Separase prevents genomic instability by controlling replication fork speed

Proper chromosome segregation is crucial for preserving genomic integrity, and errors in this process cause chromosome mis-segregation, which may contribute to cancer development. Sister chromatid separation is triggered by Separase, an evolutionary conserved protease that cleaves the cohesin complex, allowing the dissolution of sister chromatid cohesion. Here we provide evidence that Separase participates in genomic stability maintenance by controlling replication fork speed. We found that Separase interacted with the replication licensing factors MCM2-7, and genome-wide data showed that Separase co-localized with MCM complex and cohesin. Unexpectedly, the depletion of Separase increased the fork velocity about 1.5-fold and caused a strong acetylation of cohesin's SMC3 subunit and altered checkpoint response. Notably, Separase silencing triggered genomic instability in both HeLa and human primary fibroblast cells. Our results show a novel mechanism for fork progression mediated by Separase and thus the basis for genomic instability associated with tumorigenesis

Separase prevents genomic instability by controlling replication fork speed

Proper chromosome segregation is crucial for preserving genomic integrity, and errors in this process cause chromosome mis-segregation, which may contribute to cancer development. Sister chromatid separation is triggered by Separase, an evolutionary conserved protease that cleaves the cohesin complex, allowing the dissolution of sister chromatid cohesion. Here we provide evidence that Separase participates in genomic stability maintenance by controlling replication fork speed. We found that Separase interacted with the replication licensing factors MCM2-7, and genome-wide data showed that Separase co-localized with MCM complex and cohesin. Unexpectedly, the depletion of Separase increased the fork velocity about 1.5-fold and caused a strong acetylation of cohesin's SMC3 subunit and altered checkpoint response. Notably, Separase silencing triggered genomic instability in both HeLa and human primary fibroblast cells. Our results show a novel mechanism for fork progression mediated by Separase and thus the basis for genomic instability associated with tumorigenesis

KIAA1840 mutations cause ARCMT2

Charcot–Marie–Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes. Hundreds of causative DNA changes have been found, but much of the genetic basis of the disease is still unexplained. Mutations in the ALS5/SPG11/ KIAA1840 gene are a frequent cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and peripheral axonal neuropathy, and account for ∼40% of autosomal recessive juvenile amyotrophic lateral sclerosis. The overlap of axonal Charcot–Marie–Tooth disease with both diseases, as well as the common autosomal recessive inheritance pattern of thin corpus callosum and axonal Charcot–Marie–Tooth disease in three related patients, prompted us to analyse the ALS5/SPG11/ KIAA1840 gene in affected individuals with autosomal recessive axonal Charcot–Marie–Tooth disease. We investigated 28 unrelated families with autosomal recessive axonal Charcot–Marie–Tooth disease defined by clinical, electrophysiological, as well as pathological evaluation. Besides, we screened for all the known genes related to axonal autosomal recessive Charcot–Marie-Tooth disease (CMT2A2/HMSN2A2/ MFN2 , CMT2B1/ LMNA , CMT2B2/ MED25 , CMT2B5/ NEFL , ARCMT2F/dHMN2B/ HSPB1 , CMT2K/ GDAP1 , CMT2P/ LRSAM1 , CMT2R/ TRIM2 , CMT2S/ IGHMBP2 , CMT2T/ HSJ1 , CMTRID/ COX6A1 , ARAN-NM/ HINT and GAN/ GAN ), for the genes related to autosomal recessive hereditary spastic paraplegia with thin corpus callosum and axonal peripheral neuropathy (SPG7/ PGN , SPG15/ ZFYVE26, SPG21/ ACP33 , SPG35/ FA2H , SPG46/ GBA2 , SPG55/ C12orf65 and SPG56/ CYP2U1 ), as well as for the causative gene of peripheral neuropathy with or without agenesis of the corpus callosum ( SLC12A6 ) . Mitochondrial disorders related to Charcot–Marie–Tooth disease type 2 were also excluded by sequencing POLG and TYMP genes. An additional locus for autosomal recessive Charcot–Marie–Tooth disease type 2H on chromosome 8q13-21.1 was excluded by linkage analysis. Pedigrees originated in Italy, Brazil, Canada, England, Iran, and Japan. Interestingly, we identified 15 ALS5/SPG11/ KIAA1840 mutations in 12 families (two sequence variants were never reported before, p.Gln198* and p.Pro2212fs*5). No large deletions/duplications were detected in these patients. The novel mutations seemed to be pathogenic since they co-segregated with the disease in all pedigrees and were absent in 300 unrelated controls. Furthermore, in silico analysis predicted their pathogenic effect. Our results indicate that ALS5/SPG11/ KIAA1840 is the causative gene of a wide spectrum of clinical features, including autosomal recessive axonal Charcot–Marie–Tooth disease

Characteristics of people living in Italy after a cancer diagnosis in 2010 and projections to 2020

BACKGROUND: Estimates of cancer prevalence are widely based on limited duration, often including patients living after a cancer diagnosis made in the previous 5 years and less frequently on complete prevalence (i.e., including all patients regardless of the time elapsed since diagnosis). This study aims to provide estimates of complete cancer prevalence in Italy by sex, age, and time since diagnosis for all cancers combined, and for selected cancer types. Projections were made up to 2020, overall and by time since diagnosis. METHODS: Data were from 27 Italian population-based cancer registries, covering 32% of the Italian population, able to provide at least 7 years of registration as of December 2009 and follow-up of vital status as of December 2013. The data were used to compute the limited-duration prevalence, in order to estimate the complete prevalence by means of the COMPREV software. RESULTS: In 2010, 2,637,975 persons were estimated to live in Italy after a cancer diagnosis, 1.2 million men and 1.4 million women, or 4.6% of the Italian population. A quarter of male prevalent cases had prostate cancer (n\u2009=\u2009305,044), while 42% of prevalent women had breast cancer (n\u2009=\u2009604,841). More than 1.5 million people (2.7% of Italians) were alive since 5 or more years after diagnosis and 20% since 6515 years. It is projected that, in 2020 in Italy, there will be 3.6 million prevalent cancer cases (+\u200937% vs 2010). The largest 10-year increases are foreseen for prostate (+\u200985%) and for thyroid cancers (+\u200979%), and for long-term survivors diagnosed since 20 or more years (+\u200945%). Among the population aged 6575 years, 22% will have had a previous cancer diagnosis. CONCLUSIONS: The number of persons living after a cancer diagnosis is estimated to rise of approximately 3% per year in Italy. The availability of detailed estimates and projections of the complete prevalence are intended to help the implementation of guidelines aimed to enhance the long-term follow-up of cancer survivors and to contribute their rehabilitation need

Programma del gruppo di lavoro Open Science della Consulta dei Presidenti degli EPR

Programma di lavoro del gruppo Openscience della CoPER (già ConPER

Psychopathological Burden and Quality of Life in Substance Users During the COVID-19 Lockdown Period in Italy

Background Following the development of the COVID-19 pandemic, a rigid public health strategy of reduced social contact and shelter-in-place has been adopted by the Italian Government to reduce the spread of the virus. In this paper, we aim at evaluating the impact that the COVID-19 pandemic, and the relative containment measures, have had on a real-life sample of patients suffering from substance use disorders (SUDs) and/or behavioral addictions. Methods An anonymous questionnaire was filled out by 153 addicted patients, both outpatients and residential inpatients, recruited across Italy and highly representative of the current Italian population suffering from addictions. Psychopathological burden (anxiety and depressive symptomatology, somatization, irritability, and post-traumatic symptoms), quality of life, and craving changes in daily habits were assessed. Results In our sample, we found moderate rates of depression (22.9%), anxiety (30.1%), irritability (31.6%), and post-traumatic stress (5.4%) symptoms. Psychopathological burden was globally higher among residential patients. Reported levels of craving were generally low. Discussion This study is the first attempt to collect Italian data regarding the effects of the rigid quarantine period, during the COVID-19 pandemic, on patients suffering from a SUD and/or behavioral addictions. The presence of a moderate psychopathological burden correlated to poor quality of life and low craving scores represented the main outcomes. Long-term studies, with follow-up after the end of the restrictive measures, should be considered to implement our findings

Red solidaria de acompañamiento psicosocial

Objetivos - Dar contención a aquellas personas que se acercaran a la Red, contemplando el modo que estuviera siendo afectada su localidad por el Covid 19. n- Facilitar un espacio de escucha y acompañamiento Metodología: Ante la pandemia se buscó dar un acompañamiento profesional para ayudar a conectar con recursos personales ante esta situación de crisis. Se creo una Red profesional, sin fines de lucro, con pautas de trabajo que facilitaba un encuadre de trabajo. La modalidad era virtual. Se conformaron grupos invitados vía mail a participar junto con un consentimiento. La información se difundió por diferentes redes buscando llegar a la mayor cantidad de contactos. El contexto socio económico mostro la desigualdad existente para acceder a la conectividad. Eran grupos heterogéneos en cuanto sus edades actividades. Pudimos ver que muchos participantes se movilizaban para conseguir el apoyo de su entorno inmediato para poder estar presentes en los encuentros. Muchos nunca habían participado de encuentros grupales. Resultados: El intercambio y acompañamiento dentro del propio grupo profesional permitió enriquecer el tipo de intervenciones con creatividad. Compartir constantemente las devoluciones de los distintos encuentros fomentaban la revisión de las estrategias. Saber que era un apoyo brindado del espacio universitario nos dio un marco de trabajo para poder accionar desde lo individual hacia otras instituciones que podrían resolver problemas que demandaban una intervención más específica. Las intervenciones buscaban posicionar a los sujetos como actores activos en la construcción de sus propias Redes de contacto, fortalecer los vínculos pre existentes. Repensar nuevas estrategias apelando a recursos conocidos y construyendo otros nuevos. Sentirse acompañados fue una de las principales motivaciones para participar. Comprender que otras personas estaban atravesando por situaciones similares daba mucha tranquilidad, disminuyendo su sensación de angustia y temor.publishedVersionFil: Escalante, Miguel. Universidad Nacional De Córdoba. Facultad De Psicología. Unidad de Estudios Epidemiológicos en Salud Mental. Cátedra De Psicología Sanitaria; Argentina.Fil: Casella, Cecilia. Red Solidaria De Acompañamiento Psicosocial; Argentina.Fil: De Mauro, Mario Adolfo. Universidad Nacional De Córdoba. Facultad De Psicología. Unidad de Estudios Epidemiológicos en Salud Mental. Cátedra De Psicología Sanitaria; Argentina.Fil: Del Río, Paula. Red Solidaria De Acompañamiento Psicosocial; Argentina.Fil: Zarate, Jorge. Universidad Nacional De Córdoba. Facultad De Psicología. Unidad de Estudios Epidemiológicos en Salud Mental. Cátedra De Psicología Sanitaria; Argentina.Fil: Nadal, Daniela. Universidad Nacional de Psicología. Facultad de Psicología; Argentina.Fil: Bergoglio, María Antonella. Red Solidaria De Acompañamiento Psicosocial; Argentina.Fil: Ferrari, Bárbara. Red Solidaria De Acompañamiento Psicosocial; Argentina.Fil: Vázquez, Laura Natalia. Red Solidaria De Acompañamiento Psicosocial; Argentina.Fil: Jerez, María Alejandra. Red Solidaria De Acompañamiento Psicosocial; Argentina.Fil: Pinotti, Norberto Luis. Universidad Nacional De Córdoba. Facultad De Psicología. Unidad de Estudios Epidemiológicos en Salud Mental. Cátedra De Psicología Sanitaria; Argentina.Fil: Chiesa, Norma. Universidad Nacional De Córdoba. Facultad De Psicología. Unidad de Estudios Epidemiológicos en Salud Mental. Cátedra De Psicología Sanitaria; Argentina

Inquinamento atmosferico e ricoveri ospedalieri urgenti in 25 citt? italiane: risultati del progetto EpiAir2 Air pollution and urgent hospital admissions in 25 Italian cities: results from the EpiAir2 project

OBJECTIVE: to evaluate the relationship between air pollution and hospital admissions in 25 Italian cities that took part in the EpiAir (Epidemiological surveillance of air pollution effects among Italian cities) project. DESIGN: study of time series with case-crossover methodology, with adjustment for meteorological and time-dependent variables. The association air pollution hospitalisation was analyzed in each of the 25 cities involved in the study; the overall estimates of effect were obtained subsequently by means of a meta-analysis. The pollutants considered were PM10, PM2.5 (in 13 cities only), NO2 and ozone (O3); this last pollutant restricted to the summer season (April-September). SETTING AND PARTICIPANTS: the study has analyzed 2,246,448 urgent hospital admissions for non-accidental diseases in 25 Italian cities during the period 2006- 2010; 10 out of 25 cities took part also in the first phase of the project (2001-2005). MAIN OUTCOME MEASURES: urgent hospital admissions for cardiac, cerebrovascular and respiratory diseases, for all age groups, were considered. The respiratory hospital admissions were analysed also for the 0-14-year subgroup. Percentage increases risk of hospitalization associated with increments of 10 μg/m3 and interquartile range (IQR) of the concentration of each pollutant were calculated. RESULTS: reported results were related to an increment of 10 μg/m3 of air pollutant. The percent increase for PM10 for cardiac causes was 0.34% at lag 0 (95%CI 0.04-0.63), for respiratory causes 0.75%at lag 0-5 (95%CI 0.25-1.25). For PM2.5, the percent increase for respiratory causes was 1.23% at lag 0- 5 (95%CI 0.58-1.88). For NO2, the percent increase for cardiac causes was 0.57%at lag 0 (95%CI 0.13-1.02); 1.29% at lag 0-5 (95%CI 0.52-2.06) for respiratory causes. Ozone (O3) did not turned out to be positively associated neither with cardiac nor with respiratory causes as noted in the previous period (2001-2005). CONCLUSION: the results of the study confirm an association between PM10, PM2.5, and NO2 on hospital admissions among 25 Italian cities. No positive associations for ozone was noted in this period.OBIETTIVO: valutare la relazione tra inquinamento atmosferico e ricoveri ospedalieri nelle citt? italiane partecipanti alla seconda fase del progetto EpiAir (Sorveglianza epidemiologica dell\u27inquinamento atmosferico: valutazione dei rischi e degli impatti nelle citt? italiane). DISEGNO: studio di serie temporali con metodologia case-crossover, con aggiustamento per i fattori temporali e meteorologici rilevanti. L\u27associazione inquinamento atmosferico- ospedalizzazioni ? stata analizzata in ciascuna delle 25 citt? in studio, le stime complessive di effetto sono state ottenute successivamente mediante una metanalisi. Gli inquinanti considerati sono stati il particolato (PM10), il biossido di azoto (NO2) e l\u27ozono (O3), quest\u27ultimo limitatamente al semestre estivo (da aprile a settembre). In 13 citt? in cui i dati erano disponibili ? stata analizzata anche la frazione fine del particolato (PM2.5). SETTING E PARTECIPANTI: lo studio ha esaminato 2.246.448 ricoveri ospedalieri urgenti per cause naturali di pazienti residenti e ricoverati, nel periodo 2006-2010, in 25 citt? italiane, di cui 10 gi? partecipanti alla prima fase del progetto EpiAir (2001-2005). PRINCIPALIMISURE DI OUTCOME: sono stati considerati i ricoveri ospedalieri urgenti per malattie cardiache, cerebrovascolari e respiratorie per tutte le fasce di et?. I ricoveri per cause respiratorie sono stati analizzati separatamente anche per la fascia di et? 0-14 anni. L\u27esposizione ? stata valutata per incremento sia di 10 μg/m3 sia pari all\u27intervallo interquartile (IQR) della concentrazione di ciascun inquinante. RISULTATI: considerando un incremento di 10 μg/m3 per inquinante, per il PM10 ? stato osservato un incremento percentuale di rischio per patologie cardiache dello 0,34%a lag 0 (IC95% 0,04-0,63), e per patologie respiratorie dello 0,75% a lag 0-5 (IC95% 0,25-1,25). Per il PM2.5 l\u27incremento percentuale di rischio per patologie respiratorie ? risultato dell\u271,23%a lag 0-5 (IC95%0,58-1,88). Per l\u27NO2 la stima di effetto per patologie cardiache ? risultata dello 0,57% a lag 0 (IC95% 0,13-1,02), e per patologie respiratorie dell\u271,29% a lag 0-5 (IC95% 0,52-2,06). L\u27ozono non ? risultato positivamente associato n? alle patologie cardiache n? a quelle respiratorie (a differenza del periodo 2001-2005). CONCLUSIONE: i risultati dello studio confermano l\u27effetto a breve termine dell\u27inquinamento atmosferico da PM10, PM2.5 e NO2 sulla morbosit?, in particolare respiratoria, nelle citt? italiane. Non sono state rilevate associazioni positive per l\u27O3

Clinical variability at the mild end of BRAT1‐related spectrum: Evidence from two families with genotype–phenotype discordance

Biallelic mutations in the BRAT1 gene, encoding BRCA1-associated ATM activator 1, result in variable phenotypes, from rigidity and multifocal seizure syndrome, lethal neonatal to neurodevelopmental disorder, and cerebellar atrophy with or without seizures, without obvious genotype-phenotype associations. We describe two families at the mildest end of the spectrum, differing in clinical presentation despite a common genotype at the BRAT1 locus. Two siblings displayed nonprogressive congenital ataxia and shrunken cerebellum on magnetic resonance imaging. A third unrelated patient showed normal neurodevelopment, adolescence-onset seizures, and ataxia, shrunken cerebellum, and ultrastructural abnormalities on skin biopsy, representing the mildest form of NEDCAS hitherto described. Exome sequencing identified the c.638dup and the novel c.1395G>A BRAT1 variants, the latter causing exon 10 skippings. The p53-MCL test revealed normal ATM kinase activity. Our findings broaden the allelic and clinical spectrum of BRAT1-related disease, which should be suspected in presence of nonprogressive cerebellar signs, even without a neurodevelopmental disorder