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Abstract Background Significant sex differences exist in the prevalence and incidence of Alzheimer’s disease (AD). Notably, testosterone has been reported to regulate cognitive functions in the brain, with low serum testosterone levels correlating with increased AD risk. However, the specific mechanisms underlying this relationship remain unclear. Recent studies have demonstrated that microglia, the primary innate immune cells in the brain, play a crucial role in AD development. Therefore, this study aimed to explore sex differences in microglial function, specifically focusing on the role of testosterone in miRNA-mediated regulation of microglial gene expression. Methods Microglia were isolated from pooled hippocampal tissue of five 8-month-old male and female mice. Total RNA was extracted and subjected to miRNA microarray analysis. The mouse microglial cell line MG6 was used for in vitro experiments. Following testosterone treatment, miRNA, gene, and protein expression levels were investigated. An inflammatory response was induced using lipopolysaccharide (LPS) stimulation, and subsequent p65 phosphorylation was assessed. Results Sex-dependent differences were observed in miRNA-mediated biological processes, with males exhibiting greater changes. Male-enriched miRNAs were associated with fatty acid synthesis and metabolism pathways. In MG6 cells, testosterone treatment upregulated the expression of several miRNAs enriched in male microglia, particularly those targeting genes related to fatty acid synthesis. Additionally, testosterone significantly reduced the gene expression of fatty acid synthase (FASN). This testosterone-induced inhibition of FASN expression attenuated NF-κB/p65 phosphorylation. Consequently, the suppression of FASN expression led to reduced expression and secretion of tumor necrosis factor-alpha following LPS stimulation in MG6 cells. Conclusions These findings suggest that testosterone modulates inflammation in male microglia by regulating fatty acid synthesis, potentially contributing to the observed sex differences in AD pathogenesis.

Abstract Spinal cord injury (SCI) is a devastating condition that leads to motor, sensory, and autonomic dysfunction. Current therapeutic options remain limited, emphasizing the need for a comprehensive understanding of the underlying SCI-associated molecular mechanisms. This study characterized distinct SCI phases and severities at the gene and functional levels, focusing on biomarker gene identification. Our approach involved a systematic review, individual transcriptomic analysis, gene meta-analysis, and functional characterization. We compiled a total of fourteen studies with 273 samples, leading to the identification of severity- and phase-specific biomarker genes that allow the precise classification of transcriptomic profiles. We investigated the potential transferability of severity-specific biomarkers and identified a twelve-gene signature that predicted injury prognosis from human blood samples. We also report the development of MetaSCI-app - an interactive web application designed for researchers - that allows the exploration and visualization of all generated results ( https://metasci-cbl.shinyapps.io/metaSCI ). Overall, we present a transcriptomic reference and provide a comprehensive framework for assessing SCI considering severity and time perspectives, all integrated into a user-friendly tool. Graphical abstract

Our previous studies have reported that activation of the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3)-inflammasome complex in ethanol-treated astrocytes and chronic alcohol-fed mice could be associated with neuroinflammation and brain damage. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have been shown to restore the neuroinflammatory response, along with myelin and synaptic structural alterations in the prefrontal cortex, and alleviate cognitive and memory dysfunctions induced by binge-like ethanol treatment in adolescent mice. Considering the therapeutic role of the molecules contained in mesenchymal stem cell-derived extracellular vesicles, the present study analyzed whether the administration of mesenchymal stem cell-derived extracellular vesicles isolated from adipose tissue, which inhibited the activation of the NLRP3 inflammasome, was capable of reducing hippocampal neuroinflammation in adolescent mice treated with binge drinking. We demonstrated that the administration of mesenchymal stem cell-derived extracellular vesicles ameliorated the activation of the hippocampal NLRP3 inflammasome complex and other NLRs inflammasomes (e.g., pyrin domain-containing 1, caspase recruitment domain-containing 4, and absent in melanoma 2, as well as the alterations in inflammatory genes (interleukin-1β, interleukin-18, inducible nitric oxide synthase, nuclear factor-kappa B, monocyte chemoattractant protein-1, and C–X3–C motif chemokine ligand 1) and miRNAs (miR-21a-5p, miR-146a-5p, and miR-141-5p) induced by binge-like ethanol treatment in adolescent mice. Bioinformatic analysis further revealed the involvement of miR-21a-5p and miR-146a-5p with inflammatory target genes and NOD-like receptor signaling pathways. Taken together, these findings provide novel evidence of the therapeutic potential of MSC-derived EVs to ameliorate the hippocampal neuroinflammatory response associated with NLRP3 inflammasome activation induced by binge drinking in adolescence.

Abstract Background Schizophrenia is a severe neuropsychiatric disorder characterized by altered perception, mood, and behavior that profoundly impacts patients and society despite its relatively low prevalence. Sex-based differences have been described in schizophrenia epidemiology, symptomatology and outcomes. Different studies explored the impact of schizophrenia in the brain transcriptome, however we lack a consensus transcriptomic profile that considers sex and differentiates specific cerebral regions. Methods We performed a systematic review on bulk RNA-sequencing studies of post-mortem brain samples. Then, we fulfilled differential expression analysis on each study and summarized their results with regions-specific meta-analyses (prefrontal cortex and hippocampus) and a global all-studies meta-analysis. Finally, we used the consensus transcriptomic profiles to functionally characterize the impact of schizophrenia in males and females by protein-protein interaction networks, enriched biological processes and dysregulated transcription factors. Results We discovered the sex-based dysregulation of 265 genes in the prefrontal cortex, 1.414 genes in the hippocampus and 66 genes in the all-studies meta-analyses. The functional characterization of these gene sets unveiled increased processes related to immune response functions in the prefrontal cortex in male and the hippocampus in female schizophrenia patients and the overexpression of genes related to neurotransmission and synapses in the prefrontal cortex of female schizophrenia patients. Considering a meta-analysis of all brain regions available, we encountered the relative overexpression of genes related to synaptic plasticity and transmission in females and the overexpression of genes involved in organizing genetic information and protein folding in male schizophrenia patients. The protein-protein interaction networks and transcription factors activity analyses supported these sex-based profiles. Conclusions Our results report multiple sex-based transcriptomic alterations in specific brain regions of schizophrenia patients, which provides new insight into the role of sex in schizophrenia. Moreover, we unveil a partial overlapping of inflammatory processes in the prefrontal cortex of males and the hippocampus of females.

Background: Age represents a significant risk factor for the development of Alzheimer's disease (AD); however, recent research has documented an influencing role of sex in several features of AD. Understanding the impact of sex on specific molecular mechanisms associated with AD remains a critical challenge to creating tailored therapeutic interventions. Methods: The exploration of the sex-based differential impact on disease (SDID) in AD used a systematic review to first select transcriptomic studies of AD with data regarding sex in the period covering 2002 to 2021 with a focus on the primary brain regions affected by AD - the cortex (CT) and the hippocampus (HP). A differential expression analysis for each study and two tissue-specific meta-analyses were then performed. Focusing on the CT due to the presence of significant SDID-related alterations, a comprehensive functional characterization was conducted: protein-protein network interaction and over-representation analyses to explore biological processes and pathways and a VIPER analysis to estimate transcription factor activity. Results: We selected 8 CT and 5 HP studies from the Gene Expression Omnibus (GEO) repository for tissue-specific meta-analyses. We detected 389 significantly altered genes in the SDID comparison in the CT. Generally, female AD patients displayed more affected genes than males; we grouped said genes into six subsets according to their expression profile in female and male AD patients. Only subset I (repressed genes in female AD patients) displayed significant results during functional profiling. Female AD patients demonstrated more significant impairments in biological processes related to the regulation and organization of synapsis and pathways linked to neurotransmitters (glutamate and GABA) and protein folding, Aβ aggregation, and accumulation compared to male AD patients. These findings could partly explain why we observe more pronounced cognitive decline in female AD patients. Finally, we detected 23 transcription factors with different activation patterns according to sex, with some associated with AD for the first time. All results generated during this study are readily available through an open web resource Metafun-AD (https://bioinfo.cipf.es/metafun-ad/). Conclusion: Our meta-analyses indicate the existence of differences in AD-related mechanisms in female and male patients. These sex-based differences will represent the basis for new hypotheses and could significantly impact precision medicine and improve diagnosis and clinical outcomes in AD patients.

Abstract Background Alcohol use disorder (AUD) is one of the most common psychiatric disorders, with the consumption of alcohol considered a leading cause of preventable deaths worldwide. Lipids play a crucial functional role in cell membranes; however, we know little about the role of lipids in extracellular vesicles (EVs) as regulatory molecules and disease biomarkers. Methods We employed a sensitive lipidomic strategy to characterize lipid species from the plasma EVs of AUD patients to evaluate functional roles and enzymatic activity networks to improve the knowledge of lipid metabolism after alcohol consumption. We analyzed plasma EV lipids from AUD females and males and healthy individuals to highlight lipids with differential abundance and biologically interpreted lipidomics data using LINEX2, which evaluates enzymatic dysregulation using an enrichment algorithm. Results Our results show, for the first time, that AUD females exhibited more significant substrate-product changes in lysophosphatidylcholine/phosphatidylcholine lipids and phospholipase/acyltransferase activity, which are potentially linked to cancer progression and neuroinflammation. Conversely, AUD males suffer from dysregulated ceramide and sphingomyelin lipids involving sphingomyelinase, sphingomyelin phosphodiesterase, and sphingomyelin synthase activity, which relates to hepatotoxicity. Notably, the analysis of plasma EVs from AUD females and males demonstrates enrichment of lipid ontology terms associated with “negative intrinsic curvature” and “positive intrinsic curvature”, respectively. Conclusions Our methodological developments support an improved understanding of lipid metabolism and regulatory mechanisms, which contribute to the identification of novel lipid targets and the discovery of sex-specific clinical biomarkers in AUD.

Abstract Background The incidence of Alzheimer's disease (AD)—the most frequent cause of dementia—is expected to increase as life expectancies rise across the globe. While sex-based differences in AD have previously been described, there remain uncertainties regarding any association between sex and disease-associated molecular mechanisms. Studying sex-specific expression profiles of regulatory factors such as microRNAs (miRNAs) could contribute to more accurate disease diagnosis and treatment. Methods A systematic review identified six studies of microRNA expression in AD patients that incorporated information regarding the biological sex of samples in the Gene Expression Omnibus repository. A differential microRNA expression analysis was performed, considering disease status and patient sex. Subsequently, results were integrated within a meta-analysis methodology, with a functional enrichment of meta-analysis results establishing an association between altered miRNA expression and relevant Gene Ontology terms. Results Meta-analyses of miRNA expression profiles in blood samples revealed the alteration of sixteen miRNAs in female and 22 miRNAs in male AD patients. We discovered nine miRNAs commonly overexpressed in both sexes, suggesting a shared miRNA dysregulation profile. Functional enrichment results based on miRNA profiles revealed sex-based differences in biological processes; most affected processes related to ubiquitination, regulation of different kinase activities, and apoptotic processes in males, but RNA splicing and translation in females. Meta-analyses of miRNA expression profiles in brain samples revealed the alteration of six miRNAs in female and four miRNAs in male AD patients. We observed a single underexpressed miRNA in female and male AD patients (hsa-miR-767-5p); however, the functional enrichment analysis for brain samples did not reveal any specifically affected biological process. Conclusions Sex-specific meta-analyses supported the detection of differentially expressed miRNAs in female and male AD patients, highlighting the relevance of sex-based information in biomedical data. Further studies on miRNA regulation in AD patients should meet the criteria for comparability and standardization of information.

Abstract Charcot-Marie-Tooth disease is a chronic hereditary motor and sensory polyneuropathy targeting Schwann cells and/or motor neurons. Its multifactorial and polygenic origin portrays a complex clinical phenotype of the disease with a wide range of genetic inheritance patterns. The disease-associated gene GDAP1 encodes for a mitochondrial outer membrane protein. Mouse and insect models with mutations in Gdap1 have reproduced several traits of the human disease. However, the precise function in the cell types affected by the disease remains unknown. Here, we use induced-pluripotent stem cells derived from a Gdap1 knockout mouse model to better understand the molecular and cellular phenotypes of the disease caused by the loss-of-function of this gene. Gdap1-null motor neurons display a fragile cell phenotype prone to early degeneration showing (1) altered mitochondrial morphology, with an increase in the fragmentation of these organelles, (2) activation of autophagy and mitophagy, (3) abnormal metabolism, characterized by a downregulation of Hexokinase 2 and ATP5b proteins, (4) increased reactive oxygen species and elevated mitochondrial membrane potential, and (5) increased innate immune response and p38 MAP kinase activation. Our data reveals the existence of an underlying Redox-inflammatory axis fueled by altered mitochondrial metabolism in the absence of Gdap1. As this biochemical axis encompasses a wide variety of druggable targets, our results may have implications for developing therapies using combinatorial pharmacological approaches and improving therefore human welfare. A Redox-immune axis underlying motor neuron degeneration caused by the absence of Gdap1. Our results show that Gdap1 –/– motor neurons have a fragile cellular phenotype that is prone to degeneration. Gdap1 –/– iPSCs differentiated into motor neurons showed an altered metabolic state: decreased glycolysis and increased OXPHOS. These alterations may lead to hyperpolarization of mitochondria and increased ROS levels. Excessive amounts of ROS might be the cause of increased mitophagy, p38 activation and inflammation as a cellular response to oxidative stress. The p38 MAPK pathway and the immune response may, in turn, have feedback mechanisms, leading to the induction of apoptosis and senescence, respectively. CAC, citric acid cycle; ETC, electronic transport chain; Glc, glucose; Lac, lactate; Pyr, pyruvate.

Abstract 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.

Highlights Females show a significant increase in the expression of MED31 in the frontal cortex. This gene is involved in lipid metabolism and neural diseases. We found 237 genes having sex-based significantly differential expression in substantia nigra. Functional profiling of these genes reveals a differential sex-related behavior in PD regarding their biological functions, protein-protein interaction networks, and transcription factors activation. There are remarkable sex based differential mechanisms in typical PD hallmarks: inflammation, mitochondrial dysfunction, and oxidative stress. Studies on sex differences in PD are needed to improve more targeted interventions.

El artículo aborda la película No mires arriba (Mckay, 2021) atendiendo a los agentes de la comunicación científica que representa. En primer lugar, se destaca la relación del cine con la ciencia y la pragmática, para posteriormente estudiar varios personajes identificados como: los científicos, el productor tecológico, el comunicador, el político, y la ciudadanía. Se utiliza para el análisis un modelo previo de obligaciones pragmáticas, así como a otro general centrado en las categorías pragmáticas. Las interacciones observadas entre los agentes se reflejan en un mapa de relaciones. Los resultados señalan al científico como el más propenso a cumplir con las obligaciones que le vinculan con la verdad, señalando al poder político y al rol del productor-tecnológico como los menos afines a ella. El comunicador y la ciudadanía se muestran en general parcialmente cumplidores de sus respectivas obligaciones. Además, todos los roles muestran problemas con la comunicación de la verdad a excepción de dos científicos, y por último, destaca la poderosa influencia del poder político en la administración de la verdad.

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.

Serine incorporator protein 5 (SERINC5) is a key innate immunity factor that operates in the cell to restrict the infectivity of certain viruses. Different viruses have developed strategies to antagonize SERINC5 function but, how SERINC5 is controlled during viral infection is poorly understood. Here, we report that SERINC5 levels are reduced in COVID-19 patients during the infection by SARS-CoV-2 and, since no viral protein capable of repressing the expression of SERINC5 has been identified, we hypothesized that SARS-CoV-2 non-coding small viral RNAs (svRNAs) could be responsible for this repression. Two newly identified svRNAs with predicted binding sites in the 3′-untranslated region (3’-UTR) of the SERINC5 gene were characterized and we found that the expression of both svRNAs during the infection was not dependent on the miRNA pathway proteins Dicer and Argonaute-2. By using svRNAs mimic oligonucleotides, we demonstrated that both viral svRNAs can bind the 3’UTR of SERINC5 mRNA, reducing SERINC5 expression in vitro. Moreover, we found that an anti-svRNA treatment to Vero E6 cells before SARS-CoV-2 infection recovered the levels of SERINC5 and reduced the levels of N and S viral proteins. Finally, we showed that SERINC5 positively controls the levels of Mitochondrial Antiviral Signalling (MAVS) protein in Vero E6. These results highlight the therapeutic potential of targeting svRNAs based on their action on key proteins of the innate immune response during SARS-CoV-2 viral infection.

Abstract Background Cancer is a major health problem which presents a high heterogeneity. In this work we explore omics data from Breast, Kidney and Lung cancers at different levels as signalling pathways, functions and miRNAs, as part of the CAMDA 2019 Hi-Res Cancer Data Integration Challenge. Our goal is to find common functional patterns which give rise to the generic microenvironment in these cancers and contribute to a better understanding of cancer pathogenesis and a possible clinical translation down further studies. Results After a tumor versus normal tissue comparison of the signaling pathways and cell functions, we found 828 subpathways, 912 Gene Ontology terms and 91 Uniprot keywords commonly significant to the three studied tumors. Such features interestingly show the power to classify tumor samples into subgroups with different survival times, and predict tumor state and tissue of origin through machine learning techniques. We also found cancer-specific alternative activation subpathways, such as the ones activating STAT5A in ErbB signaling pathway. miRNAs evaluation show the role of miRNAs, such as mir-184 and mir-206, as regulators of many cancer pathways and their value in prognoses. Conclusions The study of the common functional and pathway activities of different cancers is an interesting approach to understand molecular mechanisms of the tumoral process regardless of their tissue of origin. The existence of platforms as the CAMDA challenges provide the opportunity to share knowledge and improve future scientific research and clinical practice.

Abstract 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. Graphical abstract

Transmission is a driver of tuberculosis (TB) epidemics in high-burden regions, with assumed negligible impact in low-burden areas. However, we still lack a full characterization of transmission dynamics in settings with similar and different burdens. Genomic epidemiology can greatly help to quantify transmission, but the lack of whole genome sequencing population-based studies has hampered its application. Here, we generate a population-based dataset from Valencia region and compare it with available datasets from different TB-burden settings to reveal transmission dynamics heterogeneity and its public health implications. We sequenced the whole genome of 785 Mycobacterium tuberculosis strains and linked genomes to patient epidemiological data. We use a pairwise distance clustering approach and phylodynamic methods to characterize transmission events over the last 150 years, in different TB-burden regions. Our results underscore significant differences in transmission between low-burden TB settings, i.e., clustering in Valencia region is higher (47.4%) than in Oxfordshire (27%), and similar to a high-burden area as Malawi (49.8%). By modeling times of the transmission links, we observed that settings with high transmission rate are associated with decades of uninterrupted transmission, irrespective of burden. Together, our results reveal that burden and transmission are not necessarily linked due to the role of past epidemics in the ongoing TB incidence, and highlight the need for in-depth characterization of transmission dynamics and specifically tailored TB control strategies.

Abstract Sclerotinia head rot (SHR), caused by the necrotrophic fungus Sclerotinia sclerotiorum, is one of the most devastating sunflower crop diseases. Despite its worldwide occurrence, the genetic determinants of plant resistance are still largely unknown. Here, we investigated the Sclerotinia-sunflower pathosystem by analysing temporal changes in gene expression in one susceptible and two tolerant inbred lines (IL) inoculated with the pathogen under field conditions. Differential expression analysis showed little overlapping among ILs, suggesting genotype-specific control of cell defense responses possibly related to differences in disease resistance strategies. Functional enrichment assessments yielded a similar pattern. However, all three ILs altered the expression of genes involved in the cellular redox state and cell wall remodeling, in agreement with current knowledge about the initiation of plant immune responses. Remarkably, the over-representation of long non-coding RNAs (lncRNA) was another common feature among ILs. Our findings highlight the diversity of transcriptional responses to SHR within sunflower breeding lines and provide evidence of lncRNAs playing a significant role at early stages of defense.

The present work describes novel copper oxide thin film-modified indium tin oxide electrodes prepared by magnetron sputtering and their application for glucose sensing. Copper oxide-modified sensors were characterized by electrochemical techniques, X-ray photoelectron spectroscopy (XPS), and scanning electron microscopy (SEM). The deposited thin film (of about 400 nm of thickness) consisted of Cu2O/CuO nanocolumns of ca. 80 nm in diameter. After optimizing the main experimental parameters, the electrodes showed noteworthy electrocatalytic properties for glucose detection (sensitivity ca. 2.89 A M−1 cm−2 and limit of detection ca. 0.29 μM (S/N = 3)). The sensor showed negligible response against common electroactive species and other sugars. Finally, recovery experiments in commercial soda drinks and the determination of glucose content in different commercial drinks, such as soda, tea, fruit juices, and sports drinks, are described.

The serotonergic system of mammals innervates virtually all the central nervous system and regulates a broad spectrum of behavioral and physiological functions. In mammals, serotonergic neurons located in the rostral raphe nuclei encompass diverse sub-systems characterized by specific circuitry and functional features. Substantial evidence suggest that functional diversity of serotonergic circuits has a molecular and connectivity basis. However, the landscape of intrinsic developmental mechanisms guiding the formation of serotonergic sub-systems is unclear. Here, we employed developmental disruption of gene expression specific to serotonergic subsets to probe the contribution of the tyrosine kinase receptor ErbB4 to serotonergic circuit formation and function. Through an in vivo loss-of-function approach, we found that ErbB4 expression occurring in a subset of serotonergic neurons, is necessary for axonal arborization of defined long-range projections to the forebrain but is dispensable for the innervation of other targets of the serotonergic system. We also found that Erbb4-deletion does not change the global excitability or the number of neurons with serotonin content in the dorsal raphe nuclei. In addition, ErbB4-deficiency in serotonergic neurons leads to specific behavioral deficits in memory processing that involve aversive or social components. Altogether, our work unveils a developmental mechanism intrinsically acting through ErbB4 in subsets of serotonergic neurons to orchestrate a precise long-range circuit and ultimately involved in the formation of emotional and social memories.

Memoria, creatividad e imagen emergen como tres factores culturales clave en la historia y el devenir de las civilizaciones. La memoria, extraordinario almacén de experiencias y conocimientos, es instrumento imprescindible en los procesos de creación y resolución de problemas. A menudo, vinculada en exclusividad al pasado, la memoria actúa en el presente y, su potencial valor de proyección, la hace imprescindible en el futuro. En la memoria, la imagen ocupa un lugar destacado, tanto en su dimensión sensorial como en su dimensión mental. El sujeto construye y perfecciona conceptos (imágenes mentales) que le empujan a comportarse de un determinado modo, e imagina, creando imágenes fantásticas, a menudo, a partir de sus recuerdos. El objetivo principal de este artículo es estudiar las conexiones entre memoria, creatividad e imagen para alcanzar un conocimiento más profundo que permita reflexionar sobre tales interacciones y sus oportunidades. Para ello, se plantea una metodología epistemológica coherente y unitaria con enfoque fenomenológico que explica la complejidad de las interrelaciones y la esencia de los tres factores, estudiados en cuanto a fenómenos vitales. Finalmente, se propone una red semántica de todas las interacciones encontradas, abriendo las puertas a investigaciones posteriores.

En este artículo, los festivales y premios de publicidad son el objeto de estudio para caracterizar la publicidad, con un doble objetivo: por un lado, validar el uso de la información registrada en los festivales de publicidad internacionales, anuncios y premios como un buen objeto de estudio donde medir la producción de calidad de las agencias publicitarias y países; por otro, ejemplificar este objeto de estudio, analizando el ámbito iberoamericano. Se desarrolla una metodología fundamentada en un análisis documental y estadístico descriptivo de los premios (6921 premios analizados) recibidos por las agencias iberoamericanas (692 agencias analizadas) en 24 festivales de publicidad iberoamericanos e internacionales en 2012 y 2013. El artículo aporta una nueva dimensión y perspectiva: la visibilidad que las agencias y los países tienen en un espacio de competición clave en el sector y, además, en una región en conjunto, sobre la que no hay información, Iberoamérica, destacando el liderazgo de Brasil, Argentina, España, México y Colombia. A su vez, se descubre un panorama muy desigual en la distribución de premios por países: la existencia de una reducida élite de agencias -mayoritariamente multinacionales- con un alto impacto en el sistema. Esta desemejanza producida entre los premios y las agencias que los acaparan se ajusta al modelo matemático de Bradford. La investigación describe, por tanto, una realidad publicitaria desigual en Iberoamérica, de gran interés para su exploración en futuros estudios.

The tree tomato (Solanum betaceum Cav.) is an underutilized fruit crop native to the Andean region and phylogenetically related to the tomato and potato. Tree tomato fruits have a high amount of nutrients and bioactive compounds. However, so far there are no studies at the genome or transcriptome level for this species. We performed a de novo assembly and transcriptome annotation for purple-fruited (A21) and an orange-fruited (A23) accessions. A total of 174,252 (A21) and 194,417 (A23) transcripts were assembled with an average length of 851 and 849 bp. A total of 34,636 (A21) and 36,224 (A23) transcripts showed a significant similarity to known proteins. Among the annotated unigenes, 22,096 (A21) and 23,095 (A23) were assigned to the Gene Ontology (GO) term and 14,035 (A21) and 14,540 (A23) were found to have Clusters of Orthologous Group (COG) term classifications. Furthermore, 22,096 (A21) and 23,095 (A23) transcripts were assigned to 155 and 161 (A23) KEGG pathways. The carotenoid biosynthetic process GO terms were significantly enriched in the purple-fruited accession A21. Finally, 68,647 intraspecific single-nucleotide variations (SNVs) and almost 2 million interspecific SNVs were identified. The results of this study provide a wealth of genomic data for the genetic improvement of the tree tomato.

TLR4 is a member of the toll-like receptors (TLR) immune family, which are activated by lipopolysaccharide, ethanol or damaged tissue, among others, by triggering proinflammatory cytokines release and inflammation. Lack of TLR4 protects against inflammatory processes and neuroinflammation linked with several neuropathologies. By considering that miRNAs are key post-transcriptional regulators of the proteins involved in distinct cellular processes, including inflammation, this study aimed to assess the impact of the miRNAs profile in mice cortices lacking the TLR4 response. Using mice cerebral cortices and next-generation sequencing (NGS), the findings showed that lack of TLR4 significantly reduced the quantity and diversity of the miRNAs expressed in WT mice cortices. The results also revealed a significant down-regulation of the miR-200 family, while cluster miR-99b/let-7e/miR-125a was up-regulated in TLR4-KO vs. WT. The bioinformatics and functional analyses demonstrated that TLR4-KO presented the systematic depletion of many pathways closely related to the immune system response, such as cytokine and interleukin signaling, MAPK and ion Channels routes, MyD88 pathways, NF-κβ and TLR7/8 pathways. Our results provide new insights into the molecular and biological processes associated with the protective effects of TLR-KO against inflammatory damage and neuroinflammation, and reveal the relevance of the TLR4 receptors response in many neuropathologies.

Human bone marrow mesenchymal stem cells (BM-MSCs) and cardiac progenitor/stem cells (CPCs) have been extensively studied as a potential therapeutic treatment for myocardial infarction (MI). Previous reports suggest that lower doses of CPCs are needed to improve cardiac function relative to their bone marrow counterparts. Here, we confirmed this observations and investigated the surface protein expression profile that might explain this effect. Myocardial infarction was performed in nude rats by permanent ligation of the left coronary artery. Cardiac function and infarct size before and after cell transplantation were evaluated by echocardiography and morphometry, respectively. The CPC and BM-MSC receptome were analyzed by proteomic analysis of biotin-labeled surface proteins. Rats transplanted with CPCs showed a greater improvement in cardiac function after MI than those transplanted with BM-MSCs, and this was associated with a smaller infarct size. Analysis of the receptome of CPCs and BM-MSCs showed that gene ontology biological processes and KEGG pathways associated with adhesion mechanisms were upregulated in CPCs compared with BM-MSCs. Moreover, the membrane protein interactome in CPCs showed a strong relationship with biological processes related to cell adhesion whereas the BM-MSCs interactome was more related to immune regulation processes. We conclude that the stronger capacity of CPCs over BM-MSCs to engraft in the infarcted area is likely linked to a more pronounced cell adhesion expression program.

Extracellular vesicles (EVs) are small membrane vesicles secreted by most cell types with important roles in cell-to-cell communication. To assess their relevance in the context of heart ischemia, EVs isolated from the AC10 ventricular cardiomyocyte cell line (CM-EVs), exposed to normoxia (Nx) or hypoxia (Hx), were incubated with fibroblasts (Fb) and endothelial cells (EC). CM-EVs were studied using electron microscopy, nanoparticle tracking analysis (NTA), western blotting and proteomic analysis. Results showed that EVs had a strong preference to be internalized by EC over fibroblasts, suggesting an active exosome-based communication mechanism between CM and EC in the heart. In Matrigel tube-formation assays, Hx CM-EVs were inferior to Nx CM-EVs in angiogenesis. By contrast, in a wound-healing assay, wound closure was faster in fibroblasts treated with Hx CM-EVs than with Nx CM-EVs, supporting a pro-fibrotic effect of Hx CM-EVs. Overall, these observations were consistent with the different protein cargoes detected by proteomic analysis under Nx and Hx conditions and the biological pathways identified. The paracrine crosstalk between CM-EVs, Fb, and EC in different physiological conditions could account for the contribution of CM-EVs to cardiac remodeling after an ischemic insult.

Se estudia la conveniencia de incluir el concepto de histéresis en las disciplinas humanistas, así como la necesidad de incorporar el análisis de los fenómenos donde aquél participa. La histéresis se produce en los más diversos campos de la acción y el pensamiento humanos, y su estudio contribuiría a completar y perfeccionar la visión que tenemos de los mismos. Al realizar la inclusión que aquí se propone, se operan varios cambios de orden epistemológico, operativo y conceptual. En las disciplinas humanistas, los conceptos vienen asumiendo por tradición el papel de herramientas analíticas en bastante mayor medida que el de contenidos sobre los que efectuar el análisis. La histéresis manifiesta su alcance como hecho a analizar y también como herramienta de análisis, pero en el caso presente hemos tenido en cuenta más aspectos del segundo enfoque que del primero. De aquí que nos hayamos centrado en ubicar su campo epistemológico.

En este artículo, los festivales y premios de publicidad son el objeto de estudio para caracterizar la publicidad, con un doble objetivo: por un lado, validar el uso de la información registrada en los festivales de publicidad internacionales, anuncios y premios como un buen objeto de estudio donde medir la producción de calidad de las agencias publicitarias y países; por otro, ejemplificar este objeto de estudio, analizando el ámbito iberoamericano. Se desarrolla una metodología fundamentada en un análisis documental y estadístico descriptivo de los premios (6921 premios analizados) recibidos por las agencias iberoamericanas (692 agencias analizadas) en 24 festivales de publicidad iberoamericanos e internacionales en 2012 y 2013. El artículo aporta una nueva dimensión y perspectiva: la visibilidad que las agencias y los países tienen en un espacio de competición clave en el sector y, además, en una región en conjunto, sobre la que no hay información, Iberoamérica, destacando el liderazgo de Brasil, Argentina, España, México y Colombia. A su vez, se descubre un panorama muy desigual en la distribución de premios por países: la existencia de una reducida élite de agencias —mayoritariamente multinacionales— con un alto impacto en el sistema. Esta desemejanza producida entre los premios y las agencias que los acaparan se ajusta al modelo matemático de Bradford. La investigación describe, por tanto, una realidad publicitaria desigual en Iberoamérica, de gran interés para su exploración en futuros estudios.

Las imágenes mentales que generan los anuncios tienen efectos, tanto en el recuerdo como en la evocación de respuestas en los públicos. Se ha utilizado una metodología de análisis de contenido de las palabras que intervienen en la descripción verbal escrita de las imágenes mentales evocadas a través de una tarea de recuerdo libre. Los resultados confirman que el recuerdo de la imagen mental varía en los sujetos según la modalidad de presentación del estímulo: imagen, palabra, sonido. Y un análisis multivariable de la varianza atribuye las diferencias, también, a la capacidad de viveza de imagen mental de los sujetos.

Este trabajo aborda el periodismo digital obedeciendo a dos frentes: realizar una revisión bilbliográfica sobre la actualidad del periodismo digital y su relación con el empoderamiento ciudadano, para luego realizar un estudio exploratorio sobre noticias de Google (en español) para extraer las tendencias temáticas referentes al empoderamiento y las TIC a lo largo del año 2017. La muestra de análisis se compuso de 332 noticias, divididas, principalmente, entre noticias de España y de Latinoamérica. Los resultados muestran cierta prevalencia entre las noticias que no muestran el nombre de su autor o autora sobre las que sí lo indican, así como un ligero predominio de las noticias que no incluyen enlaces sobre aquellas que sí lo tienen. Las tendencias con mayor presencia a lo largo de la muestra son Desarrollo, Internet, Política y gobernanza, Seguridad, Puestos de trabajo, Género y Educación.

Se analiza el uso que realizan los jóvenes universitarios de los servicios digitales en red. En función de la habilidad y la conducta autodefinidas, y la confiabilidad y la utilidad percibidas y declaradas, se evalúa la correspondencia entre dieta y el grado de utilidad y confianza de la información en internet. Los datos de una encuesta a estudiantes de las universidades públicas de Madrid ofrecen una tipología de usuarios en cinco niveles cuyos rasgos esenciales son: un bajo nivel de confianza y percepción de utilidad de la información, un repertorio de medios escaso y una dieta desequilibrada.

La investigación se centra en el estudio de la percepción que los nativos digitales y los jóvenes tienen acerca de sus conductas y relaciones sociales en la Web 2.0. Se parte de la hipótesis de que la forma en que los adolescentes y jóvenes utilizan la red a través de los servicios y contenidos digitales abiertos, está transformando sus relacionales sociales en la medida en que son abiertas, activas, globales, inmediatas, y poco controlables por otros agentes sociales (familiares, educativos o institucionales). El universo de la investigación está constituido por jóvenes y adolescentes, nativos digitales e inmigrantes digitales de ambos sexos, comprendidos entre los 14 y los 35 años de edad agrupados en los siguientes tramos: 14-16; 17-24; y25-35 años. Las conclusiones son interesantes. Entre ellas se destaca la percepción de que las relaciones sociales a través de las tecnologías de la información y la comunicación (TIC) se consideran menos personales, menos íntimas, menos comprometidas y menos sinceras que las relaciones cara a cara.

La escritora Karen Blixen apuntaba que “la cura para todo es siempre agua salada: el sudor, las lágrimas o el mar”. En el más que iniciado siglo XXI, también Internet y sus pantallas pueden ayudar en la tarea de sanar. El enfoque de la salud pública centrado en la prevención está dando un giro, marcado por la creación de capacidad y diferentes estrategias lideradas por y para la comunidad, que invitan a adoptar nuevos roles e incorporar nuevas herramientas de innovación para nuevos foros de divulgación científica y de transferencia de conocimiento: los escenarios de educación mediática para una nueva alfabetización sanitaria, la salutogénesis, el humanismo digital y las tecno-utopías, los protocolos de buenas prácticas en salud con Internet y la social media, las nuevas mediaciones para nuevos contextos, etc.

This research is set in the context of today’s societies, in which the corporate visual symbology of a business, corporation or institution constitutes an essential way to transmit its corporate image. Traditional discursive procedures can be discovered in the development of these signs. The rhetorical strategies developed by the great classical authors appear in the logo-symbols expressing the corporate values of today’s companies. Thus, rhetoric is emerging once again in the sense it had many centuries ago: A repertory of rules that, paradoxically, standardizes the deviations of language and whose control is synonymous with power. The main objective of this study is to substantiate the rhetorical construction of logos using as a model of analysis the classical process of creating discourse. This involves understanding logos as persuasive discourses addressed to a modern audience. Our findings show that the rhetorical paradigm can be considered as a creative model for the con­struction of an original logo consistent with a company’s image.

Se investigan las relaciones existentes entre la retórica y el diseño gráfico. La comparación entre un orador clásico y un diseñador gráfico, entre un discurso y una pieza de diseño, nace de las conexiones entre ambas con la comunicación y con la creatividad. En este artículo se verá cómo una aplicación de los fundamentos de la retórica clásica puede abrir nuevas puertas tanto al ejercicio profesional como a la enseñanza del diseño gráfico y a la misma teoría de la retórica de la imagen. A través del análisis de un diseño gráfico se ejemplificarán los puntos de unión que nos muestran cómo los argumentos, las operaciones, las figuras y las fases del discurso retóricos están presentes en el proceso de creación del diseño gráfico y cómo los diseñadores, tal vez de manera inconsciente, emplean técnicas inspiradas en la retórica. Dicho de otro modo, el diseño gráfico es una construcción retórica. Se produce entonces una transposición de un modelo de creación del discurso mediante signos lingüísticos a un modelo de creación del discurso formado por signos visuales y tipográficos haciendo que el Diseño sea visto como una disciplina discursiva que va más allá del componente estético.

Las imágenes mentales que generan los anuncios tienen efectos, tanto en el recuerdo como en la evocación de respuestas en los públicos. Se ha utilizado una metodología de análisis de contenido de las palabras que intervienen en la descripción verbal escrita de las imágenes mentales evocadas a través de una tarea de recuerdo libre. Los resultados confirman que el recuerdo de la imagen mental varía en los sujetos según la modalidad de presentación del estímulo: imagen, palabra, sonido. Y un análisis multivariable de la varianza atribuye las diferencias, también, a la capacidad de viveza de imagen mental de los sujetos. DOI: 10.5294/pacla.2015.18.1.9

Intrauterine growth restriction (IUGR) induces fetal cardiac remodelling and dysfunction, which persists postnatally and may explain the link between low birth weight and increased cardiovascular mortality in adulthood. However, the cellular and molecular bases for these changes are still not well understood. We tested the hypothesis that IUGR is associated with structural and functional gene expression changes in the fetal sarcomere cytoarchitecture, which remain present in adulthood.IUGR was induced in New Zealand pregnant rabbits by selective ligation of the utero-placental vessels. Fetal echocardiography demonstrated more globular hearts and signs of cardiac dysfunction in IUGR. Second harmonic generation microscopy (SHGM) showed shorter sarcomere length and shorter A-band and thick-thin filament interaction lengths, that were already present in utero and persisted at 70 postnatal days (adulthood). Sarcomeric M-band (GO: 0031430) functional term was over-represented in IUGR fetal hearts.The results suggest that IUGR induces cardiac dysfunction and permanent changes on the sarcomere.

Chemoprevention is a pragmatic approach to reduce the risk of colorectal cancer, one of the leading causes of cancer-related death in western countries. In this regard, maslinic acid (MA), a pentacyclic triterpene extracted from wax-like coatings of olives, is known to inhibit proliferation and induce apoptosis in colon cancer cell lines without affecting normal intestinal cells. The present study evaluated the chemopreventive efficacy and associated mechanisms of maslinic acid treatment on spontaneous intestinal tumorigenesis in Apc(Min/+) mice. Twenty-two mice were randomized into 2 groups: control group and MA group, fed with a maslinic acid-supplemented diet for six weeks. MA treatment reduced total intestinal polyp formation by 45% (P

Oligonucleotide-based microarrays with accurate gene coverage represent a key strategy for transcriptional studies in orphan species such as sunflower, H. annuus L., which lacks full genome sequences. The goal of this study was the development and functional annotation of a comprehensive sunflower unigene collection and the design and validation of a custom sunflower oligonucleotide-based microarray. A large scale EST (>130,000 ESTs) curation, assembly and sequence annotation was performed using Blast2GO (www.blast2go.de). The EST assembly comprises 41,013 putative transcripts (12,924 contigs and 28,089 singletons). The resulting Sunflower Unigen Resource (SUR version 1.0) was used to design an oligonucleotide-based Agilent microarray for cultivated sunflower. This microarray includes a total of 42,326 features: 1,417 Agilent controls, 74 control probes for sunflower replicated 10 times (740 controls) and 40,169 different non-control probes. Microarray performance was validated using a model experiment examining the induction of senescence by water deficit. Pre-processing and differential expression analysis of Agilent microarrays was performed using the Bioconductor limma package. The analyses based on p-values calculated by eBayes (p