bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sexual dimorphism in head size in wild burying beetles (Nicrophorus vespilloides)
Authors: Smith Jack M.L. , Catherall-Ostler Andrew M. , Mashoodh Rahia , Kilner Rebecca M. 
Published: November 2023

AbstractMale burying beetles (Nicrophorus vespilloides) carry an additional abdominal segment and produce pheromones but otherwise the species is thought to be sexually monomorphic. Both sexes bear bright orange bands on their black elytra, which probably function as part of a warning display rather than in mate choice.Although larger individuals are more likely to win contests to secure the small carrion required for reproduction, both sexes compete for this vital breeding resource. In wild populations, the sexes are alike in the mean and distribution in their body size.Here we describe a form of sexual size dimorphism in wild populations that has previously been overlooked. We show that males have wider heads than females, for any given body size, and that the scaling relationship with body size is hyperallometric in males, but isometric in females. We also show how absolute head width, and the extent of sexual dimorphism in head width differs among wild populations which are within c.10km of each other.We suggest that head size dimorphism could be adaptive, and could be due to divergent selection arising from task specialisation during biparental care, since the duties of care favoured by males are likely to require a greater bite force.
Ecological diversification in an adaptive radiation of plants: the role of de novo mutation and introgression
Authors: Stone Benjamin W. , Wessinger Carolyn A. 
Published: November 2023

AbstractAdaptive radiations are characterized by rapid ecological diversification and speciation events, leading to fuzzy species boundaries between ecologically differentiated species. Adaptive radiations are therefore key systems for understanding how species are formed and maintained, including the role of de novo mutations vs. pre-existing variation in ecological adaptation and the genome-wide consequences of hybridization events. For example, adaptive introgression, where beneficial alleles are transferred between lineages through hybridization, may fuel diversification in adaptive radiations and facilitate adaptation to new environments. In this study, we employed whole-genome resequencing data to investigate the evolutionary origin of hummingbird-pollinated flowers and to characterize genome-wide patterns of phylogenetic discordance and introgression inPenstemonsubgenusDasanthera, a small and diverse adaptive radiation of plants. We found that magenta hummingbird-adapted flowers have apparently evolved twice from ancestral blue-violet bee-pollinated flowers within this radiation. These shifts in flower color are accompanied by a variety of inactivating mutations to a key anthocyanin pathway enzyme, suggesting that independent de novo loss-of-function mutations underlie parallel evolution of this trait. Although patterns of introgression and phylogenetic discordance were heterogenous across the genome, a strong effect of gene density suggests that, in general, natural selection opposes introgression and maintains genetic differentiation in gene-rich genomic regions. Our results highlight the importance of both de novo mutation and introgression as sources of evolutionary change and indicate a role for de novo mutation in driving parallel evolution in adaptive radiations.
Somatic structural variants driving distinct modes of oncogenesis in melanoma
Authors: Conway Jake R. , Gillani Riaz , Crowdis Jett , Reardon Brendan , Park Jihye , Han Seunghun , Titchen Breanna , Benamar Mouadh , Haq Rizwan , Van Allen Eliezer M. 
Published: November 2023

AbstractThe diversity of structural variants (SVs) in melanoma and how they impact oncogenesis are incompletely known. We performed harmonized analysis of SVs across melanoma histological and genomic subtypes, and we identified distinct global properties between subtypes. These included the frequency and size of SVs and SV classes, their relation to chromothripsis events, and the role of topologically associated domain (TAD) boundary altering SVs on cancer-related genes. Following our prior identification of double-stranded break repair deficiency in a subset of triple wild-type cutaneous melanoma, we identifiedMRE11andNBNloss-of-function SVs in melanomas with this mutational signature. Experimental knockouts ofMRE11andNBN, followed by olaparib cell viability assays in melanoma cells, indicated that dysregulation of each of these genes may cause sensitivity to PARPi in cutaneous melanomas. Broadly, harmonized analysis of melanoma SVs revealed distinct global genomic properties and molecular drivers, which may have biological and therapeutic impact.Statement of SignificanceThe diversity of SVs in melanoma, and how they directly or indirectly impact oncogenesis, are incompletely known. Here we present analysis of melanoma SVs that reveal distinct global genomic properties and molecular drivers, some of which point to opportunities for further biological and therapeutic investigation.
GIN-TONIC: Non-hierarchical full-text indexing for graph-genomes
Authors: Öztürk Ünsal , Mattavelli Marco , Ribeca Paolo 
Published: November 2023

AbstractThis paper presents a new data structure, GIN-TONIC, designed to index arbitrary string-labelled directed graphs representing, for instance, pangenomes or transcriptomes. GIN-TONIC provides several capabilities not offered by other graph-indexing methods based on the FM-index. It is non-hierarchical, handling a graph as a single monolithic object; it indexes at nucleotide resolution all possible walks in the graph without the need to explicitly store them; it supports exact substring queries in polynomial time and space for all possible walk roots in the graph, even if there are exponentially many walks corresponding to such roots. Specific ad-hoc optimisations, such as a precomputed cache, allow GIN-TONIC to achieve excellent performance for input graphs of various topologies and sizes. Robust scalability capabilities and a querying performance close to that of a linear FM-Index are demonstrated for two real-world applications, a human pangenome and transcriptome. Source code and associated benchmarks are available on GitHub.Availability and implementationGIN-TONIC and all related programs are available athttps://github.com/uensalo/gin.
Phylogenetic diversity and regionalization in the temperate arid zone
Authors: Folk Ryan A. , Maassoumi Aliasghar A. , Siniscalchi Carolina M. , Kates Heather R. , Soltis Douglas E. , Soltis Pamela S. , Belitz Michael B. , Guralnick Robert P. 
Published: November 2023

ABSTRACTAstragalus(Fabaceae) is astoundingly diverse in temperate, cold arid regions of Earth, positioning this group as a model clade for investigating the distribution of plant diversity in the face of climatic challenge. Here we identify the spatial distribution of diversity and endemism inAstragalus, using species distribution models for 752 species and a phylogenetic tree comprising 847 species. We integrated these to map centers of species richness (SR) and relative phylogenetic diversity (RPD), and used grid cell randomizations to investigate centers of endemism. We also used clustering methods to identify phylogenetic regionalizations. We then assembled predictor variables of current climate conditions to test environmental factors predicting these phylogenetic diversity results, especially temperature and precipitation seasonality.We find that SR centers are distributed globally at temperate middle latitudes in arid regions, but the Mediterranean Basin is the most important center of RPD. Endemism centers also occur globally, but Iran represents a key endemic area with a concentration of both paleo- and neoendemism. Phylogenetic regionalization recovered an east-west gradient in Eurasia and an amphitropical disjunction across North and South America; American phyloregions are overall most closely related to east and central Asia. SR, RPD, and lineage turnover are driven mostly by precipitation and seasonality, but endemism is driven primarily by diurnal temperature variation. Endemism and regionalization results point to western Asia and especially Iran as a biogeographic gateway between Europe and Asia. RPD and endemism highlight the importance of temperature and drought stress in determining plant diversity and endemism centers.
Integrative analysis reveals therapeutic potential of pyrvinium pamoate in Merkel cell carcinoma
Authors: Yang Jiawen , Lim James T. , Victor Paul , Corona Marcelo G. , Chen Chen , Khawaja Hunain , Pan Qiong , Paine-Murrieta Gillian D. , Schnellmann Rick G. , Roe Denise J. , Gokhale Prafulla C. , DeCaprio James A. , Padi Megha 
Published: November 2023

AbstractMerkel Cell Carcinoma (MCC) is an aggressive neuroendocrine cutaneous malignancy arising from either ultraviolet-induced mutagenesis or Merkel cell polyomavirus (MCPyV) integration. Despite extensive research, our understanding of the molecular mechanisms driving the transition from normal cells to MCC remains limited. To address this knowledge gap, we assessed the impact of inducible MCPyV T antigens on normal human fibroblasts by performing RNA sequencing. Our data uncovered changes in expression and regulation of Wnt signaling pathway members. Building on this observation, we bioinformatically evaluated various Wnt pathway perturbagens for their ability to reverse the MCC gene expression signature and identified pyrvinium pamoate, an FDA-approved anthelminthic drug known for its anti-tumor activity in other cancers. Leveraging transcriptomic, network, and molecular analyses, we found that pyrvinium targets multiple MCC vulnerabilities. Pyrvinium not only reverses the neuroendocrine features of MCC by modulating canonical and non-canonical Wnt signaling but also inhibits cancer cell growth by activating p53-mediated apoptosis, disrupting mitochondrial function, and inducing endoplasmic reticulum stress. Finally, we demonstrated that pyrvinium reduces tumor growth in an MCC mouse xenograft model. These findings offer a new understanding of the role of Wnt signaling in MCC and highlight the utility of pyrvinium as a potential treatment for MCC.
NAD+controls circadian rhythmicity during cardiac aging
Authors: Carpenter Bryce J. , Lecacheur Margaux , Mangold Yannick N. , Cui Kai , Günther Stefan , Dierickx Pieterjan 
Published: November 2023

AbstractDisruption of the circadian clock as well as reduced NAD+levels are both hallmarks of aging. While circadian rhythms and NAD+metabolism have been linked in heart disease, their relationship during cardiac aging is less clear. Here, we show that aging leads to disruption of diurnal gene expression in the heart. Long-term supplementation with the NAD+precursor nicotinamide riboside (NR) boosts NAD+levels, reprograms the diurnal transcriptome and reverses naturally occurring cardiac enlargement in aged female mice. In addition, complete abolishment of NAD+levels in CMs impairs PER2::luc oscillations, which is rescued by NR supplementation. These findings reveal an essential role for NAD+in regulation of the cardiac circadian clock upon aging, which opens up new avenues to counteract age-related cardiac disorders.
Reconstructing prevalence dynamics of wildlife pathogens from pooled and individual samples
Authors: Borremans Benny , Falvo Caylee A. , Crowley Daniel E. , Hoegh Andrew , Lloyd-Smith James O. , Peel Alison J. , Restif Olivier , Ruiz-Aravena Manuel , Plowright Raina K. 
Published: November 2023

AbstractPathogen transmission studies require sample collection over extended periods, which can be challenging and costly, especially in the case of wildlife. A useful strategy can be to collect pooled samples, but this presents challenges when the goal is to estimate prevalence. This is because pooling can introduce a dilution effect where pathogen concentration is lowered by the inclusion of negative or lower-concentration samples, while at the same time a pooled sample can test positive even when some of the contributing samples are negative. If these biases are taken into account, the concentration of a pooled sample can be leveraged to infer the most likely proportion of positive individuals, and thus improve overall prevalence reconstruction, but few methods exist that account for the sample mixing process.We present a Bayesian multilevel model that estimates prevalence dynamics over time using pooled and individual samples in a wildlife setting. The model explicitly accounts for the complete mixing process that determines pooled sample concentration, thus enabling accurate prevalence estimation even from pooled samples only. As it is challenging to link individual-level metrics such as age, sex, or immune markers to infection status when using pooled samples, the model also allows the incorporation of individual-level samples. Crucially, when individual samples can test false negative, a potentially strong bias is introduced that results in incorrect estimates of regression coefficients. The model, however, can account for this by leveraging the combination of pooled and individual samples. Last, the model en- ables estimation of extrinsic environmental effects on prevalence dynamics.Using a simulated dataset inspired by virus transmission in flying foxes, we show that the model is able to accurately estimate prevalence dynamics, false negative rate, and covariate effects. We test model performance for a range of realistic sampling scenarios and find that while it is generally robust, there are a number of factors that should be considered in order to maximize performance.The model presents an important advance in the use of pooled samples for estimating prevalence dynamics in a wildlife setting, can be used with any biomarker of infection (Ct values, antibody levels, other infection biomarkers) and can be applied to a wide range of host-pathogen systems.
Brain Charts for People Living with Multiple Sclerosis
Authors: Keshavan A. , Peterson D. , Alexander-Bloch A. , Leyden K.M. 
Published: November 2023

AbstractMultiple sclerosis (MS) is associated with brain volume loss throughout the disease course. Currently available automated segmentation methods can measure total brain volume as well as ventricular volume, which has been advocated as a robust surrogate for brain volume based on clinically acquired magnetic resonance imaging (MRI). However, brain and ventricle volumes change naturally with age and may be susceptible to biases from differences in acquisition hardware, imaging protocol, and image quality, in addition to statistical biases such as regression to the mean. In this work, brain charts for people living with MS were established that account for patient biological sex, age, and differences in acquisition and image quality. 379 subjects were imaged longitudinally at 5 MS centers using 13 MRI scanner models from 2 scanner manufacturers employing a variety of protocols that included T1-weighted and T2-weighted FLAIR imaging. Generalized Additive Models for Location Scale and Shape (GAMLSS) were employed, and scanner metadata as well as automated assessments of image quality were modeled. Cross-sectional brain charts and conditional, longitudinal brain charts were estimated separately in female and male participants resulting in interpretable and intuitive centile estimates. These findings indicate that brain charts for people living with MS are a promising method for turning quantitative volumetrics into actionable knowledge about a patient’s disease.HighlightsInterpreting observed changes in brain volume can be challenging due to statistical biases including regression to the mean.Brain size changes naturally with age and may be susceptible to biases associated with acquisition hardware, imaging protocol, and image quality.Brain charts for people living with MS are a promising method for translating quantitative volumetrics into interpretable knowledge about a patient’s disease.
Temporal modulation of tactile perception during balance control
Authors: Wachsmann Fabian Dominik , Fiehler Katja , Voudouris Dimitris 
Published: November 2023

SummarySomatosensory feedback is essential for motor control, yet sensations from one’s own movements are often suppressed. Despite extensive research on movement-induced tactile suppression, its mechanisms remain unclear. Most studies focus on simple upper-limb movements, leaving the generalization to other body parts unexplored. This study examines tactile processing on the lower limb during balance control by varying feedback processing demands. Participants experienced visual perturbations in a virtual room challenging their posture. Tactile sensitivity was assessed using vibrotactile stimuli to the lower leg at different times around the perturbation. We found that postural behavior is both predictively tuned before and reactively adjusted to expected perturbations. Our results provide evidence that tactile sensitivity changes according to feedback processing demands on the lower limb. Such dynamic sensory modulation could reflect the continuous up- and down-regulation of feedback signals to accomplish the task at hand.
LEAFY and WAPO1 jointly regulate spikelet number per spike and floret development in wheat
Authors: Paraiso Francine , Lin Huiqiong , Li Chengxia , Woods Daniel P. , Lan Tianyu , Tumelty Connor , Debernardi Juan M. , Joe Anna , Dubcovsky Jorge 
Published: November 2023

ABSTRACTIn wheat, the transition of the inflorescence meristem to a terminal spikelet (IM→TS) determines the spikelet number per spike (SNS), an important yield component. In this study, we demonstrate that the plant-specific transcription factor LEAFY (LFY) physically and genetically interacts with WHEAT ORTHOLOG OF APO1 (WAPO1) to regulate SNS and floret development. Loss-of-function mutations in either or both genes result in significant and similar reductions in SNS, as a result of a reduction in the rate of spikelet meristems formation per day. SNS is also modulated by significant genetic interactions betweenLFYandSQUAMOSAMADS-box genesVRN1andFUL2, which promote the IM→TS transition. Single-molecule fluorescencein-situhybridization revealed a down-regulation ofLFYand up-regulation of theSQUAMOSAMADS-box genes in the distal part of the developing spike during the IM→TS transition, supporting their opposite roles in the regulation of SNS in wheat. Concurrently, the overlap ofLFYandWAPO1transcription domains in the developing spikelets contributes to normal floret development. Understanding the genetic network regulating SNS is a necessary first step to engineer this important agronomic trait.SUMMARY STATEMENTThe plant specific transcription factorLEAFYplays an important role in the regulation of the number of spikelets per spike in wheat.
Dextrin conjugation to colistin inhibits its toxicity, cellular uptake and acute kidney injuryin vivo
Authors: Varache Mathieu , Rizzo Siân , Sayers Edward J. , Newbury Lucy , Mason Anna , Liao Chia-Te , Chiron Emilie , Bourdiec Nathan , Jones Adam , Fraser Donald J. , Taylor Philip R. , Jones Arwyn T. , Thomas David W. , Ferguson Elaine L. 
Published: November 2023

AbstractThe acute kidney injury (AKI) and dose-limiting nephrotoxicity, which occurs in 20-60% of patients following systemic administration of colistin, represents a challenge in the effective treatment of multi-drug resistant gram-negative infections. To reduce clinical toxicity of colistin and improve targeting to infected /inflamed tissues, we previously developed dextrin-colistin conjugates, whereby colistin is designed to be released by amylase-triggered degradation of dextrin in infected and inflamed tissues, after passive targeting by the enhanced permeability and retention effect. Whilst it was evidentin vitrothat polymer conjugation can reduce toxicity and prolong plasma half-life, without significant reduction in antimicrobial activity of colistin, it was unclear how dextrin conjugation would alter cellular uptake and localisation of colistin in renal tubular cellsin vivo. We discovered that dextrin conjugation effectively reduced colistin’s toxicity towards human kidney proximal tubular epithelial cells (HK-2)in vitro, which was mirrored by significantly less cellular uptake of Oregon Green (OG)-labelled dextrin-colistin conjugate, when compared to colistin. Using live-cell confocal imaging, we revealed localisation of both, free and dextrin-bound colistin in endolysosome compartments of HK-2 and NRK-52E cells. Using a murine AKI model, we demonstrated dextrin-colistin conjugation dramatically diminishes both proximal tubular injury and renal accumulation of colistin. These findings reveal new insight into the mechanism by which dextrin conjugation can overcome colistin’s renal toxicity and show the potential of polymer conjugation to improve the side effect profile of nephrotoxic drugs.Graphical abstract
A computational approach for deciphering the interactions between proximal and distal regulators in B cell differentiation
Authors: Park Sung-Joon , Nakai Kenta 
Published: November 2023

AbstractDelineating the intricate interplay between promoter-proximal and -distal regulators is crucial for understanding the function of transcriptional mediator complexes implicated in the regulation of gene expression. The aim of the present study was to develop a computational method for accurately modeling the spatial proximal and distal regulatory interactions. Our method combined regression-based models to identify key regulators through gene expression prediction and a graph- embedding approach to detect coregulated genes. This approach enabled a detailed investigation of the gene regulatory mechanisms underlying peripheral B cell differentiation, accompanied by dramatic rearrangements of the genome structure. We found that while the promoter-proximal elements were the principal regulators of gene expression, the distal regulators fine-tuned transcription. Moreover, our approach unveiled the presence of modular regulators, such as structural cofactors and proximal/distal transcriptional factors, which were co-expressed with their target genes. These findings imply that the dysregulation of interactions between transcriptional and structural factors is associated with chromatin reorganization failure and ultimately an increased risk of malignancy. We envisage that our computational approach will help crack the transcriptionalcis-regulatory code of the three-dimensional network regulating gene expression.
Short-term Pre-operative Methionine Restriction Induces Browning of Perivascular Adipose Tissue and Improves Vein Graft Remodeling in Mice
Authors: Kip Peter , Sluiter Thijs J. , MacArthur Michael R. , Tao Ming , Jung Jonathan , Mitchell Sarah J. , Kooijman Sander , Kruit Nicky , Gorham Josh , Seidman Jonathan G. , Quax Paul H.A. , Aikawa Masanori , Ozaki C. Keith , Mitchell James R , de Vries Margreet R. 
Published: November 2023

AbstractShort-term preoperative methionine restriction (MetR) shows promise as a translatable strategy to modulate the body’s response to surgical injury. Its application, however, to improve post-interventional vascular remodeling remains underexplored. Here, we find that MetR protects from arterial intimal hyperplasia in a focal stenosis model and adverse vascular remodeling after vein graft surgery. RNA sequencing reveals that MetR enhances the brown adipose tissue phenotype in arterial perivascular adipose tissue (PVAT) and induces it in venous PVAT. Specifically, PPAR-α was highly upregulated in PVAT-adipocytes. Furthermore, MetR dampens the post-operative pro-inflammatory response to surgery in PVAT-macrophagesin vivoandin vitro. This study shows for the first time that the detrimental effects of dysfunctional PVAT on vascular remodeling can be reversed by MetR, and identifies pathways involved in browning of PVAT. Furthermore, we demonstrate the potential of short-term pre-operative MetR as a simple intervention to ameliorate vascular remodeling after vascular surgery.Graphical Abstract