Proteomic analysis of plasma proteins of high-flux haemodialysis and on-line haemodiafiltration patients reveals differences in transthyretin levels related with anaemia.

A large proportion of end-stage renal disease (ESRD) patients under long-term haemodialysis, have persistent anaemia and require high doses of recombinant human erythropoietin (rhEPO). However, the underlying mechanisms of renal anaemia have not been fully elucidated in these patients. In this study, we will be focusing on anaemia and plasma proteins in ESRD patients on high-flux haemodialysis (HF) and on-line haemodiafiltration (HDF), to investigate using two proteomic approaches if patients undergoing these treatments develop differences in their plasma protein composition and how this could be related to their anaemia. The demographic and biochemical data revealed that HDF patients had lower anaemia and much lower rhEPO requirements than HF patients. Regarding their plasma proteomes, HDF patients had increased levels of a protein highly similar to serotransferrin, trypsin-1 and immunoglobulin heavy constant chain alpha-1, and lower levels of alpha-1 antitrypsin, transthyretin, apolipoproteins E and C-III, and haptoglobin-related protein. Lower transthyretin levels in HDF patients were further confirmed by transthyretin-peptide quantification and western blot detection. Since ESRD patients have increased transthyretin, a protein that can aggregate and inhibit transferrin endocytosis and erythropoiesis, our finding that HDF patients have lower transthyretin and lower anaemia suggests that the decrease in transthyretin plasma levels would allow an increase in transferrin endocytosis, contributing to erythropoiesis. Thus, transthyretin could be a critical actor for anaemia in ESRD patients and a novel player for haemodialysis adequacy.This work was supported by Grants (to A.A.) from the Instituto de Salud Carlos III and cofinanced by the European Development Regional Fund (FEDER) (PI14/00705 and PI18/00255). E.M-A. is a recipient of a research.S

A generic mechanism inNeisseria meningitidisfor enhanced resistance against bactericidal antibodies

The presence of serum bactericidal antibodies is a proven correlate of protection against systemic infection with the important human pathogen Neisseria meningitidis. We have identified three serogroup C N. meningitidis (MenC) isolates recovered from patients with invasive meningococcal disease that resist killing by bactericidal antibodies induced by the MenC conjugate vaccine. None of the patients had received the vaccine, which has been successfully introduced in countries in North America and Europe. The increased resistance was not caused by changes either in lipopolysaccharide sialylation or acetylation of the alpha2-9-linked polysialic acid capsule. Instead, the resistance of the isolates resulted from the presence of an insertion sequence, IS1301, in the intergenic region (IGR) between the sia and ctr operons, which are necessary for capsule biosynthesis and export, respectively. The insertion sequence led to an increase in the transcript levels of surrounding genes and the amount of capsule expressed by the strains. The increased amount of capsule was associated with down-regulation of the alternative pathway of complement activation, providing a generic mechanism by which the bacterium protects itself against bactericidal antibodies. The strains with IS1301 in the IGR avoided complement-mediated lysis in the presence of bactericidal antibodies directed at the outer membrane protein, PorA, or raised against whole cells.S

In vivo inhibition of c-MYC in myeloid cells impairs tumor-associated macrophage maturation and pro-tumoral activities

Although tumor-associated macrophages (TAMs) are involved in tumor growth and metastasis, the mechanisms controlling their pro-tumoral activities remain largely unknown. The transcription factor c-MYC has been recently shown to regulate in vitro human macrophage polarization and be expressed in macrophages infiltrating human tumors. In this study, we exploited the predominant expression of LysM in myeloid cells to generate c-Myc(fl/fl) LysM(cre/+) mice, which lack c-Myc in macrophages, to investigate the role of macrophage c-MYC expression in cancer. Under steady-state conditions, immune system parameters in c-Myc(fl/fl) LysM(cre/+) mice appeared normal, including the abundance of different subsets of bone marrow hematopoietic stem cells, precursors and circulating cells, macrophage density, and immune organ structure. In a model of melanoma, however, TAMs lacking c-Myc displayed a delay in maturation and showed an attenuation of pro-tumoral functions (e.g., reduced expression of VEGF, MMP9, and HIF1α) that was associated with impaired tissue remodeling and angiogenesis and limited tumor growth in c-Myc(fl/fl) LysM(cre/+) mice. Macrophage c-Myc deletion also diminished fibrosarcoma growth. These data identify c-Myc as a positive regulator of the pro-tumoral program of TAMs and suggest c-Myc inactivation as an attractive target for anti-cancer therapy.The V.A. lab is supported by grant SAF2010-16044 from the Spanish Ministry of Science and Innovation (MICINN) and the European Regional Development Fund, grant RD06/0014/0021 (RECAVA, Instituto de Salud Carlos III), and the Dr. Leon Dumont Prize 2010 (Belgian Society of Cardiology). O.M.P. holds a Juan de la Cierva contract from the Spanish Ministry of Economy and Competition (MINECO). The CNIC is supported by the MINECO and the Pro-CNICS

Financial Fraud, Mental Health, and Quality of Life: A Study on the Population of the City of Madrid, Spain

Over the past few decades, the financial system has engaged in abusive practices that meet the definition of fraud. Our objective is to compare the prevalence of psychological distress and levels of health-related quality of life according to having been exposed to financial fraud and its economic impact on family finances. The City of Madrid Health Survey 2017 included specific questions on exposure to financial fraud-this section was administered to half of the participants (n = 4425). Mental health need or caseness was defined by a score greater than two on the 12-item version of the Goldberg health questionnaire. Health-related quality of life was assessed by the Darmouth Coop Functional Health Assessment Charts/WONCA (COOP/WONCA). The prevalence of financial fraud was 10.8%. The prevalence rate ratio for caseness of those who experienced severe economic impact due to fraud was 1.62 (95%, CI 1.17-2.25; reference: no fraud), after adjustment by age, sex, social class, and immigrant status. Women experienced a decreased quality of life, even with a moderate impact of fraud, while men experienced a decreased quality of life related to fraud with severe economic impact. The current study contributes to a growing body of literature showing the effects of economic shocks on health as a result of financial fraud.This research was funded by IMIENS—Joint Research Institute National Distance Education University and Health Institute Carlos III (IMIENS 2017-002).S

New species genetic approach to identify strains of mitis group streptococci that are donors of rifampin resistance to Streptococcus pneumoniae

Eight rifampin-resistant streptococci of the mitis group were identified at the species level by using a concatenated 16S rRNA gene-sodA-rpoB-hlpA sequence. Characterization of their rpoB alleles showed single amino acid changes involved in rifampin resistance. Comparison of RpoB sequences from pneumococcal recombinant isolates, viridans isolates, and type strains revealed a species-specific amino acid signature, which allowed it to be ascertained that recombinant RpoBs were originated in genetic interchanges with Streptococcus mitis and Streptococcus oralis.This work was supported by Plan Nacional de I+D+I of Ministerio de Ciencia e Innovación (grant no. BIO2008-02154) and Comunidad de Madrid (grant no. COMBACT-S-BIO-0260/2006). CIBER Enfermedades Respiratorias is an initiative from Instituto de Salud Carlos III.S

USP37 deubiquitinates Cdt1 and contributes to regulate DNA replication

DNA replication control is a key process in maintaining genomic integrity. Monitoring DNA replication initiation is particularly important as it needs to be coordinated with other cellular events and should occur only once per cell cycle. Crucial players in the initiation of DNA replication are the ORC protein complex, marking the origin of replication, and the Cdt1 and Cdc6 proteins, that license these origins to replicate by recruiting the MCM2-7 helicase. To accurately achieve its functions, Cdt1 is tightly regulated. Cdt1 levels are high from metaphase and during G1 and low in S/G2 phases of the cell cycle. This control is achieved, among other processes, by ubiquitination and proteasomal degradation. In an overexpression screen for Cdt1 deubiquitinating enzymes, we isolated USP37, to date the first ubiquitin hydrolase controlling Cdt1. USP37 overexpression stabilizes Cdt1, most likely a phosphorylated form of the protein. In contrast, USP37 knock down destabilizes Cdt1, predominantly during G1 and G1/S phases of the cell cycle. USP37 interacts with Cdt1 and is able to de-ubiquitinate Cdt1 in vivo and, USP37 is able to regulate the loading of MCM complexes onto the chromatin. In addition, downregulation of USP37 reduces DNA replication fork speed. Taken together, here we show that the deubiquitinase USP37 plays an important role in the regulation of DNA replication. Whether this is achieved via Cdt1, a central protein in this process, which we have shown to be stabilized by USP37, or via additional factors, remains to be tested.The authors are grateful to V. Smits for careful reading of the manuscript. This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (SAF2013-49149-R, BFU2014-51672-REDC), Instituto de Salud Carlos III (BA15/00092) and Fundacion CajaCanarias (AP2015/008) to RF.S

G protein-coupled receptor kinase 2 (GRK2) as a multifunctional signaling hub

Accumulating evidence indicates that G protein-coupled receptor kinase 2 (GRK2) is a versatile protein that acts as a signaling hub by modulating G protein-coupled receptor (GPCR) signaling and also via phosphorylation or scaffolding interactions with an extensive number of non-GPCR cellular partners. GRK2 multifunctionality arises from its multidomain structure and from complex mechanisms of regulation of its expression levels, activity, and localization within the cell, what allows the precise spatio-temporal shaping of GRK2 targets. A better understanding of the GRK2 interactome and its modulation mechanisms is helping to identify the GRK2-interacting proteins and its substrates involved in the participation of this kinase in different cellular processes and pathophysiological contexts.Our laboratories are supported by Ministerio de Ciencia, Innovación y Universidades (Grant SAF2017-84125-R to FM and SAF2017-82886-R to FSM), CIBERCV-Instituto de Salud Carlos III, Spain (Grant B16/11/00278 to F.M, co-funded with European FEDER contribution), Instituto de Salud Carlos III, Spain (Grant PI17-00576 to PP and grant PI18/01662 to CR), Fundacion Ramón Areces (to FM) and Programa de Actividades en Biomedicina de la Comunidad de Madrid-B2017/BMD-3671-INFLAMUNE to FM and FSM. We also acknowledge institutional support to the CBMSO from Fundación Ramón ArecesS

Access to prompt diagnosis: The missing link in preventing mental health disorders associated with neglected tropical diseases

Globally, there are an estimated 1 billion people suffering from at least one of the 20 neglected tropical diseases (NTDs) prioritized by the World Health Organization (WHO). Prevalent in tropical and subtropical regions, this group of NTDs comprises diverse diseases, including vector-borne parasitic diseases (such as human African trypanosomiasis [HAT], Chagas disease, and leishmaniasis), skin diseases caused by environmental bacteria (such as Buruli ulcer [BU]), foodborne parasitic diseases (such as taeniasis/cysticercosis) or snake bite envenoming, which—together with scabies and other ectoparasites, mycetoma, and deep mycoses—were recently added to the list [1]. Despite their differences, NTDs are synonymous with poverty, life-long disability, stigma, and discrimination, not to mention the lack of effective control tools such as vaccines, diagnostics, and drugs.S

Los registros de población y su uso para el análisis espacial de la salud

El proyecto LONGPOP que une los esfuerzos investigadores de España, Holanda, Suecia, Italia, Reino Unido, Bélgica y Suiza para formar una nueva generación de investigadores sociales en demografía y ciencias afinas y para el estudio de la evolución de la demografía y de la salud en Europa a través de metodología longitudinal y de análisis de BigData. LONGPOP es el acrónimo en inglés de Metodologías y técnicas de minería de datos para el análisis y explotación de grandes volúmenes de información basados en Registros Epidemiológicos y Longitudinales de Población. Las sociedades europeas se enfrentan a rápidos cambios sociales, que traen consigo retos y beneficios. Esta rápida transformación de la sociedad, afecta a los cambios en las formas de familia, la fecundidad, el declive de la mortalidad y el aumento de la longevidad, y los cambios son más rápidos en períodos de inestabilidad económica y social. Una de esas transformaciones, el envejecimiento de la población en toda Europa, está provocando que los países experimenten el impacto de estos cambios rápidos en la sostenibilidad de sus sistemas de bienestar. Al mismo tiempo, el uso del espacio y la movilidad residencial se ha convertido en un tema clave, convirtiéndose en el eje de la agenda política, con la migración dentro de los países de la UE y desde fuera de Europa como uno de los temas de mayor actualidad. Estos rápidos cambios sociales pueden ser estudiados con bases de datos y herramientas tradicionales de análisis, pero afrontando serias limitaciones de precisión y rapidez en la obtención de resultados. Durante la última década, equipos de investigación de toda Europa han estado involucrados en el desarrollo y construcción de registros longitudinales de población y grandes bases de datos de investigación, abriendo nuevas vías para establecer relaciones entre diferentes fuentes de datos (fundamentalmente registros de datos administrativos y epidemiológicos) con otras más heterogéneas y no estructuradas, haciendo posible conocer la causalidad de esa rápidas transformaciones sociales de forma menos costosa, con mayor precisión y prontitud. Sin embargo, el trabajo con ese tipo de conjuntos de datos requiere conocimientos avanzados, tanto en gestión de datos como en técnicas estadísticas. LONGPOP tiene como objetivo crear la red que reúne a estos diferentes equipos de investigación para compartir experiencias, construir investigación conjunta y crear una red de formación de especialistas en el campo y con ello aumentar el número de usuarios de estas grandes, y posiblemente infrautilizadas, bases de datos.N

Evaluation of the food advertisements broadcast in the Boing children’s television channel in Spain, 2016

También en inglésIntroducción: dada la relación entre el marketing de alimentos poco saludables y la obesidad infantil, el propósito de este estudio fue evaluar el uso de técnicas de marketing (persuasivo y nutricional), su nivel de cumplimiento del nuevo Código PAOS y el perfil nutricional de los alimentos y bebidas anunciados en Boing. Material y métodos: estudio descriptivo de una muestra de anuncios de alimentos y bebidas emitidos en 2016 por Boing, el canal de televisión infantil con publicidad de mayor audiencia en España. La información nutricional de los productos se obtuvo del etiquetado de estos y se clasificaron en más o menos saludables, según el perfil nutricional de la Organización Mundial de la Salud. Se analizó la presencia de las técnicas de marketing persuasivo y nutricional y su adecuación a las normas del nuevo Código PAOS. Resultados: durante las 13,5 horas de emisión se emitieron 111 anuncios, correspondientes a 20 productos, 17 alimentos y 3 bebidas, con una tasa de 8,2 anuncios por hora. El 100% de los productos utilizaron alguna de las técnicas de marketing analizadas y resultaron no saludables, según el modelo de la Organización Mundial de la Salud. El 73,9% de los anuncios incumplieron alguna norma del código PAOS. Conclusiones: los alimentos y bebidas anunciados fueron no saludables e hicieron un uso generalizado de técnicas de marketing nutricional y persuasivo. Tres de cada cuatro infringieron el código PAOS vigente en España, que se revela ineficaz, recomendándose sustituirlo por una regulación que proteja eficazmente a los menores de la publicidad de alimentos y bebidas no saludables