Activation of amino acid metabolic program in cardiac HIF1-alpha-deficient mice.

HIF1-alpha expression defines metabolic compartments in the developing heart, promoting glycolytic program in the compact myocardium and mitochondrial enrichment in the trabeculae. Nonetheless, its role in cardiogenesis is debated. To assess the importance of HIF1-alpha during heart development and the influence of glycolysis in ventricular chamber formation, herein we generated conditional knockout models of Hif1a in Nkx2.5 cardiac progenitors and cardiomyocytes. Deletion of Hif1a impairs embryonic glycolysis without influencing cardiomyocyte proliferation and results in increased mitochondrial number and transient activation of amino acid catabolism together with HIF2α and ATF4 upregulation by E12.5. Hif1a mutants display normal fatty acid oxidation program and do not show cardiac dysfunction in the adulthood. Our results demonstrate that cardiac HIF1 signaling and glycolysis are dispensable for mouse heart development and reveal the metabolic flexibility of the embryonic myocardium to consume amino acids, raising the potential use of alternative metabolic substrates as therapeutic interventions during ischemic events.This project has been supported by Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Spain and by grants to S.M.-P. from the European Research Council, European Union, FP7-PEOPLE-2010-RG_276891; Fundación TV3 La Marató, Spain, 201507.30.31; Comunidad de Madrid (CAM); Spain and European Union (EU), B2017/BMD-3875; Instituto de Salud Carlos III, Spain, PI17/01817; Universidad Francisco de Vitoria (UFV), Spain and LeDucq Foundation, France, 17CVD04. I.M.-M. was supported by La Caixa-CNIC and Fundacion Alfonso Martín Escudero fellowships, Spain. T.A.-G. was supported by a predoctoral award granted by CAM/EU and UFV, Spain, PEJD-2018-PRE/SAL-9529 and SM-P by a Contrato de Investigadores Miguel Servet (CPII16/00050) and UFV, Spain.S

Excess mortality in Spain during transmission of pandemic influenza in 2009

Fundamento: El sistema español de monitorización de la mortalidad y el "Programa Europeo de monitorización de excesos de mortalidad para la acción en salud pública" detectaron dos excesos de mortalidad en España en noviembre y diciembre de 2009. El objetivo de este trabajo es valorar su posible asociación con la transmisión de gripe pandémica. Métodos: Se analizó la evolución de la mortalidad en España en los meses citados utilizando métodos de análisis de series temporales basados en las series históricas de mortalidad y se comparó en el tiempo con la transmisión de gripe. Resultados: La mortalidad observada en la población total fue mayor de lo esperado en dos periodos: semanas 46-47/2009 con 5,75% de exceso y las semanas 51-52/2009 con 7,35% de exceso. También se registró un exceso de mortalidad en niños de 5 a 14 años en las semanas 46-48/2009 con 41 defunciones vs las 21 esperadas. El exceso de mortalidad en noviembre fue concomitante con las mayores tasas de gripe. El exceso de diciembre se observó 5 semanas después del pico de gripe y coincidió con un descenso dramático de las temperaturas. El virus sincitial respiratorio y los accidentes de tráfico fueron descartados como factores asociados. Conclusiones: Mientras que las temperaturas podrían explicar la mayoría del exceso de mortalidad observado en diciembre, ningún factor por si solo podría explicar el exceso de noviembre. BACKGROUND: The Spanish daily mortality monitoring system and the program «European monitoring of excess mortality for public health action» found two excesses of mortality in Spain in November and December 2009. METHODS: We analyzed the evolution of mortality in Spain during those months using time-series analysis methods based on historical mortality series and compared it in the time with influenza transmission. RESULTS: Observed mortality for the total population was higher than expected in two periods: weeks 46-47/2009 with 5.75% excess and weeks 51-52/2009 with 7.35% excess. Observed mortality higher than expected, was also observed in children 5-14 years old during weeks 46-48/2009 with 41 deaths vs 21 expected. Exces mortality in November occurred before or was concomitant with highest influenza incidence rates. Excess mortality in December occurred five weeks after the influenza incidence peak and along with dramatic drop in temperatures. RSV and traffic accidents were ruled out as factor associated to these excesses. CONCLUSIONS: While temperatures could explain most of the excess mortality observed in December, no single factor could be associated with observed excess mortality in November

Let's agree to disagree: learning highly debatable multirater labelling

Classification and differentiation of small pathological objects may greatly vary among human raters due to differences in training, expertise and their consistency over time. In a radiological setting, objects commonly have high within-class appearance variability whilst sharing certain characteristics across different classes, making their distinction even more difficult. As an example, markers of cerebral small vessel disease, such as enlarged perivascular spaces (EPVS) and lacunes, can be very varied in their appearance while exhibiting high inter-class similarity, making this task highly challenging for human raters. In this work, we investigate joint models of individual rater behaviour and multirater consensus in a deep learning setting, and apply it to a brain lesion object-detection task. Results show that jointly modelling both individual and consensus estimates leads to significant improvements in performance when compared to directly predicting consensus labels, while also allowing the characterization of human-rater consistency.Comment: Accepted at MICCAI 201

Fortification and bioaccessibility of saffron apocarotenoids in potato tubers

Carotenoids are C40 isoprenoids with well-established roles in photosynthesis, pollination, photoprotection, and hormone biosynthesis. The enzymatic or ROS-induced cleavage of carotenoids generates a group of compounds named apocarotenoids, with an increasing interest by virtue of their metabolic, physiological, and ecological activities. Both classes are used industrially in a variety of fields as colorants, supplements, and bio-actives. Crocins and picrocrocin, two saffron apocarotenoids, are examples of high-value pigments utilized in the food, feed, and pharmaceutical industries. In this study, a unique construct was achieved, namely O6, which contains CsCCD2L, UGT74AD1, and UGT709G1 genes responsible for the biosynthesis of saffron apocarotenoids driven by a patatin promoter for the generation of potato tubers producing crocins and picrocrocin. Different tuber potatoes accumulated crocins and picrocrocin ranging from 19.41–360 to 105–800 μg/g DW, respectively, with crocetin, crocin 1 [(crocetin-(β-D-glucosyl)-ester)] and crocin 2 [(crocetin)-(β-D-glucosyl)-(β-D-glucosyl)-ester)] being the main compounds detected. The pattern of carotenoids and apocarotenoids were distinct between wild type and transgenic tubers and were related to changes in the expression of the pathway genes, especially from PSY2, CCD1, and CCD4. In addition, the engineered tubers showed higher antioxidant capacity, up to almost 4-fold more than the wild type, which is a promising sign for the potential health advantages of these lines. In order to better investigate these aspects, different cooking methods were applied, and each process displayed a significant impact on the retention of apocarotenoids. More in detail, the in vitro bioaccessibility of these metabolites was found to be higher in boiled potatoes (97.23%) compared to raw, baked, and fried ones (80.97, 78.96, and 76.18%, respectively). Overall, this work shows that potatoes can be engineered to accumulate saffron apocarotenoids that, when consumed, can potentially offer better health benefits. Moreover, the high bioaccessibility of these compounds revealed that potato is an excellent way to deliver crocins and picrocrocin, while also helping to improve its nutritional value

Von Hippel-Lindau protein is required for optimal alveolar macrophage terminal differentiation, self-renewal, and function

The rapid transit from hypoxia to normoxia in the lung that follows the first breath in newborn mice coincides with alveolar macrophage (AM) differentiation. However, whether sensing of oxygen affects AM maturation and function has not been previously explored. We have generated mice whose AMs show a deficient ability to sense oxygen after birth by deleting Vhl, a negative regulator of HIF transcription factors, in the CD11c compartment (CD11c Delta Vhl mice). VHL-deficient AMs show an immature-like phenotype and an impaired self-renewal capacity in vivo that persists upon culture ex vivo. VHL-deficient phenotype is intrinsic in AMs derived from monocyte precursors in mixed bone marrow chimeras. Moreover, unlike control Vhl(fl/fl), AMs from CD11c Delta Vhl mice do not reverse pulmonary alveolar proteinosis when transplanted into Csf2rb(-/)(-) mice, demonstrating that VHL contributes to AM-mediated surfactant clearance. Thus, our results suggest that optimal AM terminal differentiation, self-renewal, and homeostatic function requires their intact oxygen-sensing capacity

Shoc2/Sur8 protein regulates neurite outgrowth

This is an openaccess article distributed under the terms of the Creative Commons Attribution License.-- et al.The Shoc2 protein has been implicated in the positive regulation of the Ras-ERK pathway by increasing the functional binding interaction between Ras and Raf, leading to increased ERK activity. Here we found that Shoc2 overexpression induced sustained ERK phosphorylation, notably in the case of EGF stimulation, and Shoc2 knockdown inhibited ERK activation. We demonstrate that ectopic overexpression of human Shoc2 in PC12 cells significantly promotes neurite extension in the presence of EGF, a stimulus that induces proliferation rather than differentiation in these cells. Finally, Shoc2 depletion reduces both NGF-induced neurite outgrowth and ERK activation in PC12 cells. Our data indicate that Shoc2 is essential to modulate the Ras-ERK signaling outcome in cell differentiation processes involved in neurite outgrowth.GL, TG and LMD were recipients of fellowships from the Ministerio de Educación y Ciencia (MEC) (to GL, TG), and Fondo de Investigaciones Sanitarias (FIS) (to LMD). LSR held a postdoctoral research contract from CIBERNED. This work was supported by FIS grant (PI10/00815) to JLO; CIBERNED to MC; SAF2008-01951, Comunidad Autónoma de Madrid (CAM) SSAL-0202-2006-01 and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) to TI; FIS grant PI12/00775 and ISCIII-RETIC (Red Temática de Investigación Cooperativa en Cáncer) RD12/0036/0027 from the Instituto de Salud Carlos III to PSG; and FIS grants (PI09/0562 and PI13/00703), ISCIIIRETIC (RD06/0020/0003 and RD12/0036/0021), and the Spanish Association Against Cancer (AECC) to JMR.Peer Reviewe

Shoc2/Sur8 Protein Regulates Neurite Outgrowth

The Shoc2 protein has been implicated in the positive regulation of the Ras-ERK pathway by increasing the functional binding interaction between Ras and Raf, leading to increased ERK activity. Here we found that Shoc2 overexpression induced sustained ERK phosphorylation, notably in the case of EGF stimulation, and Shoc2 knockdown inhibited ERK activation. We demonstrate that ectopic overexpression of human Shoc2 in PC12 cells significantly promotes neurite extension in the presence of EGF, a stimulus that induces proliferation rather than differentiation in these cells. Finally, Shoc2 depletion reduces both NGF-induced neurite outgrowth and ERK activation in PC12 cells. Our data indicate that Shoc2 is essential to modulate the Ras-ERK signaling outcome in cell differentiation processes involved in neurite outgrowth.This work was supported by FIS grant (PI10/00815) to JLO; CIBERNED to MC; SAF2008-01951, Comunidad Autónoma de Madrid (CAM) S-SAL-0202-2006-01 and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) to TI; FIS grant PI12/00775 and ISCIII-RETIC (Red Temática de Investigación Cooperativa en Cáncer) RD12/0036/0027 from the Instituto de Salud Carlos III to PSG; and FIS grants (PI09/0562 and PI13/00703), ISCIII-RETIC (RD06/0020/0003 and RD12/0036/0021), and the Spanish Association Against Cancer (AECC) to JMR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.S

Vigilancia de la gripe en España. Resumen de la temporada 2011-2012. Semanas 40/2011 - 04/2012 (del 02 de octubre de 2011 al 29 de enero de 2012)

El nivel de intensidad de la actividad gripal registrado en España, desde el inicio de la temporada 2011-2012, hasta la semana 04/2012 (del 23 al 29 de enero de 2012) fue moderado y se asoció a una circulación mayoritaria de virus de la gripe A(H3). La tasa de incidencia de gripe superó el umbral basal de la temporada 2011-12 en la semana 52/2011, registrándose un incremento paulatino en el porcentaje de muestras positivas a virus gripales, desde la semana 48/2011 hasta la semana 04/2012. Desde la semana 40/2011 hasta la semana 04/2012 se han notificado 103 casos graves hospitalizados confirmados de gripe, de los que siete fallecieron. La mayoría de los casos fueron infecciones por virus de la gripe A(H3). De los casos pertenecientes a los grupos elegibles para vacunación, el 44% había recibido la vacuna antigripal de esta temporada. La actividad gripal en la región templada del hemisferio norte continúa baja, aunque con notables incrementos locales de actividad en el norte de América, oeste de Europa y norte de China. El virus más común en el hemisferio norte ha sido el A(H3), a excepción de Méjico, donde ha circulado de manera predominante el virus de la gripe A(H1N1)pdm09, y China, donde ha predominado el tipo B. La actividad gripal en los países templados del hemisferio sur se sitúa de nuevo en niveles de intertemporada.N

Vigilancia de la gripe en España. Temporada 2014-2015 (Desde la semana 40/2014 hasta la semana 20/2015)

[ES] La actividad gripal en España en la temporada 2014-2015 fue moderada y se asoció a una circulación mayoritaria de virus de la gripe A(H3N2) con una creciente contribución de virus B a partir del pico de la epidemia. La onda epidémica gripal tuvo una presentación normal en el tiempo con el pico de máxima actividad gripal a finales de enero de 2015. Los menores de 15 años fueron el grupo de edad más afectado, con mayores tasas de incidencia acumulada en el grupo de 5-14 años. Se notificaron 19 brotes confirmados de gripe en ocho Comunidades Autónomas (CCAA), el 58% de ellos ubicados en residencias geriátricas y como agente causal se confirmó el virus A(H3N2). El análisis filogenético de los virus gripales que circularon en España durante la temporada muestra que el 66,8 % de los virus A(H3N2) presentarían diferencias antigénicas con respecto al virus vacunal de la temporada 2014-2015 en el hemisferio norte. Sin embargo, los virus A(H1N1)pdm09 y los virus B del linaje Yamagata estarían cubiertos por la vacuna de esta temporada. Se notificaron 1.724 casos graves hospitalizados confirmados de gripe (CGHCG) de los que 33% fueron admitidos en UCI y 16% fallecieron. El mayor porcentaje de casos graves de gripe se registró en los mayores de 64 años y en el grupo de 45-64 años. En el 77% de los casos se confirmó el virus de la gripe tipo A, siendo el 83% de los subtipados A(H3N2). El 88% de los CGHCG presentó algún factor de riesgo de complicaciones de gripe y el 48% no había recibido la vacuna antigripal en la temporada. Las defunciones en los CGHCG se concentraron fundamentalmente en los mayores de 64 años. La letalidad observada en términos de defunciones entre CGHCG fue la más alta observada después de la pandemia de 2009. En consonancia con estos indicadores de gravedad, el sistema MOMO (Monitorización de la mortalidad diaria) estimó un exceso de mortalidad por todas las causas, concentrado fundamentalmente en el grupo de mayores de 64 años, coincidiendo con el periodo epidémico de la gripe. La actividad gripal en la región templada del hemisferio norte ha sido moderada con predominio de virus A(H3N2) en Europa y Norte de América. La actividad gripal en los países templados del hemisferio sur se ha mantenido en niveles propios de inter-temporada. [EN] Influenza activity in Spain during the 2014-2015 season was moderate and dominated by influenza A (H3N2) viruses with an increasing contribution from B virus from the epidemic peak. Influenza epidemic had a normal time presentation with the maximum peak influenza activity at the end of January 2015. Children under 15 years old have been the most affected with higher rates of cumulative incidence in 5-14 age groups. Nineteen laboratory-confirmed influenza outbreaks were reported in eight Regions, 58% in long-term care facilities, the majority of them were caused by influenza A(H3N2) virus. The 66.8% of genetically characterized influenza A (H3N2) viruses were different from the influenza A(H3N2) component of the 2014–15 Northern Hemisphere vaccine. However, the virus A(H1N1) pdm09 and B/Yamagata lineage virus would be covered by the vaccine this season. A total of 1,724 severe hospitalized laboratory-confirmed influenza cases (SHCIC) were reported, of which 33% were admitted to ICU and 16% dead. The highest percentage of SHCIC occurred over 64 years and 45-64 age groups. The 77% of SHCIC were associated with influenza A virus, and the vast majority of the subtyped A viruses (83%) were A (H3N2). 88% had underlying conditions and 52% had received a seasonal influenza vaccine. Most of the deaths of SHCIC were in adults > 64 years. The case fatality rates among SHCIC was the highest observed after the pandemic of 2009. MOMO system (Monitoring daily mortality) estimated an excess mortality from all causes, concentrated mainly in the group over 64 years, concomitant with the period of maximum influenza activity In the Northern Hemisphere, influenza activity had been moderate with influenza A(H3N2) viruses predominating in Europe and North America. In the Southern Hemisphere, influenza activity remained at inter-seasonal levels