bluuebunny/crossref_metadata_2025_split huggingface dataset:
HMG box-containing protein 1 (HBP1) prevents pancreatic injury in experimental pancreatitis but accelerates pancreatic neoplasia progression
Authors: Lee Seung-Won , Ekstrom Taelor , Manalo Elise C. , Ye Shangyuan , Berry Mark , Grygoryev Dmytro , Szczepaniak Malwina , Marmolejo Carlos Origel , Haverlack Syber , Lee Jinho , Shah Vidhi M. , Keith Dove , Muschler John L. , Chin Koei , Sears Rosalie C , Weisberg Stuart P. , Morgan Terry , Kim Jungsun 
Published: January 2025

ABSTRACTBackground & AimsPancreatitis is an inflammatory disease of the exocrine pancreas and is a known risk factor for pancreatic ductal adenocarcinoma (PDAC). We previously identified HMG-box transcription factor 1 (HBP1) as a potential master transcription factor (TF) involved in the early progression of PDAC and associated with poor patient survival. However, the functional role of HBP1 in the pathophysiological mechanism for progression from acute to chronic pancreatitis to PDAC remains unclear.MethodsWe examined HBP1 expression in human chronic pancreatitis samples and cerulein-induced acute pancreatitis mouse model. We generated mice with pancreatic-specific conditional HBP1 knockout, without or with an oncogenic Kras mutation, and their corresponding controls. Then, we employed spatial proteomic and transcriptomics, histology, and immunostaining to characterize pathological changes in these mice. We validated findings from mouse models using inducible HBP1-overexpressing human pancreatic ductal epithelial cells.ResultsHBP1 was upregulated in pancreatic acinar cells in human chronic and mouse acute pancreatitis, and the expression of HBP1 in human chronic pancreatitis was associated with the presence of PDAC. Ablation of HBP1 in the pancreas disrupted acinar homeostasis by impairing the autophagic influx and exacerbated inflammation upon injury. However, in the presence of an oncogenic KRAS, HBP1 ablation delayed the formation of pancreatic intraepithelial neoplasia (PanINs), precursors of PDAC, and their progression into higher grades.ConclusionsUpregulated HBP1 in normal acinar cells limits pancreatic inflammatory injury, but HBP1 is essential for PanIN progression in the presence of an oncogenic KRAS. Thus, HBP1 is a key regulator in both pancreatitis and early neoplastic changes and a potential target for therapeutic intervention in pancreatitis and PanIN progression.
TargetingRunx1 protects against heart failure with preserved ejection fraction
Authors: Elbassioni Ali Ali Mohamed , Raheem Anmar A , Song Jian , Johnston Alexander S , Trivett Cara , Lin Hong , Zhang Haobo , Bradley Ashley , Higgins Erin , Mooney Leanne , Koay Yen Chin , O’Toole Dylan , Herzyk Pawel , Nixon Colin , Blyth Karen , O’Sullivan John F , Lang Ninian N , Berry Colin , Braun Thomas , Schiattarella Gabriele G , Giacca Mauro , McBride Martin W , Nicklin Stuart A , Cameron Ewan R , Loughrey Christopher M , MacDonald Eilidh A 
Published: January 2025

ABSTRACTHeart failure with preserved ejection fraction (HFpEF) is a public health problem and an elusive illness for which there are few treatment options. HFpEF is a systemic condition with a broad phenotype including diastolic dysfunction, pulmonary oedema, exercise intolerance, and left ventricular (LV) hypertrophy, collectively resulting in enhanced morbidity and mortality. Master-regulator transcription factor RUNX1 has recently been identified as a mediator of pathological changes in many cardiac diseases, however its role in HFpEF was unknown. Here we show that inhibition ofRunx1 limits adverse cardiac remodelling in a clinically relevant mouse model of HFpEF. Cardiomyocyte-specific tamoxifen-inducibleRunx1-deficient mice with HFpEF are protected, with preservation of diastolic function, and attenuation of pulmonary oedema, exercise intolerance, and hypertrophy. Furthermore, targetingRunx1 in HFpEF by using gene transfer or small molecule inhibitors improves diastolic function, both in female and male mice. Overall, our research enhances our understanding of RUNX1 in cardiac disease and demonstrates a novel translational target for the treatment of HFpEF. Keywords: Heart failure with preserved ejection fraction, metabolic heart failure, diastolic dysfunction, hypertrophy, pulmonary oedema, exercise intoleranceCLINICAL PERSPECTIVEHeart failure (HF) is a leading cause of death world-wide and traditionally divided into different subtypes according to cardiac ejection fraction (EF). In contrast to HF with reduced EF (HFrEF), there are limited treatment options for HF with preserved EF which is of considerable concern given that HFpEF is projected to become the dominant HF subtype in the future1. RUNX1 has been demonstrated to play an important role in the development of many cardiac and non-cardiac diseases. As a result, the potential for RUNX1 inhibitors as therapeutic agents across various conditions has become increasingly evident. In this study we established the therapeutic potential of targeting RUNX1 in the context of HFpEF. Targeting RUNX1 in cardiomyocytes markedly attenuates the development of the HFpEF phenotype and therefore this novel translational therapeutic target has great potential to address one of the biggest challenges in cardiac research.
Bioenergetic reprogramming of macrophages reduces drug tolerance inMycobacterium tuberculosis
Authors: Yadav Vikas , Sahoo Sarthak , Malhotra Nitish , Mishra Richa , Rajmani Raju S , Shanmugam Siva , Shandil Radha K , Narayanan Shridhar , Thacker Vivek V. , Jolly Mohit , Seshasayee Aswin Sai Narain , Singh Amit 
Published: January 2025

AbstractEradication ofMycobacterium tuberculosis(Mtb) requires strategies targeting bacteria inside the host.Mtbexhibits heterogeneity in redox metabolism inside macrophages to evade killing by anti-TB drugs. If and how macrophage physiology correlates with bacterial redox heterogeneity and drug tolerance remains unclear. Using a fluorescent reporter of mycobacterial redox potential, flow sorting, and RNA sequencing of infected macrophages, we characterized transcriptional and metabolic responses of macrophages harboring redox-diverseMtbpopulations. We found that macrophages with suppressed glycolysis and elevated oxidative phosphorylation (OXPHOS) correlated withMtbpopulations exhibiting reductive stress and drug tolerance. Conversely, macrophages with elevated glycolysis and suppressed OXPHOS displayed higher mitochondrial reactive oxygen species through reverse electron transport, resulting in oxidative stress inMtband enhancing drug efficacy. Computational and genetic approaches identified Nrf2 as a key regulator of macrophage bioenergetics driving redox heterogeneity and drug tolerance inMtb. Redirecting macrophage metabolism from OXPHOS to glycolysis using an FDA- approved antiemetic drug, meclizine, subverted redox heterogeneity and diminished drug tolerance in macrophages and mice. The pharmacological profile of meclizine (Cmaxand AUClast) indicated no adverse interactions with first-line anti-TB drugs in mice. Our data demonstrate the feasibility of reprogramming macrophage metabolism to reduce drug tolerance inMtbinfection.
Algorithms to Improve Fairness in Medicare Risk Adjustment
Authors: Reitsma Marissa B. , McGuire Thomas G. , Rose Sherri 
Published: January 2025

AbstractImportancePayment system design creates incentives that impact healthcare spending, access, and outcomes. With Medicare Advantage accounting for more than half of Medicare spending, changes to its risk adjustment algorithm have the potential for broad consequences.ObjectiveTo develop risk adjustment algorithms that can achieve fair spending targets, and compare their performance to a baseline that emulates the least squares regression approach used by the Centers for Medicare and Medicaid Services.DesignRetrospective analysis of Traditional Medicare enrollment and claims data between January 2017 and December 2020. Diagnoses in claims were mapped to Hierarchical Condition Categories (HCCs). Algorithms used demographic indicators and HCCs from one calendar year to predict Medicare spending in the subsequent year.SettingData from Medicare beneficiaries with documented residence in the United States or Puerto Rico.ParticipantsA random 20% sample of beneficiaries enrolled in Traditional Medicare. Included beneficiaries were aged 65 years and older, and did not have Medicaid dual eligibility. Race/ethnicity was assigned using the Research Triangle Institute enhanced indicator.Main Outcome and MeasuresProspective healthcare spending by Medicare. Overall performance was measured by payment system fit and mean absolute error. Net compensation was used to assess group-level fairness.ResultsThe main analysis included 4,398,035 Medicare beneficiaries with a mean age of 75.2 years and mean annual Medicare spending of $8,345. Out-of-sample payment system fit for the baseline regression was 12.7%. Constrained regression and post-processing both achieved fair spending targets, while maintaining payment system fit values of 12.6% and 12.7%, respectively. Whereas post-processing only increased mean payments for beneficiaries in minoritized racial/ethnic groups, constrained regression increased mean payments for beneficiaries in minoritized racial/ethnic groups and beneficiaries in other groups residing in counties with greater exposure to socioeconomic factors that can adversely affect health outcomes.Conclusions and RelevanceConstrained regression and post-processing can incorporate fairness objectives in the Medicare risk adjustment algorithm with minimal reduction in overall fit.
Apraxia as a Predictor of Post-Stroke Recovery: Insights from the Birmingham Cognitive Screening Program
Authors: Rounis Elisabeth , Ramanan Siddharth , Bickerton Wai-Ling , Demeyere Nele , Ralph Matthew A. Lambon 
Published: January 2025

AbstractOur study highlights cognitive measures underlying post-stroke recovery using the ‘Birmingham Cognitive Screening’ (BCOS) program—the only dataset with comprehensive assessments of cognition, praxis, and stroke outcomes. We analysed 256 stroke patients tested for cognitive deficits, which uniquely included apraxia and the Barthel Index for daily living activities at subacute and chronic stages. Using step-wise multivariate linear regression, we identified significant predictive factors—praxis, language, orientation, and baseline independence—linked to improved daily activities, and validated our model with 4-fold cross-validation. This research underscores the vital role of specific cognitive measures including apraxia as key cognitive predictors for stroke recovery.
A pan-respiratory virus attachment inhibitor with high potency in human airway models and in vivo
Authors: Mathez Gregory , Jacob Silva Paulo , Carlen Vincent , Deloizy Charlotte , Prompt Clémentine , Hubart Anaïs , Rocha-Pereira Joana , Galloux Marie , Le Goffic Ronan , Stellacci Francesco , Cagno Valeria 
Published: January 2025

AbstractRespiratory viruses can cause severe infections, including bronchiolitis and pneumonia, often leading to hospitalization or death. Due to their ease of transmission, they are also scrutinized for their pandemic potential. No broad-spectrum antiviral is currently available. However most respiratory viruses use sialic acid or heparan sulfates as attachment receptors. Here, we report the identification of a pan-respiratory antiviral strategy based on mimicking both glycans. We synthesized and characterized a unique modified cyclodextrin that simultaneously mimics heparan sulfate and sialic acid. This novel compound demonstrated broad-spectrum antiviral activity against important human pathogens: parainfluenza virus 3, respiratory syncytial virus, influenza virus H1N1, SARS-CoV-2. Additionally, the compound is active against different avian strains of influenza virus, revealing its importance for pandemic preparedness. The compound retains broad- spectrum activity in ex vivo models of respiratory tissues and in vivo experiments against RSV and Influenza virus, using both prophylactic and therapeutic strategies. These findings represent a significant step forward in the development of future treatments and preventive measures for respiratory viral infections.Significance StatementFollowing the SARS-CoV-2 pandemic, Influenza A H5N1 has become widespread in poultry and has already begun to spill over into mammals, posing a potential risk for the next pandemic. Indeed, respiratory viruses represent a major threat for future global health crises. Unfortunately, there is a significant lack of broad-spectrum antivirals available for such scenarios. To address this gap, our study developed a single molecule with the capacity to inhibit a wide range of clinically relevant human respiratory viruses including avian strains of influenza virus. This antiviral demonstrated verified efficacy not only in cellular systems but also in human-derived respiratory tissues and animal models.
Structural Basis of Lipid Membrane Binding by Human Ferlins
Authors: Cretu Constantin , Chernev Aleksandar , Kibedi Szabo Csaba Zoltan , Pena Vladimir , Urlaub Henning , Moser Tobias , Preobraschenski Julia 
Published: January 2025

AbstractFerlins, ancient membrane proteins with a unique architecture, are central to multiple essential, Ca2+-dependent vesicle fusion processes. Despite numerous functional studies and their link to burdening human diseases, a mechanistic understanding of how these multi-C2domain proteins interact with lipid membranes to promote their remodeling and fusion is currently lacking. Here, we elucidate the near-complete cryo-electron microscopy structures of human myoferlin and dysferlin in their Ca2+and lipid-bound states. We show that ferlins adopt compact, ring-like tertiary structures achieved upon membrane binding. The top arch of the ferlin ring, comprising the C2C-C2D region, is rigid and varies little across the observed functional states. In contrast, the N-terminal C2B and the C-terminal C2F-C2G domains cycle between alternative conformations and, in response to Ca2+, close the ferlin ring, promoting tight interaction with the target membrane. Probing key domain interfaces validates the observed architecture and informs a model of how ferlins engage lipid bilayers in a Ca2+- dependent manner. This work reveals the general principles of human ferlin structures and provides a framework for future analyses of ferlin-dependent cellular functions and disease mechanisms.
Cancer cells transfer invasive properties through microRNAs contained in collagen-tracks
Authors: Normand Léa , Rouyer Lucile , Richard Elodie , Allain Nathalie , Giraud Julie , Di-Tommaso Sylvaine , Dourthe Cyril , Raymond Anne-Aurélie , Dupuy Jean-William , Moreau Kevin , Iggo Richard , McGrogan Gaetan , Dugot-Senant Nathalie , Bouter Anthony , Tan Sisareuth , Favereaux Alexandre , Moreau Violaine , Luco Reini F. , Ros Manon , Saltel Frédéric 
Published: January 2025

AbstractInvasion is a prerequisite for metastasis formation. During tumor development, the extracellular matrix (ECM) is remodeled in part through overexpression of type I collagen, increasing tumor microenvironment stiffness, and facilitating cancer dissemination. During breast cancer cell migration, we observed membrane debris left behind, attached to the collagen fibrils, along the migration path. We named these structures collagen-tracks. These collagen-tracks can be deposited in 3D matricesin vitroandin vivoand their formation is stimulated by the interaction between the ECM and matrix receptors, such as the discoidin-domain receptor (DDR1). However, they are different from structures already known to be involved in cell-cell communication such as exosomes and migrasomes, due to their specific nucleic acid and protein contents. When deposited by highly invasive breast cancer cells, internalized collagen-tracks reprogram non-invasive cells into highly pro-metastatic ones by inducing a partial epithelial–mesenchymal transition (EMT). This cell reprogramming is dependent on specific miRNAs present in the collagen-tracks, that are necessary to promote ECM degradation, increase cell motility and invasiveness. Collagen-tracks thus represent a new form of cell-cell communication important for driving tumor invasion that could be targeted to prevent metastasis.
Targeted delivery of mRNA to the heart via extracellular vesicles or lipid nanoparticles
Authors: Nawaz Muhammad , Tangruksa Benyapa , Heydarkhan-Hagvall Sepideh , Kohl Franziska , González-King Garibotti Hernán , Jing Yujia , Payandeh Zahra , Reyahi Azadeh , Jennbacken Karin , Wiseman John , Hultin Leif , Lindfors Lennart , Synnergren Jane , Valadi Hadi 
Published: January 2025

AbstractTargeted mRNA transport plays a crucial role in enhancing the therapeutic efficacy of the molecule, reducing its side effects, and minimizing off-target effects. Systemic administration of mRNA through lipid nanoparticles (LNPs) or extracellular vesicles (EVs) predominantly results in mRNA accumulation in the liver. We hypothesized that cardiac-specific EVs could more effectively target the transport of mRNA to the heart, in comparison to non-cardiac-specific EVs or LNPs. In mice, after intravenous administration, EVs from cardiac progenitor cells (CPC-EVs) were the most efficient to transport the modified mRNA, encoding vascular endothelial growth factor A (VEGF-A), to mouse heart, with minimal liver accumulation compared to non-cardiac-specific EVs or LNPs. Additionally, intracardiac injections of CPC-EVs not only demonstrate that they are the most adapted vehicle for interacting with heart tissue, delivering the mRNA to cells, and inducing maximal VEGF-A protein production, but RNA-seq analyses also revealed their minimal impact on overall gene expression, compared to LNPs or non-cardiac-specific EVs. Furthermore, immunofluorescence staining of CD31 and α-SMA, markers of microvascular density, showed increased vessel density in mouse aortic rings following the delivery ofVEGF-AmRNA via CPC-EVs. These findings suggest that CPC-EVs are superior in mRNA targeting to heart, communication with cardiac cells, and causing minimal transcriptomic changes duringVEGF-AmRNA delivery. Therefore, CPC-EVs could be promising vectors for heart-targeted mRNA delivery, potentially reducing liver accumulation.
Glycan-Mediated Mechanosensing Regulates Megakaryocyte-Biased Hematopoietic Stem Cell Subsets
Authors: Roisman Alejandro , Rivadeneyra Leonardo , Conroy Lindsey , Lee-Sundlov Melissa M. , Weich Natalia , Glabere Simon , Zheng Shikan , Rosenbalm Katelyn E. , Zogg Mark , Steinhardt George , Veltri Anthony J. , Lau Joseph T. , Gu Tongjun , Weiler Hartmut , Sun Ramon C. , Hoffmeister Karin M. 
Published: January 2025

SUMMARYDefinitive hematopoietic stem and progenitor cells (HSPCs) development relies on intrinsic and extrinsic programs to meet homeostatic and stress-related demands. The comprehensive mechanisms governing HSPC’s fate remain poorly understood. Our study identifies B4GALT1, a glycosyltransferase essential for N-glycosylation, as a key modulator of HSPC lineage decisions. We demonstrate that B4GALT1 deficiency disrupts glycosylation patterns within the bone marrow (BM) niche, resulting in oncogenic glycan signatures and altered expression of Mucin13 in HSPCs. Loss of B4GALT1 expands HSPC pools and promotes megakaryocyte priming in HSPCs through transcriptional and chromatin modifications, enhancing the Wnt-Mucin13 axis. Mucin13, an oncogene characterized by aberrant glycosylation, underscores the critical role of B4GALT1 in sustaining BM glycosylation and mechanosensing, thereby regulating HSPC fate through functional, transcriptional, and chromatin dynamics. These observations provide insights into the impact of glycan structures on HSPC function, lineage reprogramming, and malignant transformation.
Task-specific changes in representation and connectivity between parietal and occipito-temporal areas following left hemisphere stroke
Authors: Zhang Zuo , Halai Ajay , Bracci Stefania , Pizzamiglio Gloria , Ralph Matthew Lambon , Rounis Elisabeth 
Published: January 2025

AbstractRecent studies highlight a critical role of the human lateral occipitotemporal cortex (LOTC) in action understanding, particularly in how we perceive and interpret movements and interactions with tools and bodies. This region, along with connected fronto-parietal areas, has been implicated in limb apraxia, a disorder that affects skilled movement after stroke.In this study, we focused on whether there were any changes in brain activity or connectivity in areas involving the LOTC and its interconnected perceptuo-motor network after left hemisphere stroke, a common cause of limb apraxia.We recruited 29 stroke patients and 19 age-matched healthy participants. Using functional neuroimaging, we asked participants to observe static photographs of familiar tools, bodies, non-tool objects, and scrambled images while performing a simple attention task (1-back task). The goal was to map the brain areas specifically involved in tool-related and body-related visual processing. Whole-brain analysis revealed activity changes related to tool and body stimuli in the LOTC and fronto-parietal regions. Interestingly, there were no significant differences in activation between stroke patients and controls based on the overall whole-brain analysis. However, deeper analyses revealed critical group-related differences. Using representational similarity analysis (RSA), we found that stroke patients showed reduced ability to discriminate between tools and non-tools within the right LOTC. Psychophysiological interactions (PPI) analysis further indicated increased connectivity between the left inferior parietal sulcus (IPS) and the left LOTC in stroke patients during tool-related tasks, a finding that correlated with their performance on meaningless imitation apraxia task.Our findings suggest that limb apraxia after stroke is associated with altered representation of tools and functional connectivity in the perceptuo-motor network, particularly involving parietal and occipitotemporal regions. These results suggest perceptual deficits may be more relevant than previously reported in limb apraxia after stroke.HighlightsConsistent activations in the lateral occipitotemporal cortex (LOTC) were identified during tool and body localizer tasks in both stroke patients and healthy controls.Representational similarity analysis (RSA) revealed reduced discrimination between tools and non-tools in the right LOTC of stroke patients.Differential task-related functional connectivity was observed between the LOTC and intraparietal sulcus (IPS) regions in stroke patients compared to controls during the tools localizer task.These findings provide insights into altered neural representations and connectivity underlying limb apraxia following left hemisphere stroke.