julilili42/papers huggingface dataset:
DKK3 Initially Preserves Acinar Integrity Through MEK‐Fos Signaling, but Later Switches to an Oncogenic Role in Pancreatic Cancer
2025-10-28

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by its intricate biology governed by spatiotemporal dynamics in the expression and function of specific proteins. Here, DKK3 is identified as a dynamic player with a dual role in PDAC. Using the KRAS G12D ‐driven mouse model with homozygous (DDKC) and heterozygous (DKC) DKK3 knockout, its stage and compartment‐specific functions are investigated. Knockout mice exhibited shorter lifespans with a higher incidence of high‐grade, desmoplastic, and metastatic cancers. DKK3‐deficient acini exhibited a marked increase in acinar‐to‐ductal metaplasia, with increased MAPK signaling and induction of the downstream effector Fos . During the progression of mouse and human PDAC, DKK3 expression shifted from epithelial dysplastic cells to cancer‐associated fibroblasts (CAFs). At the endpoint, DKK3‐expressing CAFs emerged as crucial contributors to tumor aggressiveness and fibrosis. Orthotopic transplantations confirm a stromal role, particularly in DDKC tumors, while mechanistic studies demonstrate that DKK3 activates IL6‐JAK‐STAT3 signaling and pro‐migratory/mesenchymal programs that are reversed by pharmacologic STAT3 inhibition in DDKC cells. Concordantly, DKK3 expression correlates with IL6‐JAK‐STAT3 gene signatures in human PDAC datasets. Together, these findings underscore the intricate and context‐sensitive role of DKK3, delaying oncogenesis during early stages while paradoxically promoting tumor progression in later stages, suggesting that therapeutic targeting strategies should be approached with caution.
Brain-age models with lower age prediction accuracy have higher sensitivity for disease detection
2025-10-28

This study critically reevaluates the utility of brain-age models within the context of detecting neurological and psychiatric disorders, challenging the conventional emphasis on maximizing chronological age prediction accuracy. Our analysis of T1 MRI data from 46,381 UK Biobank participants reveals that simpler machine learning models, and notably those with excessive regularization, demonstrate superior sensitivity to disease-relevant changes compared to their more complex counterparts, despite being less accurate in chronological age prediction. This counterintuitive discovery suggests that models traditionally deemed inferior might, in fact, offer a more meaningful biomarker for brain health by capturing variations pertinent to disease states. These findings challenge the assumption that accuracy-optimized brain-age models serve as useful normative models of brain aging. Optimizing for age accuracy appears misaligned with normative aims: it drives models to rely on low-variance aging features and to deemphasize higher-variance signals that are more informative about brain health and disease. Consequently, we propose a recalibration of focus towards models that, while less accurate in conventional terms, yield brain-age gaps with larger patient-control effect sizes, offering greater utility in early disease detection and understanding the multifaceted nature of brain aging.
Hypoxia Supports LPS-Driven Tolerance and Functional Activation in BV-2 Microglial Cells
2025-10-28

Background: Prolonged hypoxia contributes to irreversible organ damage, particularly in the brain and heart. While chronic hypoxia is harmful, mild short-term hypoxia can trigger protective mechanisms. This study investigates how such hypoxic conditions affect BV-2 tolerant microglial cells in vitro, focusing on inflammation, metabolism, and functional activity. Although in vitro models provide a controlled setting, our findings may offer insights into microglial behavior in vivo under similar conditions. Methods: We used various molecular and biochemical techniques to assess the inflammatory state of BV-2 microglia under hypoxia, measuring glycolytic activity (via lactate production), and evaluating migratory and phagocytic capacities in vitro. Results: Hypoxic conditions induced a more tolerant, anti-inflammatory phenotype in BV-2 cells, with decreased pro-inflammatory mediators and reduced glycolytic activity, regulated by the MyD88/NF-κB p65 pathway. Tolerance supports increased migration and phagocytosis, but under hypoxic conditions, these effects were significantly declined compared to normoxic conditions, mediated through the ERK1/2 pathway. Conclusions: These findings suggest that short-term hypoxia may regulate microglial behavior and restore homeostasis, with implications for neuroinflammatory conditions.
Protective Role of the Sodium Taurocholate Cotransporting Polypeptide S267F Variant Against Hepatitis B Virus Infection and Cirrhosis in the Vietnamese Population
2025-10-28

ABSTRACT The sodium taurocholate cotransporting polypeptide (NTCP) serves as both a hepatic bile acid transporter and an essential entry receptor for hepatitis B virus (HBV). The S267F (rs2296651) polymorphism in the NTCP gene has been associated with reduced HBV susceptibility in East Asian populations. However, its clinical relevance in the Vietnamese population remains underexplored. We investigated the association between the NTCP S267F variant and clinical outcomes in 743 Vietnamese individuals, including 429 HBV‐infected patients and 314 healthy controls (HCs). HBV genotyping, NTCP variant screening, and analysis of demographic and clinical parameters were conducted. Associations between genotypes, liver disease severity, and viral genotypes were assessed using logistic regression and non‐parametric tests. The heterozygous CT genotype of S267F was significantly less frequent in HBV patients (12%) compared to HCs (16%) (adjusted OR: 0.5; p = 0.013), suggesting a protective role against HBV infection. This effect was most pronounced in patients with chronic hepatitis B (CHB, OR: 0.3; p = 0.013) and liver cirrhosis (LC, OR: 0.4; p = 0.041), indicating a twofold to threefold reduced risk. No significant association was observed between the variant and hepatocellular carcinoma (HCC). HBV genotype C was associated with a significantly increased risk of progression to LC (OR: 2.4; p = 0.015) and HCC (OR: 2.5; p = 0.039) compared to predominant genotype B. The protective effect of the S267F variant was independent of HBV genotype. The NTCP S267F variant is associated with reduced susceptibility to HBV infection and progression to cirrhosis in the Vietnamese population but does not confer protection against HCC. These findings highlight the potential of host genetic factors in influencing HBV disease outcomes and may support future strategies for individualized risk assessment and management.
Integrated Single-Nucleus and Spatial Transcriptomics Elucidate Heterogeneity and Hypoxia-Driven Organization of Supratentorial Ependymoma
2025-10-28

Abstract Supratentorial ependymomas are often life-threatening brain tumors that are characterized by significant molecular heterogeneity. Hypoxia contributes to this heterogeneity, but the extent and nature of this relationship remain unclear. This poses challenges for effective treatment strategies, demanding a more holistic and detailed understanding of the underlying biology. In this study, we employed single-nucleus (n = 63) and spatial (n = 30) transcriptomics to delineate the cellular and spatial landscape of supratentorial ependymoma. Characterizing the transcriptional consensus programs of this entity revealed two previously undescribed programs that are associated with the remodeling of the extracellular matrix and the ZFTA fusion identity. These programs were related to highly unfavorable outcome and were exclusive to ZFTA fusion-positive tumors. Developing a set of spatial scoring algorithms that are sensitive to mixed spot transcriptomes enabled the identification of the role of hypoxia as the potential driver of spatial organization. Together with recurrent spatial associations inferred between programs, this informed a generalized model of the higher-order architecture. The functionally and spatially defined zones of this model displayed distinct immune presence, with the highest seen in the hypoxic zone. These results provide insights into the molecular heterogeneity and spatial organization of supratentorial ependymomas, which may aid in the development of targeted future treatments.
Feasibility of Dose Reduction in the Context of Preoperative Diagnostics in Cochlear Implant Surgery With a Photon-Counting Detector CT and Deep Learning-Supported Denoising
2025-10-28

Hypothesis: Photon-counting detector CT (PCD-CT) with deep learning-supported denoising can significantly reduce the radiation dose for cochlear implant (CI) planning without compromising the accuracy of cochlear duct length (CDL) measurements. Background: Optimal electrode placement in CI surgery requires detailed cochlear anatomy from CT scans, but reducing radiation exposure is critical. This study explores PCD-CT with denoising algorithms to lower doses while preserving diagnostic accuracy. Methods: Four body donors without inner ear malformations were scanned using PCD-CT at 100%, 50%, 25%, 10%, and 5% dose levels. Images were denoised with ClariAce, a deep learning algorithm, and CDL was measured using OTOPLAN software. Neurotologists compared the results to manual segmentations. Statistical analyses evaluated accuracy across dose levels, with Bland-Altman plots assessing systematic errors. Results: Automatic segmentation succeeded across all doses but showed increased failure below 50%. At 100% and 50% doses, CDL measurements closely matched the gold standard, with minor deviations (eg, -0.17 mm at 50%). Below 50%, CDL underestimation increased (−1.25 mm at 25% and −4.0 mm at 5%). Denoising improved segmentation but minimally affected CDL accuracy at low doses, where manual segmentation performed better. Conclusions: PCD-CT enables significant dose reduction for CI planning, with reliable CDL accuracy down to 50%. Deep learning denoising enhances image quality but is less effective below 50%, necessitating manual segmentation. These findings align with ALARA principles and suggest further refinement of AI algorithms for lower-dose applicability in CI diagnostics.
Real-time distance monitoring in magnetomyography
2025-10-28

Abstract Objective:&amp;#xD;Magnetomyography (MMG) using optically pumped magnetometers (OPM) offers a contactless, non-invasive approach to assess muscle activity. However, fluctuations in the sensor-to-source distance during MMG recordings pose a significant challenge to accurate signal interpretation since amplitude decays with distance. No established method exists for MMG to continuously monitor sensor-to-source distance changes in real-time.&amp;#xD;Approach:&amp;#xD;This study presents a new non-magnetic, cost-effective solution using a digital fiber optic sensor to continuously measure the distance between an OPM and the subject's skin. Following sensor calibration, distance measurements were recorded during an isometric muscle fatigue task in five healthy participants to assess whether MMG amplitude changes were due to physiological effects or variations in sensor-to-source distance. Alongside OPM-MMG and distance tracking, electromyography (EMG), the neurophysiological gold standard, was simultaneously recorded.&amp;#xD;Main results:&amp;#xD;We found significant changes in MMG-RMS and MMG-MDF during muscle fatigue that were not merely explained by changes in sensor-to-source distance. Furthermore, we found substantial correlations between OPM-MMG and EMG that were strongest for small sensor-to-source distance (r = 0.91).&amp;#xD;Significance:&amp;#xD;Fiber optic sensors offer non-magnetic, precise, real-time monitoring of the distance between the OPM and the skin, making it ideal for MMG applications to account for distance-related variability during measurements. Our results suggest that changes in MMG-RMS and MMG-MDF during muscle fatigue reflect genuine physiological effects rather than distance confounds.&amp;#xD;
Efficacy of praziquantel for treatment of Plasmodium falciparum infection in asymptomatic Gabonese adults: A double-blind placebo-controlled randomized phase IIb clinical trial
2025-10-28

Abstract Background Schistosomiasis and malaria are major poverty-related parasitic infectious diseases. They are often co-endemic and affect similar target populations. Mass drug administration and intermittent preventive treatment programs are commonly used for their control. From a programmatic perspective the conception of preventive treatment programs targeting both diseases simultaneously would be a great advantage. While there is preliminary evidence that certain anti-malarial drugs exert a clinically important effect on Schistosomes, little is known on whether praziquantel (PZQ), the only licensed drug to treat schistosomiasis, has activity against Plasmodium parasites. Therefore, the CORMA-MAL study was conducted to evaluate anti-malarial activity of PZQ. Methods This double-blinded, randomized, placebo-controlled phase IIb trial was conducted in Lambaréné, Gabon and recruited semi-immune adults with an asymptomatic P. falciparum parasitemia. Participants were randomized (1:1) to receive placebo or 40mg/kg PZQ once daily for three days and followed up for a total of seven days. Results 44 participants were recruited. Analytical models indicated a highly significant hourly reduction of microscopically-determined parasitemia in the PZQ arm and a non-significant decreasing trend in the placebo group (regression slopes of log10-transformed parasitemia: β=-0.006 [p&amp;lt;0.001] and β=-0.0013 [p=0.3], respectively). However, in total only 9/22 (41%) in the PZQ arm compared to 6/22 (27%) in the placebo arm reached parasite clearance by D7. Conclusions Findings demonstrate a statistically significant anti-malarial activity of PZQ; however, the observed effect is only moderate compared to current first-line anti-malarial treatments. Future research should investigate the synergistic potential of combining PZQ and antimalarial drugs in malaria and schistosomiasis control. Trial registration The trial was registered in the Pan African Clinical Trials Registry (PACTR); Registration number: PACTR202206584817951; Date of Approval: 10/JUN/2022; URL: https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=22586)
Large language models as a catalyst for opportunity recognition capability
2025-10-28

Purpose This study examines whether large language models (LLMs), such as ChatGPT, can enhance individuals' opportunity recognition (OR) capabilities and whether their impact varies across different user groups. Design/methodology/approach An experimental study was conducted with 63 participants from diverse educational backgrounds in Germany. Participants were divided into an experimental and a control group and tasked with identifying business opportunities. The experimental group used LLMs, while the control group completed tasks without artificial intelligence support. OR capability was assessed by expert evaluation of identified opportunities. Findings LLMs significantly enhanced OR capability, with greater benefits observed among participants with initially lower OR capabilities. However, proficiency in LLM utilization showed no significant improvement in outcomes. Practical implications The findings suggest that incorporating LLMs into entrepreneurial education and training programs could significantly enhance participants' ability to recognize and develop business opportunities, particularly for those with initially lower OR capabilities. Originality/value This study provides the first empirical evidence on the role of LLMs in the entrepreneurial OR process, highlighting their potential to democratize entrepreneurship by supporting individuals with varying skill levels.
Distinct senotypes in p16- and p21-positive cells across human and mouse aging tissues
2025-10-29

Abstract Senescent cells drive age-related tissue dysfunction via the induction of a chronic senescence-associated secretory phenotype (SASP). The cyclin-dependent kinase inhibitors p21 Cip1 and p16 Ink4a have long served as markers of cellular senescence. However, their individual roles remain incompletely elucidated, particularly in vivo. Thus, we conducted a comprehensive examination of multiple single-cell RNA sequencing datasets spanning both murine and human tissues during aging. Our analysis revealed that p21 Cip1 and p16 Ink4a transcripts demonstrate significant heterogeneity across distinct cell types and tissues, frequently exhibiting a lack of co-expression. Moreover, we identified tissue-specific variations in SASP profiles linked to p21 Cip1 or p16 Ink4a expression. Using RNA velocity and pseudotime analyses, we discovered that p21+ and p16+ cells follow independent trajectory dynamics, with no evidence of direct transitions between these two states. Despite this heterogeneity, we identified a limited set of shared “core” SASP factors that may drive common senescence-related functions. Our study underscores the substantial diversity of cellular senescence and the SASP, emphasizing that these phenomena are inherently cell- and tissue-dependent.
Attri-Net: A Globally and Locally Inherently Interpretable Model for Multi-Label Classification Using Class-Specific Counterfactuals
2025-10-29

Interpretability is crucial for machine learning algorithms in high-stakes medical applications. However, high-performing neural networks typically cannot explain their predictions. Post-hoc explanation methods provide a way to understand neural networks but have been shown to suffer from conceptual problems. Moreover, current research largely focuses on providing local explanations for individual samples rather than global explanations for the model itself. In this paper, we propose Attri-Net, an inherently interpretable model for multi-label classification that provides both local and global explanations. Attri-Net first counterfactually generates class-specific attribution maps to highlight the disease evidence, then performs classification with logistic regression classifiers based solely on the attribution maps. Local explanations for each prediction can be obtained by interpreting the attribution maps weighted by the classifiers’ weights. Global explanation of whole model can be obtained by jointly considering learned average representations of the attribution maps for each class (called the class centers) and the weights of the linear classifiers. To ensure the model is “right for the right reason”, we introduce a mechanism to guide the model’s explanations to align with human knowledge. Our comprehensive evaluations show that Attri-Net can generate high-quality explanations consistent with clinical knowledge while not sacrificing classification performance. Our code is available at &lt;a href='https://github.com/ss-sun/Attri-Net-V2'&gt;https://github.com/ss-sun/Attri-Net-V2&lt;/a&gt;
Therapeutic plasma exchange in amatoxin associated acute liver failure–results from the multi-center Amanita-PEX study
2025-10-30

Abstract Background Amatoxin-related acute liver failure (AT-ALF) carries high mortality without liver transplantation (LTX). While therapeutic plasma exchange (PEX) might improve LTX-free survival in other ALF cases, its role in AT-ALF is unclear. Clinical practice varies, and, given the rarity of this ALF entity, the feasibility of conducting a randomized controlled trial to investigate PEX in AT-ALF is more or less impossible. Methods The Amanita-PEX study is a multi-center, international, retrospective study analyzing patients with AT-ALF from 2013 to 2024. The primary outcome was 28-day LTX-free survival (composite endpoint: death or LTX) after ALF diagnosis. Results The study included 111 patients from 25 centers: 82 received standard-of-care (SOC), and 29 received at least one PEX-session. PEX and SOC-groups were comparable at baseline, but 76% of PEX- vs. 58% of SOC-patients developed hepatic-encephalopathy (HE) grade ≥ 2 ( p = 0.021). While the primary outcome of 28-day LTX-free survival in all patients was not different between the SOC and PEX-groups, in the subgroup of patients with maximal HE grade ≥ 2, LTX-free survival was 19.1% ( n = 8/42) in the SOC group, while it was 36.4% ( n = 8/22) in patients receiving adjunctive PEX (Gehan-Breslow-Wilcoxon- p = 0.041, Log-Rank- p = 0.060). PEX was independently associated with reduced risk of the combined endpoint death or liver transplantation within 28 days from inclusion in patients with HE grade ≥ 2 (HR 0.37, 95%-CI 0.19–0.73, p = 0.004). After propensity-score-matching, LTX-free survival was 28% in the SOC- and 52% in the PEX group (Gehan-Breslow- p = 0.036; Log-Rank- p = 0.035). Conclusions In this real-world study, adjunctive use of PEX was associated with increased LTX-free-survival in patients with AT-ALF and HE grade ≥ 2.
NUDIX hydrolases target specific inositol pyrophosphates and regulate phosphate homeostasis and bacterial pathogen susceptibility in Arabidopsis
2025-10-30

ABSTRACT Inositol pyrophosphates (PP‐InsPs) are important signaling molecules that regulate diverse cellular processes in eukaryotes, including energy homeostasis, phosphate (P i ) signaling, and phytohormone perception. Yet, in plants, the enzymes responsible for their turnover remain largely unknown. Using a non‐hydrolysable PP‐InsP analog in a pull‐down approach, we identified a family of Arabidopsis NUDIX‐type hydrolases (NUDTs) that group into two closely related subclades. Through in vitro assays, heterologous expression systems, and higher order gene‐edited mutants, we explored the substrate specificities and physiological roles of these hydrolases. Using a combination of strong anion exchange high‐performance liquid chromatography (SAX‐HPLC), polyacrylamide gel electrophoresis (PAGE), and capillary electrophoresis electrospray ionization mass spectrometry (CE‐ESI‐MS), we found that their PP‐InsP pyrophosphatase activity is enantiomer selective and Mg 2+ dependent. Specifically, Subclade I NUDTs preferentially hydrolyze 4‐InsP 7 , while Subclade II NUDTs target 3‐InsP 7 , with minor activity against other PP‐InsPs, including 5‐InsP 7 . In higher order mutants of Subclade II NUDTs, we observed defects in both P i and iron homeostasis, accompanied by increased levels of 1/3‐InsP 7 and 5‐InsP 7 , with a markedly larger increase in 1/3‐InsP 7 . Ectopic expression of NUDTs from both subclades induced local P i starvation responses (PSRs), while RNA‐seq analysis comparing wild‐type (WT) and Subclade II nudt12/13/16 loss‐of‐function plants indicates additional PSR‐independent roles, potentially involving 1/3‐InsP 7 in the regulation of plant defense. Consistently, nudt12/13/16 mutants displayed enhanced resistance to Pseudomonas syringae infection, indicating a role in bacterial pathogen susceptibility. Expanding beyond Subclade II NUDTs, we demonstrated susceptibility of the 3PP‐position of PP‐InsPs to enzymatic activities unrelated to NUDTs, and found that such activities are conserved across plants and humans. Additionally, we observed that NUDT effectors from pathogenic ascomycete fungi exhibit a substrate specificity similar to Subclade I NUDTs. Collectively, our findings reveal new roles for NUDTs in PP‐InsP signaling, plant nutrient and immune responses, and highlight a cross‐kingdom conservation of PP‐InsP‐metabolizing enzymes.