Mutations in TOP3A Cause a Bloom Syndrome-like Disorder

Bloom syndrome, caused by biallelic mutations in BLM, is characterized by prenatal-onset growth deficiency, short stature, an erythematous photosensitive malar rash, and increased cancer predisposition. Diagnostically, a hallmark feature is the presence of increased sister chromatid exchanges (SCEs) on cytogenetic testing. Here, we describe biallelic mutations in TOP3A in ten individuals with prenatal-onset growth restriction and microcephaly. TOP3A encodes topoisomerase III alpha (TopIIIα), which binds to BLM as part of the BTRR complex, and promotes dissolution of double Holliday junctions arising during homologous recombination. We also identify a homozygous truncating variant in RMI1, which encodes another component of the BTRR complex, in two individuals with microcephalic dwarfism. The TOP3A mutations substantially reduce cellular levels of TopIIIα, and consequently subjects’ cells demonstrate elevated rates of SCE. Unresolved DNA recombination and/or replication intermediates persist into mitosis, leading to chromosome segregation defects and genome instability that most likely explain the growth restriction seen in these subjects and in Bloom syndrome. Clinical features of mitochondrial dysfunction are evident in several individuals with biallelic TOP3A mutations, consistent with the recently reported additional function of TopIIIα in mitochondrial DNA decatenation. In summary, our findings establish TOP3A mutations as an additional cause of prenatal-onset short stature with increased cytogenetic SCEs and implicate the decatenation activity of the BTRR complex in their pathogenesis

Twist1 Suppresses Senescence Programs and Thereby Accelerates and Maintains Mutant Kras-Induced Lung Tumorigenesis

KRAS mutant lung cancers are generally refractory to chemotherapy as well targeted agents. To date, the identification of drugs to therapeutically inhibit K-RAS have been unsuccessful, suggesting that other approaches are required. We demonstrate in both a novel transgenic mutant Kras lung cancer mouse model and in human lung tumors that the inhibition of Twist1 restores a senescence program inducing the loss of a neoplastic phenotype. The Twist1 gene encodes for a transcription factor that is essential during embryogenesis. Twist1 has been suggested to play an important role during tumor progression. However, there is no in vivo evidence that Twist1 plays a role in autochthonous tumorigenesis. Through two novel transgenic mouse models, we show that Twist1 cooperates with KrasG12D to markedly accelerate lung tumorigenesis by abrogating cellular senescence programs and promoting the progression from benign adenomas to adenocarcinomas. Moreover, the suppression of Twist1 to physiological levels is sufficient to cause Kras mutant lung tumors to undergo senescence and lose their neoplastic features. Finally, we analyzed more than 500 human tumors to demonstrate that TWIST1 is frequently overexpressed in primary human lung tumors. The suppression of TWIST1 in human lung cancer cells also induced cellular senescence. Hence, TWIST1 is a critical regulator of cellular senescence programs, and the suppression of TWIST1 in human tumors may be an effective example of pro-senescence therapy

I. Encuentro de la Red de Asentamientos Populares : aportes teórico-metodológicos para la reflexión sobre políticas públicas de acceso al hábitat

Contenidos Introducción / M. Cecilia Marengo, Ana Laura Elorza, Virginia Monayar ; Eje 1. Acceso al hábitat y urbanizaciones informales; Asentamientos (in)formales en pequeñas metrópolis del Cono Sur. Estado de situación y debate actual / Ricardo Apaolaza, Elizabeth Zenteno Torres, Marco Sumiza; Un análisis comparativo sobre la expansión de asentamientos populares en las ciudades patagónicas / Santiago Bachiller, Mariana Giaretto, Pablo Marigo, Natalia Usach ; Acceso al Hábitat para los ¨sin techo¨: la lucha por la tierra en la Ciudad de Posadas-Misiones / Myriam Elena Barone, Jonas Dumas, Mariela Dachary, Celia Draganchuk; El mercado informal de suelo y vivienda en resistencia. El caso del asentamiento en "La Rubita" Resistencia, Argentina / María Andrea Benitez, María Victoria Cazorla; Brazos Unidos un realojo en construcción colectiva / Borelli, Lily, Halich, Verónica; Transformaciones en el hábitat de asentamientos informales y políticas públicas sociales. El caso de barrio nuestro hogar III / Renzo Cáceres; Discursividad mediática sobre el acceso y producción del hábitat popular en el barrio Costanera / Debora Leticia Decima; Trayectorias residenciales y usos de la ciudad como clave de lectura de la lucha por el acceso a la ciudad / María Mercedes Di Virgilio, Natalia Cosacov, Denise Brikman, Mercedes Najman; Asentamientos en el borde metropolitano. Avances de investigación, reflexiones y preguntas / Lucas Jordán Dombroski; Repensando el acceso al hábitat en ciudades medias. La problemática habitacional de Tandil / Agustina Girado; Narrativas de un asentamiento de comienzos de siglo: más allá de la épica y la mafia / María Maneiro; Informalidad y periferia urbana. Derivas de la política habitacional / M. Cecilia Marengo, Virginia Monayar, Florencia Sosa; Sobre las ¿nuevas? ocupaciones de tierras. Notas para una periodización de las tomas en San Francisco Solano, 1981-2002 / Santiago Nardin Memorias villeras en disputa sobre las intervenciones estatales de erradicación en Villa 20 (1976-1983) / Julieta Oxman; El Centro para Erradicación de Villas de Emergencia. Planificación, censo y viviendas, Rosario (1964-1983) / Anahí G. Pagnoni; Ensayo de una cartografía de asentamientos informales en la Ciudad de Córdoba / German Gustavo Rebord, Andrea Karina Stiefkens; Urbanización y prácticas estatales en asentamientos populares en Comodoro Rivadavia. El caso del “Barrio las Américas” / Letizia Vázquez; Eje 2: Derecho a la ciudad: conflictos y disputas por el territorio urbano; La ciudad contra el barrio. El caso de los Barrios del Sur en San José de Costa Rica / Pablo Acuña Quiel; Procesos autogestionarios de hábitat popular y políticas urbanas en la ciudad de Ushuaia. Tierra del Fuego. Argentina / Alicia Delia Alcaráz; Conflictos y tensiones en la ocupación del suelo en Posadas. Misiones, Argentina: procesos de diferenciación / Lucia Mariana Andrujovich, Laura Josefa Krujoski,Myriam Elena Barone; Políticas públicas, exclusión y conformación de identidades colectivas / Sandra Raquel Ávalos; La reurbanización del Playón de Chacarita como problema público. Arenas, actores y políticas públicas / Joaquín Benítez; Relocalización, organización y derecho a la ciudad. El caso de Barrio Nuevo (La Plata) / María Sofía Bernat; Resistencias y disputas político-judiciales en casos de desalojos de asentamientos en Buenos Aires / María Cristina Cravino; Análisis de las herramientas territoriales de la organización ArqCom (LP) en el periodo 2012-2018 / Andrea Di Croce Garay, Nahir Meline Cantar, Ángeles Belén Carrizo Romero, Tamara Dileo; Planificación y urbanización del Barrio 31 y 31 bis / Rosana Karina Espejo; Mercado de suelo: tensiones y ambigüedades. El caso de la zona Norte de Resistencia, Chaco, Argentina / Sebastián Galvaliz, María del Rosario Olmedo; Marta Graciela Giró; Experiencias de urbanización y ciudadanización en La Carbonilla. Una propuesta de análisis en escalas / María Belén Garibotti, Luciana Boroccioni, María Florencia Girola ¿Integración? A la trama formal. De complejidades a desafíos / Carolain Izaguirre, Marion Tejera y Carolina Leiva; ¿Urbanizar o aniquilar? Disyuntivas ontológicas en los procesos de urbanización de las sierras de Córdoba / Denise Mattioli; Conflicto y construcción de resistencias en el asentamiento Barrio Flores / Emilia Elisa Molina; Conflictos territoriales y recualificación de la ribera. Los pescadores artesanales y los espacios públicos / Diego Roldán; El Bajo Belgrano: del Barrio de las Latas a la Villa 30 / Valeria Laura Snitcofsky; Líneas de fuga en un barrio de resistencia. Visualización de una lucha / Rafael Ramón Franco Spatuzza; Nuevas legalidades para la reurbanización de villas en CABA. Un desafío para los derechos / Agustín Territoriale, María Julia López; Los Vacíos Urbanos. Dinámicas Urbanas y Respuestas Innovadoras frente al Derecho a la Ciudad / Ezequiel Zeitune, Silvia A Politi, Natalia Czytajlo; Eje 3: Políticas públicas para atender la informalidad y de gestión en el hábitat popular; Tolerancia y precariedad. Advertencias de la política de regularización del Gran Resistencia al RENABAP / Miguel Ángel Barreto, Evelyn Roxana Abildgaard, María Laura Puntel; Adicciones y narcomenudeo, barreras (in) franqueables para los asentamientos informales en Tucumán, Argentina / Paula Boldrini; Políticas de relocalización de villas: ¿qué pasa después? La organización consorcial como práctica comunitaria / María Florencia Bruno, Belén Demoy, Natalia Fainburg, Romina Olejarczyk; La disputa por la participación y la noción de participación en disputa: una reflexión desde el proceso de urbanización de la Villa 31 (2015-2019) / Tomás Capalbo; Economía popular en asentamientos informales del Gran San Miguel de Tucumán / Corina María Cattáneo; La producción de territorialidades en el habitar un asentamiento: procesos de intervención estatal y disociaciones socio espaciales / Magali Chanampa; Estrategias de gestión territorial desde las políticas públicas: replicando el “modelo Medellín” con acento Cordobés / Ana Laura Elorza, Mónica Alvarado Rodríguez, Fani Balcazar, Ernesto Morillo, Mariana Gamboa; Discusiones sobre la conceptualización e identificación de asentamientos informales. Análisis de la realidad en Chubut / María Paula Ferrari, Sergio Andrés Kaminker, Roxana Yanina Velásquez; Barrios autoproducidos en ciudades intermedias. El caso de Río Grande, Tierra del Fuego AIAS / Nadia B. Finck; Luces y sombras del Programa Compra de Vivienda Usada / Elena Inés Gabriel Hernández; Programas de Inclusión Socio-Urbana: ¿Producto de última generación de la Nueva Agenda Urbana? / Fernando Murillo, Gabriel Artese, Andrés Mage; Los dispositivos de espera en las políticas habitacionales / Romina Olejarczyk; Tres debates recurrentes acerca de la vivienda para la población urbana de menores ingresos / Juan Santiago Palero; Nuevos asentamientos precarios: un desafío a la Política Habitacional y Urbana Chilena / Rubén Sepúlveda Ocampo, Felipe Núñez Orrego; Irrumpir con las recetas. Reflexiones en torno a desarrollo, políticas públicas y hábitat popular / Carla Eleonora Pedrazzani, María Inés Sesma.Esta publicación presenta los trabajos del I. Encuentro de la Red de Asentamientos Populares: aportes teórico -metodológicos para la reflexión sobre políticas públicas de acceso al hábitat, desarrollado los días 23 y 24 de mayo de 2019 en la Facultad de Arquitectura, Urbanismo y Diseño de la Universidad Nacional de Córdoba. En las últimas dos décadas, el INVIHAB (Instituto de Investigación de Vivienda y Hábitat) se ha conformado como un espacio de referencia en la investigación, transferencia y formación en temáticas relativas a las políticas de vivienda, territorio, informalidad urbana, ambiente y ciudadanía. Experiencia que ha llevado a la articulación con otros espacios académicos, organizaciones socio-territoriales, gobiernos locales, en el sentido de confluir en la comprensión, reflexión y formulación de propuestas para mitigar las desigualdades socioterritoriales. En este escenario, se viene construyendo una red de investigadores que estudian la informalidad urbana desde diversos enfoques -territoriales, físico-espaciales, sociales, urbanos, laborales, entre otros- tendientes a superar las miradas parciales y locales desde los abordajes teórico metodológicos y propiciar la comprensión del fenómeno desde una perspectiva que abarque la multiplicidad de campos y su complejidad.FIL: Marengo, María Cecilia. Universidad Nacional de Córdoba. Facultad de Arquitectura, Urbanismo y Diseño; Argentina.FIL: Elorza, Ana Laura. Universidad Nacional de Córdoba. Facultad de Arquitectura, Urbanismo y Diseño; Argentina.FIL: Monayar, Virginia. Universidad Nacional de Córdoba. Facultad de Arquitectura, Urbanismo y Diseño; Argentina

Analysis of a Mediterranean Tropical-Like Cyclone. Sensitivity to WRF Parameterizations and Horizontal Resolution

Due to their rarity and intensity, Mediterranean Tropical-Like Cyclones (TLCs; also known as medicanes) have been a subject of study over the last decades and lately the interest has undoubtedly grown. The current study investigates a well-documented TLC event crossed south Sicily on November 7–8, 2014 and the added value of higher spatial horizontal resolution through a physics parameterization sensitivity analysis. For this purpose, Weather Research and Forecasting model (version 3.9) is used to dynamically downscale ECMWF Re-Analysis (version 5) (ERA5) reanalysis 31 km spatial resolution to 16 km and 4 km, as parent and inner domain, respectively. In order to increase the variability and disparity of the results, spectral nudging was implemented on both domains and the outputs were compared against satellite observations and ground-based stations. Although, the study produces mixed results, there is a clear indication that the increase of resolution benefits specific aspects of the cyclone, while it deteriorates others, based on both ground and upper air analyses. The sensitivity of the parent domain displays an overall weak variability while the simulations demonstrate a positive time-lag predicting a less symmetric cyclone with weak warm core. On the contrary, inner domain analysis shows stronger variability between the model simulations reproducing more distinct clear tropical characteristics with less delayed TLC development for most of the experiments

A Sensitivity Study of High-Resolution Climate Simulations for Greece

In the present study, the ability of the Advanced Weather Research and Forecasting numerical model (WRF-ARW) to perform climate regionalization studies in the topographically complex region of Greece, was examined in order to explore the possibility of a more reliable selection of physical schemes for the simulation of historical and future high resolution (5 km) climate model experiments to investigate the impact of climate change. This work is directly linked to a previous study investigating the performance of seven different model setups for one year, from which the need was derived for further examination of four different simulations to investigate the model sensitivity on the representation of surface variables statistics during a 5-year period. The results have been compared with observational data for maximum and minimum air temperature and daily precipitation through statistical analysis. Clear similarities were found in precipitation patterns among simulations and observations, yielding smoothly its inter-annual variability, especially during the wettest months and summer periods, with the lowest positive percentage BIAS calculated at about 19% for the selected combination of physics parameterizations (PP3). Regarding the maximum and minimum temperature, statistical analysis showed a high correlation above 0.9, and negative bias around 1−1.5 °C, and positive bias near 2 °C, respectively

Quantifying the Occurrence of Multi-Hazards Due to Climate Change

This paper introduces a climatic multi-hazard risk assessment for Greece, as the first-ever attempt to enhance scientific knowledge for the identification and definition of hazards, a critical element of risk-informed decision making. Building on an extensively validated climate database with a very high spatial resolution (5 × 5 km2), a detailed assessment of key climatic hazards is performed that allows for: (a) the analysis of hazard dynamics and their evolution due to climate change and (b) direct comparisons and spatial prioritization across Greece. The high geographical complexity of Greece requires that a large number of diverse hazards (heatwaves—TX, cold spells—TN, torrential rainfall—RR, snowstorms, and windstorms), need to be considered in order to correctly capture the country’s susceptibility to climate extremes. The current key findings include the dominance of cold-temperature extremes in mountainous regions and warm extremes over the coasts and plains. Extreme rainfall has been observed in the eastern mainland coasts and windstorms over Crete and the Aegean and Ionian Seas. Projections of the near future reveal more warm extremes in northern areas becoming more dominant all over the country by the end of the century

High Resolution Future Projections of Drought Characteristics in Greece Based on SPI and SPEI Indices

Future changes in drought characteristics in Greece were investigated using dynamically downscaled high-resolution simulations of 5 km. The Weather Research and Forecasting model simulations were driven by EC-EARTH output for historical and future periods, under Representative Concentration Pathways 4.5 and 8.5. For the drought analysis, the standardized precipitation index (SPI) and the standardized precipitation-evapotranspiration index (SPEI) were calculated. This work contributed to achieve an improved characterization of the expected high-resolution changes of drought in Greece. Overall, the results indicate that Greece will face severe drought conditions in the upcoming years, particularly under RCP8.5, up to 8/5 y of severity change signal. The results of 6-month timescale indices suggest that more severe and prolonged drought events are expected with an increase of 4 months/5 y, particularly in areas of central and eastern part of the country in near future, and areas of the western parts in far future. The indices obtained in a 12-month timescale for the period 2075–2099 and under RCP8.5 have shown an increase in the mean duration of drought events along the entire country. Drought conditions will be more severe in lowland areas of agricultural interest (e.g., Thessaly and Crete)

Projection of Forest Fire Danger due to Climate Change in the French Mediterranean Region

Fire occurrence and behaviour in Mediterranean-type ecosystems strongly depend on the air temperature and wind conditions, the amount of fuel load and the drought conditions that drastically increase flammability, particularly during the summer period. In order to study the fire danger due to climate change for these ecosystems, the meteorologically based Fire Weather Index (FWI) can be used. The Fire Weather Index (FWI) system, which is part of the Canadian Forest Fire Danger Rating System (CFFDRS), has been validated and recognized worldwide as one of the most trusted and important indicators for meteorological fire danger mapping. A number of FWI system components (Fire Weather Index, Drought Code, Initial Spread Index and Fire Severity Rating) were estimated and analysed in the current study for the Mediterranean area of France. Daily raster-based data-sets for the fire seasons (1st May–31st October) of a historic and a future time period were created for the study area based on representative concentration pathway (RCP) 4.5 and RCP 8.5 scenarios, outputs of CNRM-SMHI and MPI-SMHI climate models. GIS spatial analyses were applied on the series of the derived daily raster maps in order to provide a number of output maps for the study area. The results portray various levels of changes in fire danger, in the near future, according to the examined indices. Number of days with high and very high FWI values were found to be doubled compared to the historical period, in particular in areas of the Provence-Alpes-Côte d’Azur (PACA) region and Corsica. The areas with high Initial Spread Index and Seasonal Spread Index values increased as well, forming compact zones of high fire danger in the southern part of the study area, while the Drought Code index did not show remarkable changes. The current study on the evolution of spatial and temporal distribution of forest fire danger due to climate change can provide important knowledge to the decision support process for prevention and management policies of forest fires both at a national and EU level

Assessing the Effects of Forest Fires on Interconnected Critical Infrastructures under Climate Change. Evidence from South France

The present work introduces a case study on the climate resilience of interconnected critical infrastructures to forest fires, that was performed within the framework on H2020 EU-CIRCLE project (GA 653824). It was conducted in South France, one of the most touristic European regions, and also one of the regions at the highest forest fire risk that is projected to be amplified under future climate conditions. The case study has been implemented through a co-creation framework with local stakeholders, which is critical in moving beyond physical damages to the infrastructures, introducing the elements of infrastructure business continuity and societal resilience. Future forest fires extremes are anticipated to impact the interconnections of electricity and transportation networks that could further cascade to communities throughout South France. The work highlighted the benefits of enhancing co-operation between academia, emergency responders, and infrastructure operators as a critical element in enhancing resilience through increased awareness of climate impacts, new generated knowledge on fire extremes and better cooperation between involved agencies