Small extracellular vesicle targeting of hypothalamic AMPKα1 promotes weight loss in leptin receptor deficient mice

Background and aims: Leptin receptor (LEPR) deficiency promotes severe obesity and metabolic disorders. However, the current therapeutic options against this syndrome are scarce. Methods: db/db mice and their wildtypes were systemically treated with neuronal-targeted small extracellular vesicles (sEVs) harboring a plasmid encoding a dominant negative mutant of AMP-activated protein kinase alpha 1 (AMPKα1-DN) driven by steroidogenic factor 1 (SF1) promoter; this approach allowed to modulate AMPK activity, specifically in SF1 cells of the ventromedial nucleus of the hypothalamus (VMH). Animals were metabolically phenotyped. Results: db/db mice intravenously injected with SF1-AMPKα1-DN loaded sEVs showed a marked feeding-independent weight loss and decreased adiposity, associated with increased sympathetic tone, brown adipose tissue (BAT) thermogenesis and browning of white adipose tissue (WAT).Conclusion: Overall, this evidence indicates that specific modulation of hypothalamic AMPK using a sEV-based technology may be a suitable strategy against genetic forms of obesity, such as LEPR deficiencyMinisterio de Ciencia y Universidades co-funded by the FEDER Program of EU (CD: BFU2017-87721; RN: RTI2018-099413-B-I00 and RED2018-102379-T; ML: RTI2018-101840-B-I00, PID2021-128145NB-I00 and PDC2022-133958-I00). “la Caixa” Foundation (ID100010434), under the agreement LCF/PR/HR19/52160022 (ML); EuroNanoMed III (RA & ML: EURONANOMED2019-050-ENAMEP); European Research Council (RN: ERC Synergy Grant-2019-WATCH-810331)S

Ceruloplasmin and its clinical relevance as an indactor of cardiovascular risk factor in a school population of Granada

La ceruloplasmina también conocida como ferroxidasa, pertenece a la familia de las proteínas sensibles a la inflamación, siendo su función principal la de transportar el cobre en la sangre. Si bien, además de esta función transportadora, en la actualidad, son numerosos los estudios que han intentado hacer uso de la determinación de sus concentraciones séricas, como un indicador predictivo del riesgo de padecer trastornos cardiovasculares en pacientes que presentan sobrepeso u obesidad. Los resultados obtenidos en este estudio confirman la existencia de una correlación significativa entre los niveles séricos de ceruloplasmina y el estado nutricional de los sujetos, lo que significa que para la población de escolares valorada, las concentraciones séricas de esta proteína suponen un importante factor para predecir el riesgo de padecer trastornos cardiovasculares.Also known as ferroxidase ceruloplasmin, belongs to the family of inflammation-sensitive proteins, and its main function to transport copper in the blood. Although, in addition to this transport function, at present, there are numerous studies that have attempted to use the determination of serum concentrations as a predictive indicator of cardiovascular risk in patients who are overweight or obese. The results of this study confirm the existence of a significant correlation between serum ceruloplasmin and nutritional status of the subjects, which means that for the population of students assessed, serum levels of this protein are an important predictor the risk of cardiovascular disease

A genome-wide association study follow-up suggests a possible role for PPARG in systemic sclerosis susceptibility

Introduction: A recent genome-wide association study (GWAS) comprising a French cohort of systemic sclerosis (SSc) reported several non-HLA single-nucleotide polymorphisms (SNPs) showing a nominal association in the discovery phase. We aimed to identify previously overlooked susceptibility variants by using a follow-up strategy.<p></p> Methods: Sixty-six non-HLA SNPs showing a P value <10-4 in the discovery phase of the French SSc GWAS were analyzed in the first step of this study, performing a meta-analysis that combined data from the two published SSc GWASs. A total of 2,921 SSc patients and 6,963 healthy controls were included in this first phase. Two SNPs, PPARG rs310746 and CHRNA9 rs6832151, were selected for genotyping in the replication cohort (1,068 SSc patients and 6,762 healthy controls) based on the results of the first step. Genotyping was performed by using TaqMan SNP genotyping assays. Results: We observed nominal associations for both PPARG rs310746 (PMH = 1.90 × 10-6, OR, 1.28) and CHRNA9 rs6832151 (PMH = 4.30 × 10-6, OR, 1.17) genetic variants with SSc in the first step of our study. In the replication phase, we observed a trend of association for PPARG rs310746 (P value = 0.066; OR, 1.17). The combined overall Mantel-Haenszel meta-analysis of all the cohorts included in the present study revealed that PPARG rs310746 remained associated with SSc with a nominal non-genome-wide significant P value (PMH = 5.00 × 10-7; OR, 1.25). No evidence of association was observed for CHRNA9 rs6832151 either in the replication phase or in the overall pooled analysis.<p></p> Conclusion: Our results suggest a role of PPARG gene in the development of SSc

Unraveling the real magnitude of illegal wildlife poisoning to halt cryptic biodiversity loss

Illegal wildlife poisoning is a global threat for biodiversity, yet the magnitude of its impact on ecosystems is largely underestimated as most of poisoning episodes remain undetected. Here, we conducted a large-scale field experiment to better understand the real dimension of the illegal wildlife poisoning in terms of composition and number of species and abundance of impacted individuals, as well as the ecological factors driving it. We used camera traps to monitor simulated poison baits placed in 25 study areas in SW Europe and applied Good–Turing theory to estimate the richness of species of the entire assemblage (observed plus undetected). We recorded 3095 individuals from 39 vertebrate species that consumed 94 % of the baits (N = 590). Yet, using sample completeness to estimate the entire species assemblage yielded a total of 47 species exposed to illegal poisoning. The observed assemblage included different trophic and functional groups (from lizards and snakes to apex species among birds and mammals), as well as a 38 % of threatened and near threatened species (according to Spanish and Portuguese vertebrate red list and UICN list). The size (weight) of the bait outstands as a reliable predictor of the number of species (0–8 species/bait, mean = 2) and individuals (0–99 individuals/bait, mean = 5) susceptible to poisoning. The habitat where the bait was placed modulated the abundance of individuals affected (greater in open than in closed habitats). Type of bait and habitat drove the compositional variation of species. Our approach enables uncover entire species assemblages prone to illegal poisoning and their ecological drivers associated, advancing the understanding of the impact of wildlife poisoning in ecosystemsThis work was supported by the project TOXICO funding by “BBVA FOUNDATION GRANTS TO SCIENTIFIC RESEARCH TEAMS, CALL 2018”. WWF Spain and SEO/BirdLife provided access to the ANTíDOTO database of wildlife poisoning in Spain. The Ohio Wesleyan University supported with logistical material (5 camera-traps). JVLB was supported by the Spanish Ministry of Economy, Industry and Competitiveness (RYC-2015-18932; CGL2017-87528-R AEI/FEDER EU). JVLB and PMT were supported by a GRUPIN research grant from the Regional Government of Asturias (AYUD/2021/51314). In Portugal, this study was financed through the Sentinelas project funded by Fundo Ambiental – Minist´erio do Ambiente e da Aç˜ ao Clim´ atica. We are grateful to Instituto da Conservaçao ˜ da Natureza e das Florestas (ICNF), Principado de Asturias, Junta de Castilla y Leon, ´ Xunta de Galicia, Gobierno de Cantabria, Comunidad de Madrid, Junta de Andalucía, Picos de Europa National Park, Sierra de Guadarrama National Park, Cabaneros ˜ National Park and Monfragüe National Park for granted permission

Memoria del II Coloquio de verano de investigación de la Escuela de Negocios de ITESO, 2023

La memoria recoge cinco de las ponencias presentadas en el Coloquio de investigación de verano de la Escuela de Negocios, 2023. Durante las presentaciones y el diálogo quisimos hacer énfasis en dos aspectos de nuestra labor universitaria: 1) el fortalecimiento de la Escuela de Negocios como instancia interdepartamental que comparte una misión común; 2) el modo como las tres funciones sustantivas (docencia, investigación y vinculación) se retroalimentan y sostienen mutuamente. Se presentan resúmenes extendidos de los siguientes trabajos: Diagnóstico de cultura organizacional por alumnos del PAP de Gestión del cambio, del talento humano y la efectividad organizacional; Modelo estratégico de sostenibilidad basado en el modelo de flujos descontados (DCF); Laboratorios móviles: impulsando la industria creativa-cultural en Jalisco; Nueva estrategia de comunicación como proceso formativo para empresarios y emprendedores; Economía Social y Solidaria como un elemento para el desarrollo de talleres del sector artesanal.ITESO, A.C

Risk of cancer in family members of patients with lynch-like syndrome

Lynch syndrome (LS) is a common cause of hereditary colorectal cancer (CRC). Some CRC patients develop mismatch repair deficiency without germline pathogenic mutation, known as Lynch-like syndrome (LLS). We compared the risk of CRC in first-degree relatives (FDRs) in LLS and LS patients. LLS was diagnosed when tumors showed immunohistochemical loss of MSH2, MSH6, and PMS2; or loss of MLH1 with BRAF wild type; and/or no MLH1 methylation and absence of pathogenic mutation in these genes. CRC and other LS-related neoplasms were followed in patients diagnosed with LS and LLS and among their FDRs. Standardized incidence ratios (SIRs) were calculated for CRC and other neoplasms associated with LS among FDRs of LS and LLS patients. In total, 205 LS (1205 FDRs) and 131 LLS families (698 FDRs) had complete pedigrees. FDRs of patients with LLS had a high incidence of CRC (SIR, 2.08; 95% confidence interval (CI), 1.56-2.71), which was significantly lower than that in FDRs of patients with LS (SIR, 4.25; 95% CI, 3.67-4.90; p < 0.001). The risk of developing other neoplasms associated with LS also increased among FDR of LLS patients (SIR, 2.04; 95% CI, 1.44-2.80) but was lower than that among FDR of patients with LS (SIR, 5.01, 95% CI, 4.26-5.84; p < 0.001). FDRs with LLS have an increased risk of developing CRC as well as LS-related neoplasms, although this risk is lower than that of families with LS. Thus, their management should take into account this increased risk

Introducing high-throughput sequencing into mainstream genetic diagnosis practice in inherited platelet disorders

Inherited platelet disorders are a heterogeneous group of rare diseases, caused by inherited defects in platelet production and/or function. Their genetic diagnosis would benefit clinical care, prognosis and preventative treatments. Until recently, this diagnosis has usually been performed via Sanger sequencing of a limited number of candidate genes. High-throughput sequencing is revolutionizing the genetic diagnosis of diseases, including bleeding disorders. We have designed a novel high-throughput sequencing platform to investigate the unknown molecular pathology in a cohort of 82 patients with inherited platelet disorders. Thirty-four (41.5%) patients presented with a phenotype strongly indicative of a particular type of platelet disorder. The other patients had clinical bleeding indicative of platelet dysfunction, but with no identifiable features. The high-throughput sequencing test enabled a molecular diagnosis in 70% of these patients. This sensitivity increased to 90% among patients suspected of having a defined platelet disorder. We found 57 different candidate variants in 28 genes, of which 70% had not previously been described. Following consensus guidelines, we qualified 68.4% and 26.3% of the candidate variants as being pathogenic and likely pathogenic, respectively. In addition to establishing definitive diagnoses of well-known inherited platelet disorders, high-throughput sequencing also identified rarer disorders such as sitosterolemia, filamin and actinin deficiencies, and G protein-coupled receptor defects. This included disease-causing variants in DIAPH1 (n=2) and RASGRP2 (n=3). Our study reinforces the feasibility of introducing high-throughput sequencing technology into the mainstream laboratory for the genetic diagnostic practice in inherited platelet disorders.This study was supported by research grants from the Gerencia Regional de Salud (GRS 1370/A/16), ISCIII & Feder (PI14/01956), CIBERER CB15/00055, Fundación Séneca (19873/GERM/15) and Sociedad Española de Trombosis y Hemostasia (SETH). SPW holds a British Heart Foundation chair.Peer Reviewe

Cross-disease Meta-analysis of Genome-wide Association Studies for Systemic Sclerosis and Rheumatoid Arthritis Reveals IRF4 as a New Common Susceptibility Locus

Objectives: Systemic sclerosis (SSc) and rheumatoid arthritis (RA) are autoimmune diseases that share clinical and immunological characteristics. To date, several shared SSc- RA loci have been identified independently. In this study, we aimed to systematically search for new common SSc-RA loci through an inter-disease meta-GWAS strategy. Methods: We performed a meta-analysis combining GWAS datasets of SSc and RA using a strategy that allowed identification of loci with both same-direction and opposingdirection allelic effects. The top single-nucleotide polymorphisms (SNPs) were followed-up in independent SSc and RA case-control cohorts. This allowed us to increase the sample size to a total of 8,830 SSc patients, 16,870 RA patients and 43,393 controls. Results: The cross-disease meta-analysis of the GWAS datasets identified several loci with nominal association signals (P-value < 5 x 10-6), which also showed evidence of association in the disease-specific GWAS scan. These loci included several genomic regions not previously reported as shared loci, besides risk factors associated with both diseases in previous studies. The follow-up of the putatively new SSc-RA loci identified IRF4 as a shared risk factor for these two diseases (Pcombined = 3.29 x 10-12). In addition, the analysis of the biological relevance of the known SSc-RA shared loci pointed to the type I interferon and the interleukin 12 signaling pathways as the main common etiopathogenic factors. Conclusions: Our study has identified a novel shared locus, IRF4, for SSc and RA and highlighted the usefulness of cross-disease GWAS meta-analysis in the identification of common risk loci

Un examen actualizado de la percepción de las barreras para la implementación de la farmacogenómica y la utilidad de los pares fármaco/gen en América Latina y el Caribe

La farmacogenómica (PGx) se considera un campo emergente en los países en desarrollo. La investigación sobre PGx en la región de América Latina y el Caribe (ALC) sigue siendo escasa, con información limitada en algunas poblaciones. Por lo tanto, las extrapolaciones son complicadas, especialmente en poblaciones mixtas. En este trabajo, revisamos y analizamos el conocimiento farmacogenómico entre la comunidad científica y clínica de ALC y examinamos las barreras para la aplicación clínica. Realizamos una búsqueda de publicaciones y ensayos clínicos en este campo en todo el mundo y evaluamos la contribución de ALC. A continuación, realizamos una encuesta regional estructurada que evaluó una lista de 14 barreras potenciales para la aplicación clínica de biomarcadores en función de su importancia. Además, se analizó una lista emparejada de 54 genes/fármacos para determinar una asociación entre los biomarcadores y la respuesta a la medicina genómica. Esta encuesta se comparó con una encuesta anterior realizada en 2014 para evaluar el progreso en la región. Los resultados de la búsqueda indicaron que los países de América Latina y el Caribe han contribuido con el 3,44% del total de publicaciones y el 2,45% de los ensayos clínicos relacionados con PGx en todo el mundo hasta el momento. Un total de 106 profesionales de 17 países respondieron a la encuesta. Se identificaron seis grandes grupos de obstáculos. A pesar de los continuos esfuerzos de la región en la última década, la principal barrera para la implementación de PGx en ALC sigue siendo la misma, la "necesidad de directrices, procesos y protocolos para la aplicación clínica de la farmacogenética/farmacogenómica". Las cuestiones de coste-eficacia se consideran factores críticos en la región. Los puntos relacionados con la reticencia de los clínicos son actualmente menos relevantes. Según los resultados de la encuesta, los pares gen/fármaco mejor clasificados (96%-99%) y percibidos como importantes fueron CYP2D6/tamoxifeno, CYP3A5/tacrolimus, CYP2D6/opioides, DPYD/fluoropirimidinas, TMPT/tiopurinas, CYP2D6/antidepresivos tricíclicos, CYP2C19/antidepresivos tricíclicos, NUDT15/tiopurinas, CYP2B6/efavirenz y CYP2C19/clopidogrel. En conclusión, aunque la contribución global de los países de ALC sigue siendo baja en el campo del PGx, se ha observado una mejora relevante en la región. La percepción de la utilidad de las pruebas PGx en la comunidad biomédica ha cambiado drásticamente, aumentando la concienciación entre los médicos, lo que sugiere un futuro prometedor en las aplicaciones clínicas de PGx en ALC.Pharmacogenomics (PGx) is considered an emergent field in developing countries. Research on PGx in the Latin American and the Caribbean (LAC) region remains scarce, with limited information in some populations. Thus, extrapolations are complicated, especially in mixed populations. In this paper, we reviewed and analyzed pharmacogenomic knowledge among the LAC scientific and clinical community and examined barriers to clinical application. We performed a search for publications and clinical trials in the field worldwide and evaluated the contribution of LAC. Next, we conducted a regional structured survey that evaluated a list of 14 potential barriers to the clinical implementation of biomarkers based on their importance. In addition, a paired list of 54 genes/drugs was analyzed to determine an association between biomarkers and response to genomic medicine. This survey was compared to a previous survey performed in 2014 to assess progress in the region. The search results indicated that Latin American and Caribbean countries have contributed 3.44% of the total publications and 2.45% of the PGx-related clinical trials worldwide thus far. A total of 106 professionals from 17 countries answered the survey. Six major groups of barriers were identified. Despite the region’s continuous efforts in the last decade, the primary barrier to PGx implementation in LAC remains the same, the “need for guidelines, processes, and protocols for the clinical application of pharmacogenetics/pharmacogenomics”. Cost-effectiveness issues are considered critical factors in the region. Items related to the reluctance of clinicians are currently less relevant. Based on the survey results, the highest ranked (96%–99%) gene/drug pairs perceived as important were CYP2D6/tamoxifen, CYP3A5/tacrolimus, CYP2D6/opioids, DPYD/fluoropyrimidines, TMPT/thiopurines, CYP2D6/tricyclic antidepressants, CYP2C19/tricyclic antidepressants, NUDT15/thiopurines, CYP2B6/efavirenz, and CYP2C19/clopidogrel. In conclusion, although the global contribution of LAC countries remains low in the PGx field, a relevant improvement has been observed in the region. The perception of the usefulness of PGx tests in biomedical community has drastically changed, raising awareness among physicians, which suggests a promising future in the clinical applications of PGx in LAC

Immunodiagnosis of endemic mycoses and bronchopulmonary aspergilosis: A multicenter study in Argentina

Fil: Canteros, C. E. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas. Departamento de Micología; Argentina.Fil: Rivas, M. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas. Departamento de Micología; Argentina.Fil: Soria, M. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas. Departamento de Micología; Argentina.Fil: Lee, W. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas. Departamento de Micología; Argentina.Fil: Perrotta, Diego. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas. Departamento de Micología; Argentina.Fil: Rodero, L. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas. Departamento de Micología; Argentina.Fil: Davel, Graciela Odelsia. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas. Departamento de Micología; Argentina.Fil: Berducci, O. Grupo EMMB; Argentina.Fil: Bonardello, N. Grupo EMMB; Argentina.Fil: Castro, H. Grupo EMMB; Argentina.Fil: Chacón, Y. Grupo EMMB; Argentina.Fil: Cendán Colombo, L. Grupo EMMB; Argentina.Fil: De Vechi, M. Grupo EMMB; Argentina.Fil: Errecalde, G. Grupo EMMB; Argentina.Fil: Fernández, N. Grupo EMMB; Argentina.FIl: Gorostiaga, J. L. Grupo EMMB; Argentina.Fil: López, C. Grupo EMMB; Argentina.Fil: Mackay, P. Grupo EMMB; Argentina.Fil: Gonzalez, R. Grupo EMMB; Argentina.Fil: Cacace, María Luisa. Grupo EMMB; Argentina.Fil: Mestron, S. Grupo EMMB; Argentina.Fil: Mónaco, L. Grupo EMMB; Argentina.Fil: Nardin, M. E. Grupo EMMB; Argentina.Fil: Ramos, L. Grupo EMMB; Argentina.Fil: Pagella, H. Grupo EMMB; Argentina.Fil: Petrussi, N. Grupo EMMB; Argentina.Fil: Pizarro, M. R. Grupo EMMB; Argentina.Fil: Sánchez, R. Grupo EMMB; Argentina.Fil: Saporiti, A. M. Grupo EMMB; Argentina.Fil: Tichellio, A. G. Grupo EMMB; Argentina.Fil: Tiraboschi, N. Grupo EMMB; Argentina.Fil: Tonelli, L. Grupo EMMB; Argentina.Fil: Zanuso, A. Grupo EMMB; Argentina.Se realizó entre 01-04-2000 y 30-03-2001, un estudio de corte transversal, para conocer la frecuencia relativa de las enfermedades por hongos dimorfos y Aspergillus spp. en la República Argentina y evaluar la certeza en el diagnóstico de los laboratorios de diferentes áreas geográficas. Participaron 25 centros de salud provenientes de 12 provincias y de la Ciudad Autónoma de Buenos Aires. Fueron analizados en el laboratorio de origen 965 sueros de pacientes con sospecha clínica de histoplasmosis (HP), paracoccidioidomicosis (PCM), coccidioidomicosis (CM) y aspergilosis. Todos los sueros positivos y el 35% de los negativos fueron reevaluados en el laboratorio de referencia por inmunodifusión doble en agar. La concordancia entre los resultados obtenidos en los centros de origen y el de referencia fue de 98,8%. Se detectaron anticuerpos específicos en 120 sueros correspondientes a 98 pacientes. El 71,4% (70 casos) de los diagnósticos correspondió a micosis endémicas (HP, PCM y CM) y el resto a aspergilosis. PCM fue diagnosticada en 47,9% (47 casos), aspergilosis en 28,6% (28 casos), HP en13,3% (13 casos) y CM en 10,2% (10 casos). La participación en este estudio fue voluntaria y no todos los centros del país estaban representados, sin embargo, las frecuencias de enfermedades fúngicas fueron las esperadas y coincidentes con estudios previos realizados a nivel nacional. (EN) In order to contribute to the knowledge of the relative frequency of chronic fungal diseases and assess the performance of diagnostic laboratories in Argentina, a multicenter study was performed with the participation of 25 medical centers located in 12 different provinces and Buenos Aires City. Between 04-01- 2000 and 03-30-2001, 965 serum specimens from patients clinically suspected of having histoplasmosis (HP), paracoccidioidomycosis (PCM), coccidioidomycosis (CM) or aspergilosis were analyzed. Agar immunodiffusion tests (IDD) were done locally. All positive and 35% of negative sera were retested in the reference center. Results of laboratories of origin showed 98.8% concordance with those of reference center. Antibodies against any of the etiological agents were detected in 120 specimens from 98 patients. Endemic mycoses (HP, PCM and CM) were diagnosed in 70 patients (71.4%) and aspergilosis in 28 (28.6%). The frequencies of the different mycoses in decreasing order w ere PCM 47 patients (47.9%), aspergilosis 28 patients (28.6%), HP 13 patients (13.3%) and CM 10 patients (10.2%). The study was carried out on a voluntary basis and some areas of the country were not represented. However, the frequencies were in range with the expected rates in the population under study