bluuebunny/crossref_metadata_2025_split huggingface dataset:
NVX-CoV2373 ancestral and NVX-CoV2540 BA.5 protein nanoparticle vaccines protect against Omicron BA.5 variant in Syrian hamsters
Authors: Bricker Traci L. , Joshi Astha , Soudani Nadia , Scheaffer Suzanne M. , Patel Nita , Guebre-Xabier Mimi , Smith Gale , Diamond Michael S. , Boon Adrianus C. M. 
Published: August 2023

SUMMARYThe emergence of SARS-CoV-2 variants with greater transmissibility or immune evasion properties has jeopardized the existing vaccine and antibody-based countermeasures. Here, we evaluated the efficacy of boosting with the protein nanoparticle NVX-CoV2373 or NVX-CoV2540 vaccines containing ancestral or BA.5 S proteins, respectively, in mRNA-immunized pre-immune hamsters, against challenge with the Omicron BA.5 variant of SARS-CoV-2. Serum antibody binding and neutralization titers were quantified before challenge, and viral loads were measured 3 days after challenge. Compared to an mRNA vaccine boost, NVX-CoV2373 or NVX-CoV2540 induced higher serum antibody binding responses against ancestral Wuhan-1 or BA.5 spike proteins, and greater neutralization of Omicron BA.1 and BA.5 variants. One and three months after vaccine boosting, hamsters were challenged with the Omicron BA.5 variant. NVX-CoV2373 and NVX-CoV2540 boosted hamsters showed reduced viral infection in the nasal washes, nasal turbinates, and lungs compared to unvaccinated animals. Also, NVX-CoV2540 BA.5 boosted animals had fewer breakthrough infections than NVX-CoV2373 or mRNA-vaccinated hamsters. Thus, immunity induced by NVX-CoV2373 or NVX-CoV2540 boosting can protect against the Omicron BA.5 variant in the Syrian hamster model.IMPORTANCEAs SARS-CoV-2 variants continue to emergence, the efficacy of prior and updated COVID-19 vaccines need to be tested. Here, we tested the efficacy of two nanoparticle protein-based vaccines in pre-immune hamsters against a challenge with the BA.5 Omicron variant of SARS-CoV-2. Compared to an mRNA vaccine boost, the nanoparticle vaccine NVX-CoV2373 and NVX-CoV2540 induced higher serum antibody binding and neutralization responses against ancestral Wuhan-1 or BA.5 variants. One and three months after the last immunization, hamsters were challenged with the Omicron BA.5 variant. NVX-CoV2373 and NVX-CoV2540 boosted hamsters showed reduced viral infection in the nasal washes, nasal turbinates, and lungs compared to unvaccinated animals. Animals that received the homologous vaccine, NVX-CoV2540, had fewer breakthrough infections than NVX-CoV2373 or mRNA-vaccinated hamsters. Together, our data shows that the BA.5 nanoparticle vaccine is effective and that it is important to update the COVID-19 vaccine to match currently circulating strains of SARS-CoV-2.
A genotype-first approach identifies high incidence ofNF1pathogenic variants with distinct disease associations
Authors: Safonov Anton , Nomakuchi Tomoki T , Chao Elizabeth , Horton Carrie , Dolinsky Jill S , Yussuf Amal , Richardson Marcy , Speare Virginia , Li Shuwei , Bogus Zoe C , Bonanni Maria , Raper Anna , Kallish Staci , Ritchie Marylyn D ,   Regeneron Genetics Center,   Penn Medicine BioBank, Nathanson Katherine L , Drivas Theodore G 
Published: August 2023

AbstractLoss of function variants in theNF1gene cause neurofibromatosis type 1 (NF1), a genetic disorder characterized by complete penetrance, prevalence of 1 in 3,000, characteristic physical exam findings, and a substantially increased risk for malignancy. However, our understanding of the disorder is entirely based on patients ascertained through phenotype-first approaches. Leveraging a genotype-first approach in two large patient cohorts, we demonstrate unexpectedly high prevalence (1 in 450-750) ofNF1pathogenic variants. Half were identified in individuals lacking clinical features of NF1, with many appearing to have post-zygotic mosaicism for the identified variant. Incidentally discovered variants were not associated with classic NF1 features but were associated with an increased incidence of malignancy compared to a control population. Our findings suggest thatNF1pathogenic variants are substantially more common than previously thought, often characterized by somatic mosaicism and reduced penetrance, and are important contributors to cancer risk in the general population.
Climatic and biogeographic processes underlying the diversification of the pantropical and early divergent angiosperm family Annonaceae
Authors: Li Weixi , Wang Runxi , Liu Ming-Fai , Folk Ryan A. , Xue Bine , Saunders Richard M.K. 
Published: August 2023

AbstractAimTropical rainforests harbour the richest biodiversity among terrestrial ecosystems, but few studies have addressed underlying processes of species diversification in these ecosystems. We use the pantropical and early divergent flowering plant family Annonaceae as a model system to investigate how abiotic factors such as climate and biogeographic events contribute to the diversification process and lead to its high diversity across a long evolutionary history.LocationTropics and subtropicsTaxonAnnonaceaeMethodsA super-matrix was constructed for 835 taxa (34% of Annonaceae species), based on eight chloroplast regions. To understand the patterns of diversification, we reconstructed climatic niche evolution and historical biogeographical events, and tested their association with diversification rates.ResultsThe analysis of temperature-dependent models in Annonaceae lineages provides strong support for the significant influence of global temperature on net diversification and accumulation of species diversity. The pattern of lineage accumulation in the initial radiation is better aligned with the “museum model,” followed by later accumulation consistent with the “recent cradle model” from the late Oligocene to the present. The increase in the diversification rate of the family (around 25 Ma) lags behind the accumulation of niche divergences (around 15 Ma). Biogeographic events are related to only two of the five diversification rate shifts detected. While no direct relationship to shifts in the diversification rate was uncovered, shifts in niche evolution appear to be associated with increasingly seasonal environments.Main ConclusionsGlobal temperature plays a crucial role in driving recent rapid diversification in the Annonaceae. Our study challenges the prevailing assumption of the “museum model” alone and proposes instead a transition from the “museum model” to the “recent cradle model” during the diversification history of the family. However, our findings do not support the direct correlation of any particular climatic niche shifts or historical biogeographical events with shifts in diversification rate. Instead, Annonaceae diversification can lead to later niche divergence as a result of increasing interspecific competition arising from species accumulation. The evolutionary direction of niche shifts furthermore provides insight into the future expansion of Annonaceae into temperate regions. Our results highlight the complexity of the diversification process in taxa with long evolutionary histories, indicating that identifying isolated driving factors is simplistic and inadequate for explaining the observed patterns. Further comprehensive analyses of range evolution are necessary to delve deeper into the interplay among key opportunities, key innovation, and species diversification.
Trithoraxregulates long-term memory inDrosophilathrough epigenetic maintenance of mushroom body metabolic identity and translation capacity
Authors: Raun Nicholas , Jones Spencer G , Kerr Olivia , Keung Crystal , Ibrahim Veyan , Williams MacKayla , Top Deniz , Kramer Jamie M 
Published: August 2023

AbstractThe role of epigenetics and chromatin in the maintenance of postmitotic neuronal cell identities is not well understood. Here, we show that the histone methyltransferase trithorax (trx) is required in postmitotic memory neurons of theDrosophilamushroom body (MB) to enable their capacity for long-term memory (LTM), but not short-term memory (STM). Using MB-specific RNA-, ChIP-, and ATAC-sequencing, we find that trx maintains expression of several non-canonical MB-enriched transcripts, including the orphan nuclear receptorHr51, and the metabolic enzymelactate dehydrogenase. Through these key targets, trx establishes a metabolic state characterized by high lactate levels in MBγ neurons. This metabolic identity supports a high capacity for protein translation, a process that is essential for LTM, but not STM. These data suggest that trx, a classic regulator of cell type specification during development, has an alternative function in maintaining underappreciated aspects of postmitotic neuron identity, such as metabolic state. Our work supports a body of evidence suggesting that a high capacity for energy metabolism is an essential cell identity characteristic for neurons that mediate LTM.
Performing highly parallelized and reproducible GWAS analysis on biobank-scale data
Authors: Schönherr Sebastian , Schachtl-Riess Johanna , Maio Silvia Di , Filosi Michele , Mark Marvin , Lamina Claudia , Fuchsberger Christian , Kronenberg Florian , Forer Lukas 
Published: August 2023

AbstractMotivationGenome-wide association studies (GWAS) in large biobanks are transforming genetic research and enable the detection of novel genotype-phenotype relationships. In the last two decades, over 60,000 genetic associations across thousands of human diseases and traits have been discovered using a GWAS approach. Due to denser genotyping and increasing sample sizes, researchers are increasingly faced with computational challenges when executing GWAS analysis. A reproducible, modular and extensible pipeline with a focus on parallelization is essential to simplify data analysis and to allow researchers to devote their time to other essential tasks such as result interpretation and downstream analysis.ResultsHere we present nf-gwas, a Nextflow pipeline to run biobank-scale GWAS analysis. The pipeline automatically performs numerous pre- and post-processing steps, integrates regression modeling from the REGENIE package and currently supports single-variant, gene-based and interaction testing. nf-gwas also includes an extensive reporting functionality that allows to inspect thousands of phenotypes and navigate interactive Manhattan plots directly in the web browser. The pipeline is extensively tested using the unit-style testing framework nf-test to ensure code maintainability, a crucial requirement in clinical and pharmaceutical settings. Furthermore, we validated the pipeline against published GWAS datasets and benchmarked the pipeline on high-performance computing and cloud infrastructures to provide cost estimations to end users.Availabilitynf-gwas is free available athttps://github.com/genepi/nf-gwas.Contactlukas.forer@i-med.ac.at
ATRX guards against aberrant differentiation in mesenchymal progenitor cells
Authors: Fang Yan , Barrows Douglas , Dabas Yakshi , Carroll Thomas S , Tap William D. , Nacev Benjamin A. 
Published: August 2023

AbstractAlterations in the tumor suppressorATRXare recurrently observed in several cancer types including sarcomas, which are mesenchymal neoplasms. ATRX has multiple epigenetic functions including heterochromatin formation and maintenance and regulation of transcription through modulation of chromatin accessibility. Here, we show in murine mesenchymal progenitor cells (MPCs) thatAtrxdeficiency aberrantly activated mesenchymal differentiation programs. This includes adipogenic pathways where ATRX loss induced expression of adipogenic transcription factors (PparγandCebpα) and enhanced adipogenic differentiation in response to differentiation stimuli. These changes are linked to loss of heterochromatin near mesenchymal lineage genes together with increased chromatin accessibility and gains of active chromatin marks at putative enhancer elements and promoters. Finally, we observed depletion of H3K9me3 at transposable elements, which are derepressed including near mesenchymal genes where they could serve as regulatory elements. Our results demonstrate that ATRX functions to buffer against differentiation in mesenchymal progenitor cells, which has implications for understanding ATRX loss of function in sarcomas.
Fecal microbiomes of laboratory beagles receiving antiparasitic formulations in an experimental setting
Authors: Ottesen Andrea , Kocurek Brandon , Deaver Christine , Chiesa Oscar , Cohen Rachael , Mammel Mark , Reed Elizabeth , McDermott Patrick , Strain Errol , Myers Michael 
Published: August 2023

AbstractHere we describe the fecal microbiome of laboratory beagles in a non-invasive and humane experiment designed to contrast in vivo versus invitro bioequivalence in response to antiparasitic drug administration. The experiment provided a unique opportunity to describe the fecal microbiota of dogs in an experimental setting prior to their adoption. These data are contributed as a resource for the scientific community by the Center for Veterinary Medicine (CVM) of the U.S. Food and Drug Administration (FDA).
SHRIMP: Genetically Encoded mScarlet-derived Red Fluorescent Hydrogen Peroxide Sensor with High Brightness and Minimal Photoactivation
Authors: Pang Yu , Zhang Yiyu , Zhang Jing , Li Zefan , He Yi , Wang Yong , Oberholzer Jose , Ai Hui-wang 
Published: August 2023

AbstractRed fluorescent protein (RFP) derived indicators are popular due to advantages such as increased imaging depth and reduced autofluorescence and cytotoxicity. However, most RFP-based indicators have low brightness and are susceptible to blue-light-induced photoactivation. In this study, we aimed to overcome the limitations of existing red fluorescent indicators. We utilized mScarlet-I, a highly bright and robust monomeric RFP, to develop a circularly permuted variant called cpmScarlet. We further engineered cpmScarlet into a novel red fluorescent indicator specifically for hydrogen peroxide (H2O2), a crucial reactive oxygen species (ROS) involved in redox signaling and oxidative stress. The resultant indicator, SHRIMP (mScarlet-derived H2O2Redox Indicator with Minimal Photoactivation), exhibited excitation and emission peaks at ∼570 and 595 nm, respectively, and demonstrated a maximum five-fold fluorescence turn-off response to H2O2. Importantly, SHRIMP was not susceptible to blue-light-induced photoactivation and showed high brightness both in its purified protein form and when expressed in mammalian cells. We successfully employed SHRIMP to visualize H2O2dynamics in mammalian cells with exogenously added H2O2and in activated macrophages. Additionally, we demonstrated its utility for multiparameter imaging by co-expressing SHRIMP with GCaMP6m, a green fluorescent calcium indicator, enabling simultaneous monitoring of H2O2and calcium dynamics in mammalian cells in response to thapsigargin (TG) and epidermal growth factor (EGF) stimulation. Furthermore, we expressed SHRIMP in isolated primary mouse islet tissue, and SHRIMP exhibited excellent brightness and capability for effective detection of H2O2production during streptozotocin (STZ)-induced β-cell damage. This study successfully transformed mScarlet-I, a bright and robust monomeric RFP, into a circularly permuted variant (cpmScarlet) and developed the first cpmScarlet-based genetically encoded fluorescent indicator called SHRIMP. SHRIMP exhibits high brightness and insensitivity to photoactivation and is a valuable tool for real-time monitoring of H2O2dynamics in various biological systems. Further research may yield an expanded family of cpmScarlet-based red fluorescent indicators with enhanced photophysical properties.
DHA shortage causes the early degeneration of photoreceptors and RPE in mice with peroxisomal β-oxidation deficiency
Authors: Swinkels Daniëlle , Kocherlakota Sai , Das Yannick , Dane Adriaan D. , Wever Eric J.M. , Vaz Frédéric M. , Bazan Nicolas G. , Van Veldhoven Paul P. , Baes Myriam 
Published: August 2023

AbstractPurposePatients deficient in peroxisomal β-oxidation, which is essential for the synthesis of docosahexaenoic acid (DHA, C22:6n-3) and breakdown of very long-chain polyunsaturated fatty acids (VLC-PUFAs), both important components of photoreceptor outer segments, present with retinopathy. The representative mouse model lacking the central enzyme of this pathway, multifunctional protein 2 (Mfp2−/−), also develops early onset retinal decay and cell-autonomous retinal pigment epithelium (RPE) degeneration, accompanied by reduced plasma and retinal DHA levels. In this study, we investigated whether DHA supplementation can rescue the retinal degeneration ofMfp2−/−mice.MethodsMfp2+/−breeding pairs and their offspring were fed a 0.12% DHA or control diet during gestation, lactation and until sacrifice. Offspring were analysed for retinal function via electroretinograms, for lipid composition of neural retina and plasma with lipidome analysis and gas chromatography respectively, and histologically using retinal sections and RPE flatmounts at the age of 4, 8 and 16 weeks.ResultsDHA supplementation toMfp2−/−mice restored retinal DHA levels and prevented photoreceptor shortening, impaired functioning and death until 8 weeks. In addition, rescue of retinal DHA levels temporarily improved the ability of the RPE to phagocytose outer segments and delayed the RPE dedifferentiation. However, despite the initial rescue of retinal integrity, DHA supplementation could not prevent retinal degeneration at 16 weeks.ConclusionsWe reveal that the shortage of systemic supply of DHA is pivotal for the early retinal degeneration inMfp2−/−mice. Furthermore, we unveil that adequate retinal DHA levels are essential for both photoreceptor and RPE homeostasis.
Novel roles for the LRRC56 protein, an IFT cargo protein, in docking of dynein arms inTrypanosoma brucei
Authors: Bonnefoy Serge , Alves Aline Araujo , Bertiaux Eloïse , Bastin Philippe 
Published: August 2023

AbstractOuter dynein arms (ODAs) are responsible for ciliary beating in eukaryotes. They are assembled in the cytoplasm and shipped by intraflagellar transport (IFT) before attachment to microtubule doublets via the docking complex. The LRRC56 protein has been proposed to contribute to ODAs maturation. Mutations or deletion of theLRRC56gene lead to reduced ciliary motility in all species investigated so far, but with variable impact on dynein arm presence. Here, we investigated the role of LRRC56 in the protistTrypanosoma brucei,where its absence results in distal loss of ODAs, mostly in growing flagella. We show that LRRC56 is a transient cargo of IFT trains during flagellum construction and surprisingly, is required for efficient attachment of a subset of docking complex proteins present in the distal portion of the organelle. This relation is interdependent since the knockdown of the distal docking complex prevents LRRC56’s association with the flagellum. Intriguingly,lrrc56-/-cells display shorter flagella whose maturation is delayed. Inhibition of cell division compensates for the distal ODAs absence thanks to the redistribution of the proximal docking complex, restoring ODAs attachment but not the flagellum length phenotype. This work reveals an unexpected connection between LRRC56 and the docking complex.
Erythroid differentiation dependent interaction of VPS13A with XK at the plasma membrane of K562 cells
Authors: Amos Chase , Xu Peng , De Camilli Pietro 
Published: August 2023

AbstractMutations of the bridge-like lipid transport protein VPS13A and of the lipid scramblase XK result in Chorea Acanthocytosis (ChAc) and McLeod syndrome (MLS) respectively, two similar conditions involving neurodegeneration and deformed erythrocytes (acanthocytes). VPS13A binds XK, suggesting a model in which VPS13A forms a lipid transport bridge between the ER and the plasma membrane (PM) where XK resides. However, studies of VPS13A in HeLa and COS7 cells showed that this protein localizes primarily at contacts of the ER with mitochondria. Overexpression of XK in these cells redistributed VPS13A to the biosynthetic XK pool in the ER but not to PM localized XK. Colocalization of VPS13A with XK at the PM was only observed if overexpressed XK harbored mutations that disengage its VPS13A binding site from an intramolecular interaction. As the acanthocytosis phenotype of ChAc and MLS suggests a role of the two proteins in cells of the erythroid lineage, we explored their localization in K562 cells, which differentiate into erythroblasts upon hemin addition. When tagged VPS13A was overexpressed in hemin treated K562 cells, robust formation of ER-PM contacts positive for VPS13A were observed and their formation was abolished in XK KO cells. ER-PM contacts positive for VPS13A were seldomly observed in undifferentiated K562 cells, in spite of the presence of XK in these cells at concentrations similar to those observed after differentiation. These findings reveal that the interaction of VPS13A with XK at ER-PM contacts requires a permissive state which depends upon cell type and/or functional state of the cell.
CrWRKY42 positively regulates chlorophyll degradation and carotenoid biosynthesis in citrus
Authors: Chen Hongyan , Ji Huiyu , Huang Wenkai , Zhang Zhehui , Zhu Kaijie , Zhu Shiping , Chai Lijun , Ye Junli , Deng Xiuxin 
Published: August 2023

AbstractChlorophyll degradation and carotenoid biosynthesis, which occur almost simultaneously during fruit ripening, are essential for coloration and nutritional value of fruits. However, the synergistic regulation of these two processes at transcriptional level remains largely unknown. Here, we identified a novel WRKY transcription factor CrWRKY42 from the transcriptome data of the yellowish bud mutant ‘Jinlegan’ tangor (MT) and its wild type ‘Shiranuhi’ tangor (WT), which was involved in the transcriptional regulation of both chlorophyll degradation and carotenoid biosynthesis pathways. CrWRKY42 activated the expression ofβ-carotene hydroxylase 1(CrBCH1) by directly binding to its promoter. Overexpression and interference ofCrWRKY42in citrus calli demonstrated thatCrWRKY42promoted carotenoid accumulation by inducing the expression of multiple carotenoid biosynthetic genes. Further assays confirmed that CrWRKY42 also directly bound to and activated the promoters of the genes involved in the carotenoid biosynthesis, includingphytoene desaturase(CrPDS) andlycopene β-cyclase 2(CrLCYB2). In addition, CrWRKY42 could also bind to the promoter ofSTAY-GREEN(CrSGR) and activated its expression, thus promoting chlorophyll degradation. Overexpression and silencing ofCrWRKY42in citrus fruits indicated that CrWRKY42 positively regulated chlorophyll degradation and carotenoid biosynthesis by synergistically activating the expressions of genes involved in both pathways. In conclusion, our data revealed that CrWRKY42 acted as a positive regulator of chlorophyll degradation and carotenoid biosynthesis to alter the conversion of citrus fruit color. Our findings provide insight into the complex transcriptional regulation of chlorophyll and carotenoid metabolism during fruit ripening.One Sentence SummaryThe CrWRKY42 transcription factor coordinates chlorophyll degradation and carotenoid biosynthesis by directly regulating genes involved in these pathways to alter the conversion of citrus fruit color.