bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi-modal quantification of pathway activity with MAYA
Authors: Landais Yuna , Vallot Céline 
Published: July 2022

AbstractSignaling pathways can be activated through various cascades of genes depending on cell identity and biological context. Single-cell atlases now provide the opportunity to inspect such complexity in health and disease. Yet, existing reference tools for pathway scoring resume activity of each pathway to one unique common metric across cell types. Here, we present MAYA a computational method that enables the automatic detection and scoring of the diverse modes of activation of biological pathways across cell populations. MAYA improves the granularity of pathway analysis by detecting subgroups of genes within reference pathways, each characteristic of a cell population and how it activates a pathway. Using multiple single-cell datasets, we demonstrate the biological relevance of identified modes of activation, the robustness of MAYA to noisy pathway lists and batch effect. MAYA can also predict cell types starting from lists of reference markers in a cluster-free manner. Finally, we show that MAYA reveals common modes of pathway activation in tumor cells across patients, opening the perspective to discover shared therapeutic vulnerabilities.
Imputation of ancient genomes
Authors: Sousa da Mota Bárbara , Rubinacci Simone , Cruz Dávalos Diana Ivette , Amorim Carlos Eduardo G. , Sikora Martin , Johannsen Niels N. , Szmyt Marzena , Włodarczak Piotr , Szczepanek Anita , Przybyła Marcin M. , Schroeder Hannes , Allentoft Morten E. , Willerslev Eske , Malaspinas Anna-Sapfo , Delaneau Olivier 
Published: July 2022

AbstractDue to postmortem DNA degradation, most ancient genomes sequenced to date have low depth of coverage, preventing the true underlying genotypes from being recovered. Genotype imputation has been put forward to improve genotyping accuracy for low-coverage genomes. However, it is unknown to what extent imputation of ancient genomes produces accurate genotypes and whether imputation introduces bias to downstream analyses. To address these questions, we downsampled 43 ancient genomes, 42 of which are high-coverage (above 10x) and three constitute a trio (mother, father and son), from different times and continents to simulate data with coverage in the range of 0.1x-2.0x and imputed these using state-of-the-art methods and reference panels. We assessed imputation accuracy across ancestries and depths of coverage. We found that ancient and modern DNA imputation accuracies were comparable. We imputed most of the 42 high-coverage genomes downsampled to 1x with low error rates (below 5%) and estimated higher error rates for African genomes, which are underrepresented in the reference panel. We used the ancient trio data to validate imputation and phasing results using an orthogonal approach based on Mendel’s rules of inheritance. This resulted in imputation and switch error rates of 1.9% and 2.0%, respectively, for 1x genomes. We further compared the results of downstream analyses between imputed and high-coverage genomes, notably principal component analysis (PCA), genetic clustering, and runs of homozygosity (ROH). For these three approaches, we observed similar results between imputed and high-coverage genomes using depths of coverage of at least 0.5x, except for African genomes, for which the decreased imputation accuracy impacted ROH estimates. Altogether, these results suggest that, for most populations and depths of coverage as low as 0.5x, imputation is a reliable method with potential to expand and improve ancient DNA studies.
Vaccination shapes evolutionary trajectories of SARS-CoV-2
Authors: Meijers Matthijs , Ruchnewitz Denis , Łuksza Marta , Lässig Michael 
Published: July 2022

AbstractThe large-scale evolution of the SARS-CoV-2 virus has been marked by rapid turnover of genetic clades. New variants show intrinsic changes, notably increased transmissibility, as well as anti-genic changes that reduce the cross-immunity induced by previous infections or vaccinations1–4. How this functional variation shapes the global evolutionary dynamics has remained unclear. Here we show that selection induced by vaccination impacts on the recent antigenic evolution of SARS-CoV-2; other relevant forces include intrinsic selection and antigenic selection induced by previous infections. We obtain these results from a fitness model with intrinsic and antigenic fitness components. To infer model parameters, we combine time-resolved sequence data5, epidemiological records6,7, and cross-neutralisation assays8–10. This model accurately captures the large-scale evolutionary dynamics of SARS-CoV-2 in multiple geographical regions. In particular, it quantifies how recent vaccinations and infections affect the speed of frequency shifts between viral variants. Our results show that timely neutralisation data can be harvested to identify hotspots of antigenic selection and to predict the impact of vaccination on viral evolution.
Human Galectin-9 Promotes the Expansion of HIV Reservoirs in vivo in Humanized Mice
Authors: Yuan Zhe , Giron Leila B. , Hart Colin , Gyampoh Akwasi , Koshy Jane , Hong Kai Ying , Niki Toshiro , Premeaux Thomas A. , Ndhlovu Lishomwa C. , Montaner Luis J , Abdel-Mohsen Mohamed 
Published: July 2022

ABSTRACTObjectiveThe human endogenous β-galactoside-binding protein Galectin-9 (Gal-9) reactivates latently HIV-infected cells, which may allow for immune-mediated clearance of these cells. However, Gal-9 also activates T cell Receptor (TCR) signaling pathways, which could negatively affect HIV persistence by promoting T cell expansion and chronic activation/exhaustion. This potential “double-edged sword” effect of Gal-9 during HIV infection raises the question of the overall beneficial versus detrimental impact of Gal-9 on HIV persistence in vivo.DesignWe used the BLT (bone marrow, liver, thymus) humanized mouse model to evaluate the overall impact of Gal-9 on HIV persistence in vivo during antiretroviral therapy (ART).MethodsTwo independent cohorts of BLT mice with high human immune reconstitution were infected with HIV, placed on ART, and then treated with either recombinant human Gal-9 or PBS during ART suppression. Plasma viral loads and levels of tissue-associated HIV DNA and RNA were measured by qPCR. Markers of T cell activation/exhaustion were measured by flow cytometry, and plasma markers of inflammation were measured by multiplex cytokine arrays.ResultsGal-9 treatment was tolerable in ART-suppressed humanized mice and did not significantly induce plasma markers of inflammation or T cell markers of activation/exhaustion. However, Gal-9 treatment during ART significantly increased levels of tissue-associated HIV DNA and RNA compared to controls (P=0.0007 and P=0.011, respectively, for cohort I and P=0.002 and P=0.005, respectively, for cohort II).ConclusionsOur study highlights the overall adverse effects of Gal-9 on HIV persistence and the potential need to block Gal-9 interactions during ART-suppressed HIV infection.
Mechanism of strand displacement DNA synthesis by the coordinated activities of human mitochondrial DNA polymerase and SSB
Authors: Ismael Plaza-G.A. , Lemishko Kateryna M. , Crespo Rodrigo , Truong Thinh Q. , Kaguni Laurie S. , Cao-García Francisco J. , Ciesielski Grzegorz L. , Ibarra Borja 
Published: July 2022

AbstractMany replicative DNA polymerases couple DNA replication and unwinding activities to perform strand displacement DNA synthesis, a critical ability for DNA metabolism. Strand displacement is tightly regulated by partner proteins, such as single-stranded DNA (ssDNA) binding proteins (SSBs) by a poorly understood mechanism. Here, we use single-molecule optical tweezers and biochemical assays to elucidate the molecular mechanism of strand displacement DNA synthesis by the human mitochondrial DNA polymerase, Polγ, and its modulation by cognate and noncognate SSBs. We show that Polγ exhibits a robust DNA unwinding mechanism, which entails lowering the energy barrier for unwinding of the first base pair of the DNA fork junction, by ∼55%. However, the polymerase cannot prevent the reannealing of the parental strands efficiently, which limits by ∼30-fold its strand displacement activity. We demonstrate that SSBs stimulate the Polγ strand displacement activity through several mechanisms. SSB binding energy to ssDNA additionally increases the destabilization energy at the DNA junction, by ∼25%. Furthermore, SSB interactions with the displaced ssDNA reduce the DNA fork reannealing pressure on Polγ, in turn promoting the productive polymerization state by ∼3-fold. These stimulatory effects are enhanced by species-specific functional interactions and have significant implications in the replication of the human mitochondrial DNA.
Comprehensive analysis of platelet glycoprotein Ibα glycosylation
Authors: Hollenhorst Marie A , Tiemeyer Katherine H , Mahoney Keira E , Aoki Kazuhiro , Ishihara Mayumi , Lowery Sarah C. , Rangel-Angarita Valentina , Bertozzi Carolyn R , Malaker Stacy A 
Published: July 2022

AbstractBackgroundPlatelet glycoprotein (GP) Ibα is the major ligand-binding subunit of the GPIb-IX-V complex that binds von Willebrand Factor (VWF). GPIbα is heavily glycosylated, and its glycans have been proposed to play key roles in platelet clearance, VWF binding, and as target antigens in immune thrombocytopenia syndromes. Despite its importance in platelet biology, the glycosylation profile of GPIbα is not well characterized.ObjectivesThe aim of this study was to comprehensively analyze GPIbα amino acid sites of glycosylation (glycosites) and glycan structures.MethodsGPIbα ectodomain that was recombinantly expressed or that was purified from human platelets was analyzed by Western blot, mass spectrometry (MS) glycomics, and MS glycoproteomics to define glycosites and the structures of the attached glycans.ResultsWe identified a diverse repertoire of N- and O-glycans, including sialoglycans, Tn antigen, T antigen, and ABH blood group antigens. In the analysis of the recombinant protein, we identified 62 unique O-glycosites. In the analysis of the endogenous protein purified from platelets, we identified at least 48 unique O-glycosites and 1 N-glycosite. The GPIbα mucin domain is densely O-glycosylated. Glycosites are also located within the macroglycopeptide domain and mechanosensory domain (MSD).ConclusionsThis comprehensive analysis of GPIbα glycosylation lays the foundation for further studies to determine the functional and structural roles of GPIbα glycans.Essentials-Glycosylation of glycoprotein Ibα (GPIbα) is important for platelet function.-We report a comprehensive and site-specific analysis of human GPIbα glycosylation.-GPIbα carries sialoglycans, Tn antigen, T antigen, and ABO blood group (ABH) antigens.-We experimentally determined 48 O-glycosites and 1 N-glycosite by mass spectrometry.
Persistence of SARS-CoV-2 neutralizing antibodies longer than 13 months in naturally-infected, captive white-tailed deer (Odocoileus virginianus), Texas
Authors: Hamer Sarah A. , Nunez Chase , Roundy Christopher M. , Tang Wendy , Thomas Logan , Richison Jack , Benn Jamie S. , Auckland Lisa D. , Hensley Terry , Cook Walter E. , Pauvolid-Corrêa Alex , Hamer Gabriel L. 
Published: July 2022

AbstractAfter identifying a captive herd of white-tailed deer (WTD) in central Texas with >94% seroprevalence with SARS-CoV-2 neutralizing antibodies in September 2021, we worked retrospectively through archived serum samples of 21 deer and detected seroconversion of all animals between December 2020 and January 2021. We then collected prospective samples to conclude that the duration of persistence of neutralizing antibodies is at least 13 months for 19 (90.5%) of the animals, with two animals converting to seronegative after six and eight months. Antibody titers generally waned over this time frame, but three deer had a temporary 4 to 8-fold increases in PRNT titers over a month after seroconversion; anamnestic response cannot be ruled out.
Two point mutations in protocadherin-1 disrupt Andes hantavirus recognition and afford protection against lethal infection
Authors: Slough Megan M. , Li Rong , Herbert Andrew S. , Lasso Gorka , Kuehne Ana I. , Bakken Russell R. , Monticelli Stephanie R. , Liu Yanan , Ghosh Agnidipta , Moreau Alicia M. , Zeng Xiankun , Almo Steven C. , Dye John M. , Jangra Rohit K. , Wang Zhongde , Chandran Kartik 
Published: July 2022

AbstractAndes virus and Sin Nombre virus are the etiologic agents of severe hantavirus cardiopulmonary syndrome (HCPS) in the Americas for which no FDA-approved countermeasures are available. Protocadherin-1 (PCDH1), a cadherin-superfamily protein recently identified as a critical host factor for ANDV and SNV, represents a new antiviral target; however, its precise role remains to be elucidated. Here, we used computational and experimental approaches to delineate the binding surface of the ANDV glycoprotein complex on PCDH1’s first extracellular cadherin repeat domain. Strikingly, a single amino acid residue in this PCDH1 surface influenced the host species-specificity of SNV glycoprotein-PCDH1 interaction and cell entry. Mutation of this, and a neighboring residue, substantially protected Syrian hamsters from pulmonary disease and death caused by ANDV. We conclude that PCDH1 is a bona fide entry receptor for ANDV and SNV whose direct interaction with hantavirus glycoproteins could be targeted to develop new interventions against HCPS.
Confined keratocytes mimic in vivo migration and reveal volume-speed relationship
Authors: Labuz Ellen C. , Footer Matthew J. , Theriot Julie A. 
Published: July 2022

AbstractFish basal epidermal cells, known as keratocytes, are well-suited for cell migration studies. In vitro, isolated keratocytes adopt a stereotyped shape with a large fan-shaped lamellipodium and a nearly spherical cell body. However, in their native in vivo environment, these cells adopt a significantly different shape during their rapid migration towards wounds. Within the epidermis, keratocytes experience 2D confinement between the outer epidermal cell layer and the basement membrane; these two deformable surfaces constrain keratocyte cell bodies to be flatter in vivo than in isolation. In vivo keratocytes also exhibit a relative elongation of the front-to-back axis and substantially more lamellipodial ruffling, as compared to isolated cells. We have explored the effects of 2D confinement, separated from other in vivo environmental cues, by overlaying isolated cells with an agarose hydrogel with occasional spacers, or with a ceiling made of PDMS elastomer. Under these conditions, isolated keratocytes more closely resemble the in vivo migratory shape phenotype, displaying a flatter apical-basal axis and a longer front-to-back axis than unconfined keratocytes. We propose that 2D confinement contributes to multiple dimensions of in vivo keratocyte shape determination. Further analysis demonstrates that confinement causes a synchronous 20% decrease in both cell speed and volume. Interestingly, we were able to replicate the 20% decrease in speed using a sorbitol hypertonic shock to shrink the cell volume, which did not affect other aspects of cell shape. Collectively, our results suggest that environmentally imposed changes in cell volume may influence cell migration speed, potentially by perturbing physical properties of the cytoplasm.
CDPK2A and CDPK1 form a signaling module upstream ofToxoplasmamotility
Authors: Shortt Emily , Hackett Caroline G. , Stadler Rachel V. , Ward Gary E. , Lourido Sebastian 
Published: July 2022

ABSTRACTThe transition between parasite replication and dissemination is regulated in apicomplexan parasites by fluctuations in cytosolic calcium concentrations, effectuated by calcium-dependent protein kinases (CDPKs). We examined the role of CDPK2A in the lytic cycle ofToxoplasma, analyzing its role in the regulation of cellular processes associated with parasite motility. We used chemical-genetic approaches and conditional depletion to determine that CDPK2A contributes to the initiation of parasite motility through microneme discharge. We demonstrate that the N-terminal extension of CDPK2A is necessary for the protein’s function. Conditional depletion revealed an epistatic interaction between CDPK2A and CDPK1, suggesting that the two kinases work together to mediate motility in response to certain stimuli. This signaling module appears distinct from that of CDPK3 and PKG, which also controls egress. CDPK2A is revealed as an important regulator of theToxoplasmakinetic phase, linked to other kinases that govern this critical transition. Our work uncovers extensive interconnectedness between the signaling pathways that govern parasite motility.IMPORTANCEThis work uncovers interactions between various signaling pathways that governToxoplasma gondiiegress. Specifically, we compare the function of three canonical calcium dependent protein kinases (CDPKs) using chemical-genetic and conditional-depletion approaches. We describe the function of a previously uncharacterized CDPK, CDPK2A, in theToxoplasmalytic cycle, demonstrating it contributes to parasite fitness through regulation of microneme discharge, gliding motility, and egress from infected host cells. Comparison of analog-sensitive (AS) kinase alleles and conditionally-depleted alleles uncovered epistasis between CDPK2A and CDPK1 implying a partial functional redundancy. Understanding the topology of signaling pathways underlying key events in the parasite life cycle can aid in efforts targeting parasite kinases for anti-parasitic therapies.
Sustainability learning for improved safe work environments for construction semi-skilled workers in Zimbabwe
Authors: Moyo Tirivavi , Crafford Gerrit , Emuze Fidelis 
Published: July 2022

PurposeDespite “decent work” being pertinent, as situated in the International Labour Organisation's “Decent Work Agenda”, one of its substantive elements on the need for safe work environments remains a concern for semi-skilled construction workers. Evidently, sustainability learning objectives within this element must be identified and implemented as a remedy. Therefore, the aim of the reported study was to reveal sustainability learning objectives that are significant towards attaining safe work environments, through also assessing statistically significant differences due to demographic variables.Design/methodology/approachThe design of this research followed a quantitative questionnaire survey strategy to obtain insights from semi-skilled workers and site/project managers in Zimbabwe.FindingsKnowledge of relevant prevention strategies to foster positive physical and mental well-being in the workplace was considered the most critical sustainability learning objective. Semi-skilled workers revealed the most interest in objectives that affected their socio-economic beings while site/project managers preferred those that had more economic value to the organisations they work for. Educational levels are also critical when instituting any training interventions.Research limitations/implicationsThe absence of a database for semi-skilled workers was a limitation towards achieving the practical significance of the findings. Due to semi-skilled workers significantly contributing to unsafe work environments, structured on-the-job training schemes that are sufficiently planned, monitored and controlled are recommended.Originality/valueThe determination of sustainability learning objectives for construction semi-skilled workers, through on-the-job training schemes, will contribute to the improvement of safe work environments.
Benchmarking strategic core competencies of performance across Chinese and South Korean manufacturing companies
Authors: Pati Niranjan , Lee Jooh 
Published: July 2022

PurposeThis study empirically investigates the significance of the core competencies on various economic performance indices by utilizing accounting and market-based performance in Chinese and South Korean leading manufacturing companies.Design/methodology/approachThis research employs a series of hierarchical regression models to test the hypotheses concerning the significance of R&D and export strategy on firms' performance.FindingsThis study finds that R&D intensity and foreign trade activities through export are most likely to be significantly associated with firm performance, particularly market-based performance, across the Chinese and South Korea manufacturing companies. The significance of other core strategic factors such as capital intensity, leverage, inventory turnover, labor productivity, administrative cost efficiency, and collection policy on performance was also contemplated.Originality/valueThe relationship between R&D and firm performance has been an interesting issue concerning the performance measures employed across different country settings. Research issues addressed in this paper relate to how R&D, and foreign trade by export influence firm performance across two diverse economic environments inherent of Chinese and South Korean leading manufacturing firms. Particularly, this study explores the directions and magnitudes of the operational and strategic relationships between key strategic factors, such as R&D intensity, export by foreign trade, and the firm's economic and market-based performance.
Designing AI implications in the venture creation process
Authors: Schiavone Francesco , Pietronudo Maria Cristina , Sabetta Annamaria , Bernhard Fabian 
Published: July 2022

PurposeThe paper faces artificial intelligence issues in the venture creation process, exploring how artificial intelligence solutions intervene and forge the venture creation process. Drawing on the most recent literature on artificial intelligence and entrepreneurship, the authors propose a set of theoretical propositions.Design/methodology/approachThe authors adopt a multiple case approach to assess propositions and analyse 4 case studies from which the authors provide (1) more detailed observation about entrepreneurial process phases influenced by artificial intelligence solutions and (2) more details about mechanics enabled by artificial intelligence.FindingsThe analysis demonstrates artificial intelligence contributes alongside the entrepreneurial process, enabling mechanisms that reduce costs or resources, generate new organizational processes but simultaneously expand the network needed for venture creation.Originality/valueThe paper adopts a deductive approach analyzing the contribution of AI-based startup offerings in changing the entrepreneurial process. Thus, the paper provides a practical view of the potentiality of artificial intelligence in enabling entrepreneurial processes through the analysis of compelling propositions and the technological ability of artificial intelligence solutions.