bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modelling the demographic history of human North African genomes points to soft split divergence between populations
Authors: Serradell Jose M , Lorenzo-Salazar Jose M , Flores Carlos , Lao Oscar , Comas David 
Published: November 2023

ABSTRACTBackgroundNorth African human populations present a complex demographic scenario. The presence of an autochthonous genetic component and population substructure, plus extensive gene flow from the Middle East, Europe, and sub-Saharan Africa, have shaped the genetic composition of its people through time.ResultsWe conducted a comprehensive analysis of 364 genomes to construct detailed demographic models for the North African region, encompassing its two primary ethnic groups, the Arab and Amazigh populations. This was achieved through the utilization of the Approximate Bayesian Computation with Deep Learning (ABC-DL) framework and a novel algorithm called Genetic Programming for Population Genetics (GP4PG). This innovative approach enabled us to effectively model intricate demographic scenarios, utilizing a subset of 16 whole-genomes at >30X coverage. The demographic model suggested by GP4PG exhibited a closer alignment with the observed data compared to the ABC-DL model. Both methods point to a back-to-Africa origin of North African individuals and a close relationship of North African with Eurasian populations. Results support different origins for Amazigh and Arab populations, with Amazigh populations originating back in Epipaleolithic times, as early as 22.3 Kya. GP4PG model supports Arabization as the main source of Middle Eastern ancestry in North Africa. The GP4PG model better explaining the observed data includes population substructure in surrounding populations (sub-Saharan Africa and Middle East) with continuous gene flow after the split between populations (migration decay). In contrast to what we observed in the ABC-DL, the best GP4PG model does not require pulses of admixture from surrounding populations into North Africa pointing to soft splits as drivers of divergence in North Africa.ConclusionsWe have built a demographic model on North Africa that points to a back-to-Africa expansion and a differential origin between Arab and Amazigh populations, emphasizing the complex demographic history at a population level.
Statistical framework for calling allelic imbalance in high-throughput sequencing data
Authors: Buyan Andrey , Meshcheryakov Georgy , Safronov Viacheslav , Abramov Sergey , Boytsov Alexandr , Nozdrin Vladimir , Baulin Eugene F. , Kolmykov Semyon , Vierstra Jeff , Kolpakov Fedor , Makeev Vsevolod J. , Kulakovskiy Ivan V. 
Published: November 2023

AbstractHigh-throughput sequencing facilitates large-scale studies of gene regulation and allows tracing the associations of individual genomic variants with changes in gene expression. Compared to classic association studies, allelic imbalance at heterozygous variants captures the functional effects of the regulatory genome variation with smaller sample sizes and higher sensitivity. Yet, the identification of allele-specific events from allelic read counts remains non-trivial due to multiple sources of technical and biological variability, which induce data-dependent biases and overdispersion. Here we present MIXALIME, a novel computational framework for calling allele-specific events in diverse omics data with a repertoire of statistical models accounting for read mapping bias and copy-number variation. We benchmark MIXALIME against existing tools and demonstrate its practical usage by constructing an atlas of allele-specific chromatin accessibility, UDACHA, from thousands of available datasets obtained from diverse cell types.Availabilityhttps://github.com/autosome-ru/MixALime,https://udacha.autosome.org
Dissecting the properties of circulating IgG against Group A Streptococcus through a combined systems antigenomics-serology workflow
Authors: Chowdhury Sounak , Gomez Toledo Alejandro , Hjortswang Elisabeth , Sorrentino James T , Lewis Nathan E , Bläckberg Anna , Ekström Simon , Izadi Arman , Nordenfelt Pontus , Malmström Lars , Rasmussen Magnus , Malmström Johan 
Published: November 2023

AbstractMost individuals maintain circulating antibodies against various pathogenic bacteria as a consequence of previous exposures. However, it remains unclear to what extent these antibodies contribute to host protection. This knowledge gap is linked to the need for better methods to characterize antimicrobial polyclonal antibodies, including their antigen and epitope repertoires, subclass distribution, glycosylation status, and effector functions. Here, we showcase a generic mass spectrometry-based strategy that couples systems antigenomics and systems serology to characterize human antibodies directly in clinical samples. The method is based on automated affinity purification workflows coupled to an integrated suite of high-resolution MS-based quantitative, structural- and glyco-proteomics readouts.We focused onStreptococcus pyogenes(Group AStreptococcus; GAS), a major human pathogen still awaiting an approved vaccine. Our methodology reveals that both healthy and GAS infected individuals have circulating Immunoglobulin G (IgG) against a subset of genomically conserved streptococcal proteins, including numerous toxins and virulence factors. The antigen repertoire targeted by these antibodies was relatively constant across healthy individuals, but considerably changed in GAS bacteremia. Detailed analysis of the antigen-specific IgG indicates inter-individual variation regarding titers, subclass distributions, and Fc-signaling capacity, but not in epitope and Fc-glycosylation patterns. Importantly, we show that the IgG subclass has a major impact on the ability of GAS-antibodies to trigger immune signaling, in an antigen- and Fc receptor-specific fashion. Overall, these results uncover exceeding complexity in the properties of GAS-specific IgG, and showcase our methodology as high-throughput and flexible workflow to understand adaptive immune responses to bacterial pathogens.Significance statementMost people develop polyclonal antibodies against bacterial pathogens during infections but their structural and functional properties are poorly understood. Here, we showcase a combined systems antigenomics and systems serology strategy to quantify key antibody properties directly in clinical samples. We applied this method to characterize polyclonal antibody responses against Streptococcus pyogenes, a major human pathogen. We mapped the antigen and epitope landscape of anti-streptococcal antibodies circulating in healthy adult plasma, and their changes during blood infections. We further demonstrate the analytical power of our approach to resolve individual variations in the structure and effector functions of antigen-specific antibodies, including a dependency between immunoglobulin subclass and Fc-signaling capacity.
Early antigen receptor signaling in natural killer cells alters STAT4-dependent fate decisions via epigenetic remodeling
Authors: Grassmann Simon , Santosa Endi K. , Mujal Adriana M. , Kim Hyunu , Fan Sherry X. , Owyong Mark , Lau Colleen M. , Sun Joseph C. 
Published: November 2023

ABSTRACTNatural Killer (NK) cells are innate cytotoxic lymphocytes that possess features of adaptive immunity, including antigen specificity and clonal expansion. NK cells rapidly respond to cytokines released during the innate phase of viral infection and are thought to migrate from circulation into infected organs to execute their early effector functions. However, recent evidence suggests that tissue-resident NK cells are among the first responders to viral infection. In this study, we observe that antigen receptor signaling precedes substantial proinflammatory cytokine signaling in a population of NK cells during mouse cytomegalovirus infection. Early antigen receptor signals epigenetically prime NK cells for optimal expansion during the later adaptive phase of the antiviral response. Mechanistically, receptor signaling increases chromatin accessibility at STAT4-binding genomic sites within differentiating NK cells. To promote adaptive programming of NK cells during infection, activating receptor-dependent epigenetic remodeling antagonizes IL-12 driven terminal maturation, poises NK cells for proliferation via sustained CDK6 expression, and antagonizes early apoptosis of short-lived effector cells via suppression of Bim. Thus, antigen receptor signaling alters an IL-12 dependent fate decision during the innate-to-adaptive transition of antiviral NK cells.
Precise age estimation in clonal species using a somatic genetic clock
Authors: Yu Lei , Renton Jessie , Burian Agata , Khachaturyan Marina , Kotta Jonne , Stachowicz John J. , DuBois Katherine , Baums Iliana B. , Werner Benjamin , Reusch Thorsten B. H. 
Published: November 2023

AbstractAge and longevity are key parameters for demography and life-history evolution of organisms. In clonal species, a widespread life history among animals, plants, algae and fungi, the sexually produced offspring (the genet) grows indeterminately by producing iterative modules, or ramets. The age of large genets often remains elusive, while estimates based on their spatial extent as proxy for age are unreliable. Here, we present a method for age estimation using a molecular clock based on the accumulation of fixed somatic genetic variation (SoGV) that segregates among ramets of the same genet. Using a stochastic model of a generic clonal organism, we demonstrate that the accumulation of fixed SoGV via somatic genetic drift will approach linearity after a short lag phase, and is determined by the mitotic mutation rate, without direct dependence on asexual generation time. The lag phase decreased with lower stem cell population size (N), number of founder cells for the formation of new modules (N0), and the ratio of symmetric vs. asymmetric stem cell divisions. We apply the somatic genetic clock to the clonal plant modelZostera marina(eelgrass) and show that linearity is approached within a few years. Taking advantage of two long-term cultivation experiments forZ. marina(4 and 17 years respectively) as calibration points, we find genet ages up to 1,403 years in a global data set of 20 eelgrass populations. The somatic genetic clock is applicable to any multicellular clonal species where a small number of founder cells are recruited to form new ramets, opening novel research avenues to study longevity and hence, demography and population dynamics of clonal species.
Ubiquitinated protein levels remain high during ageing inC. elegans
Authors: Daigle Sandrine E. , Doucet Savannah , Lapierre Louis R. 
Published: November 2023

ABSTRACTA wealth of literature in different model organisms have shown that proteostasis declines with age, which results in the accumulation of aggregated proteins that generally carry polyubiquitin chains. In Koyuncu et al. (Nature, 2021), the authors use a relatively mild homogenization approach to analyze total polyubiquitinated protein levels longitudinally inC. elegansand found that the overall level of polyubiquitinated proteins decreases in wild-type nematodes. Specifically, the substantial presence of polyubiquitinated proteins in early adulthood markedly decreases at day 10 and 15 of adulthood. This finding represents the central basis of their study where they subsequently suggest that age-dependent decrease in protein polyubiquitination in wild-type animals is due to enhanced deubiquitination. Here, we find that the mild homogenization ofC. elegansused in Koyuncuet al. fails to properly extract allC. elegansproteins, because it largely omits relatively insoluble proteins in the pellet. When we perform complete homogenization of wild-type nematode proteins using SDS, sonication and heat, we unequivocally observe that polyubiquitinated protein levels do not decrease with age inC. elegans. Overall, the levels of polyubiquitinated proteins remains relatively constant post-reproduction. Therefore, our findings invalidate the main conclusion of Koyuncu et al. that the ubiquitinated proteome is rewired during ageing and demonstrate thatC. elegansharbor polyubiquitinated proteins throughout their lifespan.
Evidence for peripheral and central actions of codeine to dysregulate deglutition in the anesthetized cat
Authors: Bolser Donald C. , Shen Tabitha Y. , Musselwhite M. Nicholas , Rose Melanie J. , Hayes John A. , Pitts Teresa G. 
Published: November 2023

ABSTRACTSystemic administration of opioids has been associated with aspiration and swallow dysfunction in humans. We speculated that systemic administration of codeine would induce dysfunctional swallowing and that this effect would have a peripheral component. Experiments were conducted in spontaneously breathing, anesthetized cats. The animals were tracheotomized and electromyogram electrodes were placed in upper airway and chest wall respiratory muscles for recording swallow related motor activity. The animals were allocated into three groups: vagal intact (VI), cervical vagotomy (CVx), and supra-nodose ganglion vagotomy (SNGx). A dose response to intravenous codeine was performed in each animal. Swallowing was elicited by injection of 3 ml of water into the oropharynx. The number of swallows after vehicle was significantly higher in the VI group than in SNGx. Codeine had no significant effect on the number of swallows induced by water in any of the groups. However, the magnitudes of water swallow-related EMGs of the thyropharyngeus muscle were significantly increased in the VI and CVx groups by 2-4 fold in a dose-related manner. In the CVx group, the geniohyoid muscle EMG during water swallows was significantly increased. There was a significant codeine dose-related increase in spontaneous swallowing in each group. The spontaneous swallow number at the 10 mg/kg dose of codeine was significantly larger in the CVx than that in the SNGx groups. During water-evoked swallows, intravenous codeine increased upper airway motor drive in a dose-related manner, consistent with dysregulation. The appearance of spontaneous swallowing in response to codeine in all groups supports a central action of this drug on the swallow pattern generator and also is consistent with dysregulation. At the highest dose of codeine, the reduced spontaneous swallow number in the SNGx group relative to CVx is consistent with a peripheral excitatory action of codeine either on pharyngeal/laryngeal receptors or in the nodose ganglion itself.
Acetyl-CoA carboxylase Inhibition increases RPE cell fatty acid oxidation and limits apolipoprotein efflux
Authors: Hass Daniel T. , Pandey Kriti , Engel Abbi , Horton Noah , Robbings Brian M. , Lim Rayne , Sadilek Martin , Zhang Qitao , Autterson Gillian A. , Miller Jason M.L. , Chao Jennifer R. , Hurley James B. 
Published: November 2023

AbstractPurposeIn age-related macular degeneration (AMD) and Sorsby’s fundus dystrophy (SFD), lipid-rich deposits known as drusen accumulate under the retinal pigment epithelium (RPE). Drusen may contribute to photoreceptor and RPE degeneration in AMD and SFD. We hypothesize that stimulating β-oxidation in RPE will reduce drusen accumulation. Inhibitors of acetyl-CoA carboxylase (ACC) stimulate β-oxidation and diminish lipid accumulation in fatty liver disease. In this report we test the hypothesis that an ACC inhibitor, Firsocostat, limits the accumulation of lipid deposits in cultured RPE cells.MethodsWe probed metabolism and cellular function in mouse RPE-choroid, human fetal- derived RPE cells, and induced pluripotent stem cell-derived RPE cells. We used13C6-glucose and13C16-palmitate to determine the effects of Firsocostat on glycolytic, Krebs cycle, and fatty acid metabolism.13C labeling of metabolites in these pathways were analyzed using gas chromatography-linked mass spectrometry. We quantified ApoE and VEGF release using enzyme-linked immunosorbent assays. Immunostaining of sectioned RPE was used to visualize ApoE deposits. RPE function was assessed by measuring the trans-epithelial electrical resistance (TEER).ResultsACC inhibition with Firsocostat increases fatty acid oxidation and remodels lipid composition, glycolytic metabolism, lipoprotein release, and enhances TEER. When human serum is used to induce sub-RPE lipoprotein accumulation, fewer lipoproteins accumulate with Firsocostat. In a culture model of Sorsby’s fundus dystrophy, Firsocostat also stimulates fatty acid oxidation, improves morphology, and increases TEER.ConclusionsFirsocostat remodels intracellular metabolism and improves RPE resilience to serum-induced lipid deposition. This effect of ACC inhibition suggests that it could be an effective strategy for diminishing drusen accumulation in the eyes of patients with AMD.
Behavior Clusters in Ischemic Stroke using NIHSS
Authors: Tshimanga Louis Fabrice , Zanola Andrea , Facchini Silvia , Bisogno Antonio Luigi , Pini Lorenzo , Atzori Manfredo , Corbetta Maurizio 
Published: November 2023

AbstractBACKGROUNDStroke is one of the leading causes of death and disability. The resulting behavioral deficits can be measured with clinical scales of motor, sensory, and cognitive impairment. The most common of such scales is the National Institutes of Health Stroke Scale, or NIHSS. Computerized tomography (CT) and magnetic resonance imaging (MRI) scans show predominantly subcortical or subcortical-cortical lesions, with pure cortical lesions occurring less frequently. While many experimental studies have correlated specific deficits (e.g. motor or language impairment) with stroke lesion locations, the mapping between symptoms and lesions is not straightforward in clinical practice. The advancement of machine learning and data science in recent years has shown unprecedented opportunities even in the biomedical domain. Nevertheless, their application to medicine is not simple, and the development of data driven methods to learn general mathematical models of diseases from healthcare data is still an unsolved challenge.METHODSIn this paper we measure statistical similarities of stroke patients based on their NIHSS scores, and we aggregate symptoms profiles through two different unsupervised machine learning techniques: spectral clustering and affinity propagation.RESULTSWe identify clusters of patients with largely overlapping, coherent lesions, based on the similarity of behavioral profiles.CONCLUSIONSOverall, we show that an unsupervised learning workflow, open source and transferable to other conditions, can identify coherent mathematical representations of stroke lesions based only on NIHSS data.
High prevalence of asymptomatic and sub-patentPlasmodium falciparuminfections in Urban Bouaké, Côte d’Ivoire, but nohrp2deletions: Implications for Malaria Control
Authors: Sagna André Barembaye , Gebre Yilekal , Vera-Arias Claudia Abigail , Traoré Dipomin François , Tchekoi Bertin N’cho , Assi Serge Brice , Koffi Amnan Alphonsine , Rogier Christophe , Remoue Franck , Koepfli Cristian 
Published: November 2023

AbstractAsymptomaticPlasmodium falciparuminfections are common in endemic settings, yet diagnosing these infections remains challenging because they are often below the limit of detection of conventional light microscopy (LM) or rapid diagnostic tests (RDTs). Deletions of thehrp2/3gene, encoding the protein detected by the most sensitive class of RDTs, present a further threat. In this study, the prevalence of asymptomatic and sub-patentP. falciparuminfections was characterized in the rainy season in the city of Bouaké, Central Côte d’Ivoire. A cross-sectional survey was conducted in nine neighborhoods of Bouaké, Côte d’Ivoire, in 2016. Matched LM, RDTs, andvarATS qPCR, were used to determine the prevalence ofP. falciparuminfections and to compare the performance of the different diagnostic methods.P. falciparum hrp2/3deletions were typed by digital PCR. Among 2313 individuals, malaria prevalence was 10.8% by microscopy, 13.0% by RDT, 35.1% by qPCR, and 37.3% (863/2313) when all three methods were combined. 96.4% (832/863) of individuals withP. falciparuminfections did not report a recent fever. 57.1% (493/863) of infections were sub-patent. The prevalence was highly heterogeneous across the neighborhoods, ranging from 15% to 55.2%, and differed among age groups (<5 years: 17.7%, 5-14 years: 42.7%, ≥15 years: 35.9%). Compared tovarATS qPCR, LM and RDT had a low sensitivity of 24.3% and 34.2%, respectively, although both methods were highly specific (>96%). Sub-microscopic malaria infections were more prevalent in ≥15-year-olds (69.9%, 349/499) and in the neighborhood of Dar es Salam (75.9%, 44/58). No hrp2 deletions were observed, and two samples carriedhrp3deletion/wild-type mixed infections. The high prevalence of asymptomatic and sub-patent infections prompts the implementation of strategies targeting these parasite reservoirs to achieve reductions in malaria burden in this high-transmission city of Côte d’Ivoire.
The association of skeletal muscle energetics with recurrent falls in older adults within the Study of Muscle, Mobility and Aging (SOMMA)
Authors: Kramer Philip A. , Zamora Ezequiel , Barnes Haley N. , Strotmeyer Elsa S. , Glynn Nancy W , Lane Nancy E. , Coen Paul M. , Cawthon Peggy M. , Goodpaster Bret H. , Newman Anne B. , Kritchevsky Stephen B. , Cummings Steven R. 
Published: November 2023

AbstractBackgroundFalls in the older population are a major public health concern. While many physiological and environmental factors have been associated with fall risk, muscle mitochondrial energetics has not yet been investigated.MethodsIn this analysis, 835 Study of Muscle, Mobility and Aging (SOMMA) participants aged 70-94 were surveyed for recurrent falls (2+) after one year. Skeletal muscle energetics were assessed at baseline in vivo using31P Magnetic Resonance Spectroscopy (MRS) (ATPmax) and ex vivo by High Resolution Respirometry (HRR) of permeabilized muscle fibers from the vastus lateralis (MaxOXPHOS).ResultsSOMMA participants who reported recurrent falls (12%) had a slower 400m walk gait speed compared to those with 0-1 falls (1.0 +/-0.2 vs. 1.1 +/-0.2, p<.001) and took a greater number of medication in the 30 days before their baseline visit (5.6 +/-4.4 vs. 4.2 +/-3.4, p<0.05). MaxOXPHOS was significantly lower in those who reported recurrent falls (p=0.008) compared to those with one or fewer falls, but there was no significant difference in ATPmax (p=0.369). Neither muscle energetics measure was significantly associated with total number of falls or injurious falls, but recurrent falls were significantly higher with lower MaxOXPHOS (RR=1.33, 95% CI= 1.02-1.73, p=0.033). However, covariates accounted for the increased risk.ConclusionsEx vivo maximal muscle mitochondrial energetics were lower in older adults who experienced recurrent falls, but covariates accounted for its association with recurrent fall risk, suggesting this “hallmark of aging” may not be directly implicated in the complex etiology of falls.