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Melanoma represents a critical clinical challenge owing to its unfavorable outcomes. This type of skin cancer exhibits unique adaptability to the brain microenvironment, but its underlying molecular mechanisms are poorly understood. Recent findings have suggested that melanoma brain metastases may share biological processes similar to those found in various neurodegenerative diseases. To further characterize melanoma brain metastasis development, we explore the relationship between the transcriptional profiles of melanoma brain metastases and the neurodegenerative diseases Alzheimer's disease, Parkinson's disease, and multiple sclerosis. We take an in silico approach to unveil a neurodegenerative signature of melanoma brain metastases compared with those of melanoma nonbrain metastasis (53 dysregulated genes were enriched in 11 functional terms, such as associated terms to the extracellular matrix and development) and with those of nontumor-bearing brain controls (195 dysregulated genes, mostly involved in development and cell differentiation, chromatin remodeling and nucleosome organization, and translation). Two genes, ITGA10 and DNAJC6, emerged as key potential markers being dysregulated in both scenarios. Finally, we developed an open-source, user-friendly web tool (https://bioinfo.cipf.es/metafun-mbm/) that allows interactive exploration of the complete results., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: While sex-based differences in various health scenarios have been thoroughly acknowledged in the literature, we lack sufficient tools and methods that allow for an in-depth analysis of sex as a variable in biomedical research. To fill this knowledge gap, we created MetaFun as an easy-to-use web-based tool to meta-analyze multiple transcriptomic datasets with a sex-based perspective to gain major statistical power and biological soundness., Description: MetaFun is a complete suite that allows the analysis of transcriptomics data and the exploration of the results at all levels, performing single-dataset exploratory analysis, differential gene expression, gene set functional enrichment, and finally, combining results in a functional meta-analysis. Which biological processes, molecular functions or cellular components are altered in a common pattern in different transcriptomic studies when comparing male and female patients? This and other biological questions of interest can be answered with the use of MetaFun. This tool is available at https://bioinfo.cipf.es/metafun while additional help can be found at https://gitlab.com/ubb-cipf/metafunweb/-/wikis/Summary ., Conclusions: Overall, Metafun is the first open-access web-based tool to identify consensus biological functions across multiple transcriptomic datasets, helping to elucidate sex differences in numerous diseases. Its use will facilitate the generation of novel biological knowledge that can be used in the research and application of Personalized Medicine considering the sex of patients., (© 2024. The Author(s).)

Fire blight, caused by the plant-pathogenic bacterium Erwinia amylovora , is a highly contagious and difficult-to-control disease due to its efficient dissemination and survival and the scarcity of effective control methods. Copper and antibiotics are the most used treatments but pose environmental and human health risks. Bacteriophages (phages) constitute an ecological, safe, and sustainable fire blight control alternative. The goal of this study was to search for specific E. amylovora phages from plant material, soil, and water samples in Mediterranean environments. A collection of phages able to specifically infect and lyse E. amylovora strains was generated from former fire blight-affected orchards in Eastern Spain. Following in vitro characterization, assays in immature fruit revealed that preventively applying some of the phages or their combinations delayed the onset of fire blight symptoms and reduced the disease's severity, suggesting their biocontrol potential in Spain and other countries. The morphological and molecular characterization of the selected E. amylovora phages classified them as members of the class Caudoviricetes (former Myoviridae family) and genus Kolesnikvirus . This study reveals Mediterranean settings as plausible sources of E. amylovora -specific bacteriophages and provides the first effective European phage cocktails in plant material for the development of sustainable fire blight management measures.

High-fat diet (HFD) mouse models are widely used in research to develop medications to treat non-alcoholic fatty liver disease (NAFLD), as they mimic the steatosis, inflammation, and hepatic fibrosis typically found in this complex human disease. The aims of this study were to identify a complete transcriptomic signature of these mouse models and to characterize the transcriptional impact exerted by different experimental anti-steatotic treatments. For this reason, we conducted a systematic review and meta-analysis of liver transcriptomic studies performed in HFD-fed C57BL/6J mice, comparing them with control mice and HFD-fed mice receiving potential anti-steatotic treatments. Analyzing 21 studies broaching 24 different treatments, we obtained a robust HFD transcriptomic signature that included 2,670 differentially expressed genes and 2,567 modified gene ontology biological processes. Treated HFD mice generally showed a reversion of this HFD signature, although the extent varied depending on the treatment. The biological processes most frequently reversed were those related to lipid metabolism, response to stress, and immune system, whereas processes related to nitrogen compound metabolism were generally not reversed. When comparing this HFD signature with a signature of human NAFLD progression, we identified 62 genes that were common to both; 10 belonged to the group that were reversed by treatments. Altered expression of most of these 10 genes was confirmed in vitro in hepatocytes and hepatic stellate cells exposed to a lipotoxic or a profibrogenic stimulus, respectively. In conclusion, this study provides a vast amount of information about transcriptomic changes induced during the progression and regression of NAFLD and identifies some relevant targets. Our results may help in the assessment of treatment efficacy, the discovery of unmet therapeutic targets, and the search for novel biomarkers. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

Background: Multiple sclerosis (MS), a chronic auto-immune, inflammatory, and degenerative disease of the central nervous system, affects both males and females; however, females suffer from a higher risk of developing MS (2-3:1 ratio relative to males). The precise sex-based factors influencing risk of MS are currently unknown. Here, we explore the role of sex in MS to identify molecular mechanisms underlying observed MS sex differences that may guide novel therapeutic approaches tailored for males or females., Methods: We performed a rigorous and systematic review of genome-wide transcriptome studies of MS that included patient sex data in the Gene Expression Omnibus and ArrayExpress databases following PRISMA statement guidelines. For each selected study, we analyzed differential gene expression to explore the impact of the disease in females (IDF), in males (IDM) and our main goal: the sex differential impact of the disease (SDID). Then, for each scenario (IDF, IDM and SDID) we performed 2 meta-analyses in the main tissues involved in the disease (brain and blood). Finally, we performed a gene set analysis in brain tissue, in which a higher number of genes were dysregulated, to characterize sex differences in biological pathways., Results: After screening 122 publications, the systematic review provided a selection of 9 studies (5 in blood and 4 in brain tissue) with a total of 474 samples (189 females with MS and 109 control females; 82 males with MS and 94 control males). Blood and brain tissue meta-analyses identified, respectively, 1 (KIR2DL3) and 13 (ARL17B, CECR7, CEP78, IFFO2, LOC401127, NUDT18, RNF10, SLC17A5, STMP1, TRAF3IP2-AS1, UBXN2B, ZNF117, ZNF488) MS-associated genes that differed between males and females (SDID comparison). Functional analyses in the brain revealed different altered immune patterns in females and males (IDF and IDM comparisons). The pro-inflammatory environment and innate immune responses related to myeloid lineage appear to be more affected in females, while adaptive responses associated with the lymphocyte lineage in males. Additionally, females with MS displayed alterations in mitochondrial respiratory chain complexes, purine, and glutamate metabolism, while MS males displayed alterations in stress response to metal ion, amine, and amino acid transport., Conclusion: We found transcriptomic and functional differences between MS males and MS females (especially in the immune system), which may support the development of new sex-based research of this disease. Our study highlights the importance of understanding the role of biological sex in MS to guide a more personalized medicine., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Lipids represent essential components of extracellular vesicles (EVs), playing structural and regulatory functions during EV biogenesis, release, targeting, and cell uptake. Importantly, lipidic dysregulation has been linked to several disorders, including metabolic syndrome, inflammation, and neurological dysfunction. Our recent results demonstrated the involvement of plasma EV microRNAs as possible amplifiers and biomarkers of neuroinflammation and brain damage induced by ethanol intoxication during adolescence. Considering the possible role of plasma EV lipids as regulatory molecules and biomarkers, we evaluated how acute ethanol intoxication differentially affected the lipid composition of plasma EVs in male and female adolescents and explored the participation of the immune response., Methods: Plasma EVs were extracted from humans and wild-type (WT) and Toll-like receptor 4 deficient (TLR4-KO) mice. Preprocessing and exploratory analyses were conducted after the extraction of EV lipids and data acquisition by mass spectrometry. Comparisons between ethanol-intoxicated and control human female and male individuals and ethanol-treated and untreated WT and TLR4-KO female and male mice were used to analyze the differential abundance of lipids. Annotation of lipids into their corresponding classes and a lipid set enrichment analysis were carried out to evaluate biological functions., Results: We demonstrated, for the first time, that acute ethanol intoxication induced a higher enrichment of distinct plasma EV lipid species in human female adolescents than in males. We observed a higher content of the PA, LPC, unsaturated FA, and FAHFA lipid classes in females, whereas males showed enrichment in PI. These lipid classes participate in the formation, release, and uptake of EVs and the activation of the immune response. Moreover, we observed changes in EV lipid composition between ethanol-treated WT and TLR4-KO mice (e.g., enrichment of glycerophosphoinositols in ethanol-treated WT males), and the sex-based differences in lipid abundance are more notable in WT mice than in TLR4-KO mice. All data and results generated have been made openly available on a web-based platform ( http://bioinfo.cipf.es/sal )., Conclusions: Our results suggest that binge ethanol drinking in human female adolescents leads to a higher content of plasma EV lipid species associated with EV biogenesis and the propagation of neuroinflammatory responses than in males. In addition, we discovered greater differences in lipid abundance between sexes in WT mice compared to TLR4-KO mice. Our findings also support the potential use of EV-enriched lipids as biomarkers of ethanol-induced neuroinflammation during adolescence., (© 2023. The Author(s).)

Background: In recent decades, increasing longevity (among other factors) has fostered a rise in Parkinson's disease incidence. Although not exhaustively studied in this devastating disease, the impact of sex represents a critical variable in Parkinson's disease as epidemiological and clinical features differ between males and females., Methods: To study sex bias in Parkinson's disease, we conducted a systematic review to select sex-labeled transcriptomic data from three relevant brain tissues: the frontal cortex, the striatum, and the substantia nigra. We performed differential expression analysis on each study chosen. Then we summarized the individual differential expression results with three tissue-specific meta-analyses and a global all-tissues meta-analysis. Finally, results from the meta-analysis were functionally characterized using different functional profiling approaches., Results: The tissue-specific meta-analyses linked Parkinson's disease to the enhanced expression of MED31 in the female frontal cortex and the dysregulation of 237 genes in the substantia nigra. The global meta-analysis detected 15 genes with sex-differential patterns in Parkinson's disease, which participate in mitochondrial function, oxidative stress, neuronal degeneration, and cell death. Furthermore, functional analyses identified pathways, protein-protein interaction networks, and transcription factors that differed by sex. While male patients exhibited changes in oxidative stress based on metal ions, inflammation, and angiogenesis, female patients exhibited dysfunctions in mitochondrial and lysosomal activity, antigen processing and presentation functions, and glutamic and purine metabolism. All results generated during this study are readily available by accessing an open web resource ( http://bioinfo.cipf.es/metafun-pd/ ) for consultation and reuse in further studies., Conclusions: Our in silico approach has highlighted sex-based differential mechanisms in typical Parkinson Disease hallmarks (inflammation, mitochondrial dysfunction, and oxidative stress). Additionally, we have identified specific genes and transcription factors for male and female Parkinson Disease patients that represent potential candidates as biomarkers to diagnosis., (© 2022. The Author(s).)

Ralstonia solanacearum is the causative agent of bacterial wilt, one of the most destructive plant diseases. While chemical control has an environmental impact, biological control strategies can allow sustainable agrosystems. Three lytic bacteriophages (phages) of R. solanacearum with biocontrol capacity in environmental water and plants were isolated from river water in Europe but not fully analysed, their genomic characterization being fundamental to understand their biology. In this work, the phage genomes were sequenced and subjected to bioinformatic analysis. The morphology was also observed by electron microscopy. Phylogenetic analyses were performed with a selection of phages able to infect R. solanacearum and the closely related phytopathogenic species R. pseudosolanacearum . The results indicated that the genomes of vRsoP-WF2, vRsoP-WM2 and vRsoP-WR2 range from 40,688 to 41,158 bp with almost 59% GC-contents, 52 ORFs in vRsoP-WF2 and vRsoP-WM2, and 53 in vRsoP-WR2 but, with only 22 or 23 predicted proteins with functional homologs in databases. Among them, two lysins and one exopolysaccharide (EPS) depolymerase, this type of depolymerase being identified in R. solanacearum phages for the first time. These three European phages belong to the same novel species within the Gyeongsanvirus , Autographiviridae family (formerly Podoviridae ). These genomic data will contribute to a better understanding of the abilities of these phages to damage host cells and, consequently, to an improvement in the biological control of R. solanacearum .

Background: Previous studies have described sex-based differences in the epidemiological and clinical patterns of non-alcoholic fatty liver disease (NAFLD); however, we understand relatively little regarding the underlying molecular mechanisms. Herein, we present the first systematic review and meta-analysis of NAFLD transcriptomic studies to identify sex-based differences in the molecular mechanisms involved during the steatosis (NAFL) and steatohepatitis (NASH) stages of the disease., Methods: Transcriptomic studies in the Gene Expression Omnibus database were systematically reviewed following the PRISMA statement guidelines. For each study, NAFL and NASH in premenopausal women and men were compared using a dual strategy: gene-set analysis and pathway activity analysis. Finally, the functional results of all studies were integrated into a meta-analysis., Results: We reviewed a total of 114 abstracts and analyzed seven studies that included 323 eligible patients. The meta-analyses identified significantly altered molecular mechanisms between premenopausal women and men, including the overrepresentation of genes associated with DNA regulation, vinculin binding, interleukin-2 responses, negative regulation of neuronal death, and the transport of ions and cations in premenopausal women. In men, we discovered the overrepresentation of genes associated with the negative regulation of interleukin-6 and the establishment of planar polarity involved in neural tube closure., Conclusions: Our meta-analysis of transcriptomic data provides a powerful approach to identify sex-based differences in NAFLD. We detected differences in relevant biological functions and molecular terms between premenopausal women and men. Differences in immune responsiveness between men and premenopausal women with NAFLD suggest that women possess a more immune tolerant milieu, while men display an impaired liver regenerative response.

Fire blight caused by Erwinia amylovora affects pome fruit worldwide, generating serious economic losses. Despite the abundant literature on E. amylovora infection mechanisms of aerial plant organs, root infection routes remain virtually unexplored. Assessing these infection pathways is necessary for a full understanding of the pathogen's ecology. Using the pathosystem Pyrus communis-E. amylovora and different experimental approaches including a green fluorescent protein transformant (GFP1) and epifluorescence microscopy (EFM) and laser confocal scanning microscopy (LCSM), we demonstrated the pathogen's ability to infect, colonize and invade pear roots and cause characteristic fire blight symptoms both in the aerial part and in the root system. Plant infections after soil irrigation with E. amylovora-contaminated water were favored by root damage, which agreed with EFM and LCSM observations. E. amylovora GFP1 cells formed aggregates/biofilms on root surfaces and invaded the cortex through wounds and sites of lateral root emergence. Sugars, sugar-alcohols and amino acids typically secreted by roots, favored the in vitro biofilm development by E. amylovora. Migration of E. amylovora cells to aerial tissues mainly occurred after xylem penetration. Overall, our findings revealed, for the first time, common root infection patterns between E. amylovora and well-known soil borne plant pathogens and endophytes., (© The Author(s) 2020. Published by Oxford University Press on behalf of FEMS.)