Ancient mitochondrial pseudogenes reveal hybridization between distant lineages in the evolution of the Rupicapra genus

© The Author(s), 2017. This is the author's version of the work and is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Gene 628 (2017): 63-71, doi:10.1016/j.gene.2017.07.035.Mitochondrial pseudogenes (numts) inserted in the nuclear genome are frequently found in population studies. Its presence is commonly connected with problems and errors when they are confounded with true mitochondrial sequences. In the opposite side, numts can provide valuable phylogenetic information when they are copies of ancient mitochondrial lineages. We show that Rupicapra individuals of different geographic origin from the Cantabrian Mountains to the Apennines and the Caucasus share a nuclear COI fragment. The numt copies are monophyletic, and their pattern of differentiation shows two outstanding features: a long evolution as differentiated true mitochondrial lineage, and a recent integration and spread through the chamois populations. The COI pseudogene is much older than the present day mitochondrial clades of Rupicapra and occupies a basal position within the Rupicapra-Ammotragus- Arabitragus node. Joint analysis of this numt and a cytb pseudogene with a similar pattern of evolution places the source mitochondrial lineage as a sister branch that separated from the Ammotragus-Arabitragus lineage 6 million years ago (Mya). The occurrence of this sequence in the nucleus of chamois suggests hybridization between highly divergent lineages. The integration event seems to be very recent, more recent than the split of the present day mtDNA lineages of Rupicapra (1.9 Mya). This observation invites to think of the spread across the genus by horizontal transfer through recent male-biased dispersal.This work was funded by Ministerio de Economía y Competitividad. Spain. (Grant number CGL2011-25117).2018-07-1

Persistent Overactive Cytotoxic Immune Response in a Spanish Cohort of Individuals With Long-COVID: Identification of Diagnostic Biomarkers

Long-COVID is a new emerging syndrome worldwide that is characterized by the persistence of unresolved signs and symptoms of COVID-19 more than 4 weeks after the infection and even after more than 12 weeks. The underlying mechanisms for Long-COVID are still undefined, but a sustained inflammatory response caused by the persistence of SARS-CoV-2 in organ and tissue sanctuaries or resemblance with an autoimmune disease are within the most considered hypotheses. In this study, we analyzed the usefulness of several demographic, clinical, and immunological parameters as diagnostic biomarkers of Long-COVID in one cohort of Spanish individuals who presented signs and symptoms of this syndrome after 49 weeks post-infection, in comparison with individuals who recovered completely in the first 12 weeks after the infection. We determined that individuals with Long-COVID showed significantly increased levels of functional memory cells with high antiviral cytotoxic activity such as CD8+ TEMRA cells, CD8±TCRγδ+ cells, and NK cells with CD56+CD57+NKG2C+ phenotype. The persistence of these long-lasting cytotoxic populations was supported by enhanced levels of CD4+ Tregs and the expression of the exhaustion marker PD-1 on the surface of CD3+ T lymphocytes. With the use of these immune parameters and significant clinical features such as lethargy, pleuritic chest pain, and dermatological injuries, as well as demographic factors such as female gender and O+ blood type, a Random Forest algorithm predicted the assignment of the participants in the Long-COVID group with 100% accuracy. The definition of the most accurate diagnostic biomarkers could be helpful to detect the development of Long-COVID and to improve the clinical management of these patients.This work was supported by the Coordinated Research Activities at the National Center of Microbiology (CNM, Instituto de Salud Carlos III) (COV20_00679) to promote an integrated response against SARS-CoV-2 in Spain (Spanish Ministry of Science and Innovation), which is coordinated by Dr Inmaculada Casas (WHO National Influenza Center of the CNM); a generous donation provided by Chiesi España, S.A.U. (Barcelona, Spain); the Spanish Ministry of Science and Innovation (PID2019-110275RB-I00); and the Spanish AIDS Research Network RD16CIII/0002/0001 that is included in Acción Estratégica en Salud, Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica 2016-2020, Instituto de Salud Carlos III, European Region Development Fund (ERDF). The work of ML-H and SR-M is financed by NIH grant R01AI143567. The work of MT is supported by Instituto de Salud Carlos III (COV20_00679). The work of LV is supported by a pre-doctoral grant from Instituto de Salud Carlos III (FIS PI16CIII/00034-ISCIII-FEDER). The work of FR-M is financed by the Spanish Ministry of Science and Innovation (PID2019-110275RB-I00).S

Proximidad residencial a industrias y mortalidad por enfermedades cardiovasculares y cáncer en personas mayores: Estudio Seniors-ENRICA

XLI Reunión anual de la Sociedad Española de Epidemiología (SEE) y XVIII Congresso da Associação Portuguesa de Epidemiología (APE). Porto (Portugal), del 5 al 8 de septiembre de 2023.Antecedentes/Objetivos: Las enfermedades cardiovasculares (ECV) y el cáncer son las dos principales causas de muerte en el mundo. Su etiología no es única y, en el caso del cáncer, tiene una parte desconocida, por lo que se necesita seguir evaluando el papel de potenciales factores de riesgo asociados con estas enfermedades. El objetivo fue analizar la asociación entre proximidad residencial a industrias contaminantes y mortalidad por ECV y cáncer, teniendo en cuenta categorías de sectores industriales y contaminantes emitidos en el estudio Seniors-ENRICA. Métodos: Seniors-ENRICA es una cohorte representativa a nivel nacional de población mayor de 60 años no institucionalizada con un seguimiento de 10 años, cuyo objetivo es evaluar factores de riesgo ambientales que afectan a la salud de las personas mayores, incluyendo mortalidad por ECV y cáncer. La cohorte se estableció en 2008-2010 con 3289 individuos que contribuyeron con 8562 visitas bianuales. Se geocodificaron los domicilios de los individuos y las industrias y se calculó la distancia entre ellos. Como medida de efecto se estimó el hazard ratio (HR) y su intervalo de confianza al 95% (IC95%) asociado a la proximidad (distancias desde ≤ 2 km hasta ≤ 5 km) a industrias mediante modelos de regresión de Cox para riesgos competitivos, ajustando por variables sociodemográficas y de estilos de vida a nivel individual, y por índice de privación a nivel de sección censal. Resultados: Durante el seguimiento, se produjeron 136 muertes por ECV y 146 por cáncer. No se encontró asociación entre proximidad a industrias y mortalidad por ECV para ninguna de las distancias analizadas, con HRs oscilando entre 0,89 (≤ 4 km) y 0,99 (≤ 2 km). Para mortalidad por cáncer, se encontraron asociaciones (HR; IC95%) positivas para el conjunto de industrias en todas las distancias analizadas, desde ≤ 2 km (3,16; 1,60-6,26) hasta ≤ 5 km (2,57, 1,37-4,81). Por sectores industriales, destacan los excesos de riesgo (HR; IC95%) de morir por cáncer en el entorno (≤ 5 km) de astilleros (4,38; 1,67-11,48), cementeras (5,31; 1,31-21,49) e instalaciones de galvanizado (4,05; 1,59-10,33). Por contaminantes, los principales excesos de riesgo (HR; IC95%) se encontraron en el entorno (≤ 5 km) de industrias emisoras de antraceno (4,70; 1,71-12,93) antimonio (4,63; 2,01-10,64) y ftalatos (4,20; 1,58-11,14). Conclusiones/Recomendaciones: Los resultados sugieren que vivir cerca de industrias podría ser un factor de riesgo para la mortalidad por cáncer en población > 60 años, pero no para ECV.Financiación: CIBERESP-ESP21PI04.N

CD69 expression on regulatory T cells protects from immune damage after myocardial infarction.

Increasing evidences advocate for an important function of T cells in controlling immune homeostasis and pathogenesis after myocardial infarction (MI), although the underlying molecular mechanisms remain elusive. In this study, a broad analysis of immune markers in 283 patients revealed a significant CD69 overexpression on Treg cells after MI. Our results in mice showed that CD69 expression on Treg cells increased survival after left-anterior-descending coronary artery (LAD)-ligation. Cd69-/- mice developed strong IL-17+ γδT cell responses after ischemia that increased myocardial inflammation and, consequently, worsened cardiac function. CD69+ Treg cells, by induction of AhR-dependent CD39 ectonucleotidase activity, induced apoptosis and decreased IL-17A production in γδT cells. Adoptive transfer of CD69+ Treg cells to Cd69-/- mice after LAD-ligation reduced IL-17+ γδT cell recruitment, thus increasing survival. Consistently, clinical data from two independent cohorts of patients indicated that increased CD69 expression in peripheral blood cells after acute MI was associated with a lower risk of re-hospitalization for heart failure (HF) after 2.5 years of follow-up. This result remained significant after adjustment for age, sex and traditional cardiac damage biomarkers. Our data highlight CD69 expression on Treg cells as a potential prognostic factor and a therapeutic option to prevent HF after MI.This study was supported by competitive grants from the Ministerio de Ciencia e Innovación (MCIN), through the Carlos III Institute of Health (ISCIII)-Fondo de Investigación Sanitaria (PI22/01759) to P.M.; RTI2018-094727-B-100 to J. M-G; Comunidad de Madrid grants S2017/BMD-3671-INFLAMUNE-CM to P.M. and FSM.; Fundació La Marató TV3 (20152330 31) to J.M-G and F.S-M.; Ministerio de Ciencia e Innovación (MCIN) RTI2018-099357-B-I00, and CIBERFES (CB16/10/00282), Human Frontier Science Program (grant RGP0016/2018), and Leducq Transatlantic Networks (17CVD04) to JAE. AC is supported by Marie Skłodowska- Curie grant (agreement No. 713673). R.B-D. is supported by Formación de Profesorado Universitario (FPU16/02780) program from the Spanish Ministry of Education, Culture and Sports. The CNIC is supported by the ISCIII, the MCIN and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505).S

Zika virus infection: a new public health emergency with great media impact

[ES] La infección por virus Zika (VZ) está afectando intensamente a los países latinoamericanos y se ha convertido en una nueva epidemia mediática. Su posible asociación con microcefalia y síndrome de Guillain-Barré motivó que la Organización Mundial de la Salud (OMS) declarase el 1 de febrero de 2016 que esta epidemia constituye una emergencia de salud pública de importancia internacional. Los datos epidemiológicos muestran una incidencia creciente en países como Brasil y Colombia, y que la epidemia sigue expandiéndose por muchos otros países. Desde enero de 2007 hasta el 27 de abril de 2016, la OMS ha detectado transmisión autóctona en 55 países (en 42 de ellos ha sido el primer brote de Zika), y 1198 microcefalias y otros trastornos neurológicos en Brasil. Así mismo, durante 2015 y 2016, 13 países detectaron un incremento de los casos de síndrome de Guillain-Barré y de confirmación de VZ asociado a este. En relación a las microcefalias y otras graves alteraciones cerebrales en recién nacidos de madres afectadas por VZ, las investigaciones ya evidencian una relación causal. Clínicamente muchos casos son asintomáticos y el diagnóstico ofrece dificultades con otras arbovirosis. El control de vectores en España es prioritario, dada la existencia de Aedes albopictus (mosquito tigre). También se recomienda el diagnóstico precoz, evitar viajes a zonas endémicas, mantener relaciones sexuales protegidas y procurar que la prioridad política, que puede evitar que esta epidemia se convierta en una enfermedad endémica de alta prevalencia, no nos haga olvidar otros problemas de salud. [EN] Infection with Zika virus (ZV) has become a new epidemic, with great impact on the media, and is having a strong effect in Latin American countries. Its possible association with microcephaly and Guillain-Barré syndrome prompted the World Health Organization (WHO) to declare on 1 February 2016 that this epidemic is a public health emergency of international concern. Epidemiological data show an increasing incidence in countries like Brazil and Colombia, and that the epidemic is still expanding in many other countries. Between January 2007 and 27 April 2016, the WHO detected transmission in 55 countries (in 42 of these, this was the first outbreak of Zika) and 1,198 microcephalies and other neurological disorders in Brazil. Also, during 2015-2016, 13 countries detected an increase in Guillain-Barré syndrome and/or confirmation of ZV associated with Guillain-Barré syndrome. Research has already demonstrated a causal relationship between microcephaly and other serious brain disorders in newborns and ZV infection in the mother. Clinically, many cases are asymptomatic and it can be difficult to distinguish this diagnosis from that of other arboviruses. Vector control in Spain is a priority because of the presence of the Aedes albopictus (tiger mosquito). Early diagnosis is recommended, as is avoiding travel to endemic areas and unprotected sex, and ensuring that the high political profile, which can prevent this epidemic from becoming a high prevalence endemic disease, does not cause us to forget about other health problems.S

Molecular characterization of epithelial-mesenchymal transition and medical treatment related-genes in non-functioning pituitary neuroendocrine tumors

Different medical therapies have been developed for pituitary adenomas. However, Non-Functioning Pituitary Neuroendocrine Tumors (NF-PitNET) have shown little response to them. Furthermore, epithelial-mesenchymal transition (EMT) has been linked to resistance to medical treatment in a significant number of tumors, including pituitary adenomas. We aimed to evaluate the expression of EMT-related markers in 72 NF-PitNET and 16 non-tumoral pituitaries. To further explore the potential usefulness of medical treatment for NF-PitNET we assessed the expression of somatostatin receptors and dopamine-associated genes. We found that SNAI1, SNAI2, Vimentin, KLK10, PEBP1, Ki-67 and SSTR2 were associated with invasive NF-PitNET. Furthermore, we found that the EMT phenomenon was more common in NF-PitNET than in GH-secreting pituitary tumors. Interestingly, PEBP1 was overexpressed in recurrent NF-PitNET, and could predict growth recurrence with 100% sensitivity but only 43% specificity. In parallel with previously reported studies, SSTR3 is highly expressed in our NF-PitNET cohort. However, SSTR3 expression is highly heterogeneous among the different histological variants of NF-PitNET with very low levels in silent corticotroph adenomas. NF-PitNET showed an enhanced EMT phenomenon. SSTR3 targeting could be a good therapeutic candidate in NF-PitNET except for silent corticotroph adenomas, which express very low levels of this receptor. In addition, PEBP1 could be an informative biomarker of tumor regrowth, useful for predictive medicine in NF-PitNET

Methicillin-resistant Staphylococcus aureus (MRSA) catheter-related bacteraemia in haemodialysis patients

Background: the aim of the study was to determine clinical and microbiological differences between patients with methicillin-resistant Staphylococcus aureus (MRSA) catheter-related bacteraemia (CRB) undergoing or not undergoing haemodialysis, and to compare outcomes. Methods: prospective multicentre study conducted at 21 Spanish hospitals of patients with MRSA bacteraemia diagnosed between June 2008 and December 2009. Patients with MRSA-CRB were selected. Data of patients on haemodialysis (HD-CRB) and those not on haemodialysis (non-HD-CRB) were compared. Results: among 579 episodes of MRSA bacteraemia, 218 (37.7 %) were CRB. Thirty-four (15.6 %) were HD-CRB and 184 (84.4 %) non-HD-CRB. All HD-CRB patients acquired the infection at dialysis centres, while in 85.3 % of the non-HD-CRB group the infection was nosocomial (p < .001). There were no differences in age, gender or severity of bacteraemia (Pitt score); comorbidities (Charlson score ≥ 4) were higher in the HD-CRB group than in the non-HD-CRB group (73.5 % vs. 46.2 %, p = .003). Although there were no differences in VAN-MIC ≥1.5 mg/L according to microdilution, using the E-test a higher rate of VAN-MIC ≥1.5 mg/L was observed in HD-CRB than in non-HD-CRB patients (63.3 % vs. 44.1 %, p = .051). Vancomycin was more frequently administered in the HD-CRB group than in the non-HD-CRB group (82.3 % vs. 42.4 %, p = <.001) and therefore the appropriate empirical therapy was significantly higher in HD-CRB group (91.2 % vs. 73.9 %, p = .029). There were no differences with regard to catheter removal (79.4 % vs. 84.2 %, p = .555, respectively). No significant differences in mortality rate were observed between both groups (Overall mortality: 11.8 % vs. 27.2 %, p = .081, respectively), but there was a trend towards a higher recurrence rate in HD-CRB group (8.8 % vs. 2.2 %, p = .076). Conclusions: in our multicentre study, ambulatory patients in chronic haemodialysis represented a significant proportion of cases of MRSA catheter-related bacteraemia. Although haemodialysis patients with MRSA catheter-related bacteraemia had significantly more comorbidities and higher proportion of strains with reduced vancomycin susceptibility than non-haemodialysis patients, overall mortality between both groups was similar

Impact of SARS-Cov-2 infection in patients with hypertrophic cardiomyopathy : results of an international multicentre registry

To describe the natural history of SARS-CoV-2 infection in patients with hypertrophic cardiomyopathy (HCM) compared with a control group and to identify predictors of adverse events. Three hundred and five patients [age 56.6 ± 16.9 years old, 191 (62.6%) male patients] with HCM and SARS-Cov-2 infection were enrolled. The control group consisted of 91 131 infected individuals. Endpoints were (i) SARS-CoV-2 related mortality and (ii) severe clinical course [death or intensive care unit (ICU) admission]. New onset of atrial fibrillation, ventricular arrhythmias, shock, stroke, and cardiac arrest were also recorded. Sixty-nine (22.9%) HCM patients were hospitalized for non-ICU level care, and 21 (7.0%) required ICU care. Seventeen (5.6%) died: eight (2.6%) of respiratory failure, four (1.3%) of heart failure, two (0.7%) suddenly, and three (1.0%) due to other SARS-CoV-2-related complications. Covariates associated with mortality in the multivariable were age {odds ratio (OR) per 10 year increase 2.25 [95% confidence interval (CI): 1.12-4.51], P = 0.0229}, baseline New York Heart Association class [OR per one-unit increase 4.01 (95%CI: 1.75-9.20), P = 0.0011], presence of left ventricular outflow tract obstruction [OR 5.59 (95%CI: 1.16-26.92), P = 0.0317], and left ventricular systolic impairment [OR 7.72 (95%CI: 1.20-49.79), P = 0.0316]. Controlling for age and sex and comparing HCM patients with a community-based SARS-CoV-2 cohort, the presence of HCM was associated with a borderline significant increased risk of mortality OR 1.70 (95%CI: 0.98-2.91, P = 0.0600). Over one-fourth of HCM patients infected with SARS-Cov-2 required hospitalization, including 6% in an ICU setting. Age and cardiac features related to HCM, including baseline functional class, left ventricular outflow tract obstruction, and systolic impairment, conveyed increased risk of mortality

SELNET clinical practice guidelines for bone sarcoma

Bone sarcoma are infrequent diseases, representing < 0.2% of all adult neoplasms. A multidisciplinary management within reference centers for sarcoma, with discussion of the diagnostic and therapeutic strategies within an expert multidisciplinary tumour board, is essential for these patients, given its heterogeneity and low frequency. This approach leads to an improvement in patient's outcome, as demonstrated in several studies. The Sarcoma European Latin-American Network (SELNET), aims to improve clinical outcome in sarcoma care, with a special focus in Latin-American countries. These Clinical Practice Guidelines (CPG) have been developed and agreed by a multidisciplinary expert group (including medical and radiation oncologist, surgical oncologist, orthopaedic surgeons, radiologist, pathologist, molecular biologist and representatives of patients advocacy groups) of the SELNET consortium, and are conceived to provide the standard approach to diagnosis, treatment and follow-up of bone sarcoma patients in the Latin-American context

Novel genes and sex differences in COVID-19 severity

[EN] Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10−8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10−22 and P = 8.1 × 10−12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10−8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10−8) and ARHGAP33 (P = 1.3 × 10−8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10−8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.S