bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epigenetic changes and serotype-specific interferon-responses of lung epithelial cells in late post-influenza pneumococcal pneumonia
Authors: Boehme Julia D , Jeron Andreas , Schultz Kristin , Melcher Lars , Schott Katharina , Gelmez Elif , Kröger Andrea , Stegemann-Koniszewski Sabine , Bruder Dunja 
Published: June 2023

AbstractPneumococcal infection following influenza A virus (IAV) pneumonia is a synergistic complication with high mortality. IAV modulates host antibacterial responses and invasiveness of pneumococcal serotypes and is an important pathogenic factor2. Yet, serotype-specifc immediate-early responses of the IAV-perturbed alveolar epithelium have not been adressed. We analyzed gene transcription in alveolar type II epithelial cells (AECII) from mice infected with IAV and/or one of threeS. pneumoniae(S.pn.) serotypes of varying invasiveness (4 > 7F > 19F). IAV, 14 days post infection, rendered the lung susceptible to invasiveS.pn.infection with serotype 4 and the mildly invasive 7F but not 19F. Only 7F secondary infection induced exacerbated cytokine/chemokine responses. IAV/7F infection induced superior protein expression of type I and II interferons, exceeding that in IAV/serotype 4 infection. Inference of a scale-free-like ARACNE gene co-expression network revealed interferon-response network modules. Network-mapping unfoldedS.pn.serotype-specific transcriptional network responses/usage. SecondaryS.pn.infection abrogated the IAV-induced pneumocyte proliferative configuration and IAV infection rendered the transcriptional response to 7F comparable to that of serotype 4. This related to network genes correlating with the expression of two master regulators of interferon responses:Irf7andStat1. Epigenetic ATAC-seq analysis of AECII in resolved IAV infection identified enhanced expression of ARACNE network genesHist1h2bf,Igtp,Mki67,Rasl10b,H2-Q6andH2-Q7to be associated with increased chromatin accessability at promoter regions. We show that AECII retain a sustained IAV-associated transcriptional configuration with epigenetic involvement that serotype-specifically affects proliferation and intensifies the AECII transcriptional response, mainly to interferons, inS.pn.infection.
Profiling ofZea maysL. proteome at early stages of compatible interactions withMeloidogyne arenariaindicates changes in signaling, oxidative stress responses, and S-adenosylmethionine biosynthesis
Authors: Arnika Przybylska , Barbara Wrzesińska-Krupa , Aleksandra Obrępalska-Stęplowska 
Published: June 2023

AbstractRoot-knot nematodes (RKNs) are distributed worldwide group of plant parasitic nematodes, with a very wide host range, including mono- and dicotyledonous hosts.Meloidogyne arenariais, next toM. hapla, M. incognita, andM. javanica, one of the most economically important species from this genus. RKNs during parasitism hijack host metabolism to establish giant cells and to break down plant defense mechanisms. To date, studies on the interaction of RKN with maize (Zea maysL.) have been underrepresented, and a description of the early response to attack by these nematodes, vital to understanding the process, is scarce in the literature. We hypothesize that in the early stage of maize response toM. arenariainfection, significant changes in the accumulation level of proteins mainly related to plant defense response, plant cell wall modifications, and phytohormone biosynthesis can be observed.In this study, a mass spectrometry approach and a label-free quantification technique were used to assess the qualitative and quantitative composition of proteins changes in the proteome of maize roots afterM. arenariainfection. We used a susceptible maize variety and carried out analyses of plant proteome at two time points: 24 hours after nematode inoculation and 3 days after inoculation. Statistical analyses of significant differences between protein intensities were performed for the datasets obtained from healthy andM. arenaria-infected plants, and differentially expressed proteins (DEPs), with both lower and higher abundance were determined. DEPs were mapped, classified to the gene ontology (GO) terms into functional categories, and assigned to appropriate Kyoto Encyclopedia of Genes and Genomes (KEGG) processes and pathways.As a result, a total of 3,743 proteins were identified with 124 DEPs at 24 hpi and 66 at 3 dpi, and significant changes in the accumulation of proteins associated with processes such as cell wall modifications, reaction to stress, as well as processes and pathways related to phenylpropanoid biosynthesis and metabolism, signal transduction and to S-adenosylmethionine biosynthesis.
Non-coding mutations at enhancer clusters contribute to pancreatic ductal adenocarcinoma
Authors: Patel Minal B. , Maniati Eleni , Atanur Santosh S. , Pal Debosree , Rio-Machin Ana , Heward James , Kocher Hemant M. , Fitzgibbon Jude , Pradeepa Madapura M. , Wang Jun 
Published: June 2023

AbstractNon-coding mutations (NCMs) that perturb the function ofcis-regulatory elements (CRE, enhancers) contribute to cancer. Due to the vast search space, mutation abundance and indirect activity of non-coding sequences, it is challenging to identify which somatic NCMs are contributing to tumour development and progression. Here, we focus our investigation on the somatic NCMs that are enriched at enhancers from 659 pancreatic ductal adenocarcinoma (PDAC) tumours. We identifycis-regulatory NCMs within PDAC-specific enhancers derived from high and low-grade PDAC cell lines and patient derived organoids using two independent computational approaches. Five such CREs enriched for PDAC associated NCMs are also frequently mutated in other common solid tumours. Functional validation using STARR-seq reporter assays enables the prioritisation of 43 NCMs (7.3%) from a pool of 587 NCMs with 6,082 oligos, that significantly alter reporter enhancer activity compared to wild-type sequences. CRISPRi perturbation of an enhancer cluster harbouring NCMs over long non-coding RNA geneMIR100HG, which hosts a microRNA cluster (mir100-let7a-2-125b-1), leads to the downregulation of MIR100HG accompanied by a significant reduction in the TGF-β pathway (known to induceMIR100HG) and other PDAC critical pathways, including KRAS, p53, MTOR and TNF α signalling. Collectively, we have reported herecis-regulatory NCMs in PDAC proximal to many cancer-relevant genes, and our integrated approach paves way to explore CRE-associated NCMs in other human cancer genomes.
The long non-coding RNALINDArestrains cellular collapse following DNA damage inArabidopsis thaliana
Authors: Herbst Josephine , Nagy Solveig Henriette , Vercauteren Ilse , De Veylder Lieven , Kunze Reinhard 
Published: June 2023

SUMMARYThe genomic integrity of every organism is endangered by various intrinsic and extrinsic stresses. To maintain the genomic integrity, a sophisticated DNA damage response (DDR) network is activated rapidly after DNA damage. Notably, the fundamental DDR mechanisms are conserved in eukaryotes. However, knowledge about many regulatory aspects of the plant DDR is still limited. Important, yet little understood, regulatory factors of the DDR are the long non-coding RNAs (lncRNAs). In humans, 13 lncRNAs functioning in DDR have been characterized to date, whereas no such lncRNAs have been characterized in plants yet. By meta-analysis, we identified thelong intergenicnon-coding RNA induced by DNAdamage(LINDA) that responds strongly to various DNA double-strand break-inducing treatments, but not to replication stress induced by mitomycin C. After DNA damage,LINDAis rapidly induced in an ATM- and SOG1-dependent manner. Intriguingly, the transcriptional response ofLINDAto DNA damage is similar to that of its flanking hypothetical protein-encoding gene. Phylogenetic analysis of putative Brassicales and MalvalesLINDAhomologs indicates thatLINDAlncRNAs originate from duplication of a flanking small protein-encoding gene followed by pseudogenization. We demonstrate thatLINDAis not only needed for the regulation of this flanking gene, but also for fine-tuning of the DDR after the occurrence of DNA double-strand breaks. Moreover, Δlindamutant root stem cells are unable to recover from DNA damage, most likely due to hyper-induced cell death.SIGNIFICANT STATEMENTWe unraveled the functional relevance of the first lncRNA within the DNA damage response network ofArabidopsis thaliana.This lncRNA, termedLINDA, is an important part of the DNA damage response network, as it is needed for accurate regulation of cell death and cell cycle progression.
A Glance into the Destiny of Transcriptomic Activity, Embodied by the HOX Genes, in Neonatal and Aging Dermal Cells
Authors: Ko Doyeong , Kim Minji , Nho Youn-Hwa , Lee Dong-Geol , Kang Seunghyun , Han Kyudong , Mun Seyoung , Kim Misun 
Published: June 2023

ABSTRACTSkin is an organ having a crucial role in the protection of muscle, bone, and internal organs and undergoing continuous self-renewal and aged. The growing interest in the prevention of skin aging and rejuvenation has sparked a surge of industrial and research studies focusing on the biological and transcriptional changes that occur during skin development and aging. In this study, we aimed to identify transcriptional differences between two main types of human skin cells: the HDFs and the HEK isolated from 30 neonatal and 30 adults (old) skin. Through differentially expressed gene (DEG) profiling using DEseq2, 604 up-, and 769 down-regulated genes were identified in the old group. The functional classification analysis using Metascape Gene Ontology and Reactome pathway was performed. We report the systematic transcriptomic changes in key biological markers involved in skin formation and maintenance and a unique difference inHOXgene families which are important for developing embryonic formation and regulating numerous biological processes. Among the 39 humanHOXgenes, 10 genes (HOXA10,11,13,HOXB13,HOXC11, andHOXD9-13) were significantly down-regulated, and 25 genesHOXA2-7,HOXB1-9,HOXC4-6and8-9, andHOXD1,3,4and8) were up-regulated, especially in the old HDFs. We have successfully established a correlation betweenHOXgenes and the process of skin aging, thereby proposingHOXgenes as a novel marker for assessing skin aging. Our findings provide compelling evidence supporting the involvement ofHOXgenes in this biological phenomenon such as skin aging.
Expanding the Evo-Devo Toolkit: Generation of 3D mammary tissue from diverse mammals
Authors: Kim Hahyung Y. , Sinha Ishani , Sears Karen E. , Kuperwasser Charlotte , Rauner Gat 
Published: June 2023

ABSTRACTThe divergent events during mammary gland development between species and across evolution are not well studied mainly due to the lack of tractable model systems. In theory, advancements in the field of organoid technology now make it possible to study developmental processes adapted throughout species evolutions to accommodate advantageous phenotypes. However, its application to the mammary gland remains limited to rodents and humans.In the current study, we successfully created next-generation 3D mammary gland organoids from eight eutherian mammals and the first 3D organoid of a marsupial mammary gland (the gray short-tailed opossum), representing a more ancient version of the mammary gland. Using mammary organoids, we identified a role for ROCK protein in regulating branching morphogenesis, a role that manifests differently in human and opossum mammary organoids. This finding demonstrates the utility of 3D organoid model for understanding the evolution and adaptations of signaling pathways.Overall, the establishment of mammary organoids as animal model surrogates is a significant advancement in the field of mammary gland biology and evolution and paves the way for future studies utilizing this model. This achievement highlights the potential of organoid models to expand our understanding of mammary gland biology and evolution and their utility in studying milk production and breast cancer research.
Maltodextrin administration ameliorates brain pathology in a mouse model of mitochondrial disease
Authors: Domínguez-Martínez Adán , Molina-Menor Esther , Blanco-Ramos Marcos , Urpi Andrea , Peretó Juli , Porcar Manuel , Quintana Albert 
Published: June 2023

AbstractMitochondrial dysfunction lead to a wide group of progressive and fatal pathologies known as mitochondrial diseases (MD). One of the most common pediatric representation of MD is Leigh Syndrome, affecting 1/40.000 births. LS is characterized by neurodegeneration in specific brain areas, such as brainstem and basal ganglia, and by respiratory and motor alterations. However, the results obtained from clinical trials based on antioxidant therapies are controversial. Thus, the development novel antioxidant strategy is required to improve the efficacy of current palliative treatments. In this regard, Ndufs4KO mouse model is a suitable model to test new drugs in the field of MD and LS. Therefore, we set to assess the therapeutic potential of oral administration ofMicrococcus luteus, a high-antioxidant content microorganism. Incidentally, we identified that whileM. luteusadministration did not possess any beneficial actions, the cryopreservant maltodextrin (MDX), included in the preparation, ameliorated the phenotype of Ndufs4KO mice. Our results show that MDX treatment at a concentration of 30 g/L increased lifespan and reduced microglial reaction compared to vehicle-treated Ndufs4KO mice. However, no improvement in locomotion nor respiratory function was observed in MDX-treated mice compared to vehicle-treated Ndufs4KO mice. Metataxonomic characterization of intestinal microbiome identified differential profiles in Ndufs4KO mice at the genus level. Furthermore, MDX treatment increased the variability of the abundance ofAkkermansia sp. Thus, this work paves the way for further studies to confirm the therapeutic potential of MDX in mitochondrial disease.
Developing a Toolbox of Antibodies Validated for Array Tomography-Based Imaging of Brain Synapses
Authors: Micheva Kristina D. , Gong Belvin , Collman Forrest , Weinberg Richard J. , Smith Stephen J. , Trimmer James S. , Murray Karl D. 
Published: June 2023

AbstractAntibody-based imaging techniques rely on reagents whose performance may be application-specific. Because commercial antibodies are validated for only a few purposes, users interested in other applications may have to perform extensive in-house antibody testing. Here we present a novel application-specific proxy screening step to efficiently identify candidate antibodies for array tomography (AT), a serial section volume microscopy technique for high-dimensional quantitative analysis of the cellular proteome. To identify antibodies suitable for AT-based analysis of synapses in mammalian brain, we introduce a heterologous cell-based assay that simulates characteristic features of AT, such as chemical fixation and resin embedding that are likely to influence antibody binding. The assay was included into an initial screening strategy to generate monoclonal antibodies that can be used for AT. This approach simplifies the screening of candidate antibodies and has high predictive value for identifying antibodies suitable for AT analyses. In addition, we have created a comprehensive database of AT-validated antibodies with a neuroscience focus and show that these antibodies have a high likelihood of success for postembedding applications in general, including immunogold electron microscopy. The generation of a large and growing toolbox of AT-compatible antibodies will further enhance the value of this imaging technique.Significance StatementArray tomography (AT) is a powerful volume microscopy technique for high-dimensional analysis of complex protein populations in cells and organelles, including synapses. AT involves the use of ultrathin serial sections embedded in resin and subjected to multiple rounds of immunofluorescence antibody (Ab) labeling and imaging. AT relies on antibody-based detection of proteins but because commercial antibodies are typically validated for other applications they often fail for AT. To identify antibodies with high probability of success in AT we developed a novel screening strategy and used this to create a comprehensive database of AT-validated antibodies for neuroscience.
Metabolomic approaches highlight two mechanisms of accelerated grain filling in Mediterranean oat (Avena sativaL.) cultivars during drought
Authors: Girija Aiswarya , Canales Francisco J , Haddadi Bahareh Sadat , Dye Rachel , Corke Fiona , Han Jiwan , Brook Jason , Williams Kevin , Beckmann Manfred , Prats Elena , Doonan John H , Mur Luis A J 
Published: June 2023

AbstractGrain filling in cereals is complex process that determines the final grain yield and quality. Abiotic stresses can have major impact on grain filling. Oats (Avena sativaL.) is sensitive to drought which adversely affect yield and productivity. In this study, we characterised the grain filling responses of two Mediterranean oat cultivars Flega and Patones under severe drought. Grains from the top (older) and bottom (younger) spikelets of primary panicle were larger in size in response to drought, particularly in Patones, suggesting accelerated grain development. The metabolomes of source (sheath, flag leaf) and sink (developing grains) tissues were profiled to describe source-sink partitioning. In Patones, the developing grains showed increased sugars and amino acids which indicate accelerated grain filling. These were associated with elevated α-linolenic acid levels in source tissues but decreased in developing grains under drought. There was also a significant decrease in C18 fatty acids (FA) and jasmonates (JA) derivatives in the developing grains which suggested a role for JA signalling in Patones with drought. Flega showed a different response, with accelerated flowering and enhanced energy metabolism in both source and sink organs. The accumulation of ophthalmic acid in grains of Flega and lower levels of reduced glutathione in source tissues suggested greater oxidative stress than Patones under drought may be driving the grain filling phenotype. This study suggests that oats cultivars can use α-linolenic acid-linked signalling or oxidative events influences accelerated grain filling with drought. These could be important traits in developing oat cultivars that maintain yield in drought-prone environments.HighlightThe impact on drought in one tolerant and one susceptible oat cultivar was assessed at the grain filling stage. The drought tolerant cultivar, Patones, showed accelerated grain development which could be a strategy to escape drought. Metabolite mapping of flag leaves, sheath and grains of Flega suggested that alpha linolenic acid could be regulating the altered sink-source relationships. The drought susceptible cultivar, Metabolomics shifts in Flega suggested that oxidative stress accelerated flowering.
Yellow fever disease severity and endothelial dysfunction are associated with elevated serum levels of viral NS1 protein and syndecan-1
Authors: Sousa Francielle T. G. de , Warnes Colin M. , Manuli Erika R. , Ng Arash , Zanella Luiz G. F. A. B. D’Elia , Ho Yeh-Li , Bhat Samhita , Romano Camila M. , Beatty P. Robert , Biering Scott B. , Kallas Esper G. , Sabino Ester C. , Harris Eva 
Published: June 2023

AbstractYellow fever virus (YFV) infections can cause severe disease manifestations, including hepatic injury, endothelial damage, coagulopathy, hemorrhage, systemic organ failure, and shock, and are associated with high mortality in humans. While nonstructural protein 1 (NS1) of the related dengue virus is implicated in contributing to vascular leak, little is known about the role of YFV NS1 in severe YF and mechanisms of vascular dysfunction in YFV infections. Here, using serum samples from qRT-PCR-confirmed YF patients with severe (n=39) or non-severe (n=18) disease in a well-defined hospital cohort in Brazil, plus samples from healthy uninfected controls (n=11), we investigated factors associated with disease severity. We developed a quantitative YFV NS1 capture ELISA and found significantly increased levels of NS1, as well as syndecan-1, a marker of vascular leak, in serum from severe YF as compared to non-severe YF or control groups. We also showed that hyperpermeability of endothelial cell monolayers treated with serum from severe YF patients was significantly higher compared to non-severe YF and control groups as measured by transendothelial electrical resistance (TEER). Further, we demonstrated that YFV NS1 induces shedding of syndecan-1 from the surface of human endothelial cells. Notably, YFV NS1 serum levels significantly correlated with syndecan-1 serum levels and TEER values. Syndecan-1 levels also significantly correlated with clinical laboratory parameters of disease severity, viral load, hospitalization, and death. In summary, this study points to a role for secreted NS1 in YF disease severity and provides evidence for endothelial dysfunction as a mechanism of YF pathogenesis in humans.SignificanceYellow fever virus (YFV) infections cause a major global disease burden, and as such it is critical to identify clinical correlates of disease severity. Using clinical samples from our hospital cohort in Brazil, we show that YF disease severity is associated with increased serum levels of the viral nonstructural protein 1 (NS1) and soluble syndecan-1, a marker of vascular leak. This study extends the role of YFV NS1 in triggering endothelial dysfunction to human YF patients, previously demonstratedin vitroand in mouse models. Further, we developed a YFV NS1-capture ELISA that serves as a proof-of-concept for low-cost NS1-based diagnosis/prognosis tools for YF. Together, our data shows that YFV NS1 and endothelial dysfunction are important components of YF pathogenesis.
gARID-associated chromatin remodeling events are essential for gametocyte development inPlasmodium
Authors: Nishi Tsubasa , Kaneko Izumi , Iwanaga Shiroh , Yuda Masao 
Published: June 2023

AbstractGametocyte development of thePlasmodiumparasite is a key step for transmission of the parasite from their vertebrate hosts to mosquitoes. Male and female gametocytes are produced from a subpopulation of asexual blood-stage parasites, but the mechanisms that regulate the differentiation of sexual stages are still under investigation. In this study, we investigated the role of gARID, a putative subunit of a chromatin remodeling complex, in transcriptional regulation during the gametocyte development ofP. berghei. gARID expression starts in early gametocytes before the manifestation of male and female-specific features, and disruption of its gene results in the complete loss of male gametocytes and the production of abnormal female gametocytes. ChIP-seq analysis of gARID showed that it forms a complex with gSNF2, a core subunit of the SWI/SNF chromatin remodeling complex, associating with the malecis-regulatory element. Moreover, ChIP-seq of gARID ingsnf2-knockout parasites revealed an association of gARID with anothercis-regulatory element, which is indicated to play a role in both male and female development. Our results showed that gARID functions in two chromatin remodeling events and that remodeling of chromatin states is essential for both male and female gametocyte development.