bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of virus-specific B cell epitopes reveals extensive antigen processing prior to recognition
Authors: Ras-Carmona Alvaro , Reche Pedro A. 
Published: December 2023

ABSTRACTB cell epitopes must be solvent accessible for recognition by cognate B cells and antibodies. Here, we sought to study such premise for B cell epitopes targeted during infection in humans, available at the Immune Epitope Database. Most of these B cell epitopes were virus-specific linear B cell epitopes and so we focused on them, analyzing first the localization of the relevant antigens. Antigen localization could be unequivocally assigned to 26498 linear B cell epitopes. Of those, 18832 B cell epitopes belonged to antigens that remain enclosed in host cells and/or virus particles, hidden to antibody recognition, while just 7666 lie in ectodomains of viral envelope antigens and/or mature secreted antigens, visible to antibody recognition. Next, we selected B cell epitopes that mapped in antigens with known tertiary (3D-)structures and determined residue relative solvent accessibility (rRSA), comparing them with those of conformational B cell epitopes obtained from available 3D-structures of antigen-antibody complexes. rRSA values computed form linear B cell epitopes had a median value of 23.00%, while that of conformational B cell epitopes was 48.50%. Moreover, considering average rRSA values per entire epitopes (eRSA), only 32.72% of the linear B cell epitopes had eRSA values minimally comparable to those of conformational B cell epitopes. In sum, our results point that most virus-specific B cell epitopes targeted during infection are unreachable to antibody recognition on intact viral particles and/or host cells. Hence, we must conclude that antigen recognition by antibodies must be preceded by degradation/processing of viral particles and infected cells.
Vascular microforamina and endocranial surface: normal variation and distribution in adult humans
Authors: Bruner Emiliano , Eisová Stanislava 
Published: December 2023

AbstractThe termcraniovascular traitsrefers to the imprints left by arteries and veins on the skull bones. These features can be used in anthropology and archaeology to investigate the morphology of the vascular network in extinct species and past populations. Generally, the term refers to macrovascular features of the endocranial cavity, like those associated with the middle meningeal artery, venous sinuses, emissary foramina, and diploic channels. However, small vascular passages (here calledmicroforaminaormicrochannels) have been occasionally described on the endocranial surface. In this study, we describe and quantify the amount and distribution of these microforamina in adult humans (N = 45) and, preliminarily, in early to late juvenile subjects (N = 7). Adults display more microchannels than juvenile skulls. Females show more channels than males, and it should be evaluated whether this trait can represent a new described sexual features, influenced by sex biology. The distribution of the microforamina is particularly concentrated on the top of the vault, in particular along the sides of the sagittal, metopic, and coronal sutures, matching the course of major venous sinuses. Nonetheless, the density is lower in the region behind thebregma. A preferential pattern of distribution seems to join diagonally the coronal and dorsal parietal regions. Beyond oxygenation, these features are likely involved in endocranial thermal regulation and immune responses, and their distribution and prevalence can hence be of interest in human biology, evolutionary anthropology, and medicine.
Genetic and environmental determinants of multicellular-like phenotypes in fission yeast
Authors: Kӧvér Bence , Cohen Céleste E. , Ralser Markus , Heineike Benjamin M. , Bähler Jürg 
Published: December 2023

AbstractMulticellular fungi have repeatedly given rise to primarily unicellular yeast species. Some of these, includingSchizosaccharomyces pombe, are able to revert to multicellular-like phenotypes (MLP). Our bioinformatic analysis of existing data suggested that, besides some regulatory proteins, most proteins involved in MLP formation are not functionally conserved betweenS. pombeand budding yeast. We developed high-throughput assays for two types of MLP inS. pombe: flocculation and surface adhesion, which correlated in minimal medium, suggesting a common mechanism. Using a library of 57 naturalS. pombeisolates, we found MLP formation to widely vary across different nutrient and drug conditions. Next, in a segregantS. pombelibrary generated from an adhesive natural isolate and the standard laboratory strain, MLP formation correlated with expression levels of the transcription-factor genembx2and several flocculins. Quantitative trait locus mapping of MLP formation located a causal frameshift mutation in thesrb11gene encoding cyclin C, a part of the Cdk8 kinase module (CKM) of the Mediator complex. Other CKM deletions also resulted in MLP formation, consistently through upregulation ofmbx2, and only in minimal media. We screened a library of 3721 gene-deletion strains, uncovering additional genes involved in surface adhesion on minimal media. We identified 31 high-confidence hits, including 19 genes that have not been associated with MLPs in fission or budding yeast. Notably, deletion ofsrb11, unlike deletions of the 31 hits, did not compromise cell growth, which might explain its natural occurrence as a QTL for MLP formation.
SMPD4mediated sphingolipid metabolism regulates brain and primary cilia development
Authors: Inskeep Katherine A. , Crase Bryan , Stottmann Rolf W. 
Published: December 2023

SummaryGenetic variants in multiple sphingolipid biosynthesis genes cause human brain disorders. A recent study collected patients from twelve unrelated families with variants in the geneSMPD4, a neutral sphingomyelinase which metabolizes sphingomyelin into ceramide at an early stage of the biosynthesis pathway. These patients have severe developmental brain malformations including microcephaly and cerebellar hypoplasia. However, the mechanism ofSMPD4was not known and we pursued a new mouse model. We hypothesized that the role ofSMPD4in producing ceramide is important for making primary cilia, a crucial organelle mediating cellular signaling. We found that the mouse model has cerebellar hypoplasia due to failure of Purkinje cell development. Human induced pluripotent stem cells exhibit neural progenitor cell death and have shortened primary cilia which is rescued by adding exogenous ceramide.SMPD4production of ceramide is crucial for human brain development.
The E3 ubiquitin ligase RNF220 maintains hindbrainHoxexpression patterns through regulation of WDR5 stability
Authors: Wang Huishan , Liu Xingyan , Liu Yamin , Yang Chencheng , Ye Yaxin , Yu Xiaomei , Sheng Nengyin , Zhang Shihua , Mao Bingyu , Ma Pengcheng 
Published: December 2023

AbstractThe spatial and temporal linear expression ofHoxgenes establishes a regionalHoxcode, which is crucial for the antero-posterior (A-P) patterning, segmentation, and neuronal circuit development of the hindbrain. RNF220, an E3 ubiquitin ligase, is widely involved in neural developmentviatargeting of multiple substrates. Here, we found that the expression ofHoxgenes in the pons was markedly up-regulated at the late developmental stage (post-embryonic day E15.5) inRnf220−/−andRnf220+/−mouse embryos. Single-nucleus RNA-seq analysis revealed differentHoxde-repression profiles in different groups of neurons, including the pontine nuclei (PN). TheHoxpattern was disrupted and the neural circuits were affected in the PN ofRnf220+/−mice. We showed that this phenomenon was mediated by WDR5, a key component of the TrxG complex, which can be polyubiquitinated and degraded by RNF220. Intrauterine injection of WDR5 inhibitor (WDR5-IN-4) and genetic ablation ofWdr5inRnf220+/−mice largely recovered the de-repressedHoxexpression pattern in the hindbrain. In P19 embryonal carcinoma cells, the retinoic acid inducedHoxexpression was further stimulated byRnf220knockdown, which can also be rescued byWdr5knockdown. In short, our data suggest a new role of RNF220/WDR5 inHoxpattern maintenance and pons development in mice.
A long-acting prolactin to combat lactation insufficiency
Authors: Kready Kasia , Doiron Kailyn , Redfield Chan Katherine , Way Jeffrey , Justman Quincey , Powe Camille E. , Silver Pamela 
Published: December 2023

AbstractHuman infants are born to breastfeed. While 50% of lactating persons struggle to make enough milk, there are no governmentally-approved drugs to enhance lactation1. Here, we engineer a variant of the naturally-occurring driver of lactation, the hormone Prolactin, to increase its serum half-life and produce a viable drug candidate. Our engineered variant, Prolactin-eXtra Long-acting (Prolactin-XL), is comprised of endogenously active human prolactin fused to an engineered human IgG Fc domain designed to overcome the unique drug development challenges specific to the lactating person-infant dyad. Our Prolactin-XL has a serum half-life of 70.9h in mice, 2,625-fold longer than endogenously active prolactin alone (70.9h v. 0.027h). We demonstrate that Prolactin-XL increases milk production and restores growth of pups fed by dams with pharmacologically-ablated lactation. We show that Prolactin-XL-enhanced lactation is accompanied by reversible, lactocyte-driven changes in mammary gland morphology. This work establishes long-acting prolactins as a potentially powerful pharmacologic means to combat insufficient lactation.
Benchmarking DNA binding affinity models using allele-specific transcription factor binding data
Authors: Li Xiaoting , Melo Lucas A. N. , Bussemaker Harmen J. 
Published: December 2023

ABSTRACTTranscription factors (TFs) bind to DNA in a highly sequence-specific manner. This specificity can manifest itselfin vivoat heterozygous loci as a difference in TF occupancy between the two alleles. When applied on a genomic scale, functional genomic assays such as ChIP-seq typically lack the statistical power to detect allele-specific binding (ASB) at the level of individual variants. To address this, we propose a framework for benchmarking sequence-to-affinity models for TF binding in terms of their ability to predict allelic imbalances in ChIP-seq counts. We show that a likelihood function based on an over-dispersed binomial distribution can aggregate evidence for allelic preference across the genome without requiring statistical significance for individual variants. This allows us to systematically compare predictive performance when multiple binding models for the same TF are available. We introduce PyProBound, an easily extensible reimplementation of the ProBound biophysically interpretable machine learning framework. Configuring PyProBound to explicitly account for a confounding sequence-specific bias in DNA fragmentation rate yields improved TF binding models when training on ChIP-seq data. We also show how our likelihood function can be leveraged to performde novomotif discovery on the raw allele-aware ChIP-seq counts.
Neuronal Avalanches in Naturalistic Speech and Music Listening
Authors: Neri Matteo , Runfola Claudio , te Rietmolen Noemie , Sorrentino Pierpaolo , Schon Daniele , Morillon Benjamin , Rabuffo Giovanni 
Published: December 2023

AbstractNeuronal avalanches are cascade-like events ubiquitously observed across imaging modalities and scales. Aperiodic timing and topographic distribution of these events have been related to the systemic physiology of brain states. However, it is still unknown whether neuronal avalanches are correlates of cognition, or purely reflect physiological properties. In this work, we investigate this question by analyzing intracranial recordings of epileptic participants during rest and passive listening of naturalistic speech and music stimuli. During speech or music listening, but not rest, participants’ brains “tick” together, as the timing of neuronal avalanches is stimulus-driven and hence correlated across participants. Auditory regions are strongly participating in coordinated neuronal avalanches, but also associative regions, indicating both the specificity and distributivity of cognitive processing. The subnetworks where such processing takes place during speech and music largely overlap, especially in auditory regions, but also diverge in associative cortical sites. Finally, differential pathways of avalanche propagation across auditory and non-auditory regions differentiate brain network dynamics during speech, music and rest. Overall, these results highlight the potential of neuronal avalanches as a neural index of cognition.Author’s summaryNeuronal avalanches consist of collective network events propagating across the brain in short-lived and aperiodic instances. These salient events have garnered a great interest for studying the physics of cortical dynamics, and bear potential for studying brain data also in purely neuroscientific contexts. In this work we investigated neuronal avalanches to index cognition, analyzing an intracranial stereo electroencephalography (iEEG) dataset during speech, music listening and resting state in epileptic patients. We show that neuronal avalanches are consistently driven by music and speech stimuli: avalanches co-occur in participants listening to the same auditory stimulus; avalanche topography differs from resting state, presenting partial similarities during speech and music; avalanche propagation changes during speech, music, and rest conditions, especially along the pathways between auditory and non auditory regions. Our work underlines the distributed nature of auditory stimulus processing, supporting neuronal avalanches as a valuable and computationally advantageous framework for the study of cognition in humans.
The role of theC. albicanstranscriptional repressorNRG1during filamentation and disseminated candidiasis is strain-dependent
Authors: Wakade Rohan S. , Wellington Melanie , Krysan Damian J. 
Published: December 2023

AbstractCandida albicansis one of the most common causes of superficial and invasive fungal disease in humans. Its ability to cause disease has been closely linked to its ability to undergo a morphological transition from budding yeast to filamentous forms (hyphae and pseudohyphae). The ability ofC. albicansstrains isolated from patients to undergo filamentation varies significantly. In addition, the filamentation phenotypes of mutants involving transcription factors that positively regulate hyphal morphogenesis can also vary from strain to strain. Here, we characterized the virulence, in vitro and in vivo filamentation, and in vitro and in vivo hypha-associated gene expression profiles of four poorly filamentingC. albicansisolates and their corresponding deletion mutants of the repressor of filamentationNRG1. The two most virulent strains, 57055 and 78048, show robust in vivo filamentation while remaining predominately yeast phase exposed to RPMI+10% bovine calf serum at 37°C; the two low virulence strains (94015 and 78042) do not filament well under either condition. Deletion ofNRG1increases hyphae formation in the SC5314 derivative SN250 but only pseudohyphae are formed in the clinical isolates in vivo. Deletion ofNRG1modestly increased the virulence of 78042 which was accompanied by increased expression of hyphae-associated genes without an increase in filamentation. Strikingly, deletion ofNRG1in 78048 reduced filamentation, expression of candidalysin (ECE1) and virulence in vivo without dramatically altering establishment of infection. Thus, the function ofNRG1varies significantly within this set ofC. albicansisolates and can actually suppress filamentation in vivo.ImportanceClinical isolates of the human fungal pathogenCandida albicansshow significant variation in their ability to undergo in vitro filamentation and in the function of well-characterized transcriptional regulators of filamentation. Here, we show that Nrg1, a key repressor of filamentation and filament specific gene expression in standard reference strains, has strain dependent functions, particularly during infection. Most strikingly, loss ofNRG1function can reduce filamentation, hypha-specific gene expression such as the toxin candidalysin, and virulence in some strains. Our data emphasize that the functions of seemingly fundamental and well-conserved transcriptional regulators such as Nrg1 are contextual with respect to both environment and genetic background.
Diet-driven differential response ofAkkermansia muciniphilamodulates pathogen susceptibility
Authors: Wolter Mathis , Grant Erica T. , Boudaud Marie , Pudlo Nicholas A. , V. Pereira Gabriel , Eaton Kathryn A. , Martens Eric C. , Desai Mahesh S. 
Published: December 2023

AbstractThe erosion of the colonic mucus layer by a dietary fiber-deprived gut microbiota results in heightened susceptibility to an attaching and effacing pathogen,Citrobacter rodentium. Nevertheless, the questions of whether and how specific mucolytic bacteria aid in the increased pathogen susceptibility remain unexplored. Here, we leverage a functionally characterized, 14-member synthetic human microbiota in gnotobiotic mice to deduce which bacteria and functions are responsible for the pathogen susceptibility. Using strain dropouts of mucolytic bacteria from the community, we show thatAkkermansia muciniphilarenders the host more vulnerable to the mucosal pathogen during fiber deprivation. However, the presence ofA. muciniphilareduces pathogen load on a fiber-sufficient diet, highlighting the context-dependent beneficial effects of this mucin specialist. The enhanced pathogen susceptibility is not owing to altered host immune or pathogen responses, but is driven by a combination of increased mucus penetrability and altered activities ofA. muciniphilaand other community members. Our study provides novel insights into the mechanisms of how discrete functional responses of the same mucolytic bacterium either resist or enhance enteric pathogen susceptibility.
PhyloJunction: a computational framework for simulating, developing, and teaching evolutionary models
Authors: Mendes Fábio K. , Landis Michael J. 
Published: December 2023

AbstractWe introduce PhyloJunction, a computational framework designed to facilitate the prototyping, testing, and characterization of evolutionary models. PhyloJunction is distributed as an open-source Python library that can be used to implement a variety of models, through its flexible graphical modeling architecture and dedicated model specification language. Model design and use are exposed to users via command-line and graphical interfaces, which integrate the steps of simulating, summarizing, and visualizing data. This paper describes the features of PhyloJunction – which include, but are not limited to, a general implementation of a popular family of phylogenetic diversification models – and, moving forward, how it may be expanded to not only include new models, but to also become a platform for conducting and teaching statistical learning.
Hypoxia drives HIF2-dependent macrophage cell cycle entry and susceptibility to lentiviral transduction
Authors: Meng Bo , Zhao Na , Mlcochova Petra , Ferreira Isabella A.T.M , Ortmann Brian M. , Davis Tanja , Wit Niek , Rehwinkel Jan , Cook Simon , Maxwell Patrick H. , Nathan James A. , Gupta Ravindra K. 
Published: December 2023

AbstractMacrophages play critical roles across health and disease. Low oxygen conditions (hypoxia) have been associated primarily with cell cycle arrest in cultured dividing cells. Macrophages are typically quiescent in G0, though yolk sac and bone marrow derived macrophages frequently proliferate and monocyte-derived tissue macrophages are able to proliferate in response to tissue signals. Here we show that hypoxia (1% oxygen tension) results in reversible entry into the cell cycle in monocyte derived macrophages (MDM) and mouse peritoneal macrophages. Cell cycle progression is largely limited to G1/S phase with very little progression to G2/M. Mechanistically, this cell cycle transitioning is triggered by a HIF2α-directed transcriptional program. The response is accompanied by increased expression of cell cycle-associated proteins, including CDK1, and reversible activation of the canonical mitogen-activated MEK-ERK proliferation pathway. CDK1 associated SAMHD1 phosphorylation at T592 in hypoxic macrophages renders them hyper-susceptible to lentiviral transduction. Furthermore, PHD inhibitors, which activate HIFs, are able to recapitulate HIF2α-dependent cell cycle entry in macrophages, as well as susceptibility to lentiviral transduction. Finally, we demonstrate that tumour associated macrophages (TAM) in lung cancers exhibit transcriptomic profiles representing responses to low oxygen and cell cycle progression at single cell level. This work uncovers HIF2α driven macrophage cell cycle progression in low oxygen conditions that culminates in SAMHD1 phosphorylation and high susceptibility to lentiviral transduction. These findings have implications for inflammation, neoplasia and pathogen defence.
Towards establishing a rapid constant temperature detection method for canine parvovirus based on endonuclease activities
Authors: Weng Shaoting , Ma Shengming , Xing Yueteng , Zhang Wenhui , Wu Yinrong , Fu Mengyao , Luo Zhongyi , Li Qiuying , Lin Sen , Zhang Longfei , Wang Yao 
Published: December 2023

ABSTRACTCanine parvovirus can cause a high morbidity and mortality rate in puppies, posing a significant threat to both pet dogs and the breeding industry. Rapid, accurate and convenient detection methods are important for the early intervention and treatment of canine parvovirus. In this study, we propose a visual CPV detection system called nucleic acid mismatch enzyme digestion (NMED). This system combines reverse transcription-loop mediated isothermal amplification (RT-LAMP), endonuclease for gene mismatch detection and colloidal gold lateral chromatography. We demonstrated that NMED can induce the binding of the amplicon from the sample to the specific labeling probe, which in turn triggers digestion by the endonuclease. The sensitivity and visual visibility of RT-LAMP were increased by combining of endonuclease and colloidal gold lateral chromatography assisted by a simple temperature-controlled device. The sensitivity of the NMED assay was 1 copy/μL, which was consistent with qPCR. The method was validated with 10 clinical samples that potentially had CPV infection and achieved 100% accuracy. As a rapid, accurate and convenient molecular diagnostic method, NMED has great potential for application in the field of pathogenic microorganism detection.
STACCato: Supervised Tensor Analysis tool for studying Cell-cell Communication using scRNA-seq data across multiple samples and conditions
Authors: Dai Qile , Epstein Michael P. , Yang Jingjing 
Published: December 2023

AbstractResearch on cell-cell communication (CCC) is crucial for understanding biology and diseases. Many existing CCC inference tools neglect potential confounders, such as batch and demographic variables, when analyzing multi-sample, multi-condition scRNA-seq datasets. To address this significant gap, we introduce STACCato, aSupervisedTensorAnalysis tool for studyingCell-cellCommunication, that identifies CCC events and estimates the effects of biological conditions (e.g., disease status, tissue types) on such events, while adjusting for potential confounders. Application of STACCato to both simulated data and real scRNA-seq data of lupus and autism studies demonstrate that incorporating sample-level variables into CCC inference consistently provides more accurate estimations of disease effects and cell type activity patterns than existing methods that ignore sample-level variables. A computational tool implementing the STACCato framework is available on GitHub.