Polycomb RING1B in neural stem cells proliferation

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 23-06-2017Esta tesis tiene embargado el acceso al texto completo hasta el 23-12-2018Polycomb protein RING1B is part of the E3 ligase that makes the core component of Polycomb Repressive Complex 1 complexes responsible for monoubiquitination of histone H2A at lysine 119. RING1B has been described as transcriptional repressor and chromatin modifier, indispensable for a proper embryonic development and lineage specification in cellular differentiation. Previous work in our laboratory has revealed additional, nontranscriptional functions for RING1B i.e in S-phase progression. Using unperturbed neural stem cells (NSCs) derived from a murine conditional model of loss-of-function of RING1B, we unveil roles of RING1B in cell proliferation, DNA damage and redox homeostasis, independently of its activity as transcriptional repressor. RING1B deficiency caused p21/CDKN1A upregulation, the principal mediator of the proliferative defect. This is mostly due to activation of DNA damage response (DDR). Upregulation of p21 followed the known ATM/P53/p21 DDR axis, as shown by restoration of proliferation rate in p21/Cdkn1a and P53 knock out NSCs, or in the presence of ATM inhibitor. Concurrent with proliferation arrest of RING1B-depleted NSCs, accumulation of doublestrand breaks (DSBs) originated, at least in part, by an increase in endogenous Reactive Oxygen Species (ROS). Consistently, treatment with antioxidant was able to decrease DNA damage and recover normal proliferation. This essential function, preventing accumulation of ROS in NSCs was fulfilled by RING1B, but not its paralog RING1A through stabilization of Polycomb cofactor BMI-1. In summary, we have identified a novel function of RING1B promoting proliferation of multipotent progenitors through the maintenance of physiological levels of oxidative stress, avoiding and managing a response to DNA damage through mechanisms independent, at least partially, of its better known as transcriptional repressor and instead assuring the stability of its own cofactor in NSCs.La proteína RING1B es el componente principal del Complejo Represor Polycomb 1 (Polycomb Repressive Complex , PRC1) y cataliza la monoubiquitinación de la lisina 119 de la histona H2A. RING1B se ha descrito como un represor transcripcional y modificador de la cromatina y se conoce para su papel clave en el correcto desarrollo del embrión y especificación celular en la diferenciación celular. Recientemente, en nuestro laboratorio se han descrito para RING1B funciones adicionales a las transcripcionales, tales como la correcta progresión por la fase S del ciclo celular. En este trabajo hemos utilizado como modelo experimental células madre neurales crecidas en condiciones de proliferación, y hemos podido desvelar la participación de RING1B en la proliferación celular, daño al DNA y control de la homeostasis oxidativa. La deficiencia de RING1B causa una mayor expresión del inhibidor del ciclo celular p21/CDKN1A que ha resultado ser el principal mediador de la parada proliferativa. La expresión de p21/CDKN1A es consecuencia de la activación de una respuesta a daño al DNA y no simplemente de la ausencia de una represión transcripcional. En la respuesta a daño a DNA participan la quinasa ATM y la proteína P53, como demuestra la recuperación de la proliferación en ausencia de p21/Cdkn1a o P53, y también por tratamiento con un inhibidor de la actividad quinasa de ATM. En este trabajo se ha demostrado como RING1B es importante para prevenir la formación de rupturas dobles de cadena del DNA que se originan, principalmente, por el incremento de Especies Reactivas del Oxigeno (Reactive Oxygen Species, ROS) en las células mutantes, y que finalmente llevan a una parada de la proliferación. En consonancia, el tratamiento con el antioxidante N-acetil-cisteína previene la formación de daño a DNA y permite rescatar la proliferación. Los datos aquí presentados sugieren que el papel de RING1B, y no de RING1A, se desarrolla garantizando la estabilidad de su co-factor BMI-1, ya descrito como regulador de la homeostasis oxidativa. En conjunto, en este trabajo se han identificado nuevas funciones de RING1B en prevenir el estrés oxidativo y la consecuente activación de una respuesta de daño al ADN de manera independiente de su función como represor transcripcional, y que implica la estabilización de su co-factor BMI-1 en células madre neurales.El desarrollo del trabajo ha sido posible gracias a la financiación concedida por el Campus Excelencia Internacional-Universidad Autónoma de Madrid (CEI-UAM) a través de una beca de Formación de Personal Investigador (Resolución del Programa de Posgrado en Biociencias Moleculares de 26 de septiembre de 2012), así como a través de la Comunidad Autónoma de Madrid gracias al proyecto S2010/BMD-2470 del programa ONCOCYCLE y al proyecto SAF2013-47997-P (MINECO)

The Immune System of Mesothelioma Patients: A Window of Opportunity for Novel Immunotherapies

The interplay between the immune system and the pleural mesothelium is crucial both for the development of malignant pleural mesothelioma (MPM) and for the response of MPM patients to therapy. MPM is heavily infiltrated by several immune cell types which affect the progression of the disease. The presence of organized tertiary lymphoid structures (TLSs) witness the attempt to fight the disease in situ by adaptive immunity which is often suppressed by tumor expressed factors. In rare patients physiological, pharmacological or vaccine-induced immune response is efficient, rendering their plasma a valuable resource of anti-tumor immune cells and molecules. Of particular interest are human antibodies targeting antigens at the tumor cell surface. Here we review current knowledge regarding MPM immune infiltration, MPM immunotherapy and the harnessing of this response to identify novel biologics as biomarkers and therapeutics through innovative screening strategies

POLARIX: a pathfinder mission of X-ray polarimetry

Since the birth of X-ray astronomy, spectral, spatial and timing observation improved dramatically, procuring a wealth of information on the majority of the classes of the celestial sources. Polarimetry, instead, remained basically unprobed. X-ray polarimetry promises to provide additional information procuring two new observable quantities, the degree and the angle of polarization. POLARIX is a mission dedicated to X-ray polarimetry. It exploits the polarimetric response of a Gas Pixel Detector, combined with position sensitivity, that, at the focus of a telescope, results in a huge increase of sensitivity. Three Gas Pixel Detectors are coupled with three X-ray optics which are the heritage of JET-X mission. POLARIX will measure time resolved X-ray polarization with an angular resolution of about 20 arcsec in a field of view of 15 arcmin $\times$ 15 arcmin and with an energy resolution of 20 % at 6 keV. The Minimum Detectable Polarization is 12 % for a source having a flux of 1 mCrab and 10^5 s of observing time. The satellite will be placed in an equatorial orbit of 505 km of altitude by a Vega launcher.The telemetry down-link station will be Malindi. The pointing of POLARIX satellite will be gyroless and it will perform a double pointing during the earth occultation of one source, so maximizing the scientific return. POLARIX data are for 75 % open to the community while 25 % + SVP (Science Verification Phase, 1 month of operation) is dedicated to a core program activity open to the contribution of associated scientists. The planned duration of the mission is one year plus three months of commissioning and SVP, suitable to perform most of the basic science within the reach of this instrument.Comment: 42 pages, 28 figure

Prenatal tobacco smoke exposure increases hospitalizations for bronchiolitis in infants

BACKGROUND: Tobacco smoke exposure (TSE) is a worldwide health problem and it is considered a risk factor for pregnant women's and children's health, particularly for respiratory morbidity during the first year of life. Few significant birth cohort studies on the effect of prenatal TSE via passive and active maternal smoking on the development of severe bronchiolitis in early childhood have been carried out worldwide. METHODS: From November 2009 to December 2012, newborns born at ≥ 33 weeks of gestational age (wGA) were recruited in a longitudinal multi-center cohort study in Italy to investigate the effects of prenatal and postnatal TSE, among other risk factors, on bronchiolitis hospitalization and/or death during the first year of life. RESULTS: Two thousand two hundred ten newborns enrolled at birth were followed-up during their first year of life. Of these, 120 (5.4%) were hospitalized for bronchiolitis. No enrolled infants died during the study period. Prenatal passive TSE and maternal active smoking of more than 15 cigarettes/daily are associated to a significant increase of the risk of offspring children hospitalization for bronchiolitis, with an adjHR of 3.5 (CI 1.5-8.1) and of 1.7 (CI 1.1-2.6) respectively. CONCLUSIONS: These results confirm the detrimental effects of passive TSE and active heavy smoke during pregnancy for infants' respiratory health, since the exposure significantly increases the risk of hospitalization for bronchiolitis in the first year of lif

Risk factors for bronchiolitis hospitalization during the first year of life in a multicenter Italian birth cohort

BACKGROUND: Respiratory Syncytial Virus (RSV) is one of the main causes of respiratory infections during the first year of life. Very premature infants may contract more severe diseases and 'late preterm infants' may also be more susceptible to the infection. The aim of this study is to evaluate the risk factors for hospitalization during the first year of life in children born at different gestational ages in Italy. METHODS: A cohort of 33-34 weeks gestational age (wGA) newborns matched by sex and age with two cohort of newborns born at 35-37 wGA and > 37 wGA were enrolled in this study for a three-year period (2009-2012). Hospitalization for bronchiolitis (ICD-9 code 466.1) during the first year of life was assessed through phone interview at the end of the RSV season (November-March) and at the completion of the first year of life. RESULTS: The study enrolled 2314 newborns, of which 2210 (95.5 %) had a one year follow-up and were included in the analysis; 120 (5.4 %) were hospitalized during the first year of life for bronchiolitis. Children born at 33-34 wGA had a higher hospitalization rate compared to the two other groups. The multivariate analysis carried out on the entire population associated the following factors with higher rates for bronchiolitis hospitalization: male gender; prenatal treatment with corticosteroids; prenatal exposure to maternal smoking; singleton delivery; respiratory diseases in neonatal period; surfactant therapy; lack of breastfeeding; siblings <10 years old; living in crowded conditions and/or in unhealthy households and early exposure to the epidemic RSV season. When analysis was restricted to preterms born at 33-34 wGA the following variables were associated to higher rates of bronchiolitis hospitalization: male gender, prenatal exposure to maternal smoking, neonatal surfactant therapy, having siblings <10 years old, living in crowded conditions and being exposed to epidemic season during the first three months of life. CONCLUSION: Our study identified some prenatal, perinatal and postnatal conditions proving to be relevant and independent risk factors for hospitalization for bronchiolitis during the first year of life. The combination of these factors may lead to consider palivizumab prophylaxis in Italy

Natural disasters and demand for redistribution: lessons from an earthquake

Abstract The literature shows that when a society believes that wealth is determined by random “luck” rather than by merit, it demands more redistribution. Adverse shocks, like earthquakes, strengthen the belief that random “bad luck” can frustrate the outcomes achieved with merit. We theoretically illustrate that individuals react to such shocks by raising support for redistribution. We then present evidence of this behavior by exploiting a natural experiment provided by one of the strongest seismic events that occurred in Italy in the last three decades, the L’Aquila earthquake in 2009. We assemble a novel dataset by matching information on the ground acceleration registered throughout the National Strong Motion Network during the earthquake with survey data about individual opinions on redistribution collected a few months later. The empirical analysis illustrates that the intensity of the shakes is associated with subsequent stronger beliefs that, for a society to be fair, income inequalities should be levelled by redistribution

Repeated shocks and preferences for redistribution

Abstract A society that believes wealth to be determined by random “luck” rather than by merit, demands more redistribution. The theoretical literature shows that any increase in the volatility of income caused by unpredictable adverse shocks implies a higher support for redistribution. We present evidence of this behavior by exploiting a natural experiment provided by the L’Aquila earthquake in 2009, which hit a large area of Central Italy through a series of destructive shakes over eight days. Matching detailed information on the ground acceleration registered during each shock with survey data about individual opinions on redistribution we show that the average intensity of the shakes is associated with subsequent stronger beliefs that, for a society to be fair, income inequalities should be levelled by redistribution. The shocks, however, are not all alike. We find that only the last three shakes - occurred on the fourth and the eighth day of the earthquake - have a statistically significant impact. Overall, we find that the timing and repetition of the shock play a role in shaping redistributive preferences

Repeated shocks and preferences for redistribution

Abstract A society that believes wealth to be determined by random “luck” rather than by merit, demands more redistribution. The theoretical literature shows that any increase in the volatility of income caused by unpredictable adverse shocks implies a higher support for redistribution. We present evidence of this behavior by exploiting a natural experiment provided by the L’Aquila earthquake in 2009, which hit a large area of Central Italy through a series of destructive shakes over eight days. Matching detailed information on the ground acceleration registered during each shock with survey data about individual opinions on redistribution we show that the average intensity of the shakes is associated with subsequent stronger beliefs that, for a society to be fair, income inequalities should be levelled by redistribution. The shocks, however, are not all alike. We find that only the last three shakes - occurred on the fourth and the eighth day of the earthquake - have a statistically significant impact. Overall, we find that the timing and repetition of the shock play a role in shaping redistributive preferences