Ewing Sarcoma Eswa Protein Regulates Chondrogenesis of Meckel's Cartilage through Modulation of Sox9 in Zebrafish

Ewing sarcoma is the second most common skeletal (bone and cartilage) cancer in adolescents, and it is characterized by the expression of the aberrant chimeric fusion gene EWS/FLI1. Wild-type EWS has been proposed to play a role in mitosis, splicing and transcription. We have previously shown that EWS/FLI1 interacts with EWS, and it inhibits EWS activity in a dominant manner. Ewing sarcoma is a cancer that specifically develops in skeletal tissues, and although the above data suggests the significance of EWS, its role in chondrogenesis/skeletogenesis is not understood. To elucidate the function of EWS in skeletal development, we generated and analyzed a maternal zygotic (MZ) ewsa/ewsa line because the ewsa/wt and ewsa/ewsa zebrafish appeared to be normal and fertile. Compared with wt/wt, the Meckel’s cartilage of MZ ewsa/ewsa mutants had a higher number of craniofacial prehypertrophic chondrocytes that failed to mature into hypertrophic chondrocytes at 4 days post-fertilization (dpf). Ewsa interacted with Sox9, which is the master transcription factor for chondrogenesis. Sox9 target genes were either upregulated (ctgfa, ctgfb, col2a1a, and col2a1b) or downregulated (sox5, nog1, nog2, and bmp4) in MZ ewsa/ewsa embryos compared with the wt/wt zebrafish embryos. Among these Sox9 target genes, the chromatin immunoprecipitation (ChIP) experiment demonstrated that Ewsa directly binds to ctgfa and ctgfb loci. Consistently, immunohistochemistry showed that the Ctgf protein is upregulated in the Meckel’s cartilage of MZ ewsa/ewsa mutants. Together, we propose that Ewsa promotes the differentiation from prehypertrophic chondrocytes to hypertrophic chondrocytes of Meckel’s cartilage through inhibiting Sox9 binding site of the ctgf gene promoter. Because Ewing sarcoma specifically develops in skeletal tissue that is originating from chondrocytes, this new role of EWS may provide a potential molecular basis of its pathogenesis.This manuscript was supported by the Massman Family Ewing Sarcoma Research Fund, the Sarcoma Foundation of America, P20RR016475 / P20GM103418 and P20 RR032682-01. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Finding equipoise: CEPI revises its equitable access policy

Launched at Davos in January 2017 with funding from sovereign investors and philanthropic institutions, the Coalition for Epidemic Preparedness Innovations (CEPI) is an innovative partnership between public, private, philanthropic, and civil organisations whose mission is to stimulate, finance and co-ordinate vaccine development against diseases with epidemic potential in cases where market incentives fail. As of December 2019, CEPI has committed to investing up to $706 million in vaccine development. This includes 19 vaccine candidates against its priority pathogens (Lassa fever virus, Middle East respiratory syndrome coronavirus, Nipah virus, Chikungunya, Rift Valley fever) and three vaccine platforms to develop vaccines against Disease X, a novel or unanticipated pathogen. As an entity largely supported by public funds, ensuring equitable access to vaccines whose development it supports in low- and middle-income countries is CEPI's primary focus. CEPI developed an initial equitable access policy shortly after its formation, with key stakeholders expressing strong views about its content and prescriptive nature. The CEPI board instructed that it be revisited after a year. This paper describes the process of revising the policy, and how key issues were resolved. CEPI will continue to take an iterative, rather than prescriptive, approach to its policy-one that reflects the needs of multiple stakeholders and ensures it can meet its equitable access goals

Análisis del valor de marca para una mype de lencería en Gamarra a través del modelo de Resonancia de Marca de Kevin Keller. Caso: Minina

La presente investigación tuvo como objetivo el análisis del valor de marca de la lencería Minina, basado en el modelo de Resonancia de Marca de Kevin Keller. Este se efectúa a través de las 6 subvariables de la pirámide de resonancia; las cuales, sirvieron para determinar el vínculo emocional entre la marca Minina y sus consumidoras. La empresa Minino & Minina, la cual fabrica y comercializa lencería, tiene como objetivo aumentar su participación de mercado. Por ello, el análisis servirá como herramienta de apoyo para obtener información acerca de lo aprendido, visto, oído y sentido por las consumidoras de la marca, a través del tiempo. En el estudio, se realizó un análisis interno de la organización y externo del sector textil de Gamarra, a través de fuentes académicas y entrevistas al dueño de la empresa. Asimismo, se empleó encuestas y focus groups a las consumidoras de la marca para recaudar información. Seguidamente, se procedió a triangular la información para generar hallazgos, conclusiones y recomendaciones de cada subvariable del modelo. Finalmente, se determinó que hay una vinculación positiva entre la marca y la muestra; sin embargo, para contribuir con un desarrollo de marca fuerte se han brindado recomendaciones a la empresa

SPECTRE: A Game Theoretic Framework for Preventing Collusion in Security Games (Demonstration)

ABSTRACT Several models have been proposed for Stackelberg security games (SSGs) and protection against perfectly rational and bounded rational adversaries; however, none of these existing models addressed the destructive cooperation mechanism between adversaries. SPECTRE (Strategic Patrol planner to Extinguish Collusive ThREats) takes into account the synergistic destructive collusion among two groups of adversaries in security games. This framework is designed for the purpose of efficient patrol scheduling for security agents in security games in presence of collusion and is mainly build up on game theoretic approaches, optimization techniques, machine learning methods and theories for human decision making under risk. The major advantage of SPECTRE is involving real world data from human subject experiments with participants on Amazon Mechanical Turk (AMT)

Epidemiología y factores de riesgo asociados al cáncer de pulmón en los países de Latinoamérica y Europa

Introduction: Lung cancer is the second cause of death from cancer in men and the third cause in women, after prostate and cervical cancer respectively. Study objective: Identify the epidemiology and risk factors associated with lung cancer in Latin American and European countries. Methodology: The research was of documentary design and the type of study was explanatory and bibliographic. Result: It was indicated that lung cancer in Latin American and European countries, covering the period from 2018 to 2023, with the participation of Spain, Mexico, Cuba, Paraguay and Ecuador. The high global incidence of the disease is highlighted, mainly linked to tobacco consumption, with notable mortality disparities between men and women, addressing various risk factors, such as smoking, exposure to toxic substances and radiation, offering an updated perspective of methodological approaches in lung cancer research. Conclusion: Lung cancer, as the main cause of death from cancer, is largely preventable as it is strongly linked to smoking. Over the past century, a significant increase in the incidence of this cancer has been observed, especially in men aged 55 to 74 years. Smoking not only plays a fundamental role in the cause of lung cancer, but also affects aspects such as the histological type, the stage of the disease and the response to treatment.Introducción: El cáncer de pulmón constituye la segunda causa de muerte por cáncer en hombres y la tercera causa en mujeres, después del cáncer de próstata y cuello uterino respectivamente. Objetivo de estudio: Identificar la epidemiología y factores de riesgo asociados al cáncer de pulmón en los países de Latinoamérica y Europa. Metodología: La investigación fue de diseño documental y el tipo de estudio fue explicativo y bibliográfico. Resultado: Se indicó que el cáncer de pulmón en países de Latinoamérica y Europa, abarcando el período de 2018 a 2023, con la participación de España, México, Cuba, Paraguay y Ecuador. Se destaca la alta incidencia global de la enfermedad, principalmente vinculada al consumo de tabaco, con notables disparidades de mortalidad entre hombres y mujeres, abordando diversos factores de riesgo, como el tabaquismo, la exposición a sustancias tóxicas y radiaciones, ofreciendo una perspectiva actualizada de enfoques metodológicos en la investigación del cáncer de pulmón. Conclusión: El cáncer de pulmón, como principal causa de muerte por cáncer, es mayormente evitable al estar fuertemente vinculado al tabaquismo. A lo largo del siglo pasado, se observó un aumento significativo en la incidencia de este cáncer, especialmente en hombres de 55 a 74 años. El tabaquismo no solo desempeña un papel fundamental en la causa del cáncer de pulmón, sino que también afecta aspectos como el tipo histológico, el estadio de la enfermedad y la respuesta al tratamiento

A Prospective Study on the Impact and Out-of-Pocket Costs of Dengue Illness in International Travelers.

Although the costs of dengue illness to patients and households have been extensively studied in endemic populations, international travelers have not been the focus of costing studies. As globalization and human travel activities intensify, travelers are increasingly at risk for emerging and reemerging infectious diseases, such as dengue. This exploratory study aims to investigate the impact and out-of-pocket costs of dengue illness among travelers. We conducted a prospective study in adult travelers with laboratory-confirmed dengue and recruited patients at travel medicine clinics in eight different countries from December 2013 to December 2015. Using a structured questionnaire, we collected information on patients and their health-care utilization and out-of-pocket expenditures, as well as income and other financial losses they incurred because of dengue illness. A total of 90 patients participated in the study, most of whom traveled for tourism (74%) and visited countries in Asia (82%). Although 22% reported hospitalization and 32% receiving ambulatory care while traveling, these percentages were higher at 39% and 71%, respectively, after returning home. The out-of-pocket direct and indirect costs of dengue illness were US$421 (SD 744) and US$571 (SD 1,913) per episode, respectively, averaging to a total out-of-pocket cost of US$992 (SD 2,052) per episode. The study findings suggest that international travelers incur important direct and indirect costs because of dengue-related illness. This study is the first to date to investigate the impact and out-of-pocket costs of travel-related dengue illness from the patient's perspective and paves the way for future economic burden studies in this population

A genome-wide RNAi screen in mouse embryonic stem cells identifies Mp1 as a key mediator of differentiation

Knockdown of the scaffolding protein Mek binding protein 1 (Mp1) in mouse embryonic stem cells suppresses differentiation but not proliferation, and more invasive human germ cell tumors express lower amounts of Mp1

Gut Microbiome Dysbiosis in Antibiotic-Treated COVID-19 Patients is Associated with Microbial Translocation and Bacteremia

Although microbial populations in the gut microbiome are associated with COVID-19 severity, a causal impact on patient health has not been established. Here we provide evidence that gut microbiome dysbiosis is associated with translocation of bacteria into the blood during COVID-19, causing life-threatening secondary infections. We first demonstrate SARS-CoV-2 infection induces gut microbiome dysbiosis in mice, which correlated with alterations to Paneth cells and goblet cells, and markers of barrier permeability. Samples collected from 96 COVID-19 patients at two different clinical sites also revealed substantial gut microbiome dysbiosis, including blooms of opportunistic pathogenic bacterial genera known to include antimicrobial-resistant species. Analysis of blood culture results testing for secondary microbial bloodstream infections with paired microbiome data indicates that bacteria may translocate from the gut into the systemic circulation of COVID-19 patients. These results are consistent with a direct role for gut microbiome dysbiosis in enabling dangerous secondary infections during COVID-19

The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease

Many common variants have been associated with hematological traits, but identification of causal genes and pathways has proven challenging. We performed a genome-wide association analysis in the UK Biobank and INTERVAL studies, testing 29.5 million genetic variants for association with 36 red cell, white cell, and platelet properties in 173,480 European-ancestry participants. This effort yielded hundreds of low frequency (<5%) and rare (<1%) variants with a strong impact on blood cell phenotypes. Our data highlight general properties of the allelic architecture of complex traits, including the proportion of the heritable component of each blood trait explained by the polygenic signal across different genome regulatory domains. Finally, through Mendelian randomization, we provide evidence of shared genetic pathways linking blood cell indices with complex pathologies, including autoimmune diseases, schizophrenia, and coronary heart disease and evidence suggesting previously reported population associations between blood cell indices and cardiovascular disease may be non-causal.We thank members of the Cambridge BioResource Scientific Advisory Board and Management Committee for their support of our study and the National Institute for Health Research Cambridge Biomedical Research Centre for funding. K.D. is funded as a HSST trainee by NHS Health Education England. M.F. is funded from the BLUEPRINT Grant Code HEALTH-F5-2011-282510 and the BHF Cambridge Centre of Excellence [RE/13/6/30180]. J.R.S. is funded by a MRC CASE Industrial studentship, co-funded by Pfizer. J.D. is a British Heart Foundation Professor, European Research Council Senior Investigator, and National Institute for Health Research (NIHR) Senior Investigator. S.M., S.T, M.H, K.M. and L.D. are supported by the NIHR BioResource-Rare Diseases, which is funded by NIHR. Research in the Ouwehand laboratory is supported by program grants from the NIHR to W.H.O., the European Commission (HEALTH-F2-2012-279233), the British Heart Foundation (BHF) to W.J.A. and D.R. under numbers RP-PG-0310-1002 and RG/09/12/28096 and Bristol Myers-Squibb; the laboratory also receives funding from NHSBT. W.H.O is a NIHR Senior Investigator. The INTERVAL academic coordinating centre receives core support from the UK Medical Research Council (G0800270), the BHF (SP/09/002), the NIHR and Cambridge Biomedical Research Centre, as well as grants from the European Research Council (268834), the European Commission Framework Programme 7 (HEALTH-F2-2012-279233), Merck and Pfizer. DJR and DA were supported by the NIHR Programme ‘Erythropoiesis in Health and Disease’ (Ref. NIHR-RP-PG-0310-1004). N.S. is supported by the Wellcome Trust (Grant Codes WT098051 and WT091310), the EU FP7 (EPIGENESYS Grant Code 257082 and BLUEPRINT Grant Code HEALTH-F5-2011-282510). The INTERVAL study is funded by NHSBT and has been supported by the NIHR-BTRU in Donor Health and Genomics at the University of Cambridge in partnership with NHSBT. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, the Department of Health of England or NHSBT. D.G. is supported by a “la Caixa”-Severo Ochoa pre-doctoral fellowship