Implications of noncoding regulatory functions in the development of insulinomas

Insulinomas are rare neuroendocrine tumors arising from pancreatic β cells, characterized by aberrant proliferation and altered insulin secretion, leading to glucose homeostasis failure. With the aim of uncovering the role of noncoding regulatory regions and their aberrations in the development of these tumors, we coupled epigenetic and transcriptome profiling with whole-genome sequencing. As a result, we unraveled somatic mutations associated with changes in regulatory functions. Critically, these regions impact insulin secretion, tumor development, and epigenetic modifying genes, including polycomb complex components. Chromatin remodeling is apparent in insulinoma-selective domains shared across patients, containing a specific set of regulatory sequences dominated by the SOX17 binding motif. Moreover, many of these regions are H3K27me3 repressed in β cells, suggesting that tumoral transition involves derepression of polycomb-targeted domains. Our work provides a compendium of aberrant cis-regulatory elements affecting the function and fate of β cells in their progression to insulinomas and a framework to identify coding and noncoding driver mutations

Mental impact of Covid-19 among Spanish healthcare workers. A large longitudinal survey

Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER); Ministerio de Ciencia e Innovación; Gerencia Regional de Salud de Castilla y León (SACYL, GRS COVID 32/A/20).Aims Longitudinal data on the mental health impact of the coronavirus disease 2019 (Covid-19) pandemic in healthcare workers is limited. We estimated prevalence, incidence and persistence of probable mental disorders in a cohort of Spanish healthcare workers (Covid-19 waves 1 and 2) -and identified associated risk factors. Methods 8996 healthcare workers evaluated on 5 May-7 September 2020 (baseline) were invited to a second web-based survey (October-December 2020). Major depressive disorder (PHQ-8 ≥ 10), generalised anxiety disorder (GAD-7 ≥ 10), panic attacks, post-traumatic stress disorder (PCL-5 ≥ 7), and alcohol use disorder (CAGE-AID ≥ 2) were assessed. Distal (pre-pandemic) and proximal (pandemic) risk factors were included. We estimated the incidence of probable mental disorders (among those without disorders at baseline) and persistence (among those with disorders at baseline). Logistic regression of individual-level [odds ratios (OR)] and population-level (population attributable risk proportions) associations were estimated, adjusting by all distal risk factors, health care centre and time of baseline interview. Results 4809 healthcare workers participated at four months follow-up (cooperation rate = 65.7%; mean = 120 days s.d. = 22 days from baseline assessment). Follow-up prevalence of any disorder was 41.5%, (v. 45.4% at baseline, p < 0.001); incidence, 19.7% (s.e. = 1.6) and persistence, 67.7% (s.e. = 2.3). Proximal factors showing significant bivariate-adjusted associations with incidence included: work-related factors [prioritising Covid-19 patients (OR = 1.62)], stress factors [personal health-related stress (OR = 1.61)], interpersonal stress (OR = 1.53) and financial factors [significant income loss (OR = 1.37)]. Risk factors associated with persistence were largely similar. Conclusions Our study indicates that the prevalence of probable mental disorders among Spanish healthcare workers during the second wave of the Covid-19 pandemic was similarly high to that after the first wave. This was in good part due to the persistence of mental disorders detected at the baseline, but with a relevant incidence of about 1 in 5 of HCWs without mental disorders during the first wave of the Covid-19 pandemic. Health-related factors, work-related factors and interpersonal stress are important risks of persistence of mental disorders and of incidence of mental disorders. Adequately addressing these factors might have prevented a considerable amount of mental health impact of the pandemic among this vulnerable population. Addressing health-related stress, work-related factors and interpersonal stress might reduce the prevalence of these disorders substantially. Study registration number: NCT0455656

Integrando escalas y métodos LTER para comprender la dinámica global de un espacio protegido de montaña: el Parque Nacional de Ordesa y Monte Perdido.

Los espacios protegidos, por el hecho de albergar una gran geo-biodiversidad y asegurar una baja intervención humana, constituyen lugares muy adecuados para el seguimiento de organismos y procesos a escala ecológica, así como para la obtención de series temporales largas a escala geológica. En el marco de la red LTER-España, el Parque Nacional de Ordesa y Monte Perdido (PNOMP) y el Instituto Pirenaico de Ecología-CSIC están impulsando estudios para la detección de cambios a distintas escalas mediante variados métodos y aproximaciones. Destacamos aquí los más consolidados, entre los que se encuentran los análisis de registros de sedimentos en lagos, espeleotemas en cuevas, la dinámica de uno de los pocos glaciares activos de la Península ibérica, el análisis físico-químico de aguas corrientes e ibones de alta montaña, el registro del cambio climático actual en árboles longevos, la afección que éste ejerce sobre masas actuales de pinos en el límite superior del bosque y de abetales en zonas húmedas, la matorralización de algunos pastos y los procesos mecanicistas que subyacen, la reorganización de la diversidad florística en pastos tras el abandono paulatino o drástico de la ganadería, la biodiversidad de las comunidades alpinas y la dinámica poblacional de especies amenazadas o indicadoras de hábitats o de motores de cambio global. Los seguimientos ecológicos actuales muestran que tanto el cambio climático como el de usos del suelo están teniendo una considerable trascendencia en la fisionomía y la estructura de algunos de los ambientes más icónicos y frecuentes del parque (deterioro del glaciar, termofilización de la flora en cumbres alpinas, densificación del bosque en su límite superior, pérdida de productividad en algunos pastos supraforestales, etc.). También sugieren una importante variabilidad espacial en los procesos (por ej. en el PNOMP conviven pastos matorralizados y pastos muy estables), y evidencian que los cambios observados no siempre siguen los paradigmas establecidos (por ej., las especies amenazadas mantienen dinámicas poblacionales estables). La integración de resultados parciales proporcionados por cada aproximación relativiza la importancia de las percepciones que cada estudio destaca por separado, y permite medir los cambios actuales en el marco de referencia de los cambios a escala geológica.Predecir la resistencia y resiliencia de los ecosistemas o las poblaciones de seres vivos para enfrentarse a los futuros cambios ambientales es complicado, no sólo por la falta de conocimientos disponibles sino también porque las respuestas que observamos no siempre son tan rápidas o lineales como se espera. La modelización constituye una herramienta cada vez más utilizada, pero requiere de evidencias reales para validar sus pronósticos, por lo que la observación de los procesos que actúan en el PNOMP ha de incluir un esfuerzo continuado de monitorización multiescalar y multidisciplinar de los distintos componentes de la geo, hidro-, crio- y biosfera, sin olvidar el componente humano. Entender la complejidad supone conectar las interacciones que existen entre todos los sistemas y ponderar sus efectos según las escalas de trabajo

Revealing the last 13,500 years of environmental history from the multiproxy record of a mountain lake (Lago Enol, northern Iberian Peninsula)

This is the author's accepted manuscript. The final publication is available at Springer via http://dx.doi.org/10.1007/s10933-009-9387-7.We present the Holocene sequence from Lago Enol (43°16′N, 4°59′W, 1,070 m a.s.l.), Cantabrian Mountains, northern Spain. A multiproxy analysis provided comprehensive information about regional humidity and temperature changes. The analysis included sedimentological descriptions, physical properties, organic carbon and carbonate content, mineralogy and geochemical composition together with biological proxies including diatom and ostracod assemblages. A detailed pollen study enabled reconstruction of variations in vegetation cover, which were interpreted in the context of climate changes and human impact. Four distinct stages were recognized for the last 13,500 years: (1) a cold and dry episode that includes the Younger Dryas event (13,500–11,600 cal. year BP); (2) a humid and warmer period characterizing the onset of the Holocene (11,600–8,700 cal. year BP); (3) a tendency toward a drier climate during the middle Holocene (8,700–4,650 cal. year BP); and (4) a return to humid conditions following landscape modification by human activity (pastoral activities, deforestation) in the late Holocene (4,650–2,200 cal. year BP). Superimposed on relatively stable landscape conditions (e.g. maintenance of well established forests), the typical environmental variability of the southern European region is observed at this site.The Spanish Inter-Ministry Commission of Science and Technology (CICYT), the Spanish National Parks agency, the European Commission, the Spanish Ministry of Science, and the European Social Fund

Revealing the last 13,500 years of environmental history from the multiproxy record of a mountain lake (Lago Enol, northern Iberian Peninsula)

This is the author's accepted manuscript. The final publication is available at Springer via http://dx.doi.org/10.1007/s10933-009-9387-7.We present the Holocene sequence from Lago Enol (43°16′N, 4°59′W, 1,070 m a.s.l.), Cantabrian Mountains, northern Spain. A multiproxy analysis provided comprehensive information about regional humidity and temperature changes. The analysis included sedimentological descriptions, physical properties, organic carbon and carbonate content, mineralogy and geochemical composition together with biological proxies including diatom and ostracod assemblages. A detailed pollen study enabled reconstruction of variations in vegetation cover, which were interpreted in the context of climate changes and human impact. Four distinct stages were recognized for the last 13,500 years: (1) a cold and dry episode that includes the Younger Dryas event (13,500–11,600 cal. year BP); (2) a humid and warmer period characterizing the onset of the Holocene (11,600–8,700 cal. year BP); (3) a tendency toward a drier climate during the middle Holocene (8,700–4,650 cal. year BP); and (4) a return to humid conditions following landscape modification by human activity (pastoral activities, deforestation) in the late Holocene (4,650–2,200 cal. year BP). Superimposed on relatively stable landscape conditions (e.g. maintenance of well established forests), the typical environmental variability of the southern European region is observed at this site.The Spanish Inter-Ministry Commission of Science and Technology (CICYT), the Spanish National Parks agency, the European Commission, the Spanish Ministry of Science, and the European Social Fund

Glycemic index, glycemic load and invasive breast cancer incidence in postmenopausal women: The PREDIMED study

The objective of this study was to evaluate the prospective associations between dietary glycemic index (GI) and glycemic load (GL) and the risk for invasive breast cancer incidence in postmenopausal women at high cardiovascular disease (CVD) risk. This study was conducted within the framework of the PREvención con DIeta MEDiterránea (PREDIMED) study, a nutritional intervention trial for primary cardiovascular prevention. We included 4010 women aged between 60 and 80 years who were initially free from breast cancer but at high risk for CVD disease. Dietary information was collected using a validated 137-item food frequency questionnaire. We assigned GI values using the International Tables of GI and GL values. Cases were ascertained through yearly consultation of medical records and through consultation of the National Death Index. Only cases confirmed by results from cytology tests or histological evaluation were included. We estimated multivariable-adjusted hazard ratios for invasive breast cancer risk across tertiles of energy-adjusted dietary GI/GL using Cox regression models. We repeated our analyses using yearly repeated measures of GI/GL intakes. No associations were found between baseline dietary GI/GL and invasive breast cancer incidence. The multivariable hazard ratio and 95% confidence interval (CI) for the top tertile of dietary GI was 1.02 (95% CI: 0.42–2.46) and for dietary GL was 1.00 (95% CI: 0.44–2.30) when compared with the bottom tertile. Repeated-measures analyses yielded similar results. In sensitivity analyses, no significant associations were observed for women with obesity or diabetes. Dietary GI and GL did not appear to be associated with an increased risk for invasive breast cancer in postmenopausal women at high CVD risk

State of Fisheries in Catalonia 2020. Part 1: Methods and Results (ICATMAR, 21-02)

513 pages, 416 figures, 77 tablesThis document presents the State of Fisheries in Catalonia between October 2019 and December 2020, both inclusive. It was produced by the Catalan Institute for Ocean Governance Research (ICATMAR), which is a cooperation organism between the Directorate-General of Maritime Policy & sustainable fisheries of the Government of Catalonia and the Institute of Marine Sciences (ICM) of the Spanish National Research Council (CSIC)Peer reviewe

Integrated flow cytometry and sequencing to reconstruct evolutionary patterns from dysplasia to acute myeloid leukemia

Clonal evolution in acute myeloid leukemia (AML) originates long before diagnosis and is a dynamic process that may affect survival. However, it remains uninvestigated during routine diagnostic workups. We hypothesized that the mutational status of bone marrow dysplastic cells and leukemic blasts, analyzed at the onset of AML using integrated multidimensional flow cytometry (MFC) immunophenotyping and fluorescence-activated cell sorting (FACS) with next-generation sequencing (NGS), could reconstruct leukemogenesis. Dysplastic cells were detected by MFC in 285 of 348 (82%) newly diagnosed patients with AML. Presence of dysplasia according to MFC and World Health Organization criteria had no prognostic value in older adults. NGS of dysplastic cells and blasts isolated at diagnosis identified 3 evolutionary patterns: stable (n = 12 of 21), branching (n = 4 of 21), and clonal evolution (n = 5 of 21). In patients achieving complete response (CR), integrated MFC and FACS with NGS showed persistent measurable residual disease (MRD) in phenotypically normal cell types, as well as the acquisition of genetic traits associated with treatment resistance. Furthermore, whole-exome sequencing of dysplastic and leukemic cells at diagnosis and of MRD uncovered different clonal involvement in dysplastic myelo-erythropoiesis, leukemic transformation, and chemoresistance. Altogether, we showed that it is possible to reconstruct leukemogenesis in ∼80% of patients with newly diagnosed AML, using techniques other than single-cell multiomics.This work was supported by grants from the Área de Oncología del Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red (CIBER-ONC) (CB16/12/00369, CB16/12/00233, CB16/12/00489, and CB16/12/00284), Instituto de Salud Carlos III/Subdirección General de Investigación Sanitaria (FIS numbers PI16/01661, PI16/00517, and PI19/01518), and the Plan de Investigación de la Universidad de Navarra (PIUNA 2014-18). This work was supported internationally by the Cancer Research UK, FCAECC, and AIRC under the Accelerator Award Program (EDITOR)

Scientific Report Supporting the Management Plan for Boat Seine (MPBS) (ICATMAR, 20-04)

77 pages, figures, tablesThis document presents the Scientific Report Supporting the Management Plan for Boat Seine between August 2012 and December 2019, both inclusive and it was produced by the Catalan Institute for Ocean Governance Research (ICATMAR), which is a cooperation organism between the Directorate-General of Fisheries and Maritime Affairs (DGPAM) of the Ministry of Agriculture, Livestock, Fisheries and Food (DARP) of the Government of Catalonia and the Institute of Marine Sciences (ICM) of the Spanish National Research Council (CSIC)Peer reviewe