bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic signatures of past megafrugivore-mediated dispersal in Malagasy palms
Authors: Méndez Laura , Barratt Christopher D. , Durka Walter , Kissling W. Daniel , Eiserhardt Wolf L. , Baker William J. , Randrianasolo Vonona , Onstein Renske E. 
Published: January 2023

AbstractSeed dispersal is a key process in the generation and maintenance of genetic diversity and genetic differentiation of plant populations in tropical ecosystems. During the Last Quaternary, most seed-dispersing megafauna was lost globally, but whether this has caused dispersal limitation, loss of genetic diversity, and increased genetic differentiation between plant populations with large, ‘megafaunal’ fruits (i.e., > 4 cm - megafruits) remains unclear.Here, we assessed whether megafrugivore extinctions in Madagascar (e.g., giant lemurs, elephant birds) have affected the genetic diversity and genetic differentiation of four animal-dispersed Malagasy palm (Arecaceae) species with large (Borassus madagascariensis), medium-sized (Hyphaene coriacea, Bismarckia nobilis), and small (Chrysalidocarpus madagascariensis) fruits. We integrated double-digest restriction-site-associated DNA sequencing (ddRAD) of 167 individuals from 25 populations with (past) distribution ranges for extinct and extant seed-dispersing animal species, climate and human impact data, and applied linear mixed-effects models to explore the drivers of variation in genetic diversity and genetic differentiation across Malagasy palm populations.We detected higher genetic diversity in species with megafruits than in the species with small fruits, and genetic differentiation was lowest for the human-used medium-sized megafruit species. Furthermore, we found that a higher number of shared extinct megafrugivore species between palm population pairs was associated with less genetic differentiation, indicating higher gene flow, whereas no relationship with extant frugivores – that are not able to swallow and disperse the seeds – was found. Finally, genetic diversity decreased with road density, whereas genetic differentiation decreased with increasing human population density, but only for populations with megafruits.Our results suggest that the legacy of megafrugivores regularly achieving long dispersal distances is still reflected in the genetic diversity and genetic differentiation of palms that were formerly dispersed by such large animals. Furthermore, high genetic diversity and low genetic differentiation were possibly maintained after the megafauna extinctions through human-mediated dispersal, long generation times, and long lifespans of these palms. Our study illustrates how integrating genetics with ecological data on species interactions, climate, and human impact, provides novel insights into the consequences of megafauna extinctions for plants with megafruits.
Measuring the long arm of childhood in real-time: Epigenetic predictors of BMI and social determinants of health across childhood and adolescence
Authors: Raffington Laurel , Schneper Lisa , Mallard Travis , Fisher Jonah , Vinnik Liza , Hollis-Hansen Kelseanna , Notterman Daniel A. , Tucker-Drob Elliot M. , Mitchell Colter , Harden Kathryn P. 
Published: January 2023

AbstractChildren who are socioeconomically disadvantaged are at increased risk for high body mass index (BMI) and multiple diseases in adulthood. The developmental origins of health and disease hypothesis proposes that early life conditions affect later-life health in a manner that is only partially modifiable by later-life experiences. Epigenetic mechanisms may regulate the influence of early life conditions on later life health. Recent epigenetic studies of adult blood samples have identified DNA-methylation sites associated with higher BMI and worse health (epigenetic-BMI).Here, we used longitudinal and twin study designs to examine whether epigenetic predictors of BMI developed in adults are valid biomarkers of child BMI and are sensitive to early life social determinants of health. Salivary epigenetic-BMI was calculated from two samples: (1) N=1,183 8-to-19-year-olds (609 female,meanage=13.4) from the Texas Twin Project (TTP), and (2) N=2,020 children (1,011 female) measured at 9 and 15 years from the Future of Families and Child Well-Being Study (FFCWS).We found that salivary epigenetic-BMI is robustly associated with children’s BMI (r=0.36 tor=0.50). Longitudinal analysis suggested that epigenetic-BMI is highly stable across adolescence, but remains both a leading and lagging indicator of BMI change. Twin analyses showed that epigenetic-BMI captures differences in BMI between monozygotic twins. Moreover, children from more disadvantaged socioeconomic status (SES) and marginalized race/ethnic groups had higher epigenetic-BMI, even when controlling for concurrent BMI, pubertal development, and tobacco exposure. SES at birth relative to concurrent SES best predicted epigenetic-BMI in childhood and adolescence.We show for the first time that epigenetic predictors of BMI calculated from pediatric saliva samples are valid biomarkers of childhood BMI that are sensitive to social inequalities. Our findings are in line with the hypothesis that early life conditions are especially important factors in epigenetic regulation of later life health. Research showing that health later in life is linked to early life conditions have important implications for the development of early-life interventions that could significantly extend healthy life span.
Effects of assisted gene flow on the flowering onset of the annual legumeLupinus angustifoliusL.: from phenotype to genotype
Authors: Sacristán-Bajo Sandra , Lara-Romero Carlos , García-Fernández Alfredo , Prieto-Benítez Samuel , Morente-López Javier , Rubio Teso María Luisa , Torres Elena , Iriondo José María 
Published: January 2023

AbstractCurrent climate change may impede species to evolutionary adapt quickly enough to environmental changes, threatening their survival. In keystone populations, it may be necessary to consider the introduction of adaptive alleles through assisted gene flow. Considering that flowering time is a crucial trait in plant response to global warming, the objective of our study was to test the potential benefits and limitations of assisted gene flow for enhancing the evolutionary potential ofLupinus angustifoliusL. (Fabaceae) populations through the advancement of flowering time in the context of global warming. Previous studies have shown that southern populations ofL. angustifoliusflower earlier than northern populations. We collected seeds from four populations in Spain from two different latitudes, and we established them in a common garden environment. To advance the flowering onset of northern populations, we used pollen from southern individuals to pollinate plants from northern populations, creating an F1 gene flow line. In the following season, the F1 gene flow line was self-pollinated to create an F2 self-pollination line. In parallel, individuals from the F1 gene flow line were pollinated again with pollen from northern plants, thus creating a backcross line. We also included a control line resulting from a random selection of individuals in each population in the first generation and their descendants from self-crosses in the second generation. We measured flowering onset, reproductive success and other plant traits in all individuals resulting from these lines. To characterize the effects of the assisted gene flow line at the genomic level, we carried out a gene capture analysis to sequence genes related to reproduction, growth, stress, nitrogen, and alkaloids in individuals from the F1 gene flow line and the control line in the first generation. All gene flow-derived lines flowered significantly earlier than the control line. Furthermore, plants from the F1 gene flow line produced heavier seeds and had a lower shoot growth than the control line. Genomic analyses identified 36 SNPs outliers that were associated to flowering onset, seed weight, and shoot growth. These results highlight that assisted gene flow can increase the evolutionary potential of populations by modifying the values of a specific trait. However, the modification of one trait may affect the values of other plant traits. The characteristics of the populations will have a fundamental effect on the results of assisted gene flow. Therefore, the selection of the donor population is a critical step in this process.
A machine learning approach to quantify individual gait responses to ankle exoskeletons
Authors: Ebers Megan R. , Rosenberg Michael C. , Kutz J. Nathan , Steele Katherine M. 
Published: January 2023

ABSTRACTWe currently lack a theoretical framework capable of characterizing heterogeneous responses to exoskeleton interventions. Predicting an individual’s response to an exoskeleton and understanding what data are needed to characterize responses has been a persistent challenge. In this study, we leverage a neural network-based discrepancy modeling framework to quantify complex changes in gait in response to passive ankle exoskeletons in nondisabled adults. Discrepancy modeling aims to resolve dynamical inconsistencies between model predictions and real-world measurements. Neural networks identified models of (i)Nominalgait, (ii)Exoskeleton(Exo) gait, and (iii) theDiscrepancy(i.e., response) between them. If anAugmented(Nominal+Discrepancy) model captured exoskeleton responses, its predictions should account for comparable amounts of variance inExogait data as theExomodel. Discrepancy modeling successfully quantified individuals’ exoskeleton responses without requiring knowledge about physiological structure or motor control: a model ofNominalgait augmented with aDiscrepancymodel of response accounted for significantly more variance inExogait (medianR2for kinematics (0.928 – 0.963) and electromyography (0.665 – 0.788), (p< 0.042)) than theNominalmodel (medianR2for kinematics (0.863 – 0.939) and electromyography (0.516 – 0.664)). However, additional measurement modalities and/or improved resolution are needed to characterizeExogait, as the discrepancy may not comprehensively capture response due to unexplained variance inExogait (medianR2for kinematics (0.954 – 0.977) and electromyography (0.724 – 0.815)). These techniques can be used to accelerate the discovery of individual-specific mechanisms driving exoskeleton responses, thus enabling personalized rehabilitation.
Mutual antagonism between glucocorticoid and canonical Wnt signaling pathways in B-cell acute lymphoblastic leukemia
Authors: Bergeron Brennan P. , Barnett Kelly R. , Bhattarai Kashi Raj , Mobley Robert J. , Hansen Baranda S. , Brown Anthony , Kodali Kiran , High Anthony A. , Jeha Sima , Pui Ching-Hon , Peng Junmin , Pruett-Miller Shondra M. , Savic Daniel 
Published: January 2023

AbstractGlucocorticoids (GCs; i.e., steroids) are important chemotherapeutic agents in the treatment of B-cell precursor acute lymphoblastic leukemia (B-ALL) andde novoGC resistance predicts relapse and poor clinical outcome in patients. Glucocorticoids induce B-ALL cell apoptosis through activation of glucocorticoid receptor (GR), a ligand-induced nuclear receptor transcription factor (TF). We previously identified disruptions to glucocorticoid receptor (GR)-boundcis-regulatory elements controllingTLE1expression in GC-resistant primary B-ALL cells from patients.TLE1is a GC-response gene up-regulated by steroids and functions as a canonical Wnt signaling repressor. To better understand the mechanistic relationship between GC signaling and canonical Wnt signaling, we performed diverse functional analyses that identified extensive crosstalk and mutual antagonism between these two signaling pathways in B-ALL. We determined that crosstalk and antagonism was driven by the binding of GR and the canonical Wnt signaling TFs LEF1 and TCF7L2 to overlapping sets ofcis-regulatory elements associated with genes impacting cell death and cell proliferation, and was further accompanied by overlapping and opposing transcriptional programs. Our data additionally suggest thatcis-regulatory disruptions atTLE1are linked to GC resistance through a dampening of the GC response and GC-mediated apoptosis via enhanced canonical Wnt signaling. As a result of the extensive genomic and gene regulatory connectivity between these two signaling pathways, our data supports the importance of canonical Wnt signaling in mediating GC resistance in B-ALL.
Spatial transcriptomic brain imaging reveals the effects of immunomodulation therapy upon specific regional brain cells in mouse dementia model
Authors: Lee Eun Ji , Bae Sungwoo , Suh Minseok , Choi Hongyoon , Choi Yoori , Hwang Do Won , Lee Dong Soo 
Published: January 2023

AbstractIncreasing evidence of brain-immune crosstalk raises expectations for the efficacy of novel immunotherapies in Alzheimer’s disease (AD), but the lack of methods to understand brain tissues make it difficult to examine therapeutics. Here, we investigated the changes of spatial transcriptomic signatures and brain cell type using the 10x Genomics Visium platform in immune modulated AD models by various treatments. To proceed with an analysis suitable for a single spot-based transcriptomics, we first organized a workflow for segmentation of neuroanatomical regions, establishment of appropriate gene combinations, and comprehensive review of altered brain cell signatures. Ultimately, we investigated spatial transcriptomic changes following administration of immunomodulators, NK cell supplements and anti-CD4 antibody, that ameliorate behavior impairment, and designated brain cells and regions showing probable associations with behavior changes. We provided the customized analytic pipeline into an application named STquantool. Thus, we anticipate that our approach can help researchers to interpret real action of drug candidate by simultaneously investigating the dynamics of all transcripts for development of novel AD therapeutics.
Sample size calculation for a NanoString GeoMx spatial transcriptomics experiment to study predictors of fibrosis progression in non-alcoholic fatty liver disease
Authors: Ryaboshapkina Maria , Azzu Vian 
Published: January 2023

AbstractSample size calculation for spatial transcriptomics is a novel and understudied research topic. Prior publications focused on powering spatial transcriptomics studies to detect specific cell populations or spatially variable expression patterns on tissue slides. However, power calculations for translational or clinical studies often relate to the difference between patient groups, and this is poorly described in the literature. Here, we present a stepwise process for sample size calculation to identify predictors of fibrosis progression in non-alcoholic fatty liver disease as a case study. We illustrate how to infer study hypothesis from prior bulk RNA-sequencing data, gather input requirements and perform a simulation study to estimate required sample size to evaluate gene expression differences between patients with stable fibrosis and fibrosis progressors with NanoString GeoMx Whole Transcriptome Atlas assay.Key pointsSpatial transcriptomics is predominantly used in unpowered exploratory research.We demonstrate that spatial transcriptomics studies with NanoString GeoMx Whole Transcriptome Atlas can be powered to address differences between patient groups and illustrate the sample size calculation using fibrosis progression in non-alcoholic fatty liver disease as an example.We note that established software implementing negative binomial mixed effect models lme4 and GLMMadaptive yield more similar fold change estimates to simulated data than the recently published software GeoDiff.
No trade-off between the use of space and time for working memory
Authors: de Vries Eelke , Fejer George , van Ede Freek 
Published: January 2023

ABSTRACTSpace and time can each act as scaffolds for the individuation and selection of visual objects in working memory. Here we ask whether there is a trade-off between the use of space and time for visual working memory: whether observers will rely less on space, when memoranda can additionally be individuated through time. We tracked the use of space through directional biases in microsaccades after attention was directed to memory contents that had been encoded simultaneously or sequentially to the left and right of fixation. We found that spatial gaze biases were preserved when participants could (Experiment 1) and even when they had to (Experiment 2) additionally rely on time for object individuation. Thus, space remains a profound organizing medium for working memory even when other organizing sources are available and utilised, with no evidence for a trade-off between the use of space and time.SIGNIFICANCE STATEMENTSpace and time provide two foundational dimensions that govern not only our sensations and actions, but also the organisation of internal representations in working memory. Space and time have each been shown to provide an automatic organising principle – or scaffold – for memory retention. We uniquely address whether there is a trade-off between the use of space and time for working memory. We show that the profound and automatic reliance on memorised space is preserved not only when time can, but even when time has to be used for individuation and selection of memory contents. This shows there is no trade-off between spatial and temporal codes available for memory organisation, advancing our understanding of the spatial-temporal architecture of mind.
Landscape of IGH germline genes of Chiroptera and the pattern ofRhinolophus affinisbat IGH CDR3 repertoire
Authors: Ma Long , Liu Longyu , Li Jun , Zhou Hao , Xiao Jiaping , Ma Qingqing , Yao Xinsheng 
Published: January 2023

SummaryThe emergence and re-emergence of a number of viruses from bats that impact human and animal health has resulted in a resurgence of interest in bat immunology. Characterizing the immune receptor repertoire is critical to understanding how bats coexist with viruses in the absence of disease and developing new therapeutics to target viruses in humans and susceptible livestock. We annotated IGH germline genes ofRhinolophus ferrumequinum(RF),Phyllostomus discolor(RD) andPipistrellus pipistrellus(PP), and investigated the evolutionary relationship between bat germline genes and that of human, mouse, cow, and dog. The IGH repertoire characteristics ofRhinolophus affinisbat (RA) were also analyzed. The V gene families of all three bat species can be classified into three Clan, although PD is special with the abnormal length of IGH locus and 22 reverse V genes. Moreover, the bats germline genes are quite differed from those of human, mouse, cow, and dog in evolution, but the three bat species have high homology. The CDR3 repertoire of RA are unique in many aspects including CDR3 subclass, V/J genes access and pairing, CDR3 clones and somatic high-frequency mutation compared with that of human and mouse, which may be the immunologic basis for the asymptomatic nature of viral infection in bats. This study provide immune genome information and extensive reference for the basic research of bat and virus infection mechanism.
Comparison of force fields to study the zinc-finger containing protein NPL4, a target for Antabuse in cancer therapy
Authors: Scrima Simone , Tiberti Matteo , Ryde Ulf , Lambrughi Matteo , Papaleo Elena 
Published: January 2023

AbstractAll-atom molecular dynamics (MD) simulations are a powerful approach to study the structure and dynamics of proteins related to health and disease. Advances in the MD field allow modeling proteins with high accuracy. However, modeling metal ions and their interactions with proteins is still challenging for MD simulations. Over one-third of known protein structures bind metal ions and have various cellular functions, such as structural stability, catalysis, and regulation. NPL4 is a zinc-binding protein and works as a cofactor for p97, and together they regulate protein homeostasis. NPL4 is also of biomedical importance and has been proposed as the target of Antabuse, a drug recently repurposed for cancer treatment. Recent experimental studies have proposed that the Antabuse metabolites, bis- (diethyldithiocarbamate)-copper (CuET) and cupric ions released from CuET, induce NPL4 misfolding and consequent aggregation. However, the molecular details of the mechanisms of interactions of Antabuse metabolites with NPL4 and the consequent structural effects are still elusive. In this context, biomolecular simulations can help to shed light on the related structural details. To apply MD simulations to NPL4 and its interaction with copper or Antabuse metabolites the first important step is identifying a suitable force field to describe the protein in its zinc-bound states. We first examined different sets of non-bonded parameters, because we want to study the misfolding mechanism and cannot rule out that the zinc ion may detach from the protein structure during the process and copper replaces it in the metal binding site. We investigated the force-field ability to model the coordination geometry of the metal ions by comparing the results from MD simulations with optimized geometries from quantum mechanics (QM) calculations using model systems of the zinc coordination site for NPL4. Furthermore, we investigated the performance of a MD force field including bonded parameters to treat copper ions and metal-coordinating atoms in NPL4 that we obtained based on QM calculations.
Transcranial focused ultrasound-mediated neurochemical and functional connectivity changes in deep cortical regions in humans
Authors: Yaakub Siti N. , White Tristan A. , Roberts Jamie , Verhagen Lennart , Stagg Charlotte J. , Hall Stephen , Fouragnan Elsa F. 
Published: January 2023

AbstractLow-intensity transcranial ultrasound stimulation (TUS) is an emerging non-invasive technique for focally modulating human brain function. The mechanisms and neurochemical substrates underlying TUS neuromodulation in humans and how these relate to excitation and inhibition are still poorly understood. In 24 healthy controls, we separately stimulated two deep cortical regions and investigated the effects of theta-burst TUS, a protocol shown to increase corticospinal excitability, on the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and functional connectivity. We show for the first time in humans that theta-burst TUS selectively reduces GABA levels in the posterior cingulate, but not the dorsal anterior cingulate cortex. Functional connectivity increased following TUS in both regions. Our findings suggest that TUS changes overall excitability by reducing GABAergic inhibition, that changes in TUS-mediated neuroplasticity last at least 50 minutes after stimulation, and that these effects may be state-dependent – a mechanism increasingly recognized to influence the brain’s response to neuromodulation.