bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effects of sport-specific training on individuals action strategies while avoiding a virtual player approaching on a 45° angle while completing a secondary task
Authors: Thompson Brooke J. , Cinelli Michael E. 
Published: October 2023

AbstractSports provide varying scenarios where athletes must interact with and avoid opposing players in dynamic environments. As such, sport-specific training can improve one’s ability to integrate visual information which may result in improved collision avoidance behaviours. However, improved visuomotor capabilities are highly task dependent (i.e., athletes must be tested in sport-specific settings). The current study examined whether sport-specific training influenced individuals’ collision avoidance behaviours during a sport-specific task in virtual reality. Untrained young adults (N=21, 22.9±1.9 yrs, 11 males) and specifically trained athletes (N=18, 20±1.5 yrs, 7 males) were immersed in a virtual environment and were instructed to walk along a 7.5m path towards a goal located along the midline. Two virtual players positioned 2.83m to the left and right of the midline approached participants on a 45° angle at one of three speeds: 0.8x, 1.0x, or 1.2x each participant’s average walking speed. Participants were instructed to walk to a goal without colliding with the virtual players while performing a secondary task; reporting whether a shape changed above either of the virtual players’ heads. Results revealed that athletes had a higher percentage of correct responses on the secondary task compared to untrained young adults. However, there was no group differences in the average time to first avoidance or average minimum clearance, but athletes were more variable in their avoidance behaviours. Findings from this study demonstrate that athletes may be more adaptive in their behaviours and may perform better on attentionally demanding tasks in dynamic environments.
Extracellular vesicles from patients with coronary artery disease (CAD) demonstrate enhanced pro-coagulatory activity
Authors: Soyama Shin , Zhou Ruihan , Whyte Abigail , Mark Sharon , Dymott Leanne , Brunton Mark , Fischer Roman , Hester Svenja , McKenna Charlie , Ruparelia Neil , Yaqoob Parveen , Allen-Redpath Keith 
Published: October 2023

AbstractAimsExtracellular vesicles (EVs) carry unique repertoires of biologically active cargo that hold promise as novel biomarkers and future interventional targets for cardiovascular diseases (CVDs). However, it is unclear as to how the number, location, cellular origin, and size of these EVs within the circulation relate to the development of CVDs such as coronary artery disease (CAD). The current study compared these novel markers in arterial and venous blood samples in individuals undergoing coronary assessment with angiography.. EVs were then characterized from those presenting with and without CAD.Methods and ResultsArterial and venous blood samples were collected from individuals with confirmed CAD following coronary angiography and a matched cohort in whom there was no evidence of disease. EV fractions were isolated from 500µL of platelet free plasma (PFP) by size exclusion chromatography. EVs were analyzed by Nanoparticle Tracking Analysis and flow cytometry to characterize number, size and cellular origin. A thrombin generation assay was used to assess the pro-coagulatory activity of the isolated circulating EVs. Proteomics was used to determine the protein cargo carried within the EVs.Coagulatory activity of EVs isolated from CAD patients was significantly higher in when compared to controls, although the numbers of EVs did not differ. There were higher numbers of endothelial-derived EVs in arterial blood compared with venous blood. Linear regression models revealed that plasma triacylglycerol concentration and age independently predicted circulating EV numbers in CAD patients. Proteomics revealed several proteins associated with coagulation upregulated in patients with CAD.ConclusionsAlthough the absolute numbers of EVs in CAD patients were not elevated, EVs in CAD patients had greater pro-coagulant activity, highlighting a potentially important role for EVs in the pathogenesis of CAD.Clinical PerspectiveWhat is new?CAD patients displayed a greater EV-induced thrombin generation capability when compated to those with no disease.The proteomic profile of arterial-derived EVs in patients with CAD demonstrated several proteins associated with coagulation that may be a risk factor for developing a future event.What are the clinical implications?The identification of EVs in patients with CAD with upregulated coagulation proteins may be a novel biomarker for the development of future events and may identify a high risk patient group that may benefit for more aggressive cardiovascular risk intervention.
Reinforcement learning in Parkinson’s disease is not associated with inflammatory tone
Authors: Tichelaar Jorryt G. , Verbeek Marcel M. , Kersten Iris , Cools Roshan , Helmich Rick C. 
Published: October 2023

AbstractParkinson’s disease (PD) is associated with large variability in the development and severity of both motor and nonmotor symptoms, including depression and impulse control disorder. Neuroinflammation might contribute to this heterogeneity, given its association with dopaminergic signalling, neuropsychiatric symptoms, and reward versus punishment learning. Here, we assessed the effect of inflammatory tone on probabilistic reinforcement learning and impulse control disorders in PD. We measured computational learning model-based neural reward prediction error and expected value signals in frontostriatal circuity during reinforcement learning using functional MRI. In addition, we acquired cerebral spinal fluid of 74 PD patients and screened for 13 inflammatory factors, including our primary marker of interest IL-6, previously implicated in reward learning signaling in the ventral striatum. In contrast to our prediction, we found no association between inflammatory tone and any of the behavioural or neural reinforcement learning parameters. Furthermore, we did we not find any correlation between inflammatory tone and depressive or impulsive PD symptoms. Exploratory analyses revealed a negative association between MCP-1 and reward prediction error signals in the ventral striatum, an observation that should be replicated in future work. The null findings might reflect the fact that measurements were taken ON medication, or that our sample consists of an early disease stage cohort that may be too small to detect these effects, or that IL-6 is a suboptimal marker for inflammatory tone, or a combination of these factors.
IL-1β–mediated inflammatory signaling drives ineffective erythropoiesis in early-stage myelodysplastic syndromes
Authors: Adema Vera , Ganan-Gomez Irene , Ma Feiyang , Rodriguez-Sevilla Juan Jose , Chien Kelly , Yang Hui , Thongon Natthakan , Kanagal-Shamanna Rashmi , Loghavi Sanam , Montalban-Bravo Guillermo , Hammond Danielle , Gu Yiqian , Tan Roselyn , Tan Lin , Lorenzi Philip , Al-Atrash Gheath , Clise-Dwyer Karen , Bejar Rafael , Pellegrini Matteo , Garcia-Manero Guillermo , Colla Simona 
Published: October 2023

ABSTRACTMyelodysplastic syndromes (MDS) are a group of incurable hematopoietic stem cell (HSC) neoplasms characterized by peripheral blood cytopenias and a high risk of progression to acute myeloid leukemia. MDS represent the final stage in a continuum of HSCs’ genetic and functional alterations and are preceded by a premalignant phase, clonal cytopenia of undetermined significance (CCUS). Dissecting the mechanisms of CCUS maintenance may uncover therapeutic targets to delay or prevent malignant transformation.Here, we demonstrate thatDNMT3AandTET2mutations, the most frequent mutations in CCUS, induce aberrant HSCs’ differentiation towards the myeloid lineage at the expense of erythropoiesis by upregulating IL-1β–mediated inflammatory signaling and that canakinumab rescues red blood cell transfusion dependence in early-stage MDS patients with driver mutations inDNMT3AandTET2.This study illuminates the biological landscape of CCUS and offers an unprecedented opportunity for MDS intervention during its initial phase, when expected survival is prolonged.
The Identification of IL-4 as a Regulator of Chimeric Antigen Receptor T Cell Exhaustion
Authors: Stewart Carli M. , Siegler Elizabeth L. , Sakemura R. Leo , Cox Michelle J. , Huynh Truc , Kimball Brooke , Mai Long , Can Ismail , Manriquez Roman Claudia , Yun Kun , Sirpilla Olivia , Girsch James H. , Ogbodo Ekene , Ismail Wazim , Gaspar Maia Alexandre , Budka Justin , Kim Jenny , Scholler Nathalie , Mattie Mike , Filosto Simone , Kenderian Saad S. 
Published: October 2023

AbstractDurable response to chimeric antigen receptor T (CART) cell therapy remains limited in part due to CART cell exhaustion. We investigated the regulation of CART cell exhaustion with three independent approaches including: a genome-wide CRISPR knockout screen using a validatedin vitromodel for exhaustion, RNA and ATAC sequencing on baseline and chronically stimulated CART cells, and RNA and ATAC sequencing on pre-infusion CART cell products from responders and non-responders in the ZUMA-1 clinical trial. Each of these approaches identified IL-4 as a key regulator of CART cell dysfunction. Further, when CART cells were treated with IL-4, they developed signs of exhaustion, but when CART cells were treated with an IL-4 monoclonal antibody, they showed improved antitumor efficacy and reduced signs of exhaustion in preclinical models. Therefore, our study identified both a novel role for IL-4 on CART cells and the improvement of CART cell therapy through IL-4 neutralization.Statement of SignificanceIdentifying regulators of CART cell exhaustion will not only enhance the field’s understanding of therapeutic failure, but it will also provide avenues to enhance CART cell efficacy. This study reveals both a novel role for IL-4 in exhaustion and a strategy to improve CART cell activity through IL-4 neutralization.
Induced pluripotent stem cell derived pericytes respond to endogenous mediators of proliferation and contractility
Authors: King Natalie E. , Courtney Jo-Maree , Brown Lachlan S. , Fortune Alastair J. , Blackburn Nicholas B. , Fletcher Jessica L. , Cashion Jake M. , Talbot Jana , Pébay Alice , Hewitt Alex W. , Morris Gary P. , Young Kaylene M. , Cook Anthony L. , Sutherland Brad A. 
Published: October 2023

AbstractBackgroundPericytes are multifunctional contractile cells that reside on capillaries. Pericytes are critical regulators of cerebral blood flow and blood-brain barrier function, and pericyte dysfunction may contribute to the pathophysiology of human neurological diseases including Alzheimers disease, multiple sclerosis, and stroke. Induced pluripotent stem cell (iPSC)-derived pericytes (iPericytes) are a promising tool for vascular research. However, it is unclear how iPericytes functionally compare to primary human brain vascular pericytes (HBVPs). We differentiated iPSCs into iPericytes of either the mesoderm or neural crest lineage using established protocols. We compared iPericyte and HBVP morphologies, quantified gene expression by qPCR and bulk RNA sequencing, and visualised pericyte protein markers by immunocytochemistry. To determine whether the gene expression of neural crest iPericytes, mesoderm iPericytes or HBVPs correlated with their functional characteristicsin vitro, we quantified EdU incorporation following exposure to the key pericyte mitogen, platelet derived growth factor (PDGF)-BB and, contraction and relaxation in response to the vasoconstrictor endothelin-1 or vasodilator adenosine, respectively. iPericytes were morphologically similar to HBVPs and expressed canonical pericyte markers. However, iPericytes had 1864 differentially expressed genes compared to HBVPs, while there were 797 genes differentially expressed between neural crest and mesoderm iPericytes. Consistent with the ability of HBVPs to respond to PDGF-BB signalling, PDGF-BB enhanced and PDGF receptor-beta inhibitors impaired iPericyte proliferation. Administration of endothelin-1 led to iPericyte contraction and adenosine led to iPericyte relaxation, of a magnitude similar to the response evoked in HBVPs. We determined that neural crest iPericytes were less susceptible to PDGFR beta inhibition, but responded most robustly to vasoconstrictive meditators. iPericytes express pericyte-associated genes and proteins and, exhibit an appropriate physiological response upon exposure to a key endogenous mitogen or vasoactive mediators. Therefore, the generation of functional iPericytes would be suitable for use in future investigations exploring pericyte function or dysfunction in neurological diseases.
Impact of whole-genome duplications on structural variant evolution in the plant genusCochlearia
Authors: Hämälä Tuomas , Moore Christopher , Cowan Laura , Carlile Matthew , Gopaulchan David , Brandrud Marie K. , Birkeland Siri , Loose Matthew , Kolář Filip , Koch Marcus A. , Yant Levi 
Published: October 2023

AbstractPolyploidy, the result of whole-genome duplication (WGD), is a major driver of eukaryote evolution. All angiosperms have undergone ancient WGDs, and today stable polyploids account for a substantial portion of both wild and domesticated plant species. Despite its centrality in evolution, WGD is a hugely disruptive mutation, and we still lack a clear understanding of its fitness consequences. Here, we study whether WGD results in greater diversity of genomic structural variants (SVs) and how this influences evolutionary dynamics in nature. Using a set of long-read sequenced samples from the plant genusCochlearia(Brassicaceae), which contains diploids and a recent ploidy series up to octoploid, we show that masking of recessive mutations due to WGD has led to a substantial and progressive accumulation of genic SVs across four ploidy levels. Such SVs likely constitute a genetic load and thus reduce the adaptive potential of polyploid populations. However, this SV accumulation also provides a rich pool of standing genetic variation upon which selection may act in novel environments. By constructing a graph-based pangenome forCochlearia, we identify SVs in hundreds of samples and study the genomic basis of environmental adaptation. We find putatively beneficial SVs involved in pathogen resistance, root development, and salt tolerance, many of which are unique to polyploids. Finally, we explore the adaptive landscapes of SVs and SNPs, identify geographical regions where SVs make novel contributions to adaptive variation, and predict that the role of SVs in environmental adaptation increases due to rapid climate change.
Polyploidy is widespread in Microsporidia
Authors: Khalaf Amjad , Jaron Kamil S. , Blaxter Mark L. , Lawniczak Mara K. N. 
Published: October 2023

AbstractMicrosporidia are obligate intracellular eukaryotic parasites with an extremely broad host range. They have both economic and public health importance. Ploidy in microsporidia is variable, with a few species formally identified as diploid and one as polyploid. Given the increase in the number of studies sequencing microsporidian genomes, it is now possible to assess ploidy levels across all currently-explored microsporidian diversity. We estimate ploidy for all microsporidian datasets available on the Sequence Read Archive (SRA) using k-mer-based analyses, and demonstrate that polyploidy is widespread in Microsporidia, and that ploidy change is dynamic in the group. Using genome-wide heterozygosity estimates, we also show that polyploid microsporidian genomes are relatively homozygous, and we discuss the implications of these findings on the timing of polyploidisation events and their origin.Author SummaryMicrosporidia are single-celled intracellular parasites, distantly related to fungi, that can infect a broad range of hosts, from humans all the way to protozoans. Exploiting the wealth of microsporidian genomic data available, we use k-mer based analyses to assess ploidy status across the group. Understanding a genome’s ploidy is crucial in order to assemble it effectively, and may also be relevant for better understanding a parasite’s behaviour and life cycle. We show that tetraploidy is present in at least six species in Microsporidia, and that these polyploidisation events are likely to have occurred independently. We discuss why these findings may be paradoxical, given that Microsporidia, like other intracellular parasites, have extremely small, reduced genomes.
Revisiting the origins of theSobemovirusgenus: a case for ancient origins of plant viruses
Authors: Ghafari Mahan , Somera Merike , Sarmiento Cecilia , Niehl Annette , Hébrard Eugénie , Tsoleridis Theocharis , Ball Jonathan , Moury Benoît , Lemey Philippe , Katsourakis Aris , Fargette Denis 
Published: October 2023

AbstractThe discrepancy between short- and long-term rate estimates, known as the time-dependent rate phenomenon (TDRP), poses a challenge to extrapolating evolutionary rates over time and reconstructing evolutionary history of viruses. The TDRP reveals a decline in evolutionary rate estimates with the measurement timescale, explained empirically by a power-law rate decay, notably observed in animal and human viruses. A mechanistic evolutionary model, the Prisoner of War (PoW) model, has been proposed to address TDRP in viruses. Although TDRP has been studied in animal viruses, its impact on plant virus evolutionary history remains largely unexplored. Here, we investigated the consequences of TDRP in plant viruses by applying the PoW model to reconstruct the evolutionary history of sobemoviruses, plant pathogens with significant importance due to their impact on agriculture and plant health. Our analysis showed that theSobemovirusgenus dates back over four million years, indicating an ancient origin. We found evidence that supports deep host jumps to Poaceae, Fabaceae, and Solanaceae occurring between tens to hundreds of thousand years ago, followed by specialization. Remarkably, the TDRP-corrected evolutionary history of sobemoviruses was extended far beyond previous estimates that had suggested their emergence during the Neolithic period. By incorporating sequences collected through metagenomic analyses, the resulting phylogenetic tree showcases increased genetic diversity, reflecting a deep history of sobemovirus species with major radiation events taking place during the Neolithic period, suggesting rapid diversification in that period. Our findings make a case for the possibility of deep evolutionary origins of plant viruses.
Stability of Genomic Imprinting and X-Chromosome Inactivation in the Aging Brain
Authors: Mancino Samantha , Seneviratne Janith , Mupo Annalisa , Krueger Felix , Oxley David , Eckersley-Maslin Melanie A , da Rocha Simão Teixeira 
Published: October 2023

AbstractEpigenetic drift is a hallmark of aging that contributes to the irreversible decline in organismal fitness ultimately leading to aging-related diseases. Epigenetic modifications regulate the cellular memory of the epigenetic processes of genomic imprinting and X-chromosome inactivation to ensure monoallelic expression of imprinted and X-linked genes. Whether epigenetic drift affects maintenance of genomic imprinting and X-chromosome inactivation has not been comprehensively studied. Here, we investigate the allele-specific transcriptional and epigenetic signatures of the aging brain, by comparing juvenile and old hybrid mice obtained from C57BL/6J (BL6) & CAST/EiJ (CAST) reciprocal crosses, with an emphasis on the hippocampus (HCP). We confirm that the aged HCP shows an increase of DNA hydroxymethylation, a sign of epigenetic drift, and a typical aging transcriptional signature. Genomic imprinting was found to be largely unaffected with stable parent-of-origin-specific DNA methylation in HCP, but also other brain regions such as the cerebellum (CB), nucleus accumbens, hypothalamus and prefrontal cortex. Consistently, transcriptomics analysis confirmed unaltered imprinting expression in the aged HCP. An exception are three novel non-coding transcripts (B230209E15Rik,Ube2nlandA330076H08Rik) at the Prader-Willi syndrome/Angelman syndrome (PWS/AS) imprinted locus which lose strict monoallelic expression during aging. Like imprinting, X-chromosome inactivation was remarkably stable with no signs of aging-driven skewing or relaxation of monoallelic expression of X-linked genes. Our study provides a valuable resource for evaluating monoallelic expression in the aging brain and reveals that, despite epigenetic drift during aging, genomic imprinting and X-chromosome inactivation remain predominantly stable throughout the process of physiological aging in the mouse brain.
DNA damaged-induced phosphorylation of a viral replicative DNA helicase results in inhibition of DNA replication through attenuation of helicase function
Authors: Homiski Caleb , Dey-Rao Rama , Shen Shichen , Qu Jun , Melendy Thomas 
Published: October 2023

ABSTRACTA major function of the DNA damage responses (DDRs) that act during the replicative phase of the cell cycle is to inhibit initiation and elongation of DNA replication. The polyomavirus SV40 is an important model system for studying human DNA replication and DDRs due to its heavy reliance on host factors for viral DNA replication, and the arrest of SV40 DNA replication in response to DDR activation. The inhibition of SV40 DNA replication following DDR activation is associated with enhanced DDR kinase phosphorylation of SV40 Large T-antigen (LT), the viral origin-binding protein and DNA helicase. NetPhos prediction of LT phosphorylation on multiple sites were confirmed by mass spectroscopy, including a highly conserved DDR kinase site, T518. In cell-based DNA replication assays expression of the phosphomimetic mutant form of LT at T518 (T518D) resulted in dramatically decreased levels of SV40 DNA replication; while LT-dependent transcriptional activation was unaffected. WT and LT T518D were subsequently expressed, purified, and analyzedin vitrofor assessment of biochemical function. In concordance with the cell-based data, reactions using SV40 LT-T518D, but not T518A, showed dramatic inhibition of SV40 DNA replication. Importantly, the LT T518D mutation did not affect critical LT protein interactions or its ATPase function, but showed decreased helicase activity on long, but not very short, DNA templates. These results suggest that DDR phosphorylation at T518 inhibits SV40 DNA replication by impeding LT helicase activity, thereby slowing the DNA replication fork. This is consistent with the slowing of cellular replication forks following DDR and may provide a paradigm for another mechanism for how DNA replication forks can be slowed in response to DDR, by phosphorylation of DNA helicases.