bluuebunny/crossref_metadata_2025_split huggingface dataset:
Scorpio : Enhancing Embeddings to Improve Downstream Analysis of DNA sequences
Authors: Refahi Mohammad S. , Sokhansanj Bahrad A. , Mell Joshua C. , Brown James R. , Yoo Hyunwoo , Hearne Gavin , Rosen Gail L. 
Published: July 2024

ABSTRACTAnalysis of genomic and metagenomic sequences is inherently more challenging than that of amino acid sequences due to the higher divergence among evolutionarily related nucleotide sequences, variable k-mer and codon usage within and among genomes of diverse species, and poorly understood selective constraints. We introduce Scorpio, a versatile framework designed for nucleotide sequences that employs contrastive learning to improve embeddings. By leveraging pre-trained genomic language models and k-mer frequency embeddings, Scorpio demonstrates competitive performance in diverse applications, including taxonomic and gene classification, antimicrobial resistance (AMR) gene identification, and promoter detection. A key strength of Scorpio is its ability to generalize to novel DNA sequences and taxa, addressing a significant limitation of alignment-based methods. Scorpio has been tested on multiple datasets with DNA sequences of varying lengths (long and short) and shows robust inference capabilities. Additionally, we provide an analysis of the biological information underlying this representation, including correlations between codon adaptation index as a gene expression factor, sequence similarity, and taxonomy, as well as the functional and structural information of genes.
Modeling biases from low-pass genome sequencing to enable accurate population genetic inferences
Authors: Fonseca Emanuel M. , Tran Linh N. , Mendoza Hannah , Gutenkunst Ryan N. 
Published: July 2024

AbstractLow-pass genome sequencing is cost-effective and enables analysis of large cohorts. However, it introduces biases by reducing heterozygous genotypes and low-frequency alleles, impacting subsequent analyses such as demographic history inference. We developed a probabilistic model of low-pass biases from the Genome Analysis Toolkit (GATK) multi-sample calling pipeline, and we implemented it in the population genomic inference software dadi. We evaluated the model using simulated low-pass datasets and found that it alleviated low-pass biases in inferred demographic parameters. We further validated the model by downsampling 1000 Genomes Project data, demonstrating its effectiveness on real data. Our model is widely applicable and substantially improves model-based inferences from low-pass population genomic data.
Human iPSC-derived myelinating organoids and globoid cells to study Krabbe Disease
Authors: Evans Lisa Marie P , Gawron Joseph , Sim Fraser J , Laura Feltri M , Marziali Leandro N 
Published: July 2024

AbstractKrabbe disease (Kd) is a lysosomal storage disorder (LSD) caused by the deficiency of the lysosomal galactosylceramidase (GALC) which cleaves the myelin enriched lipid galactosylceramide (GalCer). Accumulated GalCer is catabolized into the cytotoxic lipid psychosine that causes myelinating cells death and demyelination which recruits microglia/macrophages that fail to digest myelin debris and become globoid cells. Here, to understand the pathological mechanisms of Kd, we used induced pluripotent stem cells (iPSCs) from Kd patients to produce myelinating organoids and microglia. We show that Kd organoids have no obvious defects in neurogenesis, astrogenesis, and oligodendrogenesis but manifest early myelination defects. Specifically, Kd organoids showed shorter but a similar number of myelin internodes than Controls at the peak of myelination and a reduced number and shorter internodes at a later time point. Interestingly, myelin is affected in the absence of autophagy and mTOR pathway dysregulation, suggesting lack of lysosomal dysfunction which makes this organoid model a very valuable tool to study the early events that drive demyelination in Kd. Kd iPSC-derived microglia show a marginal rate of globoid cell formation under normal culture conditions that is drastically increased upon GalCer feeding. Under normal culture conditions, Kd microglia show a minor LAMP1 content decrease and a slight increase in the autophagy protein LC3B. Upon GalCer feeding, Kd cells show accumulation of autophagy proteins and strong LAMP1 reduction that at a later time point are reverted showing the compensatory capabilities of globoid cells. Altogether, this supports the value of our cultures as tools to study the mechanisms that drive globoid cell formation and the compensatory mechanism in play to overcome GalCer accumulation in Kd.
When does the probability of evolutionary rescue increase with the strength of selection?
Authors: Xu Kuangyi , Osmond Matthew M. 
Published: July 2024

AbstractAfter an environmental change, populations may be rescued from extinction through adaptive evolution. Stronger environmental changes often cause a faster demographic decline but also more rapid adaptive evolution, with opposing effects on rescue. More generally, it is unclear if the probability of rescue increases with stronger selection, with implications for herbicide/drug resistance evolution. Here we show that, across many scenarios of rescue, stronger selection promotes rescue when: (1) the rate of evolution has a stronger response to selection and (2) the rate of population decline is more rapid. Condition (1) occurs when adaptive alleles are more dominant or the level of inbreeding is higher or, in quantitative genetic models, the genetic variance is larger and the environmental shift is more rapid. Intuitively, a stronger evolutionary response to selection increases the marginal benefit of increased selection, while a faster demographic decline lowers the marginal cost of a reduction in mean fitness.
The transcriptional landscape of the developing chick trigeminal ganglion
Authors: Leonard Carrie E. , McIntosh Alec , Sanyal Johena , Taneyhill Lisa A. 
Published: July 2024

SummaryThe trigeminal ganglion is a critical structure in the peripheral nervous system, responsible for transmitting sensations of touch, pain, and temperature from craniofacial regions to the brain. Trigeminal ganglion development depends upon intrinsic cellular programming as well as extrinsic signals exchanged by diverse cell populations. With its complex anatomy and dual cellular origin from cranial placodes and neural crest cells, the trigeminal ganglion offers a rich context for examining diverse biological processes, including cell migration, fate determination, adhesion, and axon guidance. Avian models have, so far, enabled key insights into craniofacial and peripheral nervous system development. Yet, the molecular mechanisms driving trigeminal ganglion formation and subsequent nerve growth remain elusive. In this study, we performed RNA-sequencing at multiple stages of chick trigeminal ganglion development and generated a novel transcriptomic dataset that has been curated to illustrate temporally dynamic gene expression patterns. This publicly available resource identifies major pathways involved in trigeminal gangliogenesis, particularly with respect to the condensation and maturation of placode-derived neurons, thus inviting new lines of research into the essential processes governing trigeminal ganglion development.
Proteome-wide neuropeptide identification using NeuroPeptide-HMMer (NP-HMMer)
Authors: Zandawala Meet , Amir Muhammad Bilal , Shin Joel , Yim Won C. , Yañez Guerra Luis Alfonso 
Published: July 2024

AbstractNeuropeptides are essential neuronal signaling molecules that orchestrate animal behavior and physiology via actions within the nervous system and on peripheral tissues. Due to the small size of biologically active mature peptides, their identification on a proteome-wide scale poses a significant challenge using existing bioinformatics tools like BLAST. To address this, we have developed NeuroPeptide-HMMer (NP-HMMer), a hidden Markov model (HMM)-based tool to facilitate neuropeptide discovery, especially in underexplored invertebrates. NP-HMMer utilizes manually curated HMMs for 46 neuropeptide families, enabling rapid and accurate identification of neuropeptides. Validation of NP-HMMer onDrosophila melanogaster, Daphnia pulex, Tribolium castaneumandTenebrio molitordemonstrated its effectiveness in identifying known neuropeptides across diverse arthropods. Additionally, we showcase the utility of NP-HMMer by discovering novel neuropeptides in Priapulida and Rotifera, identifying 22 and 19 new peptides, respectively. This tool represents a significant advancement in neuropeptide research, offering a robust method for annotating neuropeptides across diverse proteomes and providing insights into the evolutionary conservation of neuropeptide signaling pathways.
predicTTE: An accessible and optimal tool for time-to-event prediction in neurological diseases
Authors: Weinreich Marcel , McDonough Harry , Yacovzada Nancy , Magen Iddo , Cohen Yahel , Harvey Calum , Gornall Sarah , Boddy Sarah , Alix James , Mohseni Nima , Kurz Julian M , Kenna Kevin P , Zhang Sai , Iacoangeli Alfredo , Al-Khleifat Ahmad , Snyder Michael P , Hobson Esther , Al-Chalabi Ammar , Hornstein Eran , Elhaik Eran , Shaw Pamela J , McDermott Christopher , Cooper-Knock Johnathan 
Published: July 2024

AbstractTime-to-event prediction is a key task for biological discovery, experimental medicine, and clinical care. This is particularly true for neurological diseases where development of reliable biomarkers is often limited by difficulty visualising and sampling relevant cell and molecular pathobiology. To date, much work has relied on Cox regression because of ease-of-use, despite evidence that this model includes incorrect assumptions. We have implemented a set of deep learning and spline models for time-to-event modelling within a fully customizable ‘app’ and accompanying online portal, both of which can be used for any time-to-event analysis in any disease by a non-expert user. Our online portal includes capacity for end-users including patients, Neurology clinicians, and researchers, to access and perform predictions using a trained model, and to contribute new data for model improvement, all within a data-secure environment. We demonstrate a pipeline for use of our app with three use-cases including imputation of missing data, hyperparameter tuning, model training and independent validation. We show that predictions are optimal for use in downstream applications such as genetic discovery, biomarker interpretation, and personalised choice of medication. We demonstrate the efficiency of an ensemble configuration, including focused training of a deep learning model. We have optimised a pipeline for imputation of missing data in combination with time-to-event prediction models. Overall, we provide a powerful and accessible tool to develop, access and share time-to-event prediction models; all software and tutorials are available atwww.predictte.org.
A Suite of Biochemical and Cell-Based Assays for the Characterization of KRAS Inhibitors and Degraders
Authors: Kidane Medhanie , Hoffman Rene M. , Wolfe-Demarco Jennifer K. , Huang Ting-Yu , Teng Chi-Ling , Gonzalez Lira Luis M. , Lin-Jones Jennifer , Pallares Gabriel , Lamerdin Jane E. , Servant Nicole B. , Lee Chun-Yao , Yang Chao-Tsung , Bernatchez Jean A. 
Published: July 2024

ABSTRACTKRAS is an important oncogenic driver which is mutated in numerous cancers. Recent advances in the selective targeting of KRAS mutants via small molecule inhibitors and targeted protein degraders have generated an increase in research activity in this area in recent years. As such, there is a need for new assay platforms to profile next generation inhibitors which improve on the potency and selectivity of existing drug candidates, while evading the emergence of resistance. Here, we describe the development of a new panel of biochemical and cell-based assays to evaluate the binding and function of known chemical entities targeting mutant KRAS. Our assay panels generated selectivity profiles and quantitative binding interaction dissociation constants for small molecules and degraders against wild type, G12C, G12D, and G12V KRAS, which were congruent with published data. These assays can be leveraged for additional mutants of interest beyond those described in this study, using both overexpressed cell-free systems and cell-based systems with endogenous protein levels.TABLE OF CONTENTS/ABSTRACT GRAPHIC
Complete enzymatic depolymerization of polyethylene terephthalate (PET) plastic using aSaccharomyces cerevisiae-based whole-cell biocatalyst
Authors: Gulati Siddhant , Sun Qing 
Published: July 2024

AbstractPlastics like polyethylene terephthalate (PET) have become an integral part of everyday life, yet plastic waste management remains a significant challenge. Enzymatic biocatalysis is an eco- friendly approach for recycling and upcycling of plastic waste. PET-hydrolyzing enzymes (PHEs) such asIsPETase, along with its engineered variants like FAST-PETase, demonstrate promising PET depolymerization capabilities at ambient temperatures. Whole-cell biocatalysts, displaying PHEs on their cell surface, offer high efficiency, reusability, and stability for PET depolymerization. However, their efficacy in fully breaking down PET is hindered by the necessity of two enzymes - PETase and MHETase. Current whole-cell systems either display only one PHE or struggle with performance when displaying larger passenger proteins like the MHETase-PETase chimera. In this work, we developed aSaccharomyces cerevisiae-based whole-cell biocatalyst system for complete PET depolymerization. Leveraging a cellulosome-inspired trifunctional protein scaffoldin displayed on the yeast surface, we immobilized FAST-PETase and MHETase, forming a multi-enzyme cluster. Our whole cell biocatalyst achieved complete PET depolymerization at 30°C, yielding 4.9 mM TPA in seven days with no intermediate accumulation. Furthermore, we showed improved PET depolymerization ability by binding FAST-PETase at multiple sites on the trifunctional scaffoldin. This breakthrough in complete PET depolymerization marks an essential step towards a circular plastic economy.
Reviving the Desired Gains Index: An optimal solution for parent selection in public plant breeding programs
Authors: Werner C.R. , Gardner K.A. , Tolhurst D.J. 
Published: July 2024

AbstractThe Desired Gains Index is an optimal solution for parent selection in public plant breeding programs. It enables breeders to quantify their breeding objectives in terms of desired genetic gains (i.e., desired response to selection) and facilitates the efficient simultaneous improvement of multiple quantitative traits in a breeding population without the need for economic weights. We deliberately chose the term “optimal” here, which is typically associated with the profit-oriented selection indices commonly used in animal breeding, such as the Smith-Hazel Index. Our intention is to refute the perception that the Desired Gains Index is less efficient than the Smith-Hazel Index since both approaches maximise expected genetic gains in proportion to the breeding objective. To achieve this, we first review the relationship between the Desired Gains Index and the Smith-Hazel Index to show that desired gains are actually a form of economic weighting expressed as an improvement ratio for the traits under selection. We then present a general form of the Desired Gains Index to leverage best linear unbiased prediction (BLUP), which enables seamless integration of pedigree or genomic relationship information (e.g., genomic estimated breeding values) between the selection candidates and other related individuals. Finally, using stochastic simulation, we compare the performance of different parent selection strategies, including index selection for population improvement, independent culling, and selection of extreme genotypes. The objective of these demonstrations is to convey the potential impact and benefits of the Desired Gains Index to a broader audience without the need for a deep understanding of selection theory and the equations presented here.
SCAR-6elncRNA locus epigenetically regulatesPROZand modulates coagulation and vascular function
Authors: Ranjan Gyan , Sehgal Paras , Scaria Vinod , Sivasubbu Sridhar 
Published: July 2024

AbstractSyntenic conservation is an effective strategy to identify evolutionarily conserved lncRNA orthologs. In this study, we identified a novel uncharacterized conserved lncRNA known asSyntenic Cardiovascular Conserved Region-Associated lncRNA-6 (scar-6)and functionally validated its role in coagulation and cardiovascular function. Precise editing of thescar-6lncRNA locus in zebrafish (scar-6gib007Δ12/Δ12) resulted in cranial hemorrhage and permeability defects. Further analysis, including overexpression, locus editing, and rescue experiments, provided compelling evidence for the critical role of thescar-6transcript in the coagulation process of zebrafish. Notably, rescue attempts were unsuccessful in mitigating cranial hemorrhage. Molecular investigation revealed that thescar-6RNA acts as an enhancer lncRNA (elncRNA), and controls the expression ofprozb, an inhibitor offactor Xa, through the enhancer element on its locus. Thescar-6locus actively suppresses the loop formation betweenprozbandscar-6sequences, facilitated by methylation of CpG island via theprdm14-PRC2complex, which is stabilized by thescar-6elncRNA transcript. Disruption of this mechanism inscar-6gib007Δ12/Δ12zebrafish led to impaired vascular function and subsequent hemorrhage. This was triggered by the activation of thePAR2receptor mediated by upregulation ofprozb, which in turn causedNF-κB-mediated endothelial cell activation. This study presents novel evidence for the multifaceted function of thescar-6locus, highlighting its crucial role in regulating the coagulation cascade geneprozband maintaining homeostasis and vascular function.SynopsisProZ-PZIis a natural inhibitor of activatedcoagulation factor X (F10)and plays a major role in maintaining hemostasis in-vivo. Here, the novel evolutionary syntenic conservedscar-6elncRNA locus is shown to regulateprozbexpression and control coagulation and vascular integrity in zebrafish.Thescar-6acts as an enhancer lncRNA (elncRNA). It controlsprozbexpression and modulates coagulation and vascular function in zebrafish.Thescar-6elncRNA stabilizes thePrdm14-PRC2complex binding toscar-6locus. This inhibitsprozb/scar-6looping via methylating the CpG island under wildtype conditions.Overexpressedprozbinscar-6edited animals activatesPAR2receptor, causing endothelial cell activation and vascular dysfunction.
Telomere-to-telomere sheep genome assembly reveals new variants associated with wool fineness trait
Authors: Luo Ling-Yun , Wu Hui , Zhao Li-Ming , Zhang Ya-Hui , Huang Jia-Hui , Liu Qiu-Yue , Wang Hai-Tao , Mo Dong-Xin , EEr He-Hua , Zhang Lian-Quan , Chen Hai-Liang , Jia Shan-Gang , Wang Wei-Min , Li Meng-Hua 
Published: July 2024

AbstractOngoing efforts to improve sheep reference genome assemblies still leave many gaps and incomplete regions, resulting in a few common failures and errors in sheep genomic studies. Here, we report a complete, gap-free telomere-to-telomere (T2T) genome of a ram (T2T-sheep1.0) with a size of 2.85 Gb, including all autosomes and chromosomes X and Y. It adds 220.05 Mb of previously unresolved regions (PURs) and 754 new genes to the most updated reference assembly,ARS-UI_Ramb_v3.0, and contains four types of repeat units (SatI, SatII, SatIII, and CenY) in the centromeric regions.T2T-sheep1.0exhibits a base accuracy of >99.999%, corrects several structural errors in previous reference assemblies, and improves structural variant (SV) detection in repetitive sequences. We identified 192,265 SVs, including 16,885 new SVs in the PURs, from the PacBio long-read sequences of 18 global representative sheep. With the whole-genome short-read sequences of 810 wild and domestic sheep representing 158 global populations and seven wild species, the use ofT2T-sheep1.0as the reference genome has improved population genetic analysis based on ∼133.31 million SNPs and 1,265,266 SVs, including 2,664,979 novel SNPs and 196,471 novel SVs.T2T-sheep1.0improves selective tests by detecting several novel genes and variants, including those associated with domestication (e.g.,ABCC4) and selection for the wool fineness trait (e.g.,FOXQ1) in tandemly duplicated regions.
Perception of audio-visual synchrony is modulated by walking speed and step-cycle phase
Authors: Clouston Gabriel , Davidson Matt , Alais David 
Published: July 2024

AbstractInvestigating sensory processes in active human observers is critical for a holistic understanding of perception. Recent research has demonstrated that locomotion can alter visual detection performance in a rhythmic manner, illustrating how a very frequent and natural behaviour can influence sensory performance. Here we extend this line of work to incorporate variations in walking speed, and test whether multi-sensory processing is impacted by the speed and phase of locomotion. Participants made audio-visual synchrony judgements while walking at two speeds over a range of stimulus onset asynchronies (SOAs). We find that sensitivity to multi-sensory synchrony decreases at slow walking speeds and is accompanied by an increase in reaction times, compared to when walking at a natural pace. A further analysis of the shortest SOAs was conducted to test whether subjective synchrony modulated over the step cycle. This revealed that synchrony judgements were quadratically modulated with perceived synchrony being higher in the swing phase of each step and lower when both feet were grounded during stance phase. Together, these results extend an earlier report that walking dynamically modulates visual sensitivity by contributing two new findings: first, that walking speed modulates perceived synchrony of audio-visual stimuli, and second, that modulations within the step-cycle extend to multisensory synchrony judgements which peak in the swing phase of each step.
Disposition of the chemosensory neurons in the neurotransmitter-release mutantunc-13
Authors: Bokman Eduard , Zaslaver Alon 
Published: July 2024

SummarySecretion of neurotransmitters- and neuropeptides-containing vesicles is a regulated process orchestrated by multiple proteins. Of these, mutants, defective in theunc-13andunc-31genes, responsible for neurotransmitter and neuropeptide release, respectively, are routinely used to elucidate neural and circuitry functions. While these mutants result in severe functional deficits, their neuroanatomy is assumed to be intact. Here, usingC. elegansas the model animal system, we find that the head sensory neurons show aberrant positional layout in neurotransmitter (unc-13), but not in neuropeptide (unc-31), release mutants. This finding suggests that synaptic activity may be important for proper cell migration during neurodevelopment and warrants considering possible anatomical defects when usingunc-13neurotransmitter release mutants.