Melanoma expression analysis with Big Data technologies

Melanoma is a highly immunogenic tumor. Therefore, in recent years physicians have incorporated drugs that alter the immune system into their therapeutic arsenal against this disease, revolutionizing in the treatment of patients in an advanced stage of the disease. This has led us to explore and deepen our knowledge of the immunology surrounding melanoma, in order to optimize its approach. At present, immunotherapy for metastatic melanoma is based on stimulating an individual’s own immune system through the use of specific monoclonal antibodies. The use of immunotherapy has meant that many of patients with melanoma have survived and therefore it constitutes a present and future treatment in this field. At the same time, drugs have been developed targeting specific mutations, specifically BRAF, resulting in large responses in tumor regression (set up in this clinical study to 18 months), as well as a higher percentage of long-term survivors. The analysis of the gene expression changes and their correlation with clinical changes can be developed using the tools provided by those companies which currently provide gene expression platforms. The gene expression platform used in this clinical study is NanoString, which provides nCounter. However, nCounter has some limitations as the type of analysis is restricted to a predefined set, and the introduction of clinical features is a complex task. This paper presents an approach to collect the clinical information using a structured database and a Web user interface to introduce this information, including the results of the gene expression measurements, to go a step further than the nCounter tool. As part of this work, we present an initial analysis of changes in the gene expression of a set of patients before and after targeted therapy. This analysis has been carried out using Big Data technologies (Apache Spark) with the final goal being to scale up to large numbers of patients, even though this initial study has a limited number of enrolled patients (12 in the first analysis). This is not a Big Data problem, but the underlaying study aims at targeting 20 patients per year just in Málaga, and this could be extended to be used to analyze the 3.600 patients diagnosed with melanoma per year.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech. This work was funded in part by Grants TIN2014-58304-R (Ministerio de Ciencia e Innovación) and P11-TIC-7529 and P12-TIC-1519 (Plan Andaluz de Investigación, Desarrollo e Innovación). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

On the Use of Explainable Artificial Intelligence for the Differential Diagnosis of Pigmented Skin Lesions

En los últimos años, la Inteligencia Artificial Explicable (XAI) ha atraído la atención en la analítica de datos, ya que muestra un gran potencial en la interpretación de los resultados de complejos modelos de aprendizaje automático en la aplicación de problemas médicos. Se trata de que el resultado de las aplicaciones basadas en el aprendizaje automático deben ser comprendidos por los usuarios finales, especialmente en el contexto de los datos médicos, donde las decisiones deben tomarse cuidadosamente. decisiones. Como tal, se han realizado muchos esfuerzos para explicar el resultado de un modelo complejo de aprendizaje profundo en procesos de reconocimiento y clasificación de y clasificación de imágenes, como en el caso del cáncer de melanoma. Este representa un primer intento (hasta donde sabemos) de investigar experimental y técnicamente la explicabilidad de los métodos modernos de XAI modernos de XAI: explicaciones de modelos de diagnóstico interpretables locales (LIME) y Shapley Additive exPlanations (SHAP), en términos de reproducibilidad de resultados y el tiempo de ejecución en un conjunto de datos de clasificación de imágenes de melanoma. Este artículo muestra que los métodos XAI proporcionan ventajas en la interpretación de los resultados del modelo en la clasificación de imágenes de melanoma. interpretación de los resultados del modelo en la clasificación de imágenes de melanoma. Concretamente, LIME se comporta mejor que el explicador de gradiente SHAP en términos de reproducibilidad y tiempo de ejecución.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tec

Análisis térmico en la obtención de aceros y fundiciones

El análisis térmico consiste en determinar las temperaturas de las transformaciones alotrópicas (puntos críticos) que se originan al calentar o enfriar un metal o aleación. Con ellas se puede trazar la gráfica de las funciones entre tiempo y temperatura. Los puntos de inflexión o tramos horizontales de las curvas indican las temperaturas de las transformaciones alotrópicas que van acompañadas de un desprendimiento de calor (en el calentamiento). Para efectos prácticos, el análisis térmico solo es factible cuando las transformaciones en el metal ocurren con un efecto térmico lo suficientemente considerable como para que sea detectable y medible con instrumentos de medida industriales. En este trabajo el estudio se ha concretado en la faceta que interesa al fundidor, cual es la del enfriamiento desde el estado líquido hasta la solidificación total. El análisis de las transformaciones y puntos de inflexión permite predecir la composición, estructura y propiedades que tendrán las piezas que se cuelen en esa aleación líquida y aplicar a tiempo las correcciones pertinentes y necesarias para satisfacer las características exigidas a esas piezas. Es decir, hay dos pasos u objetivos en el análisis térmico: el primero es conocer que metal tenemos en el horno; el segundo es, basándose en ese conocimiento, determinar las adiciones correctoras que hay que introducir en el horno o cuchara para satisfacer las demandas del acero y fundición especificados. En este trabajo el estudio se ha concretado en la faceta que interesa al fundidor, cual es la del enfriamiento desde el estado líquido hasta la solidificación total. El análisis de las transformaciones y puntos de inflexión permite predecir la composición, estructura y propiedades que tendrán las piezas que se cuelen en esa aleación líquida y aplicar a tiempo las correcciones pertinentes y necesarias para satisfacer las características exigidas a esas piezas. Es decir, hay dos pasos u objetivos en el análisis térmico: el primero es conocer que metal tenemos en el horno; el segundo es, basándose en ese conocimiento, determinar las adiciones correctoras que hay que introducir en el horno o cuchara para satisfacer las demandas del acero y fundición especificados

Mating strategy is determinant of adenovirus prevalence in European bats

Adenoviruses are double-strained DNA viruses found in a great number of vertebrates, including humans. In order to understand their transmission dynamics, it is crucial, even from a human health perspective, to investigate how host traits influence their prevalence. Bats are important reservoirs for adenoviruses, and here we use the results of recent screenings in Western Europe to evaluate the association between characteristic traits of bat species and their probability of hosting adenoviruses, taking into account their phylogenetic relationships. Across species, we found an important phylogenetic component in the presence of adenoviruses and mating strategy as the most determinant factor conditioning the prevalence of adenoviruses across bat species. Contrary to other more stable mating strategies (e.g. harems), swarming could hinder transmission of adenoviruses since this strategy implies that contacts between individuals are too short. Alternatively, bat species with more promiscuous behavior may develop a stronger immune system. Outstandingly high prevalence of adenoviruses was reported for the Iberian species Pipistrellus pygmaeus, P. kuhlii and Nyctalus lasiopterus and we found that in the latter, males were more likely to be infected by adenoviruses than females, due to the immunosuppressing consequence of testosterone during the mating season. As a general trend across species, we found that the number of adenoviruses positive individuals was different across localities and that the difference in prevalence between populations was correlated with their geographic distances for two of the three studied bat species (P. pygmaeus and P.kuhlii). These results increase our knowledge about the transmission mechanisms of adenoviruses.This work received support from: grant number: SAF2006-12784-C02/01-02 to JE, JJ, IC; URLs to sponsors’ websites: http://www.ciencia.gob.es/portal/site/MICINN/menuitem.7eeac5cd345b4f34f09dfd1001432ea0/?vgnextoid=beebec05f2a7d210VgnVCM1000001d04140aRCRD; grant numbers: SAF2009-09172 to JE, JJ; URLs to sponsors’ websites: http://www.ciencia.gob.es/portal/site/MICINN/menuitem.7eeac5cd345b4f34f09dfd1001432ea0/?vgnextoid=fe5aec1eb658c310VgnVCM1000001d04140aRCRD; grant numbers: SAF2013-47194-P to JE, JJ, GP, OP; URLs to sponsors’ websites: http://www.ciencia.gob.es/portal/site/MICINN/menuitem.7eeac5cd345b4f34f09dfd1001432ea0/?vgnextoid=0b7f11a1c35d0610VgnVCM1000001d04140aRCRD; grant numbers: SAF2017-89355-P to JE, JJ, GP, OP, JB; URLs to sponsors’ websites: http://www.ciencia.gob.es/portal/site/MICINN/menuitem.7eeac5cd345b4f34f09dfd1001432ea0/?vgnextoid=abf192b9036c2210VgnVCM1000001d04140aRCRD; grant numbers: PI15CIII/00028 to IC, MMIC; URLs to sponsors’ websites: http://www.ciencia.gob.es/portal/site/MICINN. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.S

Rabia animal en España. Situación en 2012

La rabia es una de las zoonosis más importantes, resultando un serio problema de salud pública debido a su gravedad clínica, ya que produce en el hombre una encefalomielitis vírica aguda mortal. Aunque la distribución de la enfermedad es mundial, la incidencia de rabia humana se desconoce; la Organización Mundial de la Salud (OMS) estima que cada año se producen en el mundo unas 55.000 muertes por rabia, principalmente en países en desarrollo de África y Asia.N

New Adenovirus Groups in Western Palaearctic Bats

In the context of long-term screening for viruses on Western Palaearctic bats, we tested for the presence of adenovirus 1392 oropharyngeal swabs and 325 stool samples taken from 27 bat species. Adenoviruses were detected in 12 species of the Vespertilionidae and the Rhinolophidae families. Fifty positive respiratory and 26 positive stool samples were studied. Phylogenetic analyses of partial hexon protein and partial DNA-dependent DNA polymerase genes indicate that all these bat adenoviruses belong to the genus Mastadenovirus but without constituting a monophyletic cluster. According to genetic identities, the new groups are distinct to the previously described Bat mastadenovirus A and B species and contribute with potentially new members. Our data support that diversity of bat mastadenovirus is host-dependent and increase the knowledge of potentially pathogenic virus from bats. Due to the active role of bats as viral reservoirs, the characterization of these viruses is relevant for Public Health.This project was financially supported by an agreement between the Public Health Department of the Spanish Ministry of Health and the Instituto de Salud Carlos III for the development of "Rabies Surveillance in Spain" and by projects SAF 2006-12784-C02-01, SAF 2006-12784-C02-02, SAF 2009-09172 and SAF2013-47194-P of the General Research Programme of the Spanish Ministry of Science and Education

Investigating Local Patterns of Mumps Virus Circulation, Using a Combination of Molecular Tools

Mumps is a vaccine-preventable disease caused by the mumps virus (MuV). However, MuV has re-emerged in many countries with high vaccine coverage. The World Health Organization (WHO) recommends molecular surveillance based on sequencing of the small hydrophobic (SH) gene. Additionally, the combined use of SH and non-coding regions (NCR) has been described in different studies, proving to be a useful complement marker to discriminate general patterns of circulation at national and international levels. The aim of this work is to test local-level usefulness of the combination of SH and MF-NCR sequencing in tracing hidden transmission clusters and chains during the last epidemic wave (2015-2020) in Spain. A database with 903 cases from the Autonomous Community of Madrid was generated by the integration of microbiological and epidemiological data. Of these, 453 representative cases were genotyped. Eight different SH variants and thirty-four SH haplotypes were detected. Local MuV circulation showed the same temporal pattern previously described at a national level. Only two of the thirteen previously identified outbreaks were caused by more than one variant/haplotype. Geographical representation of SH variants allowed the identification of several previously undetected clusters, which were analysed phylogenetically by the combination of SH and MF-NCR, in a total of 90 cases. MF-NCR was not able to improve the discrimination of geographical clusters based on SH sequencing, showing limited resolution for outbreak investigations.A.M.G. was funded by CIBER de Epidemiología y Salud Pública (CIBERESP), ISCIII. This work was supported by the “Instituto de Salud Carlos III” (PI15CIII/00023 and PI19ICIII/0041).S

Compensatory Motor Neuron Response to Chromatolysis in the Murine hSOD1(G93A) Model of Amyotrophic Lateral Sclerosis

We investigated neuronal self-defense mechanisms in a murine model of amyotrophic lateral sclerosis (ALS), the transgenic hSOD1(G93A), during both the asymptomatic and symptomatic stages. This is an experimental model of endoplasmic reticulum (ER) stress with severe chromatolysis. As a compensatory response to translation inhibition, chromatolytic neurons tended to reorganize the protein synthesis machinery at the perinuclear region, preferentially at nuclear infolding domains enriched in nuclear pores. This organization could facilitate nucleo-cytoplasmic traffic of RNAs and proteins at translation sites. By electron microscopy analysis, we observed that the active euchromatin pattern and the reticulated nucleolar configuration of control motor neurons were preserved in ALS chromatolytic neurons. Moreover the 5'-fluorouridine (5'-FU) transcription assay, at the ultrastructural level, revealed high incorporation of the RNA precursor 5'-FU into nascent RNA. Immunogold particles of 5'-FU incorporation were distributed throughout the euchromatin and on the dense fibrillar component of the nucleolus in both control and ALS motor neurons. The high rate of rRNA transcription in ALS motor neurons could maintain ribosome biogenesis under conditions of severe dysfunction of proteostasis. Collectively, the perinuclear reorganization of protein synthesis machinery, the predominant euchromatin architecture, and the active nucleolar transcription could represent compensatory mechanisms in ALS motor neurons in response to the disturbance of ER proteostasis. In this scenario, epigenetic activation of chromatin and nucleolar transcription could have important therapeutic implications for neuroprotection in ALS and other neurodegenerative diseases. Although histone deacetylase inhibitors are currently used as therapeutic agents, we raise the untapped potential of the nucleolar transcription of ribosomal genes as an exciting new target for the therapy of some neurodegenerative diseases

A Novel Pathway of TEF Regulation Mediated by MicroRNA-125b Contributes to the Control of Actin Distribution and Cell Shape in Fibroblasts

BACKGROUND: Thyrotroph embryonic factor (TEF), a member of the PAR bZIP family of transcriptional regulators, has been involved in neurotransmitter homeostasis, amino acid metabolism, and regulation of apoptotic proteins. In spite of its relevance, nothing is known about the regulation of TEF. PRINCIPAL FINDINGS: p53-dependent genotoxic agents have been shown to be much more harmful for PAR bZIP-deficient mice as compared to wild type animals. Here we demonstrate that TEF expression is controlled by p53 through upregulation of microRNA-125b, as determined by both regulating the activity of p53 and transfecting cells with microRNA-125b precursors. We also describe a novel role for TEF in controlling actin distribution and cell shape in mouse fibroblasts. Lack of TEF is accompanied by dramatic increase of cell area and decrease of elongation (bipolarity) and dispersion (multipolarity). Staining of actin cytoskeleton also showed that TEF (-/-) cells are characterized by appearance of circumferential actin bundles and disappearance of straight fibers. Interestingly, transfection of TEF (-/-) fibroblasts with TEF induced a wild type-like phenotype. Consistent with our previous findings, transfection of wild type fibroblasts with miR-125b promoted a TEF (-/-)-like phenotype, and a similar but weaker effect was observed following exogenous expression of p53. CONCLUSIONS/SIGNIFICANCE: These findings provide the first evidence of TEF regulation, through a miR-125b-mediated pathway, and describes a novel role of TEF in the maintenance of cell shape in fibroblasts

Role of the Drosophila Non-Visual ß-Arrestin Kurtz in Hedgehog Signalling

The non-visual ß-arrestins are cytosolic proteins highly conserved across species that participate in a variety of signalling events, including plasma membrane receptor degradation, recycling, and signalling, and that can also act as scaffolding for kinases such as MAPK and Akt/PI3K. In Drosophila melanogaster, there is only a single non-visual ß-arrestin, encoded by kurtz, whose function is essential for neuronal activity. We have addressed the participation of Kurtz in signalling during the development of the imaginal discs, epithelial tissues requiring the activity of the Hedgehog, Wingless, EGFR, Notch, Insulin, and TGFβ pathways. Surprisingly, we found that the complete elimination of kurtz by genetic techniques has no major consequences in imaginal cells. In contrast, the over-expression of Kurtz in the wing disc causes a phenotype identical to the loss of Hedgehog signalling and prevents the expression of Hedgehog targets in the corresponding wing discs. The mechanism by which Kurtz antagonises Hedgehog signalling is to promote Smoothened internalization and degradation in a clathrin- and proteosomal-dependent manner. Intriguingly, the effects of Kurtz on Smoothened are independent of Gprk2 activity and of the activation state of the receptor. Our results suggest fundamental differences in the molecular mechanisms regulating receptor turnover and signalling in vertebrates and invertebrates, and they could provide important insights into divergent evolution of Hedgehog signalling in these organisms