bluuebunny/crossref_metadata_2025_split huggingface dataset:
HumanRAP2AHomolog of theDrosophilaAsymmetric Cell Division RegulatorRap2lTargets the Stemness of Glioblastoma Stem Cells
Authors: Franco Maribel , Gargini Ricardo , Barberá Víctor M. , Saceda Miguel , Carmena Ana 
Published: February 2025

AbstractAsymmetric cell division (ACD) is a fundamental process to balance cell proliferation and differentiation during development and in the adult. Cancer stem cells (CSCs), a very small but highly malignant population within many human tumors, are able to provide differentiated progeny by ACD that contribute to the intratumoral heterogeneity, as well as to proliferate without control by symmetric, self-renewing divisions. Thus, ACD dysregulation in CSCs could trigger cancer progression. Here we consistently find low expression levels ofRAP2A, the human homolog of theDrosophilaACD regulatorRap2l, in glioblastoma (GBM) patient samples, and observe that scarce levels ofRAP2Aare associated with poor clinical prognosis in GBM. Additionally, we show that restitution of RAP2A in GBM neurosphere cultures increases the ACD of glioblastoma stem cells (GSCs), decreasing their proliferation and expression of stem cell markers. Our results support that ACD failures in GSCs increases their spread, and that ACD amendment could contribute to reduce the expansion of GBM.
Revitalizing systemic immune responses in advanced NSCLC using FLT3L and SBRT
Authors: Mathew Divij , Ohri Nitin , Ngiow Shin Foong , Halmos Balazs , Wumesh KC , Garg Madhur , Levsky Jeffrey M , Cheng Haiying , Gucalp Rasim A. , Bodner William Raymond , Kabarriti Rafi , Gutierrez-Chavez Claudia , Zakharia Adel , Kalnicki Shalom , Keler Tibor , Yellin Michael , Minn Andy J , Maity Amit , Giles Josephine R , Guha Chandan , Wherry E. John 
Published: February 2025

AbstractNon-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. For patients who develop progressive disease after treatment with chemotherapy and immunotherapy, treatment options are limited. Here, we report the results of a Phase II clinical trial where twenty-nine patients with advanced, previously treated NSCLC were treated with stereotactic body radiotherapy (SBRT) targeting a single site of disease along with CDX-301, a recombinant human Fms-like tyrosine kinase 3 ligand (FLT3L). The primary study endpoint was progression-free survival four months after study entry (PFS4), which was achieved for 14 patients (48%). Abscopal responses were observed on fludeoxyglucose-18 positron emission tomography (FDG-PET) in nine patients (31%). The median overall survival for all participants was 18 months, with a median overall survival for participants with abscopal response of 31 months. To identify underlying immune signatures of response, we developed a high dimensional flow cytometric approach that quantified 31 distinct cell subsets from peripheral blood, and performed multiplex proteomic analysis of 92 proteins from plasma. SBRT combined with CDX-301 significantly increased circulating myeloid cells, including monocytes, myeloid derived suppressor cells (MDSCs) and dendritic cells (DCs). Among DCs, FceR1-expressing DC2 and DC3 subsets changed most robustly upon treatment. These dynamic changes in DCs and MDSCs following initiation of SBRT and CDX-301 returned to baseline by 8 weeks. However, these changes were also associated with treatment-induced T cell activation with quantitatively robust activation of CD4 T cells. Abscopal responses were associated with a prolonged increase in DC1 cells, Th1-like CD4 T cells, circulating IL-12 and FLT3L. Integrated analysis of multiple types of immune parameters revealed a strong association between coordinated DC induction, CD4 T cell and CD8 T cell activation, and inflammatory cytokine activity in patients with abscopal responses, compared to a stark lack of immune coordination in patients without abscopal responses. These coordinated immune responses were sustained for over 4 weeks in responders, highlighting a potential therapeutic axis engaged in a systemic immune response against multiple lesions in NSCLC. Overall, these findings underscore the potential of combiningin situvaccination, using SBRT, with strategies to enhance the activation of innate immune cells, such as DCs through FLT3L, to potentiate robust anti-tumor T cell responses.
The beta-triketone, nitisinone, kills insecticide-resistant mosquitoes through cuticular uptake
Authors: Stavrou-Dowd Zachary Thomas , Parsons George , Rose Clair , Brown Faye , Lees Rosemary Susan , Acosta-Serrano Álvaro , Haines Lee Rafuse 
Published: February 2025

AbstractThe efficacy of numerous vector control initiatives is compromised by growing insecticide resistance among disease-transmitting arthropods of agricultural, veterinary, and public health significance. Previous investigations on hematophagous (blood-feeding) arthropod vectors, including mosquitoes, have indicated that ingesting blood containing inhibitors of the second enzyme in the tyrosine metabolism pathway, 4-hydroxyphenylpyruvate dioxygenase (HPPD), results in high insect mortality. Building upon this foundation, we evaluated the insecticidal efficacy of the HPPD inhibitor, nitisinone, against susceptible and pyrethroid-resistant strains of three mosquito species:Anopheles gambiae, Aedes aegypti and Culex quinquefasciatus. These mosquitoes are vectors of historical diseases such as malaria, emerged diseases such as Dengue and Zika and emerging viral diseases such as the Oropouche and Usutu viruses. We demonstrate, by employing standard screening assays designed to assess the cuticular uptake of mosquitocidal agents, that nitisinone has mosquitocidal activity when blood-fed mosquitoes contact a nitisinone-coated surface. Notably, there is no discernible disparity in susceptibility to nitisinone between an insecticide-susceptible strain ofAnopheles gambiaeand two strains carrying multiple insecticide-resistance mechanisms. We conclude that the mosquitocidal mode of action of nitisinone differs from any of the current 37 classes of insecticides as none have a mode of action that specifically interferes with blood digestion. By highlighting the efficacy of nitisinone as a contact-based insecticide, our findings support the potential expansion of vector control strategies where nitisinone is incorporated into classic interventions like treated bednets and indoor residual spraying.
The kin-selected context of duelling in horned aphids: cooperation or conflict?
Authors: Uematsu Keigo , Yang Man-Miao , Foster William 
Published: February 2025

AbstractIn one-on-one (dyadic) contests in group-living animals, relatedness is of potentially critical importance in determining the relative value of the resources for which the individuals are fighting. We investigated the function of dyadic contests over access to a food resource (plant phloem) in the horned aphidAstegopteryx bambusae, by observing competing aphids in the field and genotyping them with microsatellite markers. Each aphid colony consists of a small number of clones, creating levels of relatedness that can be both high and variable. The contests involve only low costs in terms of time or injury.Our results indicate that there is no kin-discrimination in the duelling pairs of aphids. Genetic relatedness between duelling pairs did not differ significantly from that of randomly selected pairs and showed no association with contest duration or outcome. The mean relatedness between a duelling pair was 0.79 ± 0.12 (mean ± SD,N= 75), with 56% (42/75) of duels occurring between clonal pairs.We suggest that the duels in theseAstegopteryxaphids are not an aggressive fight for resources between different genotypes, but rather a low-cost method by which the aphids assess each other’s reproductive value. 83% (50/60) of the contests between aphids of different ages were won by the aphid that was older, and therefore of greater reproductive value, providing an indirect fitness benefit for the losing younger individual. Younger nymphs, when attacked by older aphids, yield feeding sites altruistically and gain inclusive fitness benefits: this provides a compelling selective context for the evolution of the young, rather than old, altruistic soldiers that are observed in the open colonies of many cerataphidine species.
MassVision: An open-source end-to-end platform for AI-driven mass spectrometry image analysis
Authors: Jamzad Amoon , Syeda Ayesha , Warren Jade , Kaufmann Martin , Iaboni Natasha , Nicol Christopher J. B. , Rudan John , Ren Kevin Y. M. , Hurlbut David , Varma Sonal , Fichtinger Gabor , Mousavi Parvin 
Published: February 2025

AbstractMass spectrometry imaging (MSI) combines spatial and spectral data to reveal detailed molecular compositions within biological samples. Despite their immense potential, MSI workflows are hindered by the complexity and high dimensionality of the data, making their analysis computationally intensive and often requiring expertise in coding. Existing tools frequently lack the integration needed for seamless, scalable, and end-to-end workflows, forcing researchers to rely on local solutions or multiple platforms, hindering efficiency and accessibility. We introduce MassVision, a comprehensive soft-ware platform for MSI analysis. Built on the 3D Slicer ecosystem, MassVision integrates MSI-specific functionalities while addressing general user requirements for accessibility and usability. Its intuitive interface lowers barriers for researchers with varying levels of computational expertise, while its scalability supports high-throughput studies and multi-slide datasets. Key functionalities include visualization, co-localization, dataset curation, dataset merging, spectral and spatial preprocessing, AI model training, and AI deployment on full MSI data. We detail the workflow and functionalities of MassVision and demonstrate its effectiveness through different experimental use cases such as exploratory data analysis, ion identification, and tissue-type classification, on in-house and publicly available data from different MSI modalities. These use cases underscore the MassVision’s ability to seamlessly integrate MSI data handling steps into a single platform, and highlight its potential to reveal new insights and structures when examining biological samples. By combining cutting-edge functionality with user-centric design, MassVision addresses longstanding challenges in MSI data analysis and provides a robust tool for advancing the user’s ability to achieve biologically-meaningful insights from MSI data.
CDK8 remodels the tumor microenvironment to resist the therapeutic efficacy of targeted KRASG12Dinhibition in pancreatic ductal adenocarcinoma
Authors: McAndrews Kathleen M. , Mahadevan Krishnan K. , Li Bingrui , Sockwell Amari M. , Morse Sami J. , Kelly Patience J. , Patel Sarah I. , Kirtley Michelle L. , Moreno Diaz Barbara A. , Lyu Hengyu , Zhou Xunian , Sugimoto Hikaru , Sthanam Lakshmi Kavitha , Conner Meagan R. , Kumbhar Shreyasee V. , Arian Kent A. , Barekatain Yasaman , Paradiso Francesca , Guerrero Paola A. , Bernard Vincent , Sobhani Navid , Camacho-Acevedo Alondra N. , Bornes Kiara E. , Tran Phuong Thao , Maitra Anirban , Heffernan Timothy P. , Kalluri Raghu 
Published: February 2025

AbstractMutations inKRASare a dominant driver of pancreatic ductal adenocarcinoma (PDAC), with over 40% of PDAC patients presenting withKRASG12Dmutations. The recent development of small molecule inhibitors targeting KRASG12Dhas enabled targeting of mutant KRAS signaling and suppression of PDAC; however, the contribution of the tumor microenvironment (TME) to the sustained therapeutic efficacy of KRASG12Dinhibition and mechanism/s of resistance to KRASG12Dsuppression remain to be elucidated. Here, we employed spatial transcriptomics, single cell RNA sequencing, and CODEX-based spatial proteomics to evaluate cancer cell intrinsic and extrinsic responses to KRASG12Dinhibition with MRTX1133. While KRASG12Dinhibition initially increases CD11c+cells with impactful T cell infiltration within proximity to cancer cells, long-term treatment with MRTX1133 resulted in reversal of the immune responses leading to KRASG12Dtherapy resistance promoted by CDK8, a multiprotein mediator complex associated kinase. CDK8 imparts resistance in part through induction of downstream CXCL2 chemokine secretion, inhibition of FAS expression, and remodeling of the TME to promote immune evasion. Targeting CDK8 by itself and in combination with αCTLA-4 immunotherapy overcomes resistance to KRASG12Dinhibition with prolonged survival with translational implications.
Utilizing Genomics to Identify Novel Immunotherapeutic Targets in Multiple Myeloma High-Risk Subgroups
Authors: Liu Enze , Jaouadi Oumaima , Sharma Riya , Becker Nathan , Johnson Travis S. , Sudha Parvathi , Chopra Vivek S. , Zafar Faiza , Hamidi Habib , Pawlyn Charlotte , Suvannasankha Attaya , Abonour Rafat , Walker Brian A. 
Published: February 2025

AbstractImmunotherapy is now standard of care for multiple myeloma, where the most common targets are B cell maturation antigen, CD38, and G protein-coupled receptor class C group 5 member D but strategies to identify additional targets are needed. We have utilized two large datasets of genomic data and integrated them with existing databases to identify expressed cell surface targets in myeloma patients. Importantly, we also identify targets specific to genomic defined subgroups of patients including primary translocations and high-risk subgroups. Examples of subgroup targets includeROBO3in t(4;14),CD109in t(14;16),CD20in t(11;14),GPRC5Din 1q+, andADAM28in biallelicTP53samples. Expression was validated by flow cytometry and CRISPR-Cas9 knock out models. Sub-clonal differences in expression were noted, as was alternative splicing of existing immunotherapy targets such asFCRL5. These results highlight the use of genomic stratification to identify novel therapeutic targets.Graphical Abstract
A SNP Foundation Model: Application in Whole-Genome Haplotype Phasing and Genotype Imputation
Authors: Xu Augix Guohua , Xu Yu , Xing Yiming , Yang Jianbo , Bai Yinqi , Tang Kun 
Published: February 2025

AbstractArtificial intelligence foundation models are revolutionizing biomedical research. Human genetic diversity data, predominantly in the form of single nucleotide polymorphisms (SNPs), constitutes the largest and fastest growing portions of biobank databases. However, SNP data has been a missing piece in the Bio-AI domain. Here, we present SNPBag, the first SNP foundation model for genome-scale SNP analyses. Built on a large language model (LLM), SNPBag aims to address haplotype phasing and genotype imputation simultaneously. Using data from the 1000 Genome Project, we pre-trained SNPBag on overlapping sequences by masking genotypes. For haplotype phasing task, our model achieved a state-of-the-art (SOTA) 1% switch error rate, outperforming BEAGLE5.2, EAGLE2, and SHAPEIT4. In genotype imputation for the Illumina Omni2.5 SNP array, the model reached an accuracy of 96.88%, comparable to the best available methods. Additionally, when fine-tuned for ancestry inference, the model achieved 97% accuracy in predicting the super-populations of 72 individuals from the 1000 Genome Project. This study demonstrates the great potential of SNPBag in representing and inferring global human genetic diversity. Future research will focus on training SNPBag with large-scale Genome-Wise Association Study (GWAS) data to predict phenotypes from whole-genome genotypes, opening new avenues for understanding human genetics and disease.
Auditory Enhancement of Sleep Slow Waves in People with Parkinson’s Disease: A Proof-of-Concept Study
Authors: Schreiner Simon J. , Horlacher Jana , Fattinger Sara , Renerts Klavs , Brogli Luzius , Kämpf Lydia , Scandella Maurizio , Poryazova Rositsa , Valko Philipp O. , Ferster Laura , Sassenburg Renske , Jaramillo Valeria , Poian Giulia Da , Lustenberger Caroline , Karlen Walter , Huber Reto , Baumann Christian R. , Maric Angelina 
Published: February 2025

AbstractDeep sleep supports several restorative functions and has emerged as a potential therapeutic target in neurodegenerative disorders, such as Parkinson’s disease (PD). Phase-targeted auditory stimulation (PTAS) is a non-invasive method for enhancing slow waves of deep sleep, measurable by increased slow-wave activity (SWA; spectral power 0.75–4.5 Hz). Here, we report the first study investigating whether PTAS can be successfully applied in PD patients with subjective sleep disturbance.We conducted a randomized, double-blind, sham-controlled, cross-over, within-subject study assessing the effects of PTAS over three nights with wearable devices at participants’ homes. PTAS was applied in ON and OFF windows for the entire night in 14 participants and first part of the night in nine.PTAS increased low-frequency SWA by almost 30% during ON windows in 21 analyzed participants. The SWA increased further with higher numbers of stimuli, suggesting a dose- dependent effect. Participants receiving part-night PTAS reported improved subjective daytime sleepiness after the third night.This proof-of-concept study demonstrates successful auditory enhancement of slow waves with PTAS in PD. Our observation of the potential advantages of part-night PTAS warrant further exploration. Our data encourage longer and larger trials to fully explore the potential of PTAS in PD and other neurodegenerative diseases.
Mitochondrial and Stress-Related Psychobiological Regulation of FGF21 in Humans
Authors: Kurade Mangesh , Bobba-Alves Natalia , Kelly Catherine , Behnke Alexander , Conklin Quinn , Juster Robert-Paul , Hirano Michio , Trumpff Caroline , Picard Martin 
Published: February 2025

AbstractFGF21 is a metabolic hormone induced by fasting, metabolic stress, and mitochondrial oxidative phosphorylation (OxPhos) defects that cause mitochondrial diseases (MitoD). Here we report that acute psychosocial stress alone (without physical exertion) decreases serum FGF21 by an average of 20% (p<0.0001) in healthy controls but increases FGF21 by 32% (p<0.0001) in people with MitoD—pointing to a functional interaction between the stress response and OxPhos capacity in regulating FGF21. We further define co-activation patterns between FGF21 and stress-related neuroendocrine hormones and report novel associations between FGF21 and psychosocial factors related to stress and wellbeing, highlighting a potential role for FGF21 in meeting the energetic needs of acute and chronic psychosocial stress.
META-ANALYSIS AND SYSTEMATIC REVIEW OF PULMONARY VALVE ANNULUS Z-SCORE AS A PREDICTOR OF VALVE PRESERVATION IN TETRALOGY OF FALLOT RIGHT VENTRICULAR OUTFLOW TRACT RECONSTRUCTION
Authors: Sitanggang Johan S. , Purba Salomo , Fakhri Dicky , Busro Pribadi W. , Rahmat Budi , Utomo Panji , Hernisa Latifa , Djaka Marshal B. , Pohan Doddy P. , Sitanggang Henry H. , Vinolina Noverita S. , Arvant Anisya Z. 
Published: February 2025

AbstractIntroductionTetralogy of Fallot (ToF) is the most prevalent cyanotic congenital heart defect, requiring timely surgical intervention to improve survival. Two primary techniques for right ventricular outflow tract (RVOT) reconstruction are transannular patch (TAP) repair and valve-sparing (VS) surgery as a less invasive alternative. While TAP resolves pulmonary stenosis, it often results in long-term pulmonary regurgitation (PR).Aim and ObjectivesThis meta-analysis investigates the pulmonary valve annulus (PVA) z-score as a predictor for choosing VS techniques to minimize complications, mean difference and cut-off analysis.MethodsA systematic review and meta-analysis were conducted across 32 studies (N=5,931) assessing preoperative PVA z-scores in patients undergoing TAP or VS RVOT reconstruction. Data extraction followed PRISMA guidelines, with statistical analyses using a random-effects model by Review Manager 5.4.1 and receiver operating characteristic (ROC) curve evaluation.ResultsThe meta-analysis showed significantly higher preoperative PVA z-scores in the VS group (MD: 0.99, 95% CI: 0.73–1.25, p < 0.00001). The pooled grand mean PVA z-scores were-1.48 for VS and-2.93 for TAP. ROC analysis identified a z-score threshold of ≥-2.59 (sensitivity: 81.3%, specificity: 75%) as optimal for VS surgery.ConclusionThis study establishes the PVA z-score as a robust predictor for VS approaches in ToF repair, with a proposed threshold of ≥-2.59 for optimal outcomes. Adoption of VS techniques guided by standardized z-score criteria may reduce PR- associated complications and enhance long-term survival and quality of life.
Optimising covariate allocation at design stage using Fisher Information Matrix for Non-Linear Mixed Effects Models in pharmacometrics
Authors: Fayette Lucie , Brendel Karl , Mentré France 
Published: February 2025

AbstractThis work focuses on designing experiments for pharmacometrics studies using Non-Linear Mixed Effects Models including covariates to describe between-subject variability. Before collecting and modelling new clinical trial data, choosing an appropriate design is crucial. Assuming a known model with covariate effects and a joint distribution for covariates in the target population from previous clinical studies, we propose to optimise the allocation of covariates among the subjects to be included in the new trial. It aims achieving better overall parameter estimations and therefore increase the power of statistical tests on covariate effects to detect significance, and more importantly, clinical relevance or non-relevance of relationships. We suggested dividing the domain of continuous covariates into clinically meaningful intervals and optimised their proportions, along with the proportion of each category for the discrete covariates. We used the Fisher Information Matrix and developed a fast and deterministic computation method, leveraging Gaussian quadrature and copula modelling. The optimisation problem was formulated as a convex problem subject to linear constraints, allowing resolution using Projected Gradient Descent algorithm. Different scenarios for a pharmacokinetics model were explored. We showed the benefit of covariate optimisation in reducing the number of subjects needed to achieve desired power in covariate tests.
The Impact of Rural Hospital Closures and Mergers on Health System Ecologies: A Scoping Review
Authors: Coates Alison , Probst Janice , Sarwal Kanika , Riaz Suhaib , Grudniewicz Agnes 
Published: February 2025

AbstractDespite playing a pivotal role in rural community health services delivery and in local economies, rural hospitals in the United States have closed or merged with larger health networks at alarming rates. This scoping review examines what is known about the impacts of rural hospital closures and mergers, synthesizing the literature across 2010-2024. Most of the identified studies examined closures, primarily reporting on community impacts. Using this literature, we inductively derived a new Health System Ecologies Impact Matrix research tool to assess knowledge related to health system changes. Knowledge gaps remain related to financial, workforce, and utilization-related outcomes, and little is known about closure impacts on neighboring hospitals and communities. Few studies report effects of rural hospital mergers, with those analyses primarily focusing on financial and utilization outcomes for the merged hospital. No studies examined the impacts of rural hospital mergers on patients or individuals and their social environments.ProtocolThe registered scoping review protocol may be accessed on OSF:https://doi.org/10.17605/OSF.IO/GEKJC