Development of lentiviral-based strategies to modulate angiogenesis during post-infarction heart remodeling

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 15-03-2018Esta tesis tiene embargado el acceso al texto completo hasta el 15-09-2019A pesar de la mejora notable por la implementación de la angioplastia en el tratamiento agudo del infarto de miocardio, las consecuencias a largo plazo del infarto de miocardio, incluida la insuficiencia cardíaca, siguen siendo un desafío para la medicina moderna. En las últimas décadas, la necesidad de una terapia eficaz para mejorar o, mejor dicho, evitar una remodelación adversa y, como consecuencia, la insuficiencia cardíaca después de un infarto de miocardio, sigue sin cumplirse. Hasta la fecha, las terapias probadas se han dirigido hacia diversos objetivos, incluida la prevención de la muerte de los cardiomiocitos, la reprogramación de fibroblastos cardíacos en cardiomiocitos o progenitores cardíacos, el ajuste de las respuestas inmune y la modulación de la angiogénesis. Aquí, implementamos una nueva terapia de génica-celular, que combina las acciones de dos factores proangiogénicos VEGF-A y S1P administrados por células de médula ósea infectadas con lentivirus ex vivo. La selección de los factores se basó en su eficacia para inducir angiogénesis en un ensayo de anillo aórtico. En el modelo de isquemia-reperfusión de infarto de miocardio, las células de médula ósea que sobreexpresan hVEGF o hSphK1 se inyectaron secuencialmente en los ratones los días 4 y 7 después del infarto de miocardio. El análisis de los ratones control y los tratados 28 días después de la isquemia-reperfusión mostró una mejoría leve en el volumen del latido sin impacto en la fracción de eyección en ratones tratados con VEGF/S1P. La remodelación adversa del corazón disminuyó en los animales tratados, representada como una mejoría leve en los volúmenes sistólico y diastólico finales del ventrículo izquierdo, la prevención de la hipertrofia de los cardiomiocitos y la mejor preservación de la forma elipsoide del corazón. Además, la terapia secuencial gen-célula VEGF/S1P mitigó la extensión de la cicatriz fibrótica. El análisis de los patrones de la respuesta inmune en ratones tratados y control reveló un perfil distinto de receptores de quimioquinas en los monocitos circulantes de los ratones tratados, lo que sugiere su cambio hacia un fenotipo más reparador. Además, los macrófagos cardíacos fueron menos abundantes en la zona remota de los ratones inyectados con BMVEGF/BMSphK1. Finalmente, y conforme al objetivo primario, la administración secuencial de VEGF y S1P dio como resultado un aumento de la densidad capilar, un menor angioadaptación adversa y 14 una oxigenación tisular mejorada. Además, el índice fibrótico que indica la abundancia de miofibroblastos disminuyó en la zona de infarto de los corazones de los ratones tratados. Nuestros resultados identifican una nueva estrategia basada en el suministro secuencial de células productoras de factores angiogénicos para mejorar función cardíaca después de un infarto de miocardio.The research leading to these results has received funding from the People Programme (Marie Curie Actions) of the European Union´s Seventh Framework Programme (FP7/2007-2013) under REA grant agreement nº 608027 (¨CardioNext¨ Initial Training Networks project

Breast milk-derived human milk oligosaccharides promote Bifidobacterium interactions within a single ecosystem

Diet-microbe interactions play an important role in modulating the early-life microbiota, with Bifidobacterium strains and species dominating the gut of breast-fed infants. Here, we sought to explore how infant diet drives distinct bifidobacterial community composition and dynamics within individual infant ecosystems. Genomic characterisation of 19 strains isolated from breast-fed infants revealed a diverse genomic architecture enriched in carbohydrate metabolism genes, which was distinct to each strain, but collectively formed a pangenome across infants. Presence of gene clusters implicated in digestion of human milk oligosaccharides (HMOs) varied between species, with growth studies indicating that within single infants there were differences in the ability to utilise 2'FL and LNnT HMOs between strains. Cross-feeding experiments were performed with HMO degraders and non-HMO users (using spent or 'conditioned' media and direct co-culture). Further H-NMR analysis identified fucose, galactose, acetate, and N-acetylglucosamine as key by-products of HMO metabolism; as demonstrated by modest growth of non-HMO users on spend media from HMO metabolism. These experiments indicate how HMO metabolism permits the sharing of resources to maximise nutrient consumption from the diet and highlights the cooperative nature of bifidobacterial strains and their role as 'foundation' species in the infant ecosystem. The intra- and inter-infant bifidobacterial community behaviour may contribute to the diversity and dominance of Bifidobacterium in early life and suggests avenues for future development of new diet and microbiota-based therapies to promote infant health

Community Level Physiological Profiles (CLPP), Characterization and Microbial Activity of Soil Amended with Dairy Sewage Sludge

The aim of the present work was to assess the influence of organic amendment applications compared to mineral fertilization on soil microbial activity and functional diversity. The field experiment was set up on a soil classified as an Eutric Cambisol developed from loess (South-East Poland). Two doses of both dairy sewage sludge (20 Mg·ha−1 and 26 Mg·ha−1) and of mineral fertilizers containing the same amount of nutrients were applied. The same soil without any amendment was used as a control. The soil under undisturbed native vegetation was also included in the study as a representative background sample. The functional diversity (catabolic potential) was assessed using such indices as Average Well Color Development (AWCD), Richness (R) and Shannon–Weaver index (H). These indices were calculated, following the community level physiological profiling (CLPP) using Biolog Eco Plates. Soil dehydrogenase and respiratory activity were also evaluated. The indices were sensitive enough to reveal changes in community level physiological profiles due to treatment effects. It was shown that dairy sewage amended soil was characterized by greater AWCD, R, H and dehydrogenase and respiratory activity as compared to control or mineral fertilized soil. Analysis of variance (ANOVA) and principal component analysis (PCA) were used to depict the differences of the soil bacterial functional diversity between the treatments

Perceived discrimination based on the symptoms of covid-19, mental health, and emotional responses–the international online COVISTRESS survey

Background Despite the potential detrimental consequences for individuals’ health and discrimination from covid-19 symptoms, the outcomes have received little attention. This study examines the relationships between having personally experienced discrimination based on the symptoms of covid-19 (during the first wave of the pandemic), mental health, and emotional responses (anger and sadness). It was predicted that covid-19 discrimination would be positively related to poor mental health and that this relationship would be mediated by the emotions of anger and sadness. Methods The study was conducted using an online questionnaire from January to June 2020 (the Covistress network; including 44 countries). Participants were extracted from the COVISTRESS database (Ntotal = 280) with about a half declaring having been discriminated due to covid-19 symptoms (N = 135). Discriminated participants were compared to non-discriminated participants using ANOVA. A mediation analysis was conducted to examine the indirect effect of emotional responses and the relationships between perceived discrimination and self-reported mental health. Results The results indicated that individuals who experienced discrimination based on the symptoms of covid-19 had poorer mental health and experienced more anger and sadness. The relationship between covid-19 personal discrimination and mental health disappeared when the emotions of anger and sadness were statistically controlled for. The indirect effects for both anger and sadness were statistically significant. Discussion This study suggests that the covid-19 pandemic may have generated discriminatory behaviors toward those suspected of having symptoms and that this is related to poorer mental health via anger and sadness.publishedVersio

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)

The Wnt and Notch signalling pathways in the developing cochlea : Formation of hair cells and induction of regenerative potential

The Wnt and Notch signalling pathways control proliferation, specification, and cell fate choices during embryonic development and in adult life. Hence, there is much interest in both signalling pathways in the context of stem cell biology and tissue regeneration. In the developing ear, the Wnt and Notch signalling pathways specify otic cells and refine the ventral boundary of the otic placode. Since both signalling pathways control events essential for the formation of sensory cells, such as proliferation and hair cell differentiation, these pathways could hold promise for the regeneration of hair cells in adult mammalian cochlea. Indeed, modulating either the Wnt or Notch pathways can trigger the regenerative potential of supporting cells. In the neonatal mouse cochlea, Notch-mediated regeneration of hair cells partially depends on Wnt signalling, which implies an interaction between the pathways. This review presents how the Wnt and Notch signalling pathways regulate the formation of sensory hair cells and how modulating their activity induces regenerative potential in the mammalian cochlea

Estimation of height changes of GNSS stations from the solutions of short vectors and PSI measurements

Time series of weekly and daily solutions for coordinates of permanent GNSS stations may indicate local deformations in Earth’s crust or local seasonal changes in the atmosphere and hydrosphere. The errors of the determined changes are relatively large, frequently at the level of the signal

Frailty Syndrome—Fall Risk and Rehabilitation Management Aided by Virtual Reality (VR) Technology Solutions: A Narrative Review of the Current Literature

International audienceFrailty, a physiological syndrome (FS) affecting primarily the older adults, manifests itself through significantly depleted bodily reserves, and appreciably higher (up to over threefold) individual exposure to fall risk. Concomitant medical conditions such as balance impairment, reduced visual acuity, limited mobility, and significantly diminished daily functional performance further exacerbate the patients’ condition. Their resultant susceptibility to frequent hospitalisations makes their prognosis even worse. This narrative review aimed to provide an overview of published studies focused on rehabilitation management approaches aided by virtual reality (VR) technology in frail older adults. The authors had it also augmented with their own, evidence-based body of experience in rehabilitation. Making use of technologically advanced exercise machinery, specially adapted for rehabilitating frail older adults, combined with a structured exercise regimen, further aided by the application of select virtual reality (VR) technology solutions, clearly proved effective. Consequently, the patients were helped to move back from the frail to the pre-frail stage, as well as had their motor and cognitive functions appreciably enhanced. The application of modern technology in rehabilitating older adults over 65, affected by FS, when specifically aided by the select VR technology solutions, was also proven to complement successfully the conventional rehabilitation management. The overall versatility of the VR technology solutions, e.g., adaptation for home use allowing remote supervision, also makes this novel approach to rehabilitation far more appealing to the patients. They find it both very attractive and far more mentally engaging. Its considerable potential lies mostly in being appreciably more effective in bringing in desirable therapeutic outcomes