Cord blood-derived CD34+ hematopoietic cells with low mitochondrial mass are enriched in hematopoietic repopulating stem cell function

This work was funded by the CICE/FEDER (P08-CTS-3678) de la Junta de Andalucia with a grant to PM, the FIS/FEDER (PI10/00449 to PM and PI11/00119 to CB), the MICINN (Fondo Especial del Estado para Dinamizacion de la Economia y Empleo/PLE-2009-0111) with a grant to PM, and the Foundation "Spanish Association Against Cancer"/Junta Provincial de Albacete (CI110023 to PM). DRM (PFIS scholarship FI11/0511), RM and CB (CP07/0059) are supported by the ISCIII. ON-M was supported by the Health of Department of the Junta de Andalucia.The homeostasis of the hematopoietic stem/progenitor cell pool relies on a fine-tuned balance between self-renewal, differentiation and proliferation. Recent studies have proposed that mitochondria regulate these processes. Although recent work has contributed to understanding the role of mitochondria during stem cell differentiation, it remains unclear whether the mitochondrial content/function affects human hematopoietic stem versus progenitor function. We found that mitochondrial mass correlates strongly with mitochondrial membrane potential in CD34(+) hematopoietic stem/progenitor cells. We, therefore, sorted cord blood CD34(+) cells on the basis of their mitochondrial mass and analyzed the in vitro homeostasis and clonogenic potential as well as the in vivo repopulating potential of CD34(+) cells with high (CD34(+) Mito(High)) versus low (CD34(+) Mito(Low)) mitochondrial mass. The CD34(+) Mito(Low) fraction contained 6-fold more CD34(+)CD38(-) primitive cells and was enriched in hematopoietic stem cell function, as demonstrated by its significantly greater hematopoietic reconstitution potential in immuno deficient mice. In contrast, the CD34(+) Mito(High) fraction was more enriched in hematopoietic progenitor function with higher in vitro clonogenic capacity. In vitro differentiation of CD34(+) Mito(Low) cells was significantly delayed as compared to that of CD34(+) Mito(High) cells. The eventual complete differentiation of CD34(+) Mito(Low) cells, which coincided with a robust expansion of the CD34(-) differentiated progeny, was accompanied by mitochondrial adaptation, as shown by significant increases in ATP production and expression of the mitochondrial genes ND1 and COX2. In conclusion, cord blood CD34(+) cells with low levels of mitochondrial mass are enriched in hematopoietic repopulating stem cell function whereas high levels of mitochondrial mass identify hematopoietic progenitors. A mitochondrial response underlies hematopoietic stem/progenitor cell differentiation and proliferation of lineage-committed CD34(-) cells.Junta de Andalucia P08-CTS-3678European Union (EU) Instituto de Salud Carlos III PI10/00449 PI11/00119MICINN (Fondo Especial del Estado para Dinamizacion de la Economia y Empleo) PLE-2009-0111Foundation "Spanish Association Against Cancer"/Junta Provincial de Albacete CI110023Instituto de Salud Carlos III FI11/0511 CP07/0059ICRE

KITD816V mutation in blood for the diagnostic screening of systemic mastocytosis and mast cell activation syndromes

[Background]: Current diagnostic algorithms for systemic mastocytosis (SM) rely on the detection of KITD816V in blood to trigger subsequent bone marrow (BM) investigations. [Methods]: Here, we correlated the KITD816V mutational status of paired blood and BM samples from 368 adults diagnosed with mast cell activation syndrome (MCAS) and mastocytosis and determined the potential utility of investigating KITD816V in genomic DNA from blood-purified myeloid cell populations to increase diagnostic sensitivity. In a subset of 69 patients, we further evaluated the kinetics of the KITD816V cell burden during follow-up and its association with disease outcome. [Results]: Our results showed a high correlation (P < .0001) between the KITD816V mutation burden in blood and BM (74% concordant samples), but with a lower mean of KITD816V-mutated cells in blood (P = .0004) and a high rate of discordant BM+/blood− samples particularly among clonal MCAS (73%) and BM mastocytosis (51%), but also in cutaneous mastocytosis (9%), indolent SM (15%), and well-differentiated variants of indolent SM (7%). Purification of different compartments of blood-derived myeloid cells was done in 28 patients who were BM mast cell (MC)+/blood− for KITD816V, revealing KITD816V-mutated eosinophils (56%), basophils (25%), neutrophils (29%), and/or monocytes (31%) in most (61%) patients. Prognostically, the presence of ≥3.5% KITD816V-mutated cells (P < .0001) and an unstable KITD816V mutation cell burden (P < .0001) in blood and/or BM were both associated with a significantly shortened progression-free survival (PFS). [Conclusions]: These results confirm the high specificity but limited sensitivity of KITD816V analysis in whole blood for the diagnostic screening of SM and other primary MCAS, which might be overcome by assessing the mutation in blood-purified myeloid cell populations.This work was supported by grants from the Fundación Española de Mastocitosis (Madrid, Spain; grant number: FEM2021-SAM) and Blueprint Medicines Corporation (Cambridge, MA). PNN was supported by a grant of Government of Castilla y León (Orden EDU 875 2021), Spain; co-financed with the European Social Fund (BDNS (Identif.): 540787). We also thank the Agencia Estatal de Investigación (AEI) and European Regional Development Fund (FEDER) for the grant (EQC2019-005419-P) within the Subprograma Estatal de Infraestructuras de Investigación y Equipamiento Científico Técnico de 2019

Hacia una práctica de aprendizaje-servicio a través de la literatura y el cine en el Grado de Estudios Ingleses: herramientas pedagógicas y educativas para desmantelar discursos colectivos de miedo

Memoria ID-096. Ayudas de la Universidad de Salamanca para la innovación docente, curso 2019-2020.[ES]El objetivo del proyecto es fomentar el aprendizaje-servicio en el Grado de Estudios Ingleses, en temáticas consideradas no canónicas (literaturas y cines postcoloniales de diversidad racial, de género y sexual) para estudiar y promover análisis e intervenciones sobre cómo constructos culturales y performativos vertebran discursos de miedo, y establecer dinámicas de intervención, ordenación y, en la mayoría de los casos, subalternida

Prácticas de Aprendizaje-servicio a través de la literatura y el cine en el Grado de Estudios Ingleses: Creación de un archivo virtual de pedagogías y acciones disidentes contra los discursos de miedo

Memoria ID-067 Ayudas de la Universidad de Salamanca para la innovación docente, curso 2020-2021

Flexible industrial work in the European periphery: factory regimes and changing working class cultures in the Spanish steel industry

This article explores how two steel industry firms operating in northern Spain have adapted to neoliberalism and globalization. Despite their geographical proximity, the comparison between their different trajectories, production, and ownership profiles highlights how their distinct factory regimes, while becoming entangled in global market dynamics, have allowed the emergence of contrasting definitions of workers’ identities, labor politics, and livelihood strategies, raising questions concerning (1) processes of distribution of privileges, skills, and knowledge among the workforce, and (2) the shaping of social relations, values, and meanings that result in the formation of particular factory regimes. The unequal position of steelmaking in regional economies, and the effects of economic policies that framed social relations in each firm, evince important differences between them, including contrasting expressions of resistance, discipline, and sociality on the shop floor. Our comparison considers how particular factory regimes bring forward different prospects as these firms face further industrial transformation, restructuring, and an increasingly uncertain future

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

PhDAY 2020 -FOO (Facultad de Óptica y Optometría)

Por cuarto año consecutivo los doctorandos de la Facultad de Óptica y Optometría de la Universidad Complutense de Madrid cuentan con un congreso propio organizado por y para ellos, el 4º PhDAY- FOO. Se trata de un congreso gratuito abierto en la que estos jóvenes científicos podrán presentar sus investigaciones al resto de sus compañeros predoctorales y a toda la comunidad universitaria que quiera disfrutar de este evento. Apunta en tu agenda: el 15 de octubre de 2020. En esta ocasión será un Congreso On-line para evitar que la incertidumbre asociada a la pandemia Covid-19 pudiera condicionar su celebración

RUNX1 en la hematopoyesis embrionaria humana

RUNX1 es un factor de transcripción de la familia Runt, nombre del dominio de unión al ADN conservado entre todos sus miembros a lo largo de la evolución (desde Drosophila hasta humano). Su deficiencia causa muerte en ratones a E11.5-E12.5 debido a la ausencia de hematopoyesis definitiva. En humanos RUNX1 se encuentra frecuentemente mutado o formando parte de translocaciones implicadas en distintos tipos de leucemias, sobre todo leucemia mieloide aguda (LMA) y leucemia linfoide aguda (LLA), subrayando su importancia en la hematopoyesis. Su expresión está regulada mayormente por 2 promotores (distal o P1 y proximal o P2) y por splicing alternativo de sus doce exones, produciendo numerosas isoformas, de las cuales tres son las más estudiadas conocidas como RUNX1a, RUNX1b y RUNX1c. La función de cada una de ellas no está aún muy clara y mucho menos en humanos. Nuestro objetivo básico es estudiar el patrón de expresión y el papel de RUNX1 en la hematopoyesis embrionaria humana usando CMEH como modelo biológico.Tesis Univ. Granada. Programa Oficial de Doctorado en: Biomedicin