. , Leahy Allison B. , Myers Regina M. , Yates Bonnie , Wang Hao-Wei , Shah Nirali N. , Majzner Robbie G. , Mackall Crystal L. , Grupp Stephan A. , Barrett David M. , Sotillo Elena , Davis Kara L. 
Published: November 2024

SummaryRelapse due to antigen escape is a major cause of treatment failure for patients with B-cell malignancies following targeted immunotherapies, including CD19- and CD22-directed chimeric antigen receptor T (CAR T) cells. To identify tumor intrinsic factors associated with antigen loss, we performed single-cell analyses on 61 primary patient samples or patient-derived xenografts from patients with B-cell acute lymphoblastic leukemia (B-ALL) treated with CAR T cells. We identified that low levels of the transcription factor IKAROS in pro-B-like B-ALL cells before CAR T treatment are associated with antigen escape. We demonstrate that IKAROSlowB-ALL cells lose features of B cell identity and resemble progenitor cells based on their epigenetic and transcriptional state, resulting in the downregulation of B-cell immunotherapy antigens, including surface expression of CD19 and CD22. We find that modulation of CD19 and CD22 protein expression is IKAROS dose-dependent and reversible. Further, we demonstrate that IKAROSlowcells are resistant to CD19- and CD22-targeted therapies. Together, we describe a novel role for IKAROS in the regulation of B-cell immunotherapy targets and the risk of antigen escape relapse, identifying it as a potential prognostic target.HighlightsIKAROSlowpro-B-like B-ALL cells are associated with CD19negrelapseIKAROSlowB-ALL cells resemble progenitor cells and have lower B-cell commitmentIKAROS modulates CD19 and CD22 surface expression in a dose-dependent and reversible mannerIKAROSlowB-ALL cells are more resistant to CD19- and CD22-targeted therapiesGraphical abstractBefore immunotherapy, IKAROSlowpro-B-like B-ALL cells possess chromatin and gene expression states poised for loss of B-cell identity while maintaining expression of CD19 and CD22. Under immune pressure, IKAROShighcells maintain their antigen expression, making them more susceptible to T cell-mediated killing. Conversely, IKAROSlowcells are more likely to downregulate their antigen expression, giving them a relative advantage to escape immunotherapies, resulting in antigen escape relapse.
Rare species do not disproportionately contribute to phylogenetic diversity in a subalpine plant community
Authors: Veldhuisen Leah N , Zepeda Verónica , Enquist Brian J , Dlugosch Katrina M 
Published: November 2024

ABSTRACTPremise of the studyWorldwide, 36% of all plant species are exceedingly rare, and are at the highest risk of extinction. Extinction risk has also been observed to be phylogenetically clustered, threatening the loss of lineages that contribute unique evolutionary diversity to communities. Rare plants’ contributions to phylogenetic diversity are largely unknown, however. We investigate whether rare species (as measured by local abundance and range size) contribute disproportionately to phylogenetic diversity in a subalpine plant community.MethodsWe collected abundance data at three sites in Washington Gulch near the Rocky Mountain Biological Laboratory (RMBL, Gothic, Colorado, USA) in 2021 and 2022. We then calculated range size for each species. We calculated phylogenetic signal for abundance and range size, compared community phylogenetic metrics weighted by range size and abundance to unweighted metrics, and quantified the change in phylogenetic diversity when removing single species and groups of species ranked by rarity.Key resultsWe found phylogenetic signal for abundance, but not range size. There was no difference between rarity-weighted and unweighted phylogenetic diversity metrics. Finally, phylogenetic diversity did not decline more when we removed single rare species and groups of rare species than when we removed single common species and groups of common species.ConclusionsOverall, we found that rare species do not disproportionately contribute to phylogenetic diversity. This suggests that rare species likely provide phylogenetic redundancy with common species, and losing rare species may not cause disproportionate drops in phylogenetic diversity in this system.
Transcriptomic-Based Identification of FCRL6 as a Novel Diagnostic Biomarker in Diabetic Nephropathy
Authors: Marinedrive Adarsh , Ray Sonalika , Mazumder Mohit 
Published: November 2024

AbstractDiabetic nephropathy (DN) is a microvascular complication that arises in a sizable portion of individuals with diabetes mellitus, representing a growing public health issue given its progressive injury of the kidney. DN is primarily driven by the upregulation of pro-inflammatory markers and pathways, which cause hyperfiltration and significant physiological changes to the renal structure. To further understand the molecular mechanisms by which DN progresses, we used bioinformatics and meta-analysis techniques to analyze two datasets from the Gene Expression Omnibus (GEO) database: GSE142025 and GSE142153. Differential gene expressions (DGEs) were identified using the Bioconductor DESeq2 library and further used in functional enrichment analysis. DGEs were also constructed into protein-protein interaction networks and used to find regulatory hub genes. In total, 911 DGEs were found, and enrichment using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) revealed strong correlations with immunoreactive responses and cascades. In our analysis, we discovered 12 protein-coding genes novel with regards to DN; we further identified Fc Receptor-Like 6 - FCRL6 - as a potential biomarker in nephropathy and described its involvement in the suppression of natural killer cell-mediated toxicity as a mechanism of poor immunoregulation in the diabetic kidney. The current study presents comparative analyses of the DN transcriptome and a possible diagnostic marker with applications in immunotherapy treatments of nephropathy.