bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunophenotype signatures in acute leukemias unveiled by integrative systems immunology
Authors: Bahia Ian Antunes Ferreira , Lima Rafael Duarte , de Medeiros Oliveira Gustavo Henrique , Neta Antonia Pereira Rosa , Filgueiras Igor Salerno , Marques Lena Schimke , Marques Alexandre Henrique , Dennyson Leandro M Fonseca , Barcelos Pedro Marçal , Nóbile Adriel Leal , Adri Anny Silva , Usuda Júlia Nakanishi , Ochs Hans D. , Dias Haroldo Dutra , Nakaya Helder I , de Souza Barroso Rodrigo , Luchessi André Ducati , Cabral-Marques Otávio , Junior Geraldo Barroso Cavalcanti 
Published: June 2024

ABSTRACTAcute leukemias (ALs) are complex hematological disorders, and accurate diagnosis is crucial for guiding treatment decisions and predicting patient outcomes. While changes in cell marker levels are well documented, the impact of these changes on marker relationships through an integrative systems approach remains uncharacterized. To address this gap, we conducted a 12-year study investigating 41 markers, including ontogenic markers and those used to diagnose both common and rare leukemia types, using immunophenotyping flow cytometry (IFC) data from 1,069 leukocyte samples obtained from peripheral blood (PB) or bone marrow (BM) aspirates of patients with suspected ALs. Machine learning techniques, such as principal component analysis (PCA) and random forest (RF) classification, demonstrated the stratification power of the cellular markers. Hierarchical clustering analysis of leukocyte ontogenetic markers revealed disease-specific clusters, irrespective of sex or sample type (PB or BM). Additionally, we found that patients with acute myeloid leukemia (AML) showed mild disruption in cell marker correlations, whereas the most significant dysregulation was observed in patients with T-cell acute lymphoblastic leukemia (T-ALL). Importantly, we identified ontogenic correlation changes indicating clusters of immature versus mature leukocyte markers, as well as cell lineage-specific markers influencing cellular relationships. These findings underscore the value of integrating systems strategies into conventional IFC analyses to enhance synthetic diagnosis and deepen our understanding of ALs pathophysiology.
Permanent lymphocyte subset elimination upon a single dose of AAV-delivered depletion antibody dissects immune control of chronic viral infection
Authors: Kastner Anna Lena , Marx Anna-Friederike , Dimitrova Mirela , Abreu-Mota Tiago , Ertuna Yusuf I. , Bonilla Weldy V. , Stauffer Karsten , Wagner Ingrid , Kreutzfeldt Mario , Merkler Doron , Pinschewer Daniel D. 
Published: June 2024

AbstractTo interrogate the role of specific immune cells in infection, cancer and autoimmunity, immunologists commonly use monoclonal depletion antibodies (depletion-mAbs) or genetically engineered mouse models (GEMMs). To generate a tool that combines specific advantages and avoids select drawbacks of the two methods we engineer adeno-associated viral vectors expressing depletion-mAbs (depletion-AAVs). Single-dose depletion-AAV administration permanently eliminates lymphocyte subsets in mice while avoiding accessory deficiencies of GEMMs such as marginal zone defects in B cell-deficient animals. Depletion-AAVs can be used irrespective of the animals’ genetic background, and multiple depletion-AAVs can readily be combined. Exploiting depletion-AAV technology, we show that B cells are required for unimpaired CD4 and CD8 T cell responses to chronic viral infection. Importantly, CD8 T cells fail to suppress viremia when B cells are depleted, and they only help resolving chronic infection if antibodies suppress viral loads. Our study positions depletion-AAVs as a versatile tool for immunological research.
Frequent genetic exchanges revealed by a pan-mitogenome graph of a fungal plant pathogen
Authors: van Westerhoven Anouk C. , Dijkstra Jelmer , Palop Jose L. Aznar , Wissink Kyran , Bell Jasper , Kema Gert H. J. , Seidl Michael F. 
Published: June 2024

AbstractMitochondria are present in almost all eukaryotic lineages. The mitochondrial genomes (mitogenomes) evolve separately from nuclear genomes, and they can therefore provide relevant insights into the evolution of their host species.Fusarium oxysporumis a major fungal plant pathogen that is assumed to reproduce clonally. However, horizontal chromosome transfer between strains can occur through heterokaryon formation, and recently signs of sexual recombination have been observed. Similarly, signs of recombination inF. oxysporummitogenomes challenged the prevailing assumption of clonal reproduction in this species. Here, we construct, to our knowledge, the first fungal pan-mitogenome graph of nearly 500F. oxysporummitogenome assemblies to uncover the variation and evolution. In general, the gene order of fungal mitogenomes is not well conserved, yet the mitogenome ofF. oxysporumand related species are highly co-linear. We observed two strikingly contrasting regions in theFusarium oxysporumpan-mitogenome, comprising a highly conserved core mitogenome and a long variable region (6-16 kb in size), of which we identified three distinct types. The pan-mitogenome graph reveals that only five intron insertions occurred in the core mitogenome and that the long variable regions drive the difference between mitogenomes. Moreover, we observed that their evolution is neither concurrent with the core mitogenome nor with the nuclear genome. Our large-scale analysis of long variable regions uncovers frequent recombination between mitogenomes, even between strains that belong to different taxonomic clades. This challenges the common assumption of incompatibility between genetically diverseF. oxysporumstrains and provides new insights into the evolution of this fungal species.Importance statementInsights into plant pathogen evolution is essential for the understanding and management of disease.Fusarium oxysporumis a major fungal pathogen that can infect many economically important crops. Pathogenicity can be transferred between strains by the horizontal transfer of pathogenicity chromosomes. The fungus has been thought to evolve clonally, yet recent evidence suggests active sexual recombination between related isolates, which could at least partially explain the horizontal transfer of pathogenicity chromosomes. By constructing a pan-genome graph of nearly 500 mitochondrial genomes, we describe the genetic variation of mitochondria in unprecedented detail and demonstrate frequent mitochondrial recombination. Importantly, recombination can occur between genetically diverse isolates from distinct taxonomic clades and thus can shed light on genetic exchange between fungal strains.
Morphological changes in the mandible associated with the presence of exostoses: a study in two archaeological populations from southern France
Authors: Casazza Estelle , Ballester Benoit , Philip-Alliez Camille , Ardagna Yann , Raskin Anne 
Published: June 2024

AbstractThis study aimed to investigate morphological changes in the mandible of subjects in archaeological collections associated with the presence of bony exostoses at the mandibular angle, which are described in the literature as related to specific behaviours of the manducatory apparatus like parafunctional activities. The skeletal sample investigated comprised adult individuals from two archaeological series. Sixteen measurements of the mandible were selected to evaluate anatomic variation in the two populations. Mandibles from both series were pooled for statistical analysis into two groups according to the number of exostoses at the mandibular angles: group 1 (number of exostoses ≤1) and group 2 (number of exostoses ≥ 2). Measurements could be made on eighty mandibles. A statistically significant difference was demonstrated between group 1 and group 2 for the following parameters: distance between mandibular angles, bicondylar width, ramus height, left condyle length, right and left coronoid process height. For each of these parameters, values were higher in group 2 than in group 1. This study presents an original methodology for studying anatomical variations of the mandible in the context of parafunctional activity, highlighting certain mandibular modifications. The impact of parafunctional behaviours such as bruxism on the mandible therefore has many anatomical expressions. The considerable variability of results found in the literature shows that more studies are needed to reach a consensus on the impact of parafunctional activities on the mandible.
Effectiveness and efficiency of immunisation strategies to prevent RSV among infants and older adults in Germany: a modelling study
Authors: Krauer Fabienne , Guenther Felix , Treskova-Schwarzbach Marina , Schoenfeld Viktoria , Koltai Mihaly , Jit Mark , Hodgson David , Schneider Udo , Wichmann Ole , Harder Thomas , Sandmann Frank G. , Flasche Stefan 
Published: June 2024

AbstractBackgroundRecently, several novel RSV immunisation products that protect infants and older adults against RSV disease have been licensed in Europe. We estimated the effectiveness and efficiency of introducing these RSV immunisation strategies in Germany.MethodsWe used a Bayesian framework to fit an age-structured dynamic transmission model of RSV to sentinel surveillance and RSV-specific hospitalisation data in Germany from 2015-2019. The calibrated model was used to evaluate different RSV intervention strategies over five years: long-acting, single-dose monoclonal antibodies (mAbs) in high-risk infants aged 1-5 months; long-acting mAbs in all infants aged 1-5 months; seasonal vaccination of pregnant women and one-time seasonal vaccination of older adults (75+/65+/55+ years). We performed sensitivity analysis on vaccine uptake, seasonal vs. year-round maternal vaccination, and the effect of under-ascertainment for older adults.ResultsThe model was able to match the various RSV datasets. Replacing the current short-acting mAB for high-risk infants with long-acting mAbs prevented 1.1% of RSV-specific hospitalisations in infants per year at the same uptake. Expanding the long-acting mAB programme to all infants prevented 39.3% of infant hospitalisations per year. Maternal vaccination required a larger number to be immunised to prevent one additional hospitalisation than a long-acting mAB for the same uptake. Vaccination of adults older than 75 years at an uptake of 40% in addition to Nirsevimab in all infants prevented an additional 4.5% of all RSV-hospitalisations over five years, with substantial uncertainty in the correction for under-ascertainment of the RSV burden.ConclusionsImmunisation has the potential to reduce the RSV disease burden in Germany.
One year of gluten free diet impacts gut function and microbiome in celiac disease
Authors: Costigan Carolyn M. , Warren Frederick J. , Duncan Anthony P. , Hoad Caroline L. , Lewis Nina , Hill Trevor , Crooks Colin J. , Morgan Paul S. , Ciacci Carolina , Iovino Paola , Sanders David S. , Hildebrand Falk , Gowland Penny A. , Spiller Robin C. , Marciani Luca 
Published: June 2024

AbstractBACKGROUND & AIMSCurrently, the main treatment option for coeliac disease (CD) is a gluten free diet (GFD). This observational cohort study investigated the impact of CD and 1 year of GFD on gut function and microbiome.METHODS36 newly diagnosed patients and 36 healthy volunteers (HV) were studied at baseline and at 12 months follow up. Small bowel water content (SBWC), whole gut transit time (WGTT) and colon volumes were measured by MRI. Stool samples DNA was subjected to shotgun metagenomic sequencing. Species level abundances and gene functions, including carbohydrate active enzymes (CAZymes) were determined.RESULTSSBWC was significantly higher in people with CD 157±15 mL versus HVs 100±12 mL (p=0.003). WGTT was delayed in people with CD 68±8 hours versus HVs 41±5 hours (p=0.002). The differences reduced after 12 months of GFD but not significantly. Wellbeing in the CD group significantly improved after GFD but did not recover to control values. CD faecal microbiota showed high abundance of proteolytic gene functions, associated withEscherichia coli, EnterobacterandPeptostreptococcus. GFD significantly reducedBifidobacteriaand increasedBlautia wexerelae. Microbiome composition correlated positively with WGTT, colonic volume andAkkermansia municphiliabut negatively withB.wexerelae. Following GFD the reduction in WGTT and colonic volume significantly associated with increased abundance ofB.wexerelae. There were also significant alterations in CAZyme profiles, specifically starch and arabinoxylan degrading families.CONCLUSIONSCD impacted gut function and microbiota. GFD ameliorated but did not reverse these effects, significantly reducingBifidobacteriaassociated with reduced intake of resistant starch and arabinoxylan from wheat.
Beyond brain size: disentangling the effect of sex and brain size on brain morphometry and cognitive functioning
Authors: Brzezinski-Rittner Aliza , Moqadam Roqaie , Iturria-Medina Yasser , Chakravarty Mallar , Dadar Mahsa , Zeighami Yashar 
Published: June 2024

AbstractIt is imperative to study sex differences in brain morphology and function. However, there are major observable and unobservable confounding factors that can contribute to the estimated differences. Males have larger head sizes than females. Head size differences not only act as a confounding factor in studying sex differences in the brain, but also impact its anatomy and functioning. In this work, we seek to disentangle the effect of head size from sex in studying sex differentiated aging trajectories, its relation to canonical functional networks and cytoarchitectural classes, brain allometry, cognition. Using the UK Biobank (UKBB) neuroimaging data (N = 35,732 participants, 19,281 females, 44-82 years of age), we created a subsample (N = 11,294) where females (N = 5,657) and males were matched by their total intracranial volume (TIV) and age, a subsample that maintains the UKBB sample distribution, one matched only by age, and one that exaggerated the TIV difference between sexes. We then modeled the aging trajectories at both regional and vertex-wise levels in the four subsamples, and compared the estimations of the models. Our results show that when females and males have the same head size, the overall sex estimations tend towards zero, suggesting that most of the variability results from head size differences. Our approach also revealed bidirectional sex differences in brain neuroanatomy previously masked by the effect of head size. Further, the scaling relationship between regional and total brain volume remains fairly consistent across the lifespan and is not sex differentiated overall. We evaluated how the results of cognitive tests with perceived sex differences are influenced and explained by head size and found that although the correlation between TIV and cognitive scores is low, the matching process changes the direction of the effect sizes of differences between sexes in “verbal and numerical reasoning” and “working memory” cognitive domains. Taken together, employing a matching approach that is widely used in causal modeling studies, we provide new evidence for disentanglement of sex differences in the brain from head size as a biological confound.
Large-scale genomic analysis of SARS-CoV-2 Omicron BA.5 emergence in the United States
Authors: Pham Kien , Chaguza Chrispin , Lopes Rafael , Cohen Ted , Taylor-Salmon Emma , Wilkinson Melanie , Katebi Volha , D. Grubaugh Nathan , Hill Verity 
Published: June 2024

AbstractThe COVID-19 pandemic is marked by the continuing emergence of novel SARS-CoV-2 variants. Questions remain about the mechanisms with which these lineages establish themselves in new geographical areas. In this study, we performed a discrete phylogeographic analysis on ∼19,000 SARS-CoV-2 sequences of Omicron BA.5 lineages between February and June 2022 to better understand how it emerged in different regions of the United States (U.S.). We found that the earliest introductions came from Africa, the putative origin of the variant, but the majority were from Europe, correlating with the high volume of air travelers. Additionally, the analysis revealed extensive domestic transmission between different regions of the U.S. driven by population size and cross-country transmission. Results suggest that most of the within-U.S. spread was between three regions that include California, New York, and Florida. Our results form a framework for understanding novel SARS-CoV-2 variant emergence in the U.S.
ACE2 decoy Fc-fusions and bi-specific killer engager (BiKEs) require Fc engagement forin vivoefficacy against SARS-CoV-2
Authors: Dick Jenna K. , Hicks Dustin , Krishna Venkatramana D , Sangala Jules A. , Zandstra Benjamin T. , Baehr Carly , Verbeek J Sjef , Cragg Mark S. , Cheeran Maxim C-J , Pravetoni Marco , Hart Geoffrey T 
Published: June 2024

AbstractSARS-CoV-2 virus has continued to evolve over time necessitating the adaptation of vaccines to maintain efficacy. Monoclonal antibodies (mAbs) against SARS-CoV-2 were a key line of defense for unvaccinated or immunocompromised individuals. However, these mAbs are now ineffective against current SARS-CoV-2 variants. Here, we tested three aspects of αSARS-CoV-2 therapeutics. First, we tested whether Fc engagement is necessary forin vivoclearance of SARS-CoV-2. Secondly, we tested bi-specific killer engagers (BiKEs) that simultaneously engage SARS-CoV-2 and a specific Fc receptor. Benefits of these engagers include the ease of manufacturing, stability, more cell-specific targeting, and high affinity binding to Fc receptors. Using both mAbs and BiKEs, we found that both neutralization and Fc receptor engagement were necessary for effective SARS-CoV-2 clearance. Thirdly, due to ACE2 being necessary for viral entry, ACE2 will maintain binding to SARS-CoV-2 despite viral evolution. Therefore, we used an ACE2 decoy Fc-fusion or BiKE, instead of an anti-SARS-CoV-2 antibody sequence, as a potential therapeutic that would withstand viral evolution. We found that the ACE2 decoy approach also required Fc receptor engagement and, unlike traditional neutralizing antibodies against specific variants, enabled the clearance of two distinct SARS-CoV-2 variants. These data show the importance of Fc engagement for mAbs, the utility of BiKEs as therapies for infectious disease, and thein vivoeffectiveness of the ACE2 decoy approach. With further studies, we predict combining neutralization, the cellular response, and this ACE2 decoy approach will benefit individuals with ineffective antibody levels.AbbreviationsACE2, scFv, mAb, BiKE, COVID-19, Fc, CD16, CD32b, CD64, d.p.iKey pointsWith equal dosing, both neutralization and Fc engagement are necessary for the optimal efficacy ofin vivoantibodies and bi-specific killer engagers (BiKEs) against SARS-CoV-2.BiKEs can clear SARS-CoV-2 virus and protect against severe infection in the hACE2-K18 mouse model.ACE2 decoys as part of Fc-fusions or BiKEs providein vivoclearance of two disparate SARS-CoV-2 variants.
EngineeringSaccharomyces cerevisiaefor the production of punicic acid-rich yeast biomass
Authors: Wang Juli , Chen Guanqun 
Published: June 2024

AbstractPunicic acid (PuA), an unusual conjugated linolenic acid found in pomegranate, offers diverse health benefits and potential applications in the food industry. The limited production of PuA from its natural plant sources has led to a growing interest in producing it through microbial fermentation. In this study, the “generally recognized as safe” yeastSaccharomyces cerevisiaewas engineered to produce PuA. Candidate genes related to PuA synthesis were directly shuffled within the yeast genome. Subsequent screening and optimization resulted in a strain that synthesized 26.7% of its total fatty acids as PuA. Further analyses revealed that the strain’s storage lipids contained over 22% PuA. By incorporating the health-promoting lipid component into the nutritional profile ofS. cerevisiae, the engineered strain could potentially serve as a sustainable source of yeast biomass with enhanced nutritional value.
The Inverse Association between Testosterone Replacement Therapy and Cardiovascular Disease Risk: A Systematic 25-year Review and Meta-Analysis Analysis of Prospective Cohort Studies from 1999 to 2024
Authors: Borges Julian Yin Vieira 
Published: June 2024

AbstractBackgroundTestosterone deficiency in men has historically been associated with an increased risk of cardiovascular disease (CVD), including myocardial infarction, heart failure, and mortality. The potential benefits of testosterone replacement therapy (TRT) on cardiovascular outcomes remain controversial. This systematic review and meta-analysis aimed to investigate if there could be potential benefits of TRT on cardiovascular disease risk and, if so, uncover the underlying mechanisms.MethodsA comprehensive literature search for Level A evidence in multiple databases (PubMed, Embase, Cochrane Library) was conducted, including randomized controlled trials (RCTs), systematic reviews, meta-analyses, cohort studies, review articles and experimental studies published between 1999 and 2024 that investigated the association between TRT and cardiovascular outcomes in men. The primary outcome was the risk of major adverse cardiovascular events (MACE), including myocardial infarction, stroke, and cardiovascular mortality. Secondary outcomes included changes in ejection fraction, lipid profiles, side effects, and other cardiovascular risk factors.ResultsFrom 3,727 records identified using the selected criteria, a total of 51 studies were selected for the meta-analysis, comprising 4 RCTs, 9 cohort studies, 6 experimental studies, 23 review articles, 4 systematic reviews, and 5 meta-analyses, with a combined sample size of approximately 3,134,054 men. The findings from the meta-analysis suggests an 18% reduction in the risk of cardiovascular events among men receiving TRT compared to those receiving a placebo.TRT was found to be associated with significant improvements in ejection fraction, lipid profiles (reduction in total cholesterol and low-density lipoprotein cholesterol), and other cardiovascular risk factors, including insulin resistance and inflammatory markers. Potential mechanisms underlying the cardioprotective effects of TRT include improvements in endothelial function, vasodilation, and myocardial remodeling.Subgroup analyses revealed that the beneficial effects of TRT were more pronounced in men with established cardiovascular disease or risk factors, such as diabetes or metabolic syndrome.ConclusionThis systematic review and meta-analysis of high-quality evidence suggest that testosterone deficiency is associated with an increased risk of cardiovascular disease. Conversely, TRT is associated with a reduced risk of cardiovascular events, particularly in men with pre-existing cardiovascular disease or risk factors. TRT was linked to a reduced risk of MACE, improved ejection fraction, and favorable changes in lipid profiles and other cardiovascular risk factors. Despite the relatively large sample size, further long-term studies are needed to confirm these findings and establish optimal dosing and monitoring strategies for TRT in cardiovascular disease prevention.