bluuebunny/crossref_metadata_2025_split huggingface dataset:
Resistance patterns in drug-adapted cancer cell lines reflect the complex evolution in clinical tumours
Authors: Grimsley Helen E. , Antczak Magdalena , Reddin Ian G. , McLaughlin Katie-May , Nist Andrea , Mernberger Marco , Stiewe Thorsten , Fenton Tim R. , Speidel Daniel , Harper-Wynne Catherine , Cox Karina , Cinatl Jindrich , Wass Mark N. , Garrett Michelle D. , Michaelis Martin 
Published: January 2024

AbstractBackgroundHere, we introduce a novel set of triple-negative breast cancer (TNBC) cell lines consisting of MDA-MB-468, HCC38, and HCC1806 and their sublines adapted to cisplatin, doxorubicin, eribulin, paclitaxel, gemcitabine, or 5-fluorouracil.MethodsThe cell lines were characterized by whole exome sequencing and the determination of drug-response profiles. Moreover, genes harbouring resistance-associated mutations were investigated using TCGA data for potential clinical relevance.ResultSequencing combined with TCGA-derived patient data resulted in the identification of 682 biomarker candidates in the pan-cancer analysis. Thirty-five genes were considered the most promising candidates because they harboured resistance-associated variants in at least two resistant sublines, and their expression correlated with TNBC patient survival. Exome sequencing and response profiles to cytotoxic drugs and DNA damage response inhibitors identified revealed remarkably little overlap between the resistant sublines, suggesting that each resistance formation process follows a unique route. All of the drug-resistant TNBC sublines remained sensitive or even displayed collateral sensitivity to a range of tested compounds. Cross-resistance levels were lowest for the CHK2 inhibitor CCT241533, the PLK1 inhibitor SBE13, and the RAD51 recombinase inhibitor B02, suggesting that CHK2, PLK1, and RAD51 are potential drug targets for therapy-refractory TNBC.ConclusionsWe present novel preclinical models of acquired drug resistance in TNBC and many novel candidate biomarkers for further investigation. The finding that each cancer cell line adaptation process follows an unpredictable route reflects recent findings on cancer cell evolution in patients, supporting the relevance of drug-adapted cancer cell lines as preclinical models of acquired resistance.
Toxicological evaluation of Vanillin Flavor in E-Liquid Aerosols on Endothelial Cell Function: Findings from the Replica Project
Authors: Emma R. , Sun A. , Partsinevelos K. , Rust S. , Volarevic V. , Lesmana R. , Giordano A. , Goenawan H. , Barliana M. I. , Arsenijevic A. , Kastratovic N. , Markovic V. , Spasic B. , Distefano A. , Orlando L. , Carota G. , Polosa R. , Caruso M. , Li Volti G. 
Published: January 2024

AbstractBackgroundThere are challenges that require collaboration among researchers to ensure that tobacco harm reduction strategies are evidence-based. One key challenge is evaluating the safety of flavors used in electronic cigarettes (e-cigarettes). While many flavorings are approved as food additives or deemed “generally recognized as safe” (GRAS) for ingestion, this does not guarantee their safety when inhaled. In this context, the international research group Replica replicated a study conducted by Fetterman and colleagues in 2018, investigating the effects of aerosolized vanillin - one of the most popular flavors in vaping - on vascular endothelium when vaporized by an electronic cigarette.MethodsWe used Aspire Zelos 3 e-cigarette and prepared e-liquids containing propylene glycol, vegetable glycerin and vanillin. The e-liquids were vaporized under two settings - regular (1 ohm coil using wattage control mode at 14 watts) and sub-ohm (0.3 ohm coil using temperature control mode at 200 °C) – using a vaping machine, following the standardized puffing regime, ISO20768:2018. The vapor was then collected into a trapping solution to prepare aqueous extracts for the treatment of human aortic endothelial cells. We evaluated cytotoxicity, oxidative stress, nitric oxide bioavailability, and inflammation addressing some gaps reported in the original study.ResultsWe observed some harmful effects, mostly attributable to ethanol, used to dilute vanillin in the original work by Fetterman, but no harmful effects on cell viability, their ability to produce nitric oxide, or oxidative stress from vanillin. Furthermore, no pro-inflammatory effects of vanillin were observed in terms of ICAM-1 and IL-6 gene expression.ConclusionsOur results confirm the endothelial cell dysfunction observed in the original paper, but clarify that these effects are mainly attributable to ethanol and not to vaporized vanillin. These findings suggest that vanillin could be a safer flavoring agent for e-cigarette, without causing adverse effects on the cardiovascular system.
Walk This Way: Modeling Foraging Ant Dynamics in Multiple Food Source Environments
Authors: Hartman Sean , Ryan Shawn D. , Karamched Bhargav R. 
Published: January 2024

AbstractForaging for resources is an essential process for the daily life of an ant colony. What makes this process so fascinating is the self-organization of ants into trails using chemical pheromone in the absence of direct communication. Here we present a stochastic lattice model that captures essential features of foraging ant dynamics inspired by recent agent-based models while forgoing more detailed interactions that may not be essential to trail formation. Nevertheless, our model’s results coincide with those presented in more sophisticated theoretical models and experiment. Furthermore, it captures the phenomenon of multiple trail formation in environments with multiple food sources. This latter phenomenon is not described well by other more detailed models. An additional feature of this approach is the ability to derive a corresponding macroscopic PDE from the stochastic lattice model which can be described via first principle interactions and is amenable to analysis. Linear stability analysis of this PDE reveals the key biophysical parameters that give rise to trail formation. We also highlight universal features of the modeling framework that this simple formation may allow it to be used to study complex systems beyond ants.
Rbbp8nl contributes to resistance to anticancer immunotherapy by creating a non-inflamed tumor microenvironment and attenuating CD8+ T cell infiltration
Authors: Yi Zhenglin , Liu Jinhui , Deng Hao , Hu Jiao , Zu Xiongbing 
Published: January 2024

AbstractImmune checkpoint blockade (ICB) monotherapy has limited efficacy, and it is crucial to explore predictive markers for the efficacy of immunotherapy and its use as new therapeutic targets or sensitization targets in combination with immunotherapy. Pan-cancer research using RNA sequencing data from The Cancer Genome Atlas (TCGA) revealed that RBBP8NL is particularly overexpressed in the tumor microenvironment (TME) of different malignancies. Additionally, there is a negative correlation between RBBP8NL and immune modulators, T cell inflammatory scores, immunological checkpoints, cancer immune cycle, and tumor-infiltrating immune cells (TIICs), so it can be inferred that RBBP8NL shapes the non-inflammatory TME in BLCA. BLCA patients with high RBBP8NL expression have a low response rate to immunotherapy, and they are more likely to experience hyperprogression of the illness. Interestingly, anti-RBBP8NL with immunotherapy could work better together than they do separately. According to the results of the multi-omics analysis, RBBP8NL inhibits the recruitment of cytotoxic lymphocytes. Furthermore, RBBP8NL’s predictive significance for immunotherapy success has been confirmed across several immunotherapy cohorts. In summary, RBBP8NL is a crucial component of the TME and a developing target for binding to ICB as well as a biomarker to direct precision medicine.
Community-aware explanations in knowledge graphs with XP-GNN
Authors: Mora Andrés Martínez , Polychronopoulos Dimitris , Ughetto Michaël , Nilsson Sebastian 
Published: January 2024

ABSTRACTMachine learning applications for the drug discovery pipeline have exponentially increased in the last few years. An example of these applications is the biological Knowledge Graph. These graphs represent biological entities and the relations between them based on existing knowledge. Graph machine learning models such as Graph Neural Networks can be applied on top of knowledge graphs to support the development of novel therapeutics. Nevertheless, Graph Neural Networks present an improved performance at the expense of complexity, becoming difficult to explain their decisions. State-of-the-art explanation algorithms for Graph Neural Networks focus on determining the most relevant subgraphs involved in their decision-making while considering graph elements (nodes and edges) as independent entities and ignoring any communities these graphs could present. We explore in this work the idea that graph community structure in biological Knowledge Graphs could provide a better grasp of the decision-making of Graph Neural Networks. For that purpose, we introduceXP-GNN, a novel explanation technique for Graph Neural Networks in Knowledge Graphs. XP-GNN exploits the communities of nodes or edges in graphs to refine their explanations, inspired bycooperative game theory. We characterize XP-GNN in a basic example and in terms of scalability and stability. In two relevant use cases for the drug discovery pipeline, XP-GNN provides more relevant explanations than previous techniques, being evaluated quantitatively and by domain experts. At the same time, XP-GNN presents limitations on scalability and stability, which we will address.ACM Reference FormatAndrés Martínez Mora, Dimitris Polychronopoulos, Michaël Ughetto, and Sebastian Nilsson. 2024. Community-aware explanations in knowledge graphs with XP-GNN. InProceedings of ACM Conference (Conference’17). ACM, New York, NY, USA, 21 pages.https://doi.org/10.1145/nnnnnnn.nnnnnnnThis work has been funded by AstraZeneca AB, Mölndal, Sweden and AstraZeneca Cambridge. Unfortunately, due to proprietary reasons from AstraZeneca AB, the data used in this work cannot be shared.
Mammalian SWI/SNF complex activity regulates POU2F3 and constitutes a targetable dependency in small cell lung cancer
Authors: Duplaquet Leslie , So Kevin , Ying Alexander W. , Li Xinyue , Li Yixiang , Qiu Xintao , Li Rong , Singh Shilpa , Wu Xiaoli S. , Liu Qi , Qi Jun , Somerville Tim D.D. , Heiling Hillary , Mazzola Emanuele , Lee Yenarae , Zoller Thomas , Vakoc Christopher R. , Doench John G. , Forrester William C. , Abrams Tinya , Long Henry W. , Niederst Matthew J. , Kadoch Cigall , Oser Matthew G. 
Published: January 2024

AbstractSmall cell lung cancers (SCLC) are comprised of heterogeneous subtypes marked by lineage-specific transcription factors, including ASCL1, NEUROD1, and POU2F3. POU2F3-positive SCLC, ∼12% of all cases, are uniquely dependent on POU2F3 itself; as such, approaches to attenuate POU2F3 expression may represent new therapeutic opportunities. Here using genome-scale screens for regulators of POU2F3 expression and SCLC proliferation, we define mSWI/SNF complexes, including non-canonical BAF (ncBAF) complexes, as top dependencies specific to POU2F3-positive SCLC. Notably, clinical-grade pharmacologic mSWI/SNF inhibition attenuates proliferation of all POU2F3-positive SCLCs, while disruption of ncBAF via BRD9 degradation is uniquely effective in pure non-neuroendocrine POU2F3-SCLCs. mSWI/SNF maintains accessibility over gene loci central to POU2F3-mediated gene regulatory networks. Finally, chemical targeting of SMARCA4/2 mSWI/SNF ATPases and BRD9 decrease POU2F3-SCLC tumor growth and increase survivalin vivo. Taken together, these results characterize mSWI/SNF-mediated global governance of the POU2F3 oncogenic program and suggest mSWI/SNF inhibition as a therapeutic strategy for SCLC.
Turnover rates of human muscle proteins in vivo reported in fractional, mole and absolute units
Authors: Stansfield Ben N. , Barrett Jennifer S. , Bennett Samuel , Stead Connor A. , Pugh Jamie , Shepherd Sam O. , Strauss Juliette A. , Louis Julien , Close Graeme L. , Lisboa Paulo J. , Burniston Jatin G. 
Published: January 2024

AbstractProtein fractional turnover rates (FTR) represent measurements of flux through a protein pool, i.e. net abundance (ABD) of the protein. If protein abundance is not measured or is different between experimental conditions the interpretation of FTR data may be confounded. This project investigates the consequences of reporting turnover rates of human muscle proteinsin vivoin mole and absolute units (that incorporate protein abundance data) compared to fractional (%/d) data that ignore protein abundance. Three physically active males (21 ± 1 years) were recruited and underwent a 12-d protocol of daily deuterium oxide (D2O) consumption and biopsies of vastus lateralis on days 8 and 12. Protein abundances were normalised to yeast alcohol dehydrogenase, added during sample preparation, and FTR was calculated from time-dependent changes in peptide mass isotopomer profiles. FTR and abundance data (fmol/ μg protein) were combined to calculate mole turnover rates (MTR; fmol/ μg protein/ d) and absolute turnover rates (ATR; ng/ μg protein/ d). Abundance data were collected for 1,772 proteins and FTR data were calculated from 3,944 peptides representing 935 proteins (average 3 peptides per protein). The median (M), lower- (Q1) and upper-quartile (Q3) values for protein FTR (%/d) were M = 4.3, Q1 = 2.52, Q3 = 7.84. Our analyses suggest MTR data is preferred over FTR, particularly for studies on multiprotein complexes, wherein MTR takes account of potential differences amongst the molecular weight of the component subunits. ATR data may be preferred over MTR and FTR, particularly when comparing samples with different abundance profiles.
Information Dynamics of the Heart and Respiration Rates: a Novel Venue for Digital Phenotyping in Humans
Authors: Keshmiri Soheil , Tomonaga Sutashu , Mizutani Haruo , Doya Kenji 
Published: January 2024

AbstractIn recent decade, wearable digital devices have shown potentials for the discovery of novel biomarkers of humans’ physiology and behavior. Heart rate (HR) and respiration rate (RR) are most crucial bio-signals in humans’ digital phenotyping research. HR is a continuous and non-invasive proxy to autonomic nervous system and ample evidence pinpoints the critical role of respiratory modulation of cardiac function. In the present study, we recorded longitudinal (up to 6 days, 4.63±1.52) HR and RR of 89 freely-behaving human subjects (Female: 39, age 57.28±5.67, Male: 50, age 58.48±6.32) and analyzed their HR and RR dynamics using linear models and information theoretic measures. While the predictability by linear autoregressive (AR) showed correlation with subjects’ age, an information theoretic measure of predictability, active information storage (AIS), captured these correlations more clearly. Furthermore, analysis of the information flow between HR and RR by transfer entropy (i.e.,HR → RRandRR → HR) revealed thatRR → HRis correlated with alcohol consumption and exercise habits. Thus we propose the AIS of HR and the transfer entropyRR → HRas two-dimensional biomarkers of cardiorespiratory physiology for digital phenotyping. The present findings provided evidence for the critical role of the respiratory modulation of HR, which was previously only studied in non-human animals.
PRRGO: A Tool for Visualizing and Mapping Globally Expressed Genes in Public Gene Expression Omnibus RNA-Sequencing Studies to PageRank-scored Gene Ontology Terms
Authors: Solano Luis E. , D’Sa Nicholas M. , Nikolaidis Nikolas 
Published: January 2024

ABSTRACTWe herein report PageRankeR Gene Ontology (PRRGO), a downloadable web application that can integrate differentially expressed gene (DEG) data from the gene expression omnibus (GEO) GEO2R web tool with the gene ontology (GO) database [1]. Unlike existing tools, PRRGO computes the PageRank for the entire GO network and can generate both interactive GO networks on the web interface and comma-separated values (CSV) files containing the DEG statistics categorized by GO term. These hierarchical and tabular GO-DEG data are especially conducive to hypothesis generation and overlap studies with the use of PageRank data, which can provide a metric of GO term centrality. We verified the tool for accuracy and reliability across nine independent heat shock (HS) studies for which the RNA-seq data was publicly available on GEO and found that the tool produced increasing concordance between study DEGs, GO terms, and select HS-specific GO terms.
Molecular characterization, localization, and physiological roles of ITP and ITP-L in the mosquito,Aedes aegypti
Authors: Sajadi Farwa , Paluzzi Jean-Paul 
Published: January 2024

AbstractThe insect ion transport peptide (ITP) and its alternatively spliced variant, ITP-like peptide (ITP-L), belong to the crustacean hyperglycemic hormone family of peptides and are widely conserved among insect species. While limited, studies have characterized the ITP/ITP-L signaling system within insects, and putative functions including regulation of ion and fluid transport, ovarian maturation, and thirst/excretion have been proposed. Herein, we aimed to molecularly investigateItpandItp-lexpression profiles in the mosquitoAedes aegypti,examine peptide immunolocalization and distribution within the adult central nervous system, and elucidate physiological roles for these neuropeptides. Transcript expression profiles of bothAedaeItpandAedaeItp-lrevealed distinct enrichment patterns in adults, withAedaeItpexpressed in the brain andAedaeItp-lexpression predominantly within the abdominal ganglia. Immunohistochemical analysis within the central nervous system revealed expression ofAedaeITP peptide in a number of cells in the brain and in the terminal ganglion. Comparatively,AedaeITP-L peptide was localized solely within the pre-terminal abdominal ganglia of the central nervous system. Interestingly, prolonged desiccation stress caused upregulation ofAedaeItpandAedaeItp-llevels in adult mosquitoes, suggesting possible functional roles in water conservation and feeding-related activities. RNAi-mediated knockdown ofAedaeItpcaused an increase in urine excretion, while knockdown of bothAedaeItpandAedaeItp-lreduced blood feeding and egg-laying in females as well as hindered egg viability, suggesting roles in reproductive physiology and behaviour. Altogether, this study identifiesAedaeITP andAedaeITP-L as key pleiotropic hormones, regulating various critical physiological processes in the disease vector,A. aegypti.
scaDA: A Novel Statistical Method for Differential Analysis of Single-Cell Chromatin Accessibility Sequencing Data
Authors: Zhao Fengdi , Ma Xin , Yao Bing , Chen Li 
Published: January 2024

AbstractSingle-cell ATAC-seq sequencing data (scATAC-seq) has been widely used to investigate chromatin accessibility on the single-cell level. One important application of scATAC-seq data analysis is differential chromatin accessibility analysis. However, the data characteristics of scATAC-seq such as excessive zeros and large variability of chromatin accessibility across cells impose a unique challenge for DA analysis. Existing statistical methods focus on detecting the mean difference of the chromatin accessible regions while overlooking the distribution difference. Motivated by real data exploration that distribution difference exists among cell types, we introduce a novel composite statistical test named “scaDA”, which is based on zero-inflated negative binomial model (ZINB), for performing differential distribution analysis of chromatin accessibility by jointly testing the abundance, prevalence and dispersion simultaneously. Benefiting from both dispersion shrinkage and iterative refinement of mean and prevalence parameter estimates, scaDA demonstrates its superiority to both ZINB-based likelihood ratio tests and published methods by achieving the highest power and best FDR control in a comprehensive simulation study. In addition to demonstrating the highest power in three real sc-multiome data analyses, scaDA successfully identifies differentially accessible regions in microglia from sc-multiome data for an Alzheimer ‘s disease (AD) study, regions which are most enriched in GO terms related to neurogenesis, the clinical phenotype of AD, and SNPs identified in AD-associated GWAS.Author summaryUnderstanding the cis-regulatory elements that control the fundamental gene regulatory process is important to basic biology. scATAC-seq data offers an unprecedented opportunity to investigate chromatin accessibility on the single-cell level and explore cell heterogeneity to reveal the dynamic changes of cis-regulatory elements among different cell types. To understand the dynamic change of gene regulation using scATAC-seq data, differential chromatin (DA) analysis, which is one of the most fundamental analyses for scATAC-seq data, can enable the identification of differentially accessible regions between cell types or between multiple conditions. Subsequently, DA analysis has many applications such as identifying cell type-specific chromatin accessible regions to reveal the cell type-specific gene regulatory program, assessing disease-associated changes in chromatin accessibility to detect potential biomarkers, and linking differentially accessible regions to differentially expressed genes for building a comprehensive gene regulatory map. This paper proposes a novel statistical method named “scaDA” to improve the detection of differentially accessible regions by performing differential distribution analysis. scaDA is believed to benefit the research community of single-cell genomics.
Reproducing within-reef variability in coral dynamics with a metacommunity modelling framework
Authors: Cresswell Anna K , Haller-Bull Vanessa , Gonzalez-Rivero Manuel , Gilmour James P , Bozec Yves-Marie , Barneche Diego R , Robson Barbara , Anthony Ken , Doropoulos Christopher , Roelfsema Chris , Lyons Mitchell , Mumby Peter J , Condie Scott , Lago Veronique , Ortiz Juan-Carlos 
Published: January 2024

AbstractReef systems span spatial scales from 10s to 100s and even 1000s of kilometres, with substantial spatial variability across these scales. Managing and predicting the future of coral reefs requires insights into reef functioning at all spatial scales. However, investigations of reef functioning often consider individual reefs as the smallest unit (10s of kilometres), despite substantial spatiotemporal variability occurring within-reefs (100s of meters). We developedC∼scape,a coral metacommunity modelling framework that integrates the demography of corals with population-level responses to physical and environmental spatial layers, to simulate a mosaic of interacting coral communities across a heterogenous seascape. Coral communities are linked using biophysical connectivity modelling. Coral community growth is modelled with a logistic growth model, with the intrinsic growth parameter determined from taxa-specific Integral Projection Models to incorporate demographic mechanisms. Site-specific coral habitat parameters, derived from satellite-based geomorphic and benthic habitat maps, define the maximum coral cover and are used to modulate community growth spatially and temporally as a function of the available space suitable for corals. These parameters are a proxy for the many interacting physical and environmental factors — e.g., depth, light, wave exposure, temperature, and substrate type — that drive within-reef variability in coral demography. Using a case study from the Great Barrier Reef, we show that modulating community growth using site-specific habitat parameters enables more accurate hindcasts of coral cover dynamics, while overlooking within-reef variability may lead to misleading conclusions about metacommunity dynamics. More generally,C∼scapeprovides a valuable framework for predicting spatiotemporal dynamics of coral communities within and between reefs, offering a mechanistic approach to test a range of management and restoration options.