Systemic Type I IFN Inflammation in Human ISG15 Deficiency Leads to Necrotizing Skin Lesions

Most monogenic disorders have a primary clinical presentation. Inherited ISG15 deficiency, however, has manifested with two distinct presentations to date: susceptibility to mycobacterial disease and intracranial calcifications from hypomorphic interferon-II (IFN-II) production and excessive IFN-I response, respectively. Accordingly, these patients were managed for their infectious and neurologic complications. Herein, we describe five new patients with six novel ISG15 mutations presenting with skin lesions who were managed for dermatologic disease. Cellularly, we denote striking specificity to the IFN-I response, which was previously assumed to be universal. In peripheral blood, myeloid cells display the most robust IFN-I signatures. In the affected skin, IFN-I signaling is observed in the keratinocytes of the epidermis, endothelia, and the monocytes and macrophages of the dermis. These findings define the specific cells causing circulating and dermatologic inflammation and expand the clinical spectrum of ISG15 deficiency to dermatologic presentations as a third phenotype co-dominant to the infectious and neurologic manifestations.Fil: Martin Fernandez, Marta. Icahn School Of Medicine At Mount Sinai; Estados Unidos. King Saud University; Arabia SauditaFil: Bravo García Morato, María. Instituto de Investigacion del Hospital de la Paz.; EspañaFil: Gruber, Conor. Icahn School Of Medicine At Mount Sinai; Estados Unidos. King Saud University; Arabia SauditaFil: Murias Loza, Sara. Instituto de Investigacion del Hospital de la Paz.; EspañaFil: Malik, Muhammad Nasir Hayat. Twincore; Alemania. University Of Lahore; Países Bajos. Leibniz Universitat Hannover; Alemania. Helmholtz Gemeinschaft; AlemaniaFil: Alsohime, Fahad. King Saud University; Arabia SauditaFil: Alakeel, Abdullah. King Saud University; Arabia SauditaFil: Valdez, Rita. Gobierno de la Ciudad Autónoma de Buenos Aires. Hospital General de Agudos Doctor Cosme Argerich; ArgentinaFil: Buta, Sofija. Icahn School Of Medicine At Mount Sinai; Estados UnidosFil: Buda, Guadalupe. Bitgenia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Biología Celular e Histología; ArgentinaFil: Marti, Marcelo Adrian. Bitgenia; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Biología Celular e Histología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Larralde, Margarita. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Boisson, Bertrand. L'institut Des Maladies Génétiques Imagine; Francia. The Rockefeller University; Estados Unidos. Universite de Paris; FranciaFil: Feito Rodriguez, Marta. Instituto de Investigacion del Hospital de la Paz.; EspañaFil: Qiu, Xueer. Icahn School Of Medicine At Mount Sinai; Estados UnidosFil: Chrabieh, Maya. L'institut Des Maladies Génétiques Imagine; FranciaFil: Al Ayed, Mohammed. Najran University; Arabia SauditaFil: Al Muhsen, Saleh. King Saud University; Arabia SauditaFil: Desai, Jigar V.. National Institutes of Health; Estados UnidosFil: Ferre, Elise M.N.. National Institutes of Health; Estados UnidosFil: Rosenzweig, Sergio D.. National Institutes of Health; Estados UnidosFil: Amador-Borrero, Blanca. Icahn School Of Medicine At Mount Sinai; Estados UnidosFil: Bravo-Gallego, Luz Yadira. Instituto de Investigacion del Hospital de la Paz.; EspañaFil: Olmer, Ruth. Hannover Medical School; Alemania. German Center for Lung Research; AlemaniaFil: Merkert, Sylvia. Hannover Medical School; Alemania. German Center for Lung Research; AlemaniaFil: Bret, Montserrat. Instituto de Investigacion del Hospital de la Paz.; EspañaFil: Sood, Amika K.. University of North Carolina; Estados UnidosFil: Al-rabiaah, Abdulkarim. King Saud University; Arabia SauditaFil: Temsah, Mohamad Hani. King Saud University; Arabia SauditaFil: Halwani, Rabih. University of Sharjah; Emiratos Arabes UnidosFil: Hernandez, Michelle Marilyn. University of North Carolina; Estados UnidosFil: Pessler, Frank. Twincore; Alemania. Helmholtz Centre for Infection Research; AlemaniaFil: Casanova, Jean Laurent. The Rockefeller University; Estados Unidos. Necker Hospital for Sick Children; Francia. Howard Hughes Medical Institute; Estados Unidos. Universite de Paris; FranciaFil: Bustamante, Jacinta. The Rockefeller University; Estados Unidos. Necker Hospital for Sick Children; Francia. Universite de Paris; FranciaFil: Lionakis, Michail S.. National Institutes of Health; Estados UnidosFil: Bogunovic, Dusan. Icahn School Of Medicine At Mount Sinai; Estados Unido

A six-attribute classification of genetic mosaicism

Mosaicism denotes an individual who has at least two populations of cells with distinct genotypes that are derived from a single fertilized egg. Genetic variation among the cell lines can involve whole chromosomes, structural or copy-number variants, small or single-nucleotide variants, or epigenetic variants. The mutational events that underlie mosaic variants occur during mitotic cell divisions after fertilization and zygote formation. The initiating mutational event can occur in any types of cell at any time in development, leading to enormous variation in the distribution and phenotypic effect of mosaicism. A number of classification proposals have been put forward to classify genetic mosaicism into categories based on the location, pattern, and mechanisms of the disease. We here propose a new classification of genetic mosaicism that considers the affected tissue, the pattern and distribution of the mosaicism, the pathogenicity of the variant, the direction of the change (benign to pathogenic vs. pathogenic to benign), and the postzygotic mutational mechanism. The accurate and comprehensive categorization and subtyping of mosaicisms is important and has potential clinical utility to define the natural history of these disorders, tailor follow-up frequency and interventions, estimate recurrence risks, and guide therapeutic decisions.Peer reviewe

Image_1_Exploring candidate biomarkers for rheumatoid arthritis through cardiovascular and cardiometabolic serum proteome profiling.tiff

IntroductionRA patients are at higher risk of cardiovascular disease, influenced by therapies. Studying their cardiovascular and cardiometabolic proteome can unveil biomarkers and insights into related biological pathways.MethodsThis study included two cohorts of RA patients: newly diagnosed individuals (n=25) and those with established RA (disease duration >25 years, n=25). Both cohorts were age and sex-matched with a control group (n=25). Additionally, a longitudinal investigation was conducted on a cohort of 25 RA patients treated with methotrexate and another cohort of 25 RA patients treated with tofacitinib for 6 months. Clinical and analytical variables were recorded, and serum profiling of 184 proteins was performed using the Olink technology platform. ResultsRA patients exhibited elevated levels of 75 proteins that might be associated with cardiovascular disease. In addition, 24 proteins were increased in RA patients with established disease. Twenty proteins were commonly altered in both cohorts of RA patients. Among these, elevated levels of CTSL1, SORT1, SAA4, TNFRSF10A, ST6GAL1 and CCL18 discriminated RA patients and HDs with high specificity and sensitivity. Methotrexate treatment significantly reduced the levels of 13 proteins, while tofacitinib therapy modulated the expression of 10 proteins. These reductions were associated with a decrease in DAS28. Baseline levels of SAA4 and high levels of BNP were associated to the non-response to methotrexate. Changes in IL6 levels were specifically linked to the response to methotrexate. Regarding tofacitinib, differences in baseline levels of LOX1 and CNDP1 were noted between non-responder and responder RA patients. In addition, response to tofacitinib correlated with changes in SAA4 and TIMD4 levels. ConclusionIn summary, this study pinpoints molecular changes linked to cardiovascular disease in RA and proposes candidate protein biomarkers for distinguishing RA patients from healthy individuals. It also highlights how methotrexate and tofacitinib impact these proteins, with distinct alterations corresponding to each drug’s response, identifying potential candidates, as SAA4, for the response to these therapies.</p

Table_1_Exploring candidate biomarkers for rheumatoid arthritis through cardiovascular and cardiometabolic serum proteome profiling.docx

IntroductionRA patients are at higher risk of cardiovascular disease, influenced by therapies. Studying their cardiovascular and cardiometabolic proteome can unveil biomarkers and insights into related biological pathways.MethodsThis study included two cohorts of RA patients: newly diagnosed individuals (n=25) and those with established RA (disease duration >25 years, n=25). Both cohorts were age and sex-matched with a control group (n=25). Additionally, a longitudinal investigation was conducted on a cohort of 25 RA patients treated with methotrexate and another cohort of 25 RA patients treated with tofacitinib for 6 months. Clinical and analytical variables were recorded, and serum profiling of 184 proteins was performed using the Olink technology platform. ResultsRA patients exhibited elevated levels of 75 proteins that might be associated with cardiovascular disease. In addition, 24 proteins were increased in RA patients with established disease. Twenty proteins were commonly altered in both cohorts of RA patients. Among these, elevated levels of CTSL1, SORT1, SAA4, TNFRSF10A, ST6GAL1 and CCL18 discriminated RA patients and HDs with high specificity and sensitivity. Methotrexate treatment significantly reduced the levels of 13 proteins, while tofacitinib therapy modulated the expression of 10 proteins. These reductions were associated with a decrease in DAS28. Baseline levels of SAA4 and high levels of BNP were associated to the non-response to methotrexate. Changes in IL6 levels were specifically linked to the response to methotrexate. Regarding tofacitinib, differences in baseline levels of LOX1 and CNDP1 were noted between non-responder and responder RA patients. In addition, response to tofacitinib correlated with changes in SAA4 and TIMD4 levels. ConclusionIn summary, this study pinpoints molecular changes linked to cardiovascular disease in RA and proposes candidate protein biomarkers for distinguishing RA patients from healthy individuals. It also highlights how methotrexate and tofacitinib impact these proteins, with distinct alterations corresponding to each drug’s response, identifying potential candidates, as SAA4, for the response to these therapies.</p

Implementation of a University Guidance Service (SOU) in the Faculty of Biological Sciences: Comprehensive Student Support and Monitoring Program

El acompañamiento y el seguimiento académico de los estudiantes son tareas de gran importancia, necesarias para garantizar el éxito de su carrera profesional durante su vida universitaria, y después de ésta. Estos procesos no comienzan necesariamente con el ingreso de los estudiantes en la Universidad, sino que se extienden a los estudiantes de último curso de educación secundaria y bachillerato. Existe por tanto la necesidad de incluir dentro de las acciones que realizamos en la facultad (información, formación, inclusión) a los estudiantes de bachillerato, dándoles a conocer nuestro entorno de cara a su incorporación en la facultad. Por otro lado, la experiencia del equipo que trabajará en este proyecto, nos ha llevado a ser conscientes de los innumerables problemas que tienen los estudiantes de nuestra facultad para obtener información, formación, acompañamiento, seguimiento o inclusión en cuestiones que pueden afectar de una forma directa en sus actividades académica cotidianas y en su formación integral que reciben en nuestra facultad. La falta de una unidad o servicio centralizado para satisfacer estas necesidades ha sido aún más patente desde la pandemia. En la Facultad de Ciencias Biológicas se realizan multitud de actividades relacionadas con estas iniciativas y que son desconocidas por gran parte de la comunidad universitaria. Las acciones que se vienen realizando desde la facultad de Ciencias Biológicas estas dispersas entre distintos servicios y vicedecanatos (Vicedecanato de Calidad, Innovación y Sostenibilidad, Vicedecanato de Estudiantes, Practicas Externas y Movilidad, Vicedecanato de Estudios, Coordinadora de Grado, Oficina Erasmus, Vicedecanato de Investigación, Secretaría Académica, Delegación de Estudiantes, Oficina de Diversidad, etc.). En este sentido, con este proyecto pretendemos potenciar, sincronizar, coordinar y dar visibilidad a todas estas, mostrando la inmensa utilidad que suponen para nuestros estudiantes, cómo influyen en la mejora de sus actividades académicas curriculares y extracurriculares y su proyección hacia el mundo laboral. Analizaremos cómo cada una de estas actividades influyen positivamente generando una retroalimentación entre los distintos grupos de participantes del proyecto: Estudiantes, Profesores y Personal de Administración y Servicios. Todo ello, será evaluado cualitativa y cuantitativamente mediante la elaboración de encuestas a cada uno de los sectores y los comentarios y evaluaciones que el programa Docentia nos pueda aportar. La finalidad, por tanto, de este proyecto es crear de forma integrativa un Servicio de Orientación Universitario (SOU) para los estudiantes de nuestra facultad, donde se engloben todas las actividades de acompañamiento y seguimiento que venimos realizando, junto con otras que puedan surgir. Todo ello permitirá mejorar la integración y el desenvolvimiento de nuestros estudiantes en el centro mediante su participación en distintas acciones que, a su vez, redundarán en un mejor aprovechamiento de los recursos del centro, una mejora curricular y, en último término, facilitarán su proyección laboral. Este proyecto, también tiene por objetivo solventar la necesidad existente de dar visibilidad a las actividades de acompañamiento y seguimiento de estudiantes que los distintos colectivos de la facultad realizan, con la finalidad de mejorar su aprovechamiento y su optimización a través un análisis de fortalezas y debilidades, lo que nos permitirá generar futuras nuevas acciones que se integrarán en el SOU de la Facultad de Ciencias Biológicas.UCMDecanatoDepto. de Genética, Fisiología y MicrobiologíaFac. de Ciencias BiológicasFALSEsubmitte

Annual Report 2023 and Phase-I Closeout

This report summarises the activities of the CERN strategic R&D programme on technologies for future experiments during the year 2023, and highlights the achievements of the programme during its first phase 2020-2023