bluuebunny/crossref_metadata_2025_split huggingface dataset:
Temperature-driven coordination of circadian transcriptome regulation
Authors: Xu Bingxian , Hwangbo Dae-Sung , Saurabh Sumit , Rosensweig Clark , Allada Ravi , Kath William L. , Braun Rosemary 
Published: November 2023

AbstractThe circadian rhythm is an evolutionarily-conserved molecular oscillator that enables species to anticipate rhythmic changes in their environment. At a molecular level, the core clock genes induce a circadian oscillation in thousands of genes in a tissue–specific manner, orchestrating myriad biological processes. While studies have investigated how the core clock circuit responds to environmental perturbations such as temperature, the downstream effects of such perturbations on circadian regulation remain poorly understood. By analyzing bulk-RNA sequencing ofDrosophilafat bodies harvested from flies subjected to different environmental conditions, we demonstrate a highly condition-specific circadian transcriptome. Further employing a reference-based gene regulatory network (Reactome), we find evidence of increased gene-gene coordination at low tem-peratures and synchronization of rhythmic genes that are network neighbors. Our results point to the mechanisms by which the circadian clock mediates the fly’s response to seasonal changes in temperature.Significance StatementThe circadian rhythm enables organisms to anticipate and adapt to changes in their environment. While behavioral changes have been observed inDrosophila melanogastersubjected to low temperatures, little is known regarding how these changes are enacted at a molecular level. By conducting bulk RNA sequencing from fruit flies, we observe that genome-wide circadian oscillation patterns are temperature dependent. Intriguingly, we find that morning and evening peaks of transcriptomic activity shift closer together, consistent with anticipation of a shorter photoperiod in cooler winter weather. We further find that the low-temperature dynamics are highly coordinated with respect to a reference-based gene regulatory network. Our findings provide insights into the mechanisms by which flies adapt to environmental temperature changes.
MiceVAPORDot: A novel automated approach for high-throughput behavioral characterization during E-cigarette exposure in mice
Authors: Han Yaning , Xu Zhibin , Mo Zhizhun , Huang HongYi , Wu Zehong , Jiang Xingtao , Tian Ye , Wang Liping , Wei Pengfei , Chen Zuxin , Liu Xin-an 
Published: November 2023

AbstractThe prosperity of electronic nicotine delivery systems (ENDS) or e-cigarette use has been regarded to lead an increasing risk of nicotine addiction, especially among youth. Understanding and evaluating the behaviors induced by ENDS are fundamental to the study of neuropsychiatric effects of e-cigarettes. However, little is known regarding the behavioral features during e-cigarette exposure in mice. Current behavioral assessments for nicotine addiction are based on nicotine withdrawal-induced anxiety which can be only performed after ENDS exposures. Here we developed MiceVAPORDot, a novel high-throughput tool for automatedin situbehavioral characterization during e-cigarette exposure. The integration of a deep learning-based animal pose tracking method by MiceVAPORDot allows precise characterization on behavioral phenotypes of e-vapor exposed mice, which were unable revealed by traditional evaluation methodology such as conditioned place preference and elevated plus maze tests. The behavioral fingerprints recognized by MiceVAPORDot can be used for high-throughput screening on incentive nature of e-cigarette flavors as well as medications for smoking cessation.
Medial temporal lobe functional network architecture supports sleep-related emotional memory processing in older adults
Authors: Chappel-Farley Miranda G. , Adams Jenna N. , Betzel Richard F. , Janecek John C. , Sattari Negin S. , Berisha Destiny E. , Meza Novelle J. , Niknazar Hamid , Kim Soyun , Dave Abhishek , Chen Ivy Y. , Lui Kitty K. , Neikrug Ariel B. , Benca Ruth M. , Yassa Michael A. , Mander Bryce A. 
Published: November 2023

SUMMARYMemory consolidation occurs via reactivation of a hippocampal index during non-rapid eye movement slow-wave sleep (NREM SWS) which binds attributes of an experience existing within cortical modules. For memories containing emotional content, hippocampal-amygdala dynamics facilitate consolidation over a sleep bout. This study tested if modularity and centrality—graph theoretical measures that index the level of segregation/integration in a system and the relative import of its nodes—map onto central tenets of memory consolidation theory and sleep-related processing. Findings indicate that greater network integration is tied to overnight emotional memory retention via NREM SWS expression. Greater hippocampal and amygdala influence over network organization supports emotional memory retention, and hippocampal or amygdala control over information flow are differentially associated with distinct stages of memory processing. These centrality measures are also tied to the local expression and coupling of key sleep oscillations tied to sleep-dependent memory consolidation. These findings suggest that measures of intrinsic network connectivity may predict the capacity of brain functional networks to acquire, consolidate, and retrieve emotional memories.
Localized Rift Valley Fever Virus Persistence Depends on a High Transovarial Transmission Fraction
Authors: Rostal Melinda K. , Prentice Jamie , Ross Noam , Kemp Alan , Thompson Peter N. , Anyamba Assaf , Cleaveland Sarah , Cordel Claudia , Msimang Veerle , van Vuren Petrus Jansen , Haydon Daniel T. , Karesh William B. , Paweska Janusz T. , Matthews Louise 
Published: November 2023

AbstractRift Valley fever virus (RVFV) has spread beyond continental Africa and threatens to follow West Nile, chikungunya and Zika viruses into the Americas. Its impact in new localities and the capacity to control future outbreaks, depends on whether and how RVFV persists at small spatial scales. Transovarial transmission (TOT) is hypothesized as an important mechanism for local persistence, yet its role in RVFV ecology remains poorly understood. We examine whether RVFV can persist locally via TOT while maintaining a realistic seroprevalence pattern of interepidemic and epidemic transmission. We developed a mechanistic, compartmental model of RVFV dynamics within a single host (sheep) and two vector (mosquito) populations, driven by temperate climatic factors. Decades-long persistence was possible in our simulations, which generally captured the observed outbreak patterns in central South Africa with a mean annual seroprevalence (∼23%) within the range reported during interepidemic periods (5-40%). Persistence was only possible with a substantial TOT fraction and over a narrow range of parameters. The basic reproduction number (R0) was close to one at mean vector population sizes, suggesting a relatively limited expansion of the infected vector population during outbreaks. This limited expansion provides the system with the flexibility to support both low-level transmission and large outbreaks and, counterintuitively, large outbreaks resulted in smaller infectedAedesegg populations. This has important consequences for control: low-level vaccination may prevent large outbreaks without eliminating RVFV and local control efforts may be most effective immediately following an outbreak, suggesting elimination may be possible after emergence in temperate regions.
Immunosuppression is a conserved driver of tuberculosis susceptibility
Authors: Kotov Dmitri I. , Lee Ophelia V. , Ji Daisy X. , Jaye David L. , Suliman Sara , Gabay Cem , Vance Russell E. 
Published: November 2023

SummaryMycobacterium tuberculosis(Mtb) causes 1.6 million deaths a year1. However, no individual mouse model fully recapitulates the hallmarks of human tuberculosis disease. Here we report that a comparison across three different susceptible mouse models identifiesMtb-induced gene signatures that predict active TB disease in humans significantly better than a signature from the standard C57BL/6 mouse model. An increase in lung myeloid cells, including neutrophils, was conserved across the susceptible mouse models, mimicking the neutrophilic inflammation observed in humans2,3. Myeloid cells in the susceptible models and non-human primates exhibited high expression of immunosuppressive molecules including the IL-1 receptor antagonist, which inhibits IL-1 signaling. Prior reports have suggested that excessive IL-1 signaling impairsMtbcontrol4–6. By contrast, we found that enhancement of IL-1 signaling via deletion of IL-1 receptor antagonist promoted bacterial control in all three susceptible mouse models. IL-1 signaling enhanced cytokine production by lymphoid and stromal cells, suggesting a mechanism for IL-1 signaling in promotingMtbcontrol. Thus, we propose that myeloid cell expression of immunosuppressive molecules is a conserved mechanism exacerbatingMtbdisease in mice, non-human primates, and humans.
Detection, characterization, and phylogenetic analysis of a near-whole genome sequence of a novel astrovirus in an endemic Malagasy fruit bat,Rousettus madagascariensis
Authors: Horigan Sophia , Kistler Amy , Ranaivoson Hafaliana Christian , Andrianianina Angelo , Andry Santino , Kettenburg Gwenddolen , Raharinosy Vololoniaina , Randriambolamanantsoa Tsiry Hasina , Tato Cristina M. , Lacoste Vincent , Heraud Jean-Michel , Dussart Philippe , Brook Cara E. 
Published: November 2023

ABSTRACTBats (order:Chiroptera) are known to host a diverse range of viruses, some of which present a public health risk. Thorough viral surveillance is therefore essential to predict and potentially mitigate zoonotic spillover. Astroviruses (family:Astroviridae) are an understudied group of viruses with a growing amount of indirect evidence for zoonotic transfer. Astroviruses have been detected in bats with significant prevalence and diversity, suggesting that bats may act as important astrovirus hosts. Most astrovirus surveillance in wild bat hosts has, to date, been restricted to single-gene PCR detection and concomitant Sanger sequencing; additionally, many bat species and many geographic regions have not yet been surveyed for astroviruses at all. Here, we use metagenomic Next Generation Sequencing (mNGS) to detect astroviruses in three species of Madagascar fruit bats,Eidolon dupreanum, Pteropus rufus,andRousettus madagascariensis. We detect numerous partial sequences from all three species and one near-full length astrovirus sequence fromRousettus madagascariensis, which we use to characterize the evolutionary history of astroviruses both within bats and the broader mammalian clade,Mamastrovirus. Taken together, applications of mNGS implicate bats as important astrovirus hosts and demonstrate novel patterns of bat astrovirus evolutionary history, particularly in the Southwest Indian Ocean region.
HeterozygousKmt2dloss diminishes enhancers to render medulloblastoma cells vulnerable to combinatory inhibition of lysine demethylation and oxidative phosphorylation
Authors: Dhar Shilpa S. , Brown Calena , Rizvi Ali , Reed Lauren , Kotla Sivareddy , Zod Constantin , Abraham Janak , Abe Jun-Ichi , Rajaram Veena , Chen Kaifu , Lee Min Gyu 
Published: November 2023

SUMMARYThe histone H3 lysine 4 (H3K4) methyltransferase KMT2D (also called MLL4) is one of the most frequently mutated epigenetic modifiers in medulloblastoma (MB) and many other types of cancer. Notably, heterozygous loss ofKMT2Dis prevalent in MB and other cancer types. However, what role heterozygousKMT2Dloss plays in tumorigenesis has not been well characterized. Here, we show that heterozygousKmt2dloss highly promotes MB driven by heterozygous loss of the MB suppressor genePtchin mice. HeterozygousKmt2dloss upregulated tumor-promoting programs, including oxidative phosphorylation and G-protein-coupled receptor signaling, inPtch+/−-driven MB genesis. Mechanistically, both downregulation of the transcription-repressive tumor suppressor gene NCOR2 by heterozygousKmt2dloss and upregulation of the oncogeneMycNby heterozygousPtchloss increased the expression of tumor-promoting genes. Moreover, heterozygousKmt2dloss extensively diminished enhancer signals (e.g., H3K27ac) and H3K4me3 signature, including those for tumor suppressor genes (e.g.,Ncor2). Combinatory pharmacological inhibition of oxidative phosphorylation and the enhancer-decommissioning H3K4 demethylase LSD1 drastically reduced tumorigenicity of MB cells bearing heterozygousKmt2dloss. These findings reveal the mechanistic basis underlying the MB-promoting effect of heterozygousKMT2Dloss, provide a rationale for a therapeutic strategy for treatment of KMT2D-deficient MB, and have mechanistic implications for the molecular pathogenesis of other types of cancer bearing heterozygousKMT2Dloss.
MethylBERT: A Transformer-based model for read-level DNA methylation pattern identification and tumour deconvolution
Authors: Jeong Yunhee , Gerhäuser Clarissa , Sauter Guido , Schlomm Thorsten , Rohr Karl , Lutsik Pavlo 
Published: November 2023

AbstractDNA methylation (DNAm) is a key epigenetic mark that shows profound alterations in cancer. Read-level methylomes enable more in-depth DNAm analysis due to the broad coverage and preservation of rare cell-type signals, compared to array-based data such as 450K/EPIC array. Here, we propose MethylBERT, a novel Transformer-based model for read-level methylation pattern classification. MethylBERT identifies tumour-derived sequence reads based on their methylation patterns and genomic sequence. Using the read classification probability, the method estimates tumour cell fractions within bulk samples and provides an assessment of the model precision. In our evaluation, MethylBERT outperforms existing deconvolution methods and demonstrates high accuracy regardless of methylation pattern complexity, read length and read coverage. Moreover, we show its applicability to cell-type deconvolution as well as its potential for accurate non-invasive early cancer diagnostics using liquid biopsy samples. MethylBERT represents a significant advancement in read-level methylome analysis and enables accurate tumour purity estimation. The broad applicability of MethylBERT will enhance studies on both solid tumour tissues and circulating tumour DNA as well as non-cancerous bulk methylomes.
Sex-dependent effects of infection on guppy reproductive fitness and offspring parasite resistance
Authors: Weiler Isabella L. G. , Kramp Rachael D. , Rovenolt Faith , Stephenson Jessica F. 
Published: November 2023

AbstractInfection imposes energetic costs on hosts. Hosts typically respond by shifting resources, potentially affecting the quantity and quality of offspring they produce. As the sexes differ in their optimal reproductive strategies, infection of mothers versus fathers may affect offspring quantity and quality in different ways.Here, we test how experimental infection of guppiesPoecilia reticulatawith the ectoparasiteGyrodactylus turnbulliaffects parental reproductive fitness and offspring parasite resistance. We compared breeding pairs in which one or neither parent had previously been infected.In terms of reproductive fitness, parental infection experience did not affect the size, body condition, or number of offspring produced, but fathers who experienced the heaviest infections produced offspring ∼55 days sooner than average. This result may represent terminal investment by the males most affected by infection, or may indicate that these males have a faster pace of life, investing in reproduction at the expense of parasite defence.We found that offspring age, parental infection experience, and parental infection severity together strongly predicted offspring parasite resistance. Only among pairs in which one parent had been infected, older offspring, which were those born soonest after the parent’s infection, tended to experience heavier infections. This result may therefore reflect temporary infection-induced reductions in parental investment in offspring quality. Beyond this effect of offspring age, offspring of infected mothers experienced 105 fewer worm days than those of infected fathers: fathers, but not mothers, that experienced heavy infections themselves produced offspring that also experienced heavy infections. The parent-offspring regression for infected fathers is therefore consistent with previous evidence that parasite resistance is heritable in this system, and yields a narrow sense heritability estimate of 0.69±0.13. By contrast, the mother-offspring regression (slope: -0.13±0.17) provides novel insight that mothers may engage in transgenerational immune priming.Overall, our results suggest that the sexes strike a different balance between offspring quantity and quality when faced with infection, with potentially broad implications for disease and host-parasite coevolutionary dynamics in nature.
Unearthing SRSF1’s Novel Function in Binding and Unfolding of RNA G-Quadruplexes
Authors: De Silva Naiduwadura Ivon Upekala , Lehman Nathan , Fargason Talia , Paul Trenton , Zhang Zihan , Zhang Jun 
Published: November 2023

AbstractSRSF1 governs splicing of over 1,500 mRNA transcripts. SRSF1 contains two RNA-recognition motifs (RRMs) and a C-terminal Arg/Ser-rich region (RS). It has been thought that SRSF1 RRMs exclusively recognize single-stranded exonic splicing enhancers, while RS lacks RNA-binding specificity. With our success in solving the insolubility problem of SRSF1, we can explore the unknown RNA-binding landscape of SRSF1. We find that SRSF1 RS prefers purine over pyrimidine. Moreover, SRSF1 binds to the G-quadruplex (GQ) from the ARPC2 mRNA, with both RRMs and RS being crucial. Our binding assays show that the traditional RNA-binding sites on the RRM tandem and the Arg in RS are responsible for GQ binding. Interestingly, our FRET and circular dichroism data reveal that SRSF1 unfolds the ARPC2 GQ, with RS leading unfolding and RRMs aiding. Our saturation transfer difference NMR results discover that Arg residues in SRSF1 RS interact with the guanine base but other nucleobases, underscoring the uniqueness of the Arg/guanine interaction. Our luciferase assays confirm that SRSF1 can alleviate the inhibitory effect of GQ on gene expression in the cell. Given the prevalence of RNA GQ and SR proteins, our findings unveil unexplored SR protein functions with broad implications in RNA splicing and translation.
Spatial tumor immune heterogeneity facilitates subtype co-existence and therapy response via AP1 dichotomy in pancreatic cancer
Authors: Klein Lukas , Tu Mengyu , Krebs Niklas , Urbach Laura , Grimm Daniela , Latif Muhammad Umair , Penz Frederike , Chan Nathan , Aliar Kazeera , Vyas Foram , Kishore Uday , Hessmann Elisabeth , Trumpp Andreas , Espinet Elisa , Papantonis Argyris , Khokha Rama , Ellenrieder Volker , Grünwald Barbara T. , Singh Shiv K. 
Published: November 2023

AbstractPancreatic ductal adenocarcinoma (PDAC) displays a high degree of spatial subtype heterogeneity. This intratumoral co-existence of classical and basal-like programs is evident in multi-scale transcriptomic and spatial analyses of resected, advanced-stage and chemotherapy-treated specimens and reciprocally linked to a diverse stromal immune microenvironment as well as worse clinical outcome. However, the underlying mechanisms of intratumoral subtype heterogeneity remain largely unclear. Here, by combining preclinical models, multi-center clinical, bulk and compartment-specific transcriptomic, proteomic, and bioimaging data from human specimens, we identified an interplay between neoplastic intrinsic AP1 transcription factor dichotomy and extrinsic CD68+macrophages as a driver of intratumoral subtype co-existence along with an immunosuppressive tumor microenvironment with T cell exclusion. Our ATAC-, ChIP-, and RNA-seq analyses revealed that JUNB/AP1- and HDAC-mediated epigenetic programs repress pro-inflammatory immune signatures in tumor cells, antagonizing cJUN/AP1 signaling to favor a therapy-responsive classical neoplastic identity. Through the tumor microenvironment, this dichotomous regulation was further amplified via regional macrophage populations. Moreover, CD68+/TNF-α+cells associated with a reactive phenotype and reduced CD8+T cell infiltration in human PDAC tumors. Consequently, combined anti-TNF-α immunotherapy and chemotherapy resulted in reduced macrophage counts and promoted CD3+/CD8+T cell infiltration in basal-like PDAC, leading to improved survival in preclinical murine models. We conclude that tumor cell intrinsic epigenetic programs, together with extrinsic microenvironmental cues, facilitate intratumoral subtype heterogeneity and disease progression.
Superovulation and aging perturb oocyte-granulosa cell communication
Authors: Daugelaite Klaudija , Lacour Perrine , Winkler Ivana , Koch Marie-Luise , Schneider Anja , Schneider Nina , Tolkachov Alexander , Nguyen Xuan Phuoc , Vilkaite Adriana , Rehnitz Julia , Odom Duncan T. , Goncalves Angela 
Published: November 2023

AbstractIn vitrofertilization has been developed to overcome reduced fertility, which is increasingly due to a decline in reproductive cell quality during aging. Here, we quantitatively investigated the interplay between superovulation and aging in mouse oocytes and their paired granulosa cells using newly adapted isolation techniques. We tested the hypothesis that superovulation disrupts oocyte maturation, revealing the key intercellular communication pathways dysregulated by forced hormonal stimulation. We further demonstrated that granulosa cell transcriptional markers can prospectively predict an associated oocyte’s early developmental potential. By using naturally ovulated old mice as a non-stimulated reference, we showed that aging and superovulation dysregulate similar genes and interact with each other. By comparing mice and human transcriptional responses of granulosa cells, we found that age-related dysregulation of hormonal responses and cell cycle pathways was shared, though substantial divergence exists in other pathways.HighlightsSuperovulation perturbs cumulus-oocyte communicationGranulosa cell transcription predicts superovulated oocyte qualitySuperovulation and aging non-additively perturb similar sets of genes
Robustly interrogating machine learning-based scoring functions: what are they learning?
Authors: Durant Guy , Boyles Fergus , Birchall Kristian , Marsden Brian , Deane Charlotte M. 
Published: November 2023

AbstractMotivationMachine learning-based scoring functions (MLBSFs) have been found to exhibit inconsistent performance on different benchmarks and be prone to learning dataset bias. For the field to develop MLBSFs that learn a generalisable understanding of physics, a more rigorous understanding of how they perform is required.ResultsIn this work, we compared the performance of a diverse set of popular MLBSFs (RFScore, SIGN, OnionNet-2, Pafnucy, and PointVS) to our proposed baseline models that can only learn dataset biases on a range of benchmarks. We found that these baseline models were competitive in accuracy to these MLBSFs in almost all proposed benchmarks, indicating these models only learn dataset biases. Our tests and provided platform, ToolBoxSF, will enable researchers to robustly interrogate MLBSF performance and determine the effect of dataset biases on their predictions.Availability and Implementationhttps://github.com/guydurant/toolboxsfContactdeane@stats.ox.ac.ukSupplementary informationSupplementary data are available at Bioinformatics online.