bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD4 Co-Receptor Regulates Sex-Specific NK Cell Responses to AcuteToxoplasma gondiiInfection
Authors: Roy Tathagato , Bernstein Leah , Keplinger Hunter K. , Fisk Kaatje , Ng Sai K. , Denton Stephen L. , Gigley Jason P. 
Published: December 2024

AbstractImmunity toToxoplasma gondii(T. gondii) is sexually dimorphic in humans and mice, with females having higher morbidity and mortality during immune dysfunction and HIV-AIDS. The mechanisms underlying these sex differences are unclear. We investigated how a lack of CD4+ T cells (CD4 co-receptor KO) impactedT. gondiisurvival in mice. Female CD4 co-receptor KO mice succumbed toT. gondiimuch faster than males. To dissect why female CD4 co-receptor KO mice died faster, we tested their NK cell responses to acuteT. gondiiinfection compared to males. Although in wild-type (WT) animals, both sexes had similar increases in total NK cells and IFNγ + NK cells, infected CD4 co-receptor KO female mice had 50% fewer IFNγ+ NK cells than infected WT female mice. Infected male CD4 co-receptor KO had a similar increase in IFNγ+ NK cells as WT male mice. Since CD4 co-receptor deficient mice still have functional helper T cells that are CD4−, we next tested survival and NK cell responses in female and male MHCII deficient (MHCIIKO) animals, which completely lack helper CD4+T cells. Surprisingly, survival, NK cell numbers, and IFNγ+ NK cells were not significantly different between WT or MHCIIKO female and male mice. These results suggest CD4 co-receptor expression is required for survival via optimal NK cell responses during acuteT. gondiiinfection only in female mice and not in male mice. Our findings reveal an unappreciated sexual dimorphic role of CD4 co-receptor expression in regulating NK cell responses to acuteT. gondiiinfection.
Combination of live attenuated and adenovirus-based vaccines completely protects interferon gamma (IFNγ) knockout mice against pneumonic plague
Authors: Hendrix Emily K. , Sha Jian , Kilgore Paul B. , Neil Blake H. , Chopra Ashok K. 
Published: December 2024

AbstractTwo live attenuated vaccines (LAVs), LMA and LMP, were evaluated alone or in combination with a trivalent adenoviral vector-based vaccine (Ad5-YFV) for their efficacy and immune responses in wild type (WT) and interferon gamma (IFNγ) knockout (KO) mice in a C57BL/6 background. While LMA and LMP are triple deletion mutants ofYersinia pestisCO92 strain, Ad5-YFV incorporates three protective plague immunogens. An impressive 80-100% protection was observed in all vaccinated animals against highly lethal intranasal challenge doses of parentalY. pestisCO92. All vaccinated mice generated robust humoral and cellular immune responses. The immunized WT mice showed overall better antibody responses in both serum and bronchoalveolar lavage fluid with much higher percentages of polyfunctional T cell populations. On the other hand, vaccinated IFNγ KO mice displayed better B cell activity in germinal centers with higher percentages of activated antigen specific T cells and memory T cells. In addition, depletion of IFNγ and tumor necrosis factor alpha (TNFα) from immunized WT mice prior to and during infection did not reduce protection against pulmonaryY. pestisCO92 challenge. These data demonstrated a dispensable nature of IFNγ in mediating protection by the aforementioned vaccines. This is the first detailed immunogenicity study of two plague LAVs administered either alone or in combination with an Ad5-YFV vaccine in a prime-boost immunization strategy in IFNγ KO mice. Further, by combining advantages of live-attenuated and adenovirus-based vaccines, augmentation of generalized immune responses were observed which could be beneficial in providing long-lasting immunity in the host.
Default mode and motor networks facilitate early learning of implicit motor sequences: a multimodal MR spectroscopy and fMRI study
Authors: Hendrikse Joshua , Brooks Emily , Wallis Sarah , Curtin Dylan , Rogasch Nigel C. , Yücel Murat , Biabani Mana , Stagg Charlotte J , Bellgrove Mark , McIntyre Richard , Suo Chao , Coxon James 
Published: December 2024

AbstractLearning new motor skills is a fundamental process that involves the sequencing of actions. Skill develops with practice and time, and manifests as performance that is fast and accurate. Although we know that learning can occur through animplicitprocess in the absence of conscious awareness, and across multiple temporal scales, the precise neural mechanisms mediating implicit motor sequence learning remain poorly understood. Similarly, the capacity for interventions with known influence on learning and memory, such as cardiovascular exercise, to facilitate implicit learning is yet to be clearly established. Here, we investigated the neuroplasticity of implicit motor sequence learning and the effect of acute exercise priming. Healthy adults (39.5% female) aged 22.55 ± 2.69 years were allocated to either a high-intensity exercise (HIIT) group (n = 16) or to a very low-intensity control group (n = 17). Following exercise, participants performed a serial reaction time task. MR spectroscopy estimates of sensorimotor gamma-aminobutyric acid (GABA) were acquired before and after exercise, and during task performance, and resting-state fMRI was acquired at the end of the protocol. We show that early stages of learning are linked to default mode network connectivity, while the overall degree of learning following sustained practice is associated with motor network connectivity. Sensorimotor GABA concentration was linked to the early stages of learning, and GABA concentration was modulated following HIIT, although the two were not related. Overall, via integration of multiple neuroimaging modalities we demonstrate that interactions between hippocampal and motor networks underlieimplicitmotor sequence learning.Key points summary-Motor learning occurs across different temporal scales and can arise implicitly in the absence of conscious awareness.-Explicitmotor learning is linked to the brain’s primary inhibitory neurotransmitter, GABA, and interactions across motor and hippocampal networks.-Whether these same neural mechanisms are implicated inimplicitlearning is unclear. Similarly, the capacity to influence learning via priming with cardiovascular exercise is yet to be clearly established.-We show that early implicit learning is underpinned by default mode network connectivity and sensorimotor GABA concentration, while total learning following sustained practice is linked to motor network connectivity. We also found that HIIT exercise elevated sensorimotor GABA concentration, but not the magnitude of implicit learning.-Overall, our results highlight shared involvement of default mode and motor networks in implicit motor sequence learning.
SPE-CZE-MS quantifies zeptomole concentrations of phosphorylated peptides
Authors: Serrano Lia R. , Mellors J. Scott , Thompson J. Will , Lancaster Noah M. , Robinson Margaret Lea , Overmyer Katherine A. , Quarmby Scott T. , Coon Joshua J. 
Published: December 2024

ABSTRACTCapillary zone electrophoresis (CZE) is gaining attention in the field of single-cell proteomics for its ultra-low-flow and high-resolution separation abilities. Even more sample-limited yet rich in biological information are phosphoproteomics experiments, as the phosphoproteome composes only a fraction of the whole cellular proteome. Rapid analysis, high sensitivity, and maximization of sample utilization are paramount for single-cell analysis. Some challenges of coupling CZE analysis with mass spectrometry analysis (MS) of complex mixtures include 1. sensitivity due to volume loading limitations of CZE and 2. incompatibility of MS duty cycles with electrophoretic timescales. Here, we address these two challenges as applied to single-cell equivalent phosphoproteomics experiments by interfacing a microchip-based CZE device integrated with a solid-phase-extraction (SPE) bed with the Orbitrap Astral mass spectrometer. Using 225 phosphorylated peptide standards and phosphorylated peptide-enriched mouse brain tissue, we investigate microchip-based SPE-CZE functionality, quantitative performance, and complementarity to nano-LC-MS (nLC-MS) analysis. We highlight unique SPE-CZE separation mechanisms that can empower fit-for-purpose applications in single-cell-equivalent phosphoproteomics.
Plant-induced transcriptional plasticity diverges between generalist and specialist herbivores
Authors: Wu Jun , Lin Zhimou , Li Guomeng , Yu Wenyuan , Zhang Yangzhi , Kou Yishuo , Peng Pengshuai , He Tingfen , Wang Yu , Zhan Shuai , Simon Jean-Christophe , Hogenhout Saskia A. , Chen Yazhou 
Published: December 2024

AbstractMost herbivores are specialized on particular host plants but some are generalists that can exploit distinct hosts. Generalists may have evolved adaptive transcriptional plasticity to cope with the defenses of the different hosts. However, the fundamental differences in plant-induced transcriptional plasticity between generalists and specialists remain poorly understood. Here, we investigated transcriptional plasticity of the generalist aphidMyzus persicaeand two specialist aphids,Brevicoryne brassicaeandRhopalosiphum padi, by transferring them betweenBrassica napus(a host forB. brassicaebut not forR. padi) andZea mays(a host forR. padibut not forB. brassicae), both suitable hosts forM. persicae. Generalist and specialist aphids exhibited transcriptional plasticity coordinately in response to different plant species, but their gene expression patterns often diverged. Generalists suppressed plant-defense salicylic acid (SA) signaling in the host plants, while specialist aphids provoked it in nonhost plants. SA signaling had limited effects on gene expression in the generalist aphids, but significantly shaped transcriptional responses of the specialists. These findings underscore the fundamental differences in plant-induced transcriptional plasticity between generalists and specialists and highlight the critical role of plasticity directionality in insect adaptation.Significance statementMost insects specialize in feeding on just a few specific plants, but some generalists can thrive on many plant species. This study compares the gene expression of green peach aphidMyzus persicae, a generalist, with two specialist aphids in response to different types of plants. Generalists showed adaptive plasticity in their gene responses, while specialists often exhibited opposite gene expression changes. Interestingly, generalists appeared to suppress plant defense signals like salicylic acid, while specialists tended to trigger them. These findings highlight how gene expression plasticity enables generalists to adapt and survive, providing new insights into the evolution of insect-plant interactions.
Single-cell mass spectrometry reveals heterogeneous triterpenic acid accumulation in apple callus-derived cells
Authors: Laezza Carmen , Heinicke Sarah , Wurlitzer Jens , D’Amelia Vincenzo , Caputi Lorenzo , Rigano Maria M. , O’Connor Sarah E. 
Published: December 2024

AbstractThe use of plant cell cultures for large scale production of natural compounds, although promising, has been hindered by their genetic instability and heterogeneity. Here, we show how single cell mass spectrometry can be used to characterize the natural product profile of a callus culture at a highly resolved level. We identify and quantify triterpenic acids in a population of callus cells derived from Annurca apple (Malus pumila Miller cv Annurca) leaf. The analysis demonstrated that a high degree of metabolic heterogeneity exists in the cell population, with the levels of detected metabolites varying significantly across the callus cells. This metabolic heterogeneity was underpinned by variable expression levels of key biosynthetic genes in the single cells. The application of an abiotic stress, near ultraviolet radiation (NUV), to the callus culture resulted in increased levels of triterpenic acids. Single cell mass spectrometry analysis revealed that after treatment, a larger percentage of callus cells produced detectable amounts of these metabolites, ultimately resulting in a more homogeneous production of the metabolites. Furthermore, it showed that intracellular concentrations of ursolic acid derivatives can reach more than 100 mM. Single cell mass spectrometry analyses provide a starting foundation for understanding the molecular mechanisms responsible for metabolic heterogeneity in plant cell cultures, which could in turn facilitate efforts to improve these cell cultures for commercial purposes.
LSD1 demethylase inhibition prevents cardiac fibrosis in both ischemic and congenital diseases in mice and pig models
Authors: Arnaud Denis , Lambert Virginie , Benoîst David , Martin Amandine , Gauthier Jean , Pucéat Michel 
Published: December 2024

ABSTRACTFibrosis is part of a clinical burden in cardiovascular diseases. The pathological process has been the subject of intensive research with still mitigated therapeutic options. Recently chromatin modifiers have turned out to be potential drugs to modulate fibrosis. Here, in order to address the question of pharmacological inhibition of fibrosis, we used both a mouse model of myocardial infarction with left ventricular fibrosis and a more clinically relevant pig model of right ventricular failure featuring interstitial fibrosis. Treatment of these diseased animal models with an inhibitor of the Lysine Demethylase 1 (LSD1) significantly prevented both left and right ventricular failure in both the mouse and the pig, respectively. This was revealed by a significant recovery of left ventricular function post-myocardial infarction in the mouse and a limitation of remodeling of the pig right ventricle, thus preserving its function. Fibrosis was significantly decreased in both mouse and pig hearts, which likely account for improvement in ventricular function. We thus provide evidence of the beneficial effect of LSD1 inhibitors in cardiac fibrosis and of the use of such drugs to preserve ventricular function in both ischemic and congenital heart diseases.NEW & NOTEWORTHYDrugs to prevent cardiac fibrosis has been the subject of intensive research with limited outcomes. This work inspired by oncology, provides evidence that an epigenetic modifier which targets the process of epithelial-to-mesenchymal transition turns out to be an efficient inhibitor of fibrosis for both ischemic and non-ischemic myocardial diseases.
Two-fold Red Excess (TREx): A simple and novel digital color index that enables non-invasive real-time health assessment of green-leaved as well as anthocyanin-rich crops
Authors: Agarwal Avinash , de Jesus Colwell Filipe , Galvis Viviana Andrea Correa , Hill Tom R. , Boonham Neil , Prashar Ankush 
Published: December 2024

AbstractBackgroundDigital color indices provide a reliable means for assessing plant health status by enabling real-time estimation of chlorophyll (Chl) content, and are thus adopted widely for crop monitoring. However, as all prevalent leaf color indices used for this purpose have been developed using green-leaved plants, they do not perform reliably for anthocyanin (Anth)-rich red-leaved varieties. Hence, the present study investigates digital color indices for six types of leafy vegetables with different levels of Anth to identify congruent trends that could be implemented universally for non-invasive crop monitoring irrespective of species and leaf Anth content. For this, datasets from three digital color spaces, viz., RGB (Red, Green, Blue), HSV (Hue, Saturation, Value), andL*a*b*(Lightness, Redness-greenness, Yellowness-blueness), as well as various derived plant color indices were compared with SPAD Chl meter readings and Anth/Chl ratio ofn= 320 leaf samples.ResultsWhile most digital color features and indices presented abrupt shifts between Anth-rich and green-leaved samples, the newly-developed color index Two-fold Red Excess (TREx) as well as the color feature R showed very strong correlation with SPAD readings (R2> 0.84), and did not exhibit any deviation due to leaf Anth content. Moreover, both parameters could predict SPAD values reliably (R2> 0.75). Further, logarithmic decline of G/R and Augmented Green-Red Index (AGRI) with increasing Anth/Chl ratio (R2> 0.82) revealed that relative Anth content affected digital color indices markedly by shifting the R:G balance until the Anth/Chl ratio reached a certain threshold.ConclusionThe present study provides the first in-depth assessment of variations in RGB-based digital color indices due to high leaf Anth contents, and uses the data for Anth-rich as well as green-leaved crops belonging to different species to develop a universal digital color index TREx that can be used as a reliable alternative to handheld Chl meters for rapid high-throughput monitoring of green-leaved as well as red-leaved crop varieties.
Computational prediction of cyclotides fromViola odorataas potential inhibitors against the neuraminidase ofStreptococcus pneumoniae
Authors: Sankar Sreejanani , Sahoo Ajaya Kumar , Baskaran Shanmuga Priya , Babu R. , Srivastava Smita , Samal Areejit 
Published: December 2024

AbstractCyclotides are naturally occurring peptides characterized by a cyclic cystine knot, which provides them with exceptional structural stability. In addition to their stability, cyclotides exhibit diverse therapeutic activities including antimicrobial, antiviral and antitumor activities, making them promising candidates in drug discovery. However, computational studies aimed at identifying cyclotide-based inhibitors for infectious diseases remain limited. To this end, we conducted a virtual screening of cyclotides from an Indian medicinal plantViola odoratato identify potential inhibitors against a bacterial pathogen causing respiratory infections. We compiled a library of 93 cyclotides by retrieving their structures from public domain or predicting them using the AlphaFold server. We then docked these cyclotides against the neuraminidase protein ofStreptococcus pneumoniaeand analyzed the interacting residues and binding energies to identify top five potential inhibitors namely, kalata S, kalata B1, cycloviolacin O15, vodo L12, and cycloviolacin O36. Thereafter, we performed molecular dynamics simulations of the protein-cyclotide complexes, and observed that the cyclotides remained stable within the complex. Altogether, this study is the first computational effort to identify potential cyclotide inhibitors against bacterial pathogen causing respiratory diseases, which can be further pursued for experimental validation to develop novel therapeutic agents for respiratory infections.
Dominant negativeADA2mutations cause ADA2 deficiency in heterozygous carriers
Authors: Wouters Marjon , Ehlers Lisa , Van Eynde Wout , Kars Meltem Ece , Delafontaine Selket , Kienapfel Verena , Dzhus Mariia , Schrijvers Rik , De Haes Petra , Struyf Sofie , Bucciol Giorgia , Itan Yuval , Bolze Alexandre , Voet Arnout , Hombrouck Anneleen , Moens Leen , Ogunjimi Benson , Meyts Isabelle 
Published: December 2024

AbstractHuman ADA2 deficiency (DADA2) is an inborn error of immunity with a broad clinical phenotype which encompasses vasculopathy including livedo racemosa and lacunar strokes, as well as hemato-immunological features. Diagnosis is based on the combination of decreased serum ADA2 activity and the identification of biallelic deleterious alleles in theADA2gene. DADA2 carriers harbor a single pathogenic variant inADA2and are mostly considered healthy and asymptomatic. However, some DADA2 carriers present a phenotype compatible with DADA2. Here, we report ten patients from seven kindreds presenting with a phenotype indicative of DADA2, in whom only a single pathogenic variant (p.G47R, p.G47V, p.R169Q, p.H424N) was identified. To test whether being heterozygote for specific variants could explain the patients’ phenotype, we investigated the effect of the ADA2 missense variants p.G47A, p.G47R, p.G47V, p.G47W, p.R169Q, p.E328K, p.T360A, p.N370K, p.H424N and p.Y453C on ADA2 protein expression, secretion and enzymatic activity. Functional studies indicate that they exert a dominant negative effect on ADA2 enzymatic activity, dimerization and/or secretion. At the molecular level, heterozygosity for these variants mimics what is observed in DADA2. We conclude that humans with heterozygous dominant negative missense variants in ADA2 are at risk of DADA2.Graphical abstract
Intestinal somatic mutations in inflammatory bowel disease patients are enriched in very early onset IBD and primary immunodeficiency genes
Authors: Hidding Iwan J. , Vich Vila Arnau , Hu Shixian , Bourgonje Arno R. , van Gijn Marielle , Maassen W.T.K. , van der Vries Gerben B. , Ruigrok Renate A.A.A. , Andreu-Sánchez Sergio , Jansen Bernadien H. , van Dullemen Hendrik M. , Visschedijk Marijn C. , Dijkstra Gerard , Swertz Morris A. , van Diemen Cleo C. , Festen Eleonora A.M. , Weersma Rinse K. , Imhann Floris 
Published: December 2024

AbstractThe genetic predisposition of Inflammatory bowel disease (IBD) in the germline is well-established, while the potential role of somatic mutations in IBD remains underexplored. We aim to identify somatic mutations in intestinal mucosa and study their potential role in IBD pathogenesis. We identified somatic mutations using 538 intestinal biopsies and 268 blood samples from 268 IBD patients and 51 intestinal biopsies from 19 non-IBD controls. Mutations were called from RNA-seq data and whole exome sequencing data using Mutect2 software. Pathogenicity of mutations was predicted using the Variant Interpretation Pipeline. Mutation frequency and patterns were compared between IBD and controls, and within IBD-subgroups, considering both inflammation status and tissue of origin. IBD-affected tissue exhibited a significantly higher burden of somatic mutations compared to controls (p=0.02), with a striking enrichment for predicted likely pathogenic or pathogenic (pLP-P) mutations (p=2.07e-09). Notably, within IBD biopsies, pLP-P mutations were enriched in very early onset-IBD (VEO-IBD) genes (p≤2.2e-16) and primary immune deficiency (PID) genes (p≤2.2e-16), showing a 5.5-fold increase compared to non-IBD. Inflamed tissue showed an increase in mutations in PID and IBD-GWAS associated genes. Additionally, we identified pathogenic mutations in many IBD genes, such as the stop-gained mutation (c.517C>T) inHPS1, and many pLP-P mutations across the JAK-STAT pathway. Our analysis reveals widespread accumulation of pLP-P somatic mutations in IBD-affected tissue compared to non-IBD controls, with significant enrichment in genes that cause monogenic VEO-IBD. These findings suggest that somatic mutations can contribute to the initiation and perpetuation of inflammation in IBD.