bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting Pre-existing Club-Like Cells in Prostate Cancer Potentiates Androgen Deprivation Therapy
Authors: Baurès Manon , Aleixo Anne-Sophie Vieira , Pacreau Emeline , Koshy Aysis , Diedisheim Marc , Raigel Martin , Hua Yichao , Dariane Charles , Boutillon Florence , Kenner Lukas , Marine Jean-Christophe , Laverny Gilles , Metzger Daniel , Rambow Florian , Guidotti Jacques-Emmanuel , Goffin Vincent 
Published: February 2025

AbstractA critical knowledge gap in prostate cancer research is understanding whether castration-tolerant progenitor-like cells that reside in treatment-naïve tumors play a direct role in therapy resistance and tumor progression. Herein, we reveal that the castration tolerance of LSCmed(Lin-, Sca-1+, CD49fmed) progenitor cells, the mouse equivalent of human prostatic Club cells, arises not from intrinsic properties but from significant transcriptional reprogramming. Utilizing single-cell RNA sequencing of LSCmedcells isolated from prostate-specific Pten-deficient (Ptenpc-/-) mice, we identify the emergence of castration-resistant LSCmedcells enriched in stem-like features, driven by the transcription factor Fosl1/AP-1. We demonstrate that cells exhibiting Ptenpc-/-LSCmedcharacteristics are prevalent in the aggressive mesenchymal stem-like prostate cancer (MSPC) subtype recently identified in human castration-resistant prostate cancer (CRPC). Furthermore, our findings show that the dual-targeting agents JQ-1 and CX-6258—focused on Fosl1/AP-1 and PIM kinases, respectively—effectively suppress both the progenitor properties and the growth of mouse and human MSPC surrogatesin vitroandin vivo. Thus, early eradication of castration-tolerant Club-like cells presents a promising therapeutic strategy to mitigate prostate cancer progression toward CRPC.
RUNX1::RUNX1T1 Depletion Eliminates Stemness and Induces Bidirectional Differentiation of Acute Myeloid Leukemia
Authors: Derevyanko Polina K , Swart Laura E. , Casimiro L. Daniel Mata , van den Brink Luca , van Oort Anita T. , Ashtiani Minoo , Zwaan C. Michel , Krippner-Heidenreich Anja , Bonifer Constanze , Schiffelers Raymond , Vormoor H. Josef , Kellaway Sophie G. , Heidenreich Olaf 
Published: February 2025

AbstractChromosomal rearrangements that generate novel fusion genes are a hallmark of acute myeloid leukemia (AML). Depletion experiments in cell line models have suggested that continued expression is required for maintaining their leukemic phenotype and they therefore represent ideal cancer-specific therapeutic targets. However, to which extent this result holds true for the different stages of hematopoietic development in primary cells and whether therapeutic agents can be efficiently delivered to those cells is still unclear. In this study, we demonstrate that primary AML cells harboring the chromosomal translocation t(8;21) are critically dependent on the corresponding fusion gene,RUNX1::RUNX1T1, to suppress differentiation and maintain stemness. SilencingRUNX1::RUNX1T1expression using siRNA-loaded lipid nanoparticles induces substantial changes in chromatin accessibility, thereby redirecting the leukemia-associated transcriptional network towards a myeloid differentiation program. Single-cell analyses reveal that this transcriptional reprogramming is associated with the depletion of immature stem and progenitor-like cell populations, accompanied by an expansion of granulocytic and eosinophilic/mast cell-like populations with impaired self-renewal capacity. These findings underscore the essential role ofRUNX1::RUNX1T1in sustaining AML and highlight the therapeutic potential of targeting fusion gene expression in primary AML cells.Abstract Figure
Clonal memory of colitis accumulates and promotes tumor growth
Authors: Nagaraja Surya , Ojeda-Miron Lety , Zhang Ruochi , Oreskovic Ena , Hu Yan , Zeve Daniel , Sharma Karina , Hyman Roni R. , Zhang Qiming , Castillo Andrew , Breault David T. , Yilmaz Ömer H. , Buenrostro Jason D. 
Published: February 2025

AbstractChronic inflammation is a well-established risk factor for cancer, but the underlying molecular mechanisms remain unclear. Using a mouse model of colitis, we demonstrate that colonic stem cells retain an epigenetic memory of inflammation following disease resolution, characterized by a cumulative gain of activator protein 1 (AP-1) transcription factor activity. Further, we develop SHARE-TRACE, a method that enables simultaneous profiling of gene expression, chromatin accessibility and clonal history in single cells, enabling high resolution tracking of epigenomic memory. This reveals that inflammatory memory is propagated cell-intrinsically and inherited through stem cell lineages, with certain clones demonstrating dramatically stronger memory than others. Finally, we show that colitis primes stem cells for amplified expression of regenerative gene programs following oncogenic mutation that accelerate tumor growth. This includes a subpopulation of tumors that have exceptionally high AP-1 activity and the additional upregulation of pro-oncogenic programs. Together, our findings provide a mechanistic link between chronic inflammation and malignancy, revealing how long-lived epigenetic alterations in regenerative tissues may contribute to disease susceptibility and suggesting potential therapeutic strategies to mitigate cancer risk in patients with chronic inflammatory conditions.
Robust analytical methods for bis(monoacylglycero)phosphate profiling in health and disease
Authors: Dong Wentao , Nyame Kwamina , Rawat Eshaan S. , Medoh Uche N. , Xiong Jian , Bonin Caio C. , Alsohybe Hisham N. , Liu Hunter Y. , Gomes Sara , Hsieh Tammy , Arnold Marianna , Hsieh Frank , Sammler Esther , Abu-Remaileh Monther 
Published: February 2025

AbstractBis(monoacylglycero)phosphate (BMP), a distinct anionic phospholipid predominantly found in late endosomes and lysosomes, plays a pivotal role in supporting lysosomal functions and maintaining metabolic homeostasis. Its impaired function is associated with an array of disorders, notably neurodegenerative diseases. However, the identification and quantitation of BMP remains difficult due to its structural similarity to isomer phosphatidylglycerol (PG), thus necessitating robust analytical methods for accurate and reliable BMP profiling. In this study, we present comprehensive liquid chromatography – tandem mass spectrometry (MS2) methodologies for the precise and systematic analysis of BMP species in biological samples. We detail LC/MS methods for both an untargeted Orbitrap mass spectrometer and a targeted triple quadrupole (QQQ) mass spectrometer. We utilize differences in polarity and structure to annotate BMPs and PGs based on retention time and positive mode MS2 fragmentation patterns, respectively. Further, we propose a new approach for overcoming common challenges in BMP profiling by leveraging the newly discovered biochemical function of CLN5 as the BMP synthase. Since genetic ablation of CLN5 leads to specific depletion of BMPs but not PGs, we use lipid extracts fromCLN5knockout (KO) and wild-type (WT) cells as biological standards to confidently annotate BMPs as targets with significantly low BMP Identification Index (BMPII), defined as BMPII =CLN5KO / WT. We additionally propose the BMP enrichment score (BMPES) as a secondary validation metric, defined as lysosomal abundance of BMP / whole-cell abundance. Altogether, this approach constitutes a robust method for BMP profiling and annotation, furthering research into health and disease.
A flexible Bayesian method for estimating stratigraphic intervals and their co-occurrence in time
Authors: Ballen Gustavo A. 
Published: February 2025

1AbstractThe fossil record is both incomplete and full of biases, which hinders making inferences about the past of life on earth. Stratigraphic intervals help us estimate two important quantities from the fossil record of a given lineage, its origination and extinction times.Many models are available in the literature. This toolset is complemented here by proposing a flexible method which allows to estimate origination and extinction times, as well as model preservation potential in flexible ways.A method is presented for representing the stratigraphic interval as a continuous distribution by integrating over parameter uncertainty throughthe use of the posterior predictive distribution. It is possible then to combine these distributions using conflation, to build a time probabilistic model for the co-occurrence of these intervals.Empirical examples using Palynomorphs and the origination time of the marine Barracudas are used for illustrating the potential of the method. The methods are implemented in theStratIntervals.jlJulia package, which allows a big amount of possible prior distributions, and MCMC samplers.
Identifying clusters of people with Multiple Long-Term Conditions using Large Language Models: a population-based study
Authors: Smith Alexander , Beaney Thomas , Hockham Carinna , Su Bowen , Elliott Paul , Downey Laura , Denaxas Spiros , Barnaghi Payam , Dehghan Abbas , Tzoulaki Ioanna 
Published: February 2025

AbstractBackgroundIdentifying clusters of people with similar patterns of Multiple Long-Term Conditions (MLTC) could help healthcare services to tailor management for each group. Large Language Models (LLMs) can utilise complex longitudinal electronic health records (EHRs) which may enable deeper insights into patterns of disease. Here, we develop a pipeline, incorporating an LLM, to generate gender-specific clusters using clinical codes recorded in EHRs.MethodsIn this population-based study, we used EHRs from individuals aged ≥50 years from Clinical Practice Research Datalink in the UK. Longitudinal sequences of medical histories including diagnoses, diagnostic tests and medications were used to pre-train an LLM based on DeBERTa. The LLM, called EHR-DeBERTa, includes embedding layers for age of diagnosis, calendar year of diagnosis, gender, and visit number with a diagnosis vocabulary of 3776 tokens, covering the entire ICD-10 hierarchy. We fine-tuned EHR-DeBERTa using contrastive learning and generated patient embeddings for all individuals. A bootstrapping clustering pipeline was applied separately for females and males and gender-specific patient clusters were characterised by disease prevalence, ethnicity and deprivation.FindingsA total of 5,846,480 patients were included. We identified fifteen clusters in females and seventeen clusters in males, grouped into five categories: i) low disease burden; ii) mental health; iii) cardiometabolic diseases; iv) respiratory diseases, and v) mixed diseases. Cardiometabolic and mental health conditions showed the strongest separation across clusters. People in low disease burden and mental health clusters were younger, whereas those in cardiometabolic clusters were older, with females in cardiometabolic clusters older than their male counterparts.InterpretationUsing an LLM applied to longitudinal EHRs, we generated interpretable and gender-specific clusters of diseases, providing insights into patterns of diseases. Extending these methods in future to incorporate clinical outcomes could enable identification of high-risk patients and support precision-medicine approaches for managing MLTC.
Infections in the Atlantic Blue CrabCallinectes sapidus(Rathbun, 1896) in coastal Adriatic, Aegean sea, and Atlantic Iberian coast
Authors: Schott Eric , Šćepanović Marina Brailo , Lučić Jasna Maršić , Pares Olivia , Zhao Mingli , Hrabar Jerko , Glamuzina Luka , Pećarević Marijana , Grđan Sanja , da Silva Encarnação João Pedro , Ana Pešić Pedro Morais , Ćetković Ilija , Glamuzina Branko 
Published: February 2025

AbstractIn the Mediterranean Sea, the abundance of the invasive portunid crab,Callinectes sapidus, has dramatically increased in recent years. This raises concerns about damage to ecosystems, but also offers opportunities for exploitation of a new fishery. Newly invasive species may escape from pathogens in their endemic range, may introduce new pathogens, or can become host to endemic pathogens. Understanding these factors is important for predicting or managing natural resources in the invaded range. This study investigated the prevalence of two pathogens common inC. sapidusin its home range of North America: the reovirus CsRV1 and the protozoan parasiteHematodiniumsp. In crabs collected from Aegean, Adriatic, and Atlantic waters, the CsRV1 virus was not detected. In contrast, the parasiteHematodiniumsp. was found in all areas except the Aegean Sea. Sequence analysis of theHematodiniumsp. ITS1 gene indicated that the strains observed are most related toHematodiniumsp. strains already described in Europe and the Mediterranean, and not to strains from the Americas. The arrival of new species and new potential pathogens is ongoing through transfer of ballast water to the Atlantic and Mediterranean. Although systems are in place to exchange or inactivate ballast water, it is advisable to continue and expand surveillance for pathogens in introduced species, to inform management of movement of these species between regions.
Evolution of the conformational ensemble and allosteric networks of apoptotic caspases in chordates
Authors: Joglekar Isha , Karadi Giridhar Mithun Nag , Diaz David A. , Deo Ankit , Clay Clark A. 
Published: February 2025

AbstractCaspases, known for their role in apoptosis and inflammation, have recently emerged as potential regulators of cell differentiation and proliferation. The regulation of caspase conformations to affect these specific pathways is not well understood. Understanding the conformational landscapes, intermediate states, and mechanisms for fine-tuning these ensembles is critical for unraveling their diverse regulatory functions. We combined experimental and computational techniques to characterize the evolution of conformational ensemble in caspases. Using ancestral protein reconstruction, molecular dynamics simulations, and network analysis, we identify a network of residues that serve as a scaffold for conformational variation, and the network has been faithfully passed down over 500 million years of apoptotic caspase evolution. In addition, investigations of free energy landscapes provide thermodynamic insights into how initiator and effector caspase subfamilies stabilize monomeric and dimeric conformations while undergoing conformational dynamics. We find, through mutational in-vitro folding analysis, that the small subunit and amino acid networks at the base of the structure are essential for conformational dynamics beyond a ubiquitous intermediate present in the conformational ensemble of all apoptotic chordate caspases. We identify key allosteric hub residues that regulate the equilibrium in the conformational ensembles of all apoptotic caspases in chordates. Lastly, by combining our new data set with previous folding studies we provide a comprehensive model for folding of all apoptotic caspases in chordates.
Biochemical and structural basis of Dicer helicase function unveiled by resurrecting ancient proteins
Authors: Aderounmu Adedeji M. , Maus-Conn Josephine , Consalvo Claudia D. , Shen Peter S. , Bass Brenda L. 
Published: February 2025

AbstractA fully functional Dicer helicase, present in the modern arthropod, uses energy generated during ATP hydrolysis to power translocation on bound dsRNA, enabling the processive dsRNA cleavage required for efficient antiviral defense. However, modern Dicer orthologs exhibit divergent helicase functions that affect their ability to contribute to antiviral defense, and moreover, mechanisms that couple ATP hydrolysis to Dicer helicase movement on dsRNA remain enigmatic. Here, we used biochemical and structural analyses of ancestrally reconstructed Dicer helicases to map evolution of dsRNA binding affinity, ATP hydrolysis and translocation. We found that loss of affinity for dsRNA occurred early in Dicer evolution, coinciding with a decline in translocation activity, despite preservation of ATP hydrolysis activity, exemplified by the ancient deuterostome Dicer. Ancestral nematode Dicer also exhibited significant decline in ATP hydrolysis and translocation, but studies of antiviral activities in the modern nematodeC. elegansindicate Dicer retained a role in antiviral defense by recruiting a second helicase. Cryo-EM analyses of an ancient metazoan Dicer allowed capture of multiple helicase states revealing the mechanism that connects each step of ATP hydrolysis to unidirectional movement along dsRNA. Overall, our study rationalizes the diversity in modern Dicer helicases by connecting ancestral functions to observations in extant enzymes.Significance StatementAmong invertebrates, the contribution of Dicer’s helicase to recognition and elimination of viral double-stranded RNA varies from phylum to phylum. At the extreme end of the spectrum, vertebrate Dicers show no helicase activity. On the other end, an arthropod ortholog uses helicase translocation to efficiently move double-stranded RNA into Dicer’s cleavage site. The biochemical and structural basis of Dicer’s helicase function, as well as the evolutionary events that contribute to a divergence in function, have remained unknown. This study shows how ancient Dicer helicase tightly binds double-stranded RNA and couples ATP hydrolysis to movement along this substrate. In addition, the data reveal how components of this intricate system declined along different clades of animal evolution.
Structural patterns and transcriptional effects of integrated Epstein-Barr virus revealed by long-read sequencing and RNA-sequencing in Nasopharyngeal Carcinoma
Authors: Kardan Zahra , Kadam Adway , Chai Annie Wai Yeeng , Cheong Sok Ching , Loganathan Sampath Kumar 
Published: February 2025

AbstractIntegration of Epstein–Barr virus (EBV) DNA into the human genome is a critical event in nasopharyngeal carcinogenesis. Here, we comprehensively characterize large-scale virus-human integration events in four EBV-positive nasopharyngeal carcinoma (NPC) cell lines and tumors using Nanopore long-read sequencing technology. We identified four distinct integration types, with Type I being particularly notable, characterized by continuous long reads covering nearly the entire EBV genome. Our findings reveal the involvement of multiple integration events in inducing inter-chromosomal translocations, leading to significant genomic disruption through chromosomal rearrangements. Additionally, we explore the relationship between EBV integration sites and structural variations, further supporting the role of EBV integration in driving genomic instability. By integrating RNA-seq data, we demonstrate the potential for EBV integration to disrupt gene expression, highlighting several integration sites within cancer-associated genes such as CD96, ARHGAP27, ASH1L, KDM3B, ZMYM2, and PIK3C2A. Notably, EBV-human fusion events were prevalent in EBV-associated NPCs, including intriguing fusion transcripts such as LRRC8C-RPMS1 and LINC00486-RPMS1, which provide further evidence of the oncogenic potential of EBV integration. Taken together, this study uncovers EBV integration patterns in Nasopharyngeal carcinogenesis using long-read sequencing technology.
CITEgeist: Cellular Indexing of Transcriptomes and Epitopes for Guided Exploration of Intrinsic Spatial Trends
Authors: Chang Alexander Chih-Chieh , Schlegel Brent T. , Carleton Neil , McAuliffe Priscilla F. , Oesterreich Steffi , Schwartz Russell , Lee Adrian V. 
Published: February 2025

ABSTRACTSpatial transcriptomics provides insights into tissue architecture by linking gene expression with spatial localization. Current deconvolution methods rely heavily on single-cell RNA sequencing (scRNA-seq) references, which are costly and often unavailable, mainly if the tissue under evaluation is limited, such as in a core biopsy specimen. We present a novel tool, CITEgeist, that deconvolutes spatial transcriptomics data using antibody capture from the same slide as the reference, directly leveraging cell surface protein measurements from the same tissue section. This approach circumvents the limitations of scRNA-seq as a reference, offering a cost-effective and biologically grounded alternative. Our method employs mathematical optimization to estimate cell type proportions and gene expression profiles, incorporating sparsity constraints for robustness and interpretability. Benchmarks against state-of-the-art deconvolution methods show improved accuracy in cell type resolution, particularly in dense tumor microenvironments, while maintaining computational efficiency. This antibody-based tool advances spatial transcriptomics by providing a scalable, accurate, and reference-independent solution for deconvolution in complex tissues. We validate this tool by using a combined approach of simulated data and clinical samples by applying CITEgeist to translational pre-treatment and post-treatment ER+ breast tumors from an ongoing clinical trial, emphasizing the applicability and robustness of CITEgeist.
A dual mechanism of sensitivity to PLK4 inhibition by RP-1664 in neuroblastoma
Authors: Soria-Bretones Isabel , Casás-Selves Matias , Goodfellow Elliot , Li Li , Caron Cathy , Shiwram Ariya , Kim Hyeyeon , Henry Danielle , Laterreur Nancy , Bowlan Julian , Álvarez-Quilón Alejandro , Vallée Frédéric , Veloso Artur , Young Jordan T.F. , Hyer Marc L. , Morris Stephen J. , Marshall C. Gary , Zimmermann Michal 
Published: February 2025

ABSTRACTA novel therapeutic strategy was recently proposed for high-risk neuroblastoma carrying copy number gain of theTRIM37gene: centriole loss upon inhibition of polo-like kinase 4 (PLK4), while tolerated by normal cells, induces aberrant mitotic spindle formation and p53-dependent cell death inTRIM37-overexpressing cells. Interestingly, while full PLK4 inhibition causes centriole loss, partial inhibition is known to elevate centriole numbers. Here we show using a novel selective PLK4 inhibitor RP-1664 that both centriole loss and amplification contribute to hypersensitivity of neuroblastoma cells. Whereas inactivation ofTRIM37andTP53rescues neuroblastoma cell death at higher concentrations of RP-1664, at lower doses cell death isTRIM37/TP53-independent. With CRISPR screens and live cell imaging we demonstrate that upon centriole amplification, neuroblastoma cells succumb to multipolar mitoses due to inability to cluster or inactivate supernumerary centrosomes.In vivo, RP-1664 shows robust efficacy in neuroblastoma xenografts at doses consistent with centriole amplification.STATEMENT OF SIGNIFICANCEHigh-risk neuroblastoma is associated with poor outcomes in pediatric patients and novel therapies need to be developed. We show that neuroblastoma cells are remarkably sensitive to PLK4 inhibitors due to a combination of two complementary mechanisms, supporting the evaluation of PLK4 inhibitors in clinical trials of high-risk neuroblastoma.