bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantitative and geometric motor unit analysis using magnetomyography
Authors: Broser Philip J. , Middelmann Thomas , Noury Nima , Siegel Markus , Hartwig Stefan , Klotz Thomas , Marquetand Justus 
Published: June 2023

ABSTRACTObjectiveMagnetomyography (MMG) is currently a rather unexplored neurophysiological modality and it is not known to which extent the number of motor units have an influence on the amplitude and the direction of the MMG-signal.MethodsA simultaneous invasive electromyography (iEMG), surface EMG (sEMG) and MMG using optically pumped magnetometer (OPM-MMG) of the right abductor digiti minimi muscle (ADM) of two healthy participants was recorded during a stepwise increasing electrical stimulation of the ADM innervating ulnar nerve. Then, the number of electrically evoked motor units was estimated (MUNE), the magnetic field vectors were reconstructed and aligned to the muscular anatomy. In addition, a finite element simulation of the ADM muscle was performed and compared to the experimental data.ResultsThe more motor units were activated by increasing electrical stimulation, the stronger the MMG signal became, which was the same for iEMG&sEMG (r>0.96). The finite element simulation showed the same relation between the magnetic and electric signal. Further, based on the simulation the number of activated muscular fibers and neuromuscular units could be estimated the ratio of signal to fibers determined.In addition, the precise vector direction of the magnetomyography (MMG) signal can reliably be recorded following the electric stimulation of the ulnar nerve and followed the muscle fiber direction.ConclusionThe MMG signal can be used to determine the amount of activated motor units, but also analysis of the magnetic field vector corresponds to the muscle fiber direction, offering a functional as well as structural characterization of muscles. The modelling and simulation is especially helpful to understand the magnetic muscular signal in detail.SignificanceNext to establishing MUNE in MMG, our results provide the first quantitative comparison between MMG vs. iEMG&sEMG and highlight the possibilities of the vector component analysis in MMG.Highlights- Comparative study of MMG, iEMG&sEMG using electrically induced activation of motor units.- MUNE in MMG is possible and is potentially superior to surface EMG.- The vector components of the MMG-signal correspond to the muscle fiber direction of the muscle.- Finite element simulation of the muscular magnetic and electric signal
Polygenic risk of idiopathic pulmonary fibrosis and COVID-19 severity
Authors: Guillen-Guio Beatriz , Marcelino-Rodriguez Itahisa , Lorenzo-Salazar Jose Miguel , Leavy Olivia C , Allen Richard J ,   Scourge Cohort Group, Riancho José A. , Rojas Augusto , Lapunzina Pablo , Carracedo Ángel , Wain Louise V , Flores Carlos 
Published: June 2023

AbstractIntroductionCoronavirus disease 2019 (COVID-19) survivors can develop residual lung abnormalities consistent with lung fibrosis. A shared genetic component between COVID-19 and idiopathic pulmonary fibrosis (IPF) has been shown. However, genetic overlap studies of IPF and COVID-19 have primarily concentrated on the IPF genome-wide significant risk variants that have been previously identified, rather than combined into a genome-wide polygenic risk. Here we used IPF genome-wide association study (GWAS) results to calculate polygenic risk scores (PRSs) and study their association with COVID-19 severity.MethodsWe used results from the largest meta-GWAS of clinically defined IPF risk (base dataset; n=24,589) and individual-level imputed data from the SCOURGE study of patients with COVID-19 (target dataset; n=15,024). We calculated IPF PRSs using PRSice-2 and assessed their association with COVID-19 hospitalisation, severe illness, and critical illness. We also evaluated the effect of age and sex stratification. Results were validated using an independent PRS method. Enrichment analyses and pathway-specific PRSs were performed to study biological pathways associated with COVID-19 severity.ResultsIPF PRSs were significantly associated with COVID-19 hospitalisation and severe illness. The strongest association was found in patients aged <60 years, especially among younger males (OR=1.16; 95%CI=1.08-1.25; p=6.39×10−5). A pathway enrichment analysis of the variants included in the best model fit and subsequent pathway-specific PRSs analyses supported the link of Cadherin and Integrin signalling pathways to COVID-19 severity when stratified by age and sex.ConclusionOur results suggest that there is genome-wide genetic overlap between IPF and severe COVID-19 that is dependent on age and sex and adds further support that the pathogenesis of both IPF and severe COVID-19 share underlying biological mechanisms. This could imply that individuals with a high IPF genetic risk are at an overall increased risk of developing lung sequelae resulting from severe COVID-19.
A pilot study of the quality of care of atrial fibrillation in Irish general practice
Authors: McErlean Sarah , Broughan John , McCombe Geoff , Fawsitt Ronan , Ledwidge Mark , Cullen Walter , Gallagher Joe 
Published: June 2023

AbstractAimThe aim of this pilot study is to develop and test a quality of care score for patients with permanent atrial fibrillation (AF) in general practice, and identify the patterns of quality of care using this score.We developed a quality of care score based on the Atrial Fibrillation Better Care pathway recommended by the European Society of Cardiology and the European Heart Rhythm Association guidelines. This is a 14-point score that we have termed the MAGIC score(Management of Atrial Fibrillation in Integrated Care and General Practice).Methods & ResultsAn observational cross-sectional pilot study was undertaken. Proportionate sampling was used across 11 practices from the Ireland East practice-based research network. The GPs completed a report form on each patient provided by the research team by undertaking a retrospective chart review.11 practices participated with a total number of 1855 patients with AF. We received data on 153 patients.The main findings were that:No patient met all 14 guideline based recommendations Mean MAGIC score was 11.3Points were most commonly deducted because the creatinine-clearance and HAS-BLED score were not recorded and the patient was not on the correct dose of oral anti-coagulation.ConclusionThis study demonstrates the feasibility of using a quality of care score to measure quality of AF management in general practice. This scoring system; which is based on internationally recognised quality of care markers, highlights key areas that can be targeted with intervention to improve care.
Large-scale blood mitochondrial genome-wide study provides novel insights into mitochondrial disease-related traits
Authors: Cannon S , Hall T , Hawkes G , Colclough K , Boggan RM , Wright CF , Pickett SJ , Hattersley AT , Weedon MN , Patel KA 
Published: June 2023

AbstractBackground/ObjectivesWhole genome sequencing (WGS) from large cohorts enables the study of mitochondrial DNA (mtDNA) variation on human health. We aimed to investigate the influence of common, rare, and pathogenic mtDNA variants on 15 mitochondrial disease-related phenotypes.MethodsUsing WGS from 179,862 individuals from in the UK Biobank, we identified mtDNA variants using MitoHPC. We performed extensive association analyses with 15 mitochondrial disease-relevant phenotypes. We compared the results for the m.3243A>G variant with those from a clinically referred patient cohort.ResultsOf 15,881 mtDNA variants, 12 homoplasmic and one heteroplasmic variant had genome-wide significant associations. All homoplasmic variants increased aspartate aminotransferase level and three were novel, low frequency, variants (MAF∼0.002 and beta∼0.3 SD). Only m.3243A>G (MAF=0.0002) associated with diabetes (OR=5.6, 95%CI [3.2-9.9]), deafness (OR=12.3, 95%CI [6.2-24.4]) and heart failure (OR=39.5, 95%CI [9.76-160.1]). Multi-system disease risk and penetrance of all three traits increased with m.3243A>G level. Diabetes risk was further influenced by common nuclear genome variation. The penetrance of diabetes with m.3243A>G in the UK Biobank was lower than clinically referred patients, partly attributed to lower heteroplasmy. Of 73 pathogenic mitochondrial disease variants, most were rare in the population with low penetrance.ConclusionOur study highlights the utility of WGS for investigating mitochondrial genetics within a large, unselected population. We identified novel associations and demonstrated that pathogenic mitochondrial variants have lower penetrance in clinically unselected than clinically referred settings. m.3243A>G associated with mitochondrial-related phenotypes at higher heteroplasmy. Our findings suggest potential benefits of reporting incidentally identified m.3243A>G at high heteroplasmy levels.
Spatial proteomics reveals heterogeneity in neural markers underpinning high-fat diet-induced myopathy in male mice
Authors: Hardowar Lydia , Vadakekolathu Jayakumar , Rutella Sergio , Hulse Richard P. , Doig Craig L. 
Published: June 2023

AbstractMetabolic dysfunction in skeletal muscle disturbs its contractile response as well as its innervation and vascular networks. The molecular drivers responsible for affecting decline in function remain poorly defined. To provide insight and locate these, we mapped changes in the spatial proteome occurring as a result of impaired metabolic health. We exposed male mice (C57/BL6J) to diet induced obesity to investigate the impairment of muscle metabolic function and myopathy. We conducted digital spatial profiling using the NanoString GeoMx® platform on recovered skeletal muscle (tibialis anterior) comparing it to standard fed controls. Digital spatial profiling revealed areas with shifts in the contractile protein desmin and CD31 expression, a marker of tissue stress and cellular maladaptation. We find increased expression of proinflammatory markers were identified in areas of elevated Desmin in obese samples compared to controls. Our data suggest a dietary-driven relationship between the spatial abundance of the sarcomere protein desmin and the influx of neural and inflammatory mediators to muscle. This supports the concept of pro-inflammatory events underpinning the muscle metabolic dysfunction associated with chronic non-communicative diseases such as type 2 diabetes, metabolic syndrome, and chronic obstructive pulmonary disorder.
Zfp697 is an RNA-binding protein that regulates skeletal muscle inflammation and regeneration
Authors: Correia Jorge C. , Jannig Paulo R. , Gosztyla Maya L. , Cervenka Igor , Ducommun Serge , Præstholm Stine M. , Dumont Kyle , Liu Zhengye , Liang Qishan , Edsgärd Daniel , Emanuelsson Olof , Gregorevic Paul , Westerblad Håkan , Venckunas Tomas , Brazaitis Marius , Kamandulis Sigitas , Lanner Johanna T. , Yeo Gene W. , Ruas Jorge L. 
Published: June 2023

AbstractMuscular atrophy is a mortality risk factor that happens with disuse, chronic disease, and aging. Recovery from atrophy requires changes in several cell types including muscle fibers, and satellite and immune cells. Here we show that Zfp697/ZNF697 is a damage-induced regulator of muscle regeneration, during which its expression is transiently elevated. Conversely, sustained Zfp697 expression in mouse muscle leads to a gene expression signature of chemokine secretion, immune cell recruitment, and extracellular matrix remodeling. Myofiber-specific Zfp697 ablation hinders the inflammatory and regenerative response to muscle injury, compromising functional recovery. We uncover Zfp697 as an essential interferon gamma mediator in muscle cells, interacting primarily with ncRNAs such as the pro-regenerative miR-206. In sum, we identify Zfp697 as an integrator of cell-cell communication necessary for tissue regeneration.One Sentence SummaryZfp697 is necessary for interferon gamma signaling and muscle regeneration.
Targeting Fibroblast-Endothelial Interactions in LAM Pathogenesis: 3D Spheroid and Spatial Transcriptomic Insights for Therapeutic Innovation
Authors: Koc-Gunel Sinem , Liu Emily C. , Gautam Lalit K. , Calvert Ben A. , Murthy Shubha , Harriott Noa C. , Nawroth Janna C. , Zhou Beiyun , Krymskaya Vera P. , Ryan Amy L. 
Published: June 2023

AbstractLymphangioleiomyomatosis (LAM) is a progressive lung disease with limited treatments, largely due to an incomplete understanding of its pathogenesis. Lymphatic endothelial cells (LECs) invade LAM cell clusters, which include HMB-45-positive epithelioid cells and smooth muscle α-actin-expressing LAM-associated fibroblasts (LAMFs). Recent evidence shows that LAMFs resemble cancer-associated fibroblasts, with LAMF-LEC interactions contributing to disease progression. To explore these mechanisms, we used spatial transcriptomics on LAM lung tissues and identified a gene cluster enriched in kinase signaling pathways linked to myofibroblasts and co-expressed with LEC markers. Kinase arrays revealed elevated PDGFR and FGFR in LAMFs. Using a 3D co-culture spheroid model of primary LAMFs and LECs, we observed increased invasion in LAMF-LEC spheroids compared to non-LAM fibroblasts. Treatment with sorafenib, a multikinase inhibitor, significantly reduced invasion, outperforming Rapamycin. We also confirmed TSC2-null AML cells as key VEGF-A secretors, which was suppressed by sorafenib in both AML cells and LAMFs. These findings highlight VEGF-A and bFGF as potential therapeutic targets and suggest multikinase inhibition as a promising strategy for LAM.One Sentence SummaryUsing 3D spheroids and spatial transcriptomics, we identified LAMFs and LECs as key contributors to LAM, with bFGF and VEGF-A as potential therapeutic targets
Combination EZH2 inhibition and retinoic acid treatment promotes differentiation and apoptosis in rhabdomyosarcoma cells
Authors: O’Brien Eleanor , Tse Carmen , Tracy Ian , Reddin Ian , Selfe Joanna , Gibson Jane , Tapper William , Pengelly Reuben J , Gao Jinhui , Aladowicz Ewa , Petts Gemma , Thway Khin , Popov Sergey , Kelsey Anna , Underwood Timothy J , Shipley Janet , Walters Zoë S 
Published: June 2023

AbstractRhabdomyosarcomas (RMS) are predominantly pediatric sarcomas thought to originate from muscle precursor cells due to impaired myogenic differentiation. Despite intensive treatment, 5-year survival for patients with advanced disease remains low (<30%), highlighting a need for novel therapies to improve outcomes. Differentiation therapeutics are agents that induce differentiation of cancer cells from malignant to benign. The histone methyltransferase, Enhancer of Zeste Homolog 2 (EZH2) suppresses normal skeletal muscle differentiation and is highly expressed in RMS tumors. We demonstrate combining EZH2 inhibition with the differentiating agent retinoic acid (RA) is more effective at reducing cell proliferation in RMS cell lines than single agents alone. In PAX3 -FOXO1 positive RMS cells this is due to an RA-driven induction of the interferon pathway resulting in apoptosis. In fusion negative RMS, combination therapy led to an EZH2i-driven upregulation of myogenic signaling resulting in differentiation. These results provide insight into the mechanism that drives the anti-cancer effect of the EZH2/RA single agent and combination treatment and indicate that the reduction of EZH2 activity combined with the induction of RA signalling represents a potential novel therapeutic strategy to treat both subtypes of RMS.HighlightsEZH2 expression is upregulated fusion positive (FPRMS) and fusion negative (FNRMS) rhabdomyosarcomasEZH2 inhibition combined with retinoic acid treatment was investigated RMS cell models.Combination treatment reduced cell proliferation and tumor spheroid volume.Combination treatment in FPRMS resulted in apoptosis in FPRMS via interferon signaling.Conversely, combination treatment in fusion negative RMS resulted in myogenic differentiation.
The effect of parental age on the quantity and quality of offspring inSyngnathus typhle, a species with male pregnancy
Authors: Pappert Freya Adele , Kolbe Daniel , Dubin Arseny , Roth Olivia 
Published: June 2023

AbstractOffspring quantity and quality are known to vary according to parental age, with most studies focusing on the mother’s age, who produces costly eggs and often carries out pregnancy, hampering to distinction between trans-generational age effects due to egg quality or physiological deterioration. We investigated the ramification of parental age on the offspring in the broad-nosed pipefishSyngnathus typhle, a fish species with male pregnancy, allowing us to separate these two female traits. By mating parents of different sizes we examined the impact of parental age on offspring number, size and gene expression. Our results show that older parents produced more and larger-sized offspring. However, we revealed intriguing insights into the differential gene expression patterns in offspring, strongly influenced by the paternal lineage but minimally affected by maternal age. Offspring from old fathers exhibited notable changes in gene expression profiles, particularly related to cell cycle regulation, metabolism, protein synthesis, stress response, DNA repair and neurogenesis. Our findings provide valuable insights into the role of pregnancy in shaping offspring physiology. Moreover, we recognize the value of assessing a broader range of species that have evolved with sex-specific differences in parental investment vs. gamete provisioning, as the age of either the mother or father may hold greater significance than the other in influencing offspring fitness.
Gut-associated microbes are present and active in the pig nasal cavity
Authors: Obregon-Gutierrez Pau , Bonillo-Lopez Laura , Correa-Fiz Florencia , Sibila Marina , Segalés Joaquim , Kochanowski Karl , Aragon Virginia 
Published: June 2023

AbstractBackgroundThe nasal microbiota is a key contributor to animal health, and characterizing the nasal microbiota composition is an important step towards elucidating the role of its different members. Efforts to characterize the nasal microbiota composition of domestic pigs and other farm animals frequently report the presence of bacteria that are typically found in the gut, including many anaerobes from theBacteroidalesandClostridialesorders. However, thein vivorole of these gut-microbiota associated taxa is currently unclear. Here, we tackled this issue by examining the prevalence, origin, and activity of these taxa in the nasal microbiota of piglets.ResultsFirst, analysis of the nasal microbiota of farm piglets sampled in this study, as well as various publicly available data sets, revealed that gut-microbiota associated taxa indeed constitute a substantial fraction of the pig nasal microbiota that is highly variable across individual animals. Second, comparison of herd-matched nasal and rectal samples at amplicon sequencing variant (ASV) level showed that these taxa are largely shared in the nasal and rectal microbiota, suggesting a common origin driven presumably by the transfer of fecal matter. Third, surgical sampling of the inner nasal tract showed that gut-microbiota associated taxa are found throughout the nasal cavity, indicating that these taxa do not stem from contaminations introduced during sampling with conventional nasal swabs. Finally, analysis of cDNA from the 16S rRNA gene in these nasal samples indicated that gut-microbiota associated taxa are indeed active in the pig nasal cavity.ConclusionThis study shows that gut-microbiota associated taxa are not only present, but also active, in the nasal cavity of domestic pigs, and paves the way for future efforts to elucidate thein vivofunction of these taxa within the nasal microbiota.
Antero-posterior gradients of cell plasticity and proliferation modulate posterior regeneration in the annelidPlatynereis
Authors: Bideau Loïc , Baduel Loeiza , Basso Marianne , Gilardi-Hebenstreit Pascale , Ribes Vanessa , Vervoort Michel , Gazave Eve 
Published: June 2023

AbstractRegenerative abilities are extremely variable among animals and may be substantial in some phyla, such as the annelids. So far, the cellular mechanisms underlying regeneration in annelids remain elusive. To precisely determine the origin(s), plasticity and fate of the cells participating in the blastema formation during posterior regeneration in the annelidPlatynereis dumerilii, we developed specific tools to track proliferative cells as well as gut epithelial cells. We showed that two populations of progenitors are at play during regeneration and that, among them, gut progenitors from differentiated tissues are lineage-restricted. Strikingly, gut progenitors from less differentiated and more proliferative tissues are much more plastic and can produce ectodermal and mesodermal derivatives, in addition to gut cells. However, their plasticity isde factolimited as exemplified by their inability to regenerate populations of stem cells responsible for the constant growth of the worms. We evidenced that those stem cells are from local origin (i.e.from the segment abutting the amputation plan) as most of the blastema cells. Our results are in favour of a hybrid and flexible cellular model for posterior regeneration inPlatynereisrelying on a gradient of cell plasticity along the antero-posterior axis of the animal.