An exosomal urinary miRNA signature for early diagnosis of renal fibrosis in lupus nephritis

Lupus nephritis; Urinary exosomes; Renal fibrosisNefritis lúpica; Exosomas urinarios; Fibrosis renalNefritis lúpica; Exosomes urinaris; Fibrosi renalFor lupus nephritis (LN) management, it is very important to detect fibrosis at an early stage. Urinary exosomal miRNAs profiling can be used as a potential multi-marker phenotyping tool to identify early fibrosis. We isolated and characterised urinary exosomes and cellular pellets from patients with biopsy-proven LN (n = 45) and healthy controls (n = 20). LN chronicity index (CI) correlated with urinary exosomal miR-21, miR-150, and miR-29c (r = 0.565, 0.840, -0.559,respectively). This miRNA profile distinguished low CI from moderate-high CI in LN patients with a high sensitivity and specificity (94.4% and 99.8%). Furthermore, this multimarker panel predicted an increased risk of progression to end-stage renal disease (ESRD). Pathway analysis identified VEGFA and SP1 as common target genes for the three miRNAs. Immunohistochemistry in LN renal biopsies revealed a significant increase of COL1A1 and COL4A1 correlated with renal chronicity. SP1 decreased significantly in the high-CI group (p = 0.002). VEGFA levels showed no di_erences. In vitro experiments suggest that these miRNA combinations promote renal fibrosis by increasing profibrotic molecules through SP1 and Smad3/TGF_ pathways. In conclusion, a urinary exosomal multimarker panel composed of miR-21, miR-150, and miR-29c provides a non-invasive method to detect early renal fibrosis and predict disease progression in LNThis work was supported by a grant from Instituto de Salud Carlos III, PI15/02117. This research also received donations from Catalan Lupus Foundation and A. Bosch Foundation

Desempeño en modalidades de trabajo a distancia y teletrabajo en Cuba desde una perspectiva de género. / Performance in distance work and telework modalities in Cuba from a gender perspective.

In Cuba, the implementation of telework and distance work has expanded with the arrival of the Covid-19 pandemic. This happened in atypical confinement conditions in the family home, that leads to greater overload for women remote workers, due to the traditional gender roles. This paper discusses the results of the national study on distance work / telework seen from a gender perspective, that show the inequalities that these modalities have on men and women. The need of this approach is confirmed if a more equitable, inclusive and healthy work environment is to achieved for all. / RESUMEN En Cuba se ha originado una expansión en la implementación del trabajo a distancia y el teletrabajo con la llegada de la pandemia de la COVID-19. Esto se produce en condiciones atípicas de confinamiento de la familia en el hogar. Ello conduce a una mayor sobrecarga de las mujeres en trabajo remoto, debido a los roles tradicionales de género. En el artículo se debaten los resultados del estudio nacional sobre trabajo a distancia y teletrabajo desde una perspectiva de género. Se demuestran los impactos desiguales que tienen estas modalidades en hombres y mujeres. La necesidad de este enfoque se confirma si se quiere lograr un ambiente laboral más equitativo, inclusivo y saludable para todos(as)

Condiciones y resultados del teletrabajo en profesores universitarios

Objetivo: Evaluar las condiciones laborales y los resultados del teletrabajo, en un grupo de profesores de una institución de la educación superior en Cuba. Métodos y técnicas: Se aplicó como instrumento un cuestionario de teletrabajo elaborado por especialistas de la Facultad de Psicología de la Universidad de La Habana, Cuba, a una muestra representativa de 43 trabajadores y directivos. Para el procesamiento de los datos se utilizaron: frecuencias absolutas y relativas, t de Student y Chi cuadrado, a través del paquete estadístico IBM SPSS Statistics v 22 para Windows Principales resultados: Las condiciones laborales fueron valoradas como positivas, con destaque en la planificación y organización del trabajo, la claridad de los objetivos y sus plazos de cumplimiento; no obstante, la organización no facilitó los medios para el trabajo a distancia y no ofreció una capacitación previa sobre esta modalidad. Los resultados del teletrabajo también fueron favorables; mejoraron las competencias de los teletrabajadores en el empleo de las tecnologías de la información y las comunicaciones, la gestión de la información, su autonomía y autocontrol y la administración del tiempo; aunque se evidenció como negativo un incremento de la cantidad de horas dedicadas a la actividad laboral, el ritmo y volumen de trabajo. Conclusiones: Los teletrabajadores reconocieron los beneficios de esta modalidad y valoraron positivamente las condiciones laborales y los resultados del teletrabajo; aunque se mostraron algunas dificultades que afectan su salud laboral. No existieron diferencias estadísticamente significativas entre la valoración de trabajadores y directivos. Se ofrecieron recomendaciones para el perfeccionamiento del teletrabajo

Condiciones y resultados del teletrabajo en profesores universitarios

Objetivo: Evaluar las condiciones laborales y los resultados del teletrabajo, en un grupo de profesores de una institución de la educación superior en Cuba. Métodos  y  técnicas:  Se  aplicó  como  instrumento  un  cuestionario  de  teletrabajo elaborado  por  especialistas  de  la  Facultad  de  Psicología  de  la  Universidad  de  La Habana, Cuba, a una muestra representativa de 43 trabajadores y directivos. Para el procesamiento de los datos se utilizaron: frecuencias absolutas y relativas, t de Student y  Chi  cuadrado,  a  través  del  paquete  estadístico  IBM  SP SS  Statistics  v  22  para Windows Principales  resultados:  Las condiciones laborales fueron valoradas como positivas, con destaque en la planificación y organización del trabajo, la claridad de los objetivos y sus plazos de cumplimiento; no obstante, la organización no facilitó los medios para el trabajo  a  distancia  y no  ofreció  una  capacitación previa sobre esta modalidad. Los resultados del teletrabajo también fueron favorables; mejoraron las competencias de los teletrabajadores   en   el   empleo   de   las   tecnologías   de   la   información   y   las comunicaciones, la gestión de la información, su autonomía y autocontrol y la administración del tiempo; aunque  se  evidenció  como  negativo  un incremento de la  cantidad  de  horas  dedicadas  a  la  actividad  laboral, el ritmo  y volumen de  trabajo. Conclusiones:  Los teletrabajadores reconocieron los beneficios de esta modalidad y valoraron  positivamente  las  condiciones  laborales  y  los  resultados  del  teletrabajo; aunque se mostraron algunas dificultades que afectan su salud laboral. No existieron diferencias   estadísticamente   significativas   entre   la   valoración  de   trabajadores  y directivos. Se ofrecieron recomendaciones para el perfeccionamiento del teletrabajo.

Unravelling the genetic basis of simplex Retinitis Pigmentosa cases

Retinitis Pigmentosa (RP) is the most common form of inherited retinal dystrophy (IRD) characterized ultimately by photoreceptors degeneration. Exhibiting great clinical and genetic heterogeneity, RP can be inherited as an autosomal dominant (ad), autosomal recessive (ar) and X-linked (xl) disorder. Although the relative prevalence of each form varies somewhat between populations, a major proportion (41% in Spain) of patients represent simplex cases (sRP) in which the mode of inheritance is unknown. Molecular genetic diagnostic is crucial, but also challenging, for sRP patients because any of the 81 RP genes identified to date may be causative. Herein, we report the use of a customized targeted gene panel consisting of 68 IRD genes for the molecular characterization of 106 sRP cases. The diagnostic rate was 62.26% (66 of 106) with a proportion of clinical refinements of 30.3%, demonstrating the high efficiency of this genomic approach even for clinically ambiguous cases. The high number of patients diagnosed here has allowed us to study in detail the genetic basis of the sRP. The solved sRP cohort is composed of 62.1% of arRP cases, 24.2% of adRP and 13.6% of xlRP, which implies consequences for counselling of patients and families.Union Europea PI15-01648España Ministerio de Economía y Competitividad PI11-02923Junta de Andalucía,Ministerio de Economía, Innovación, Ciencia y Empleo CTS-166

The interface of science: the case for a broader definition of research management

This paper results from on-going reflection within the practitioners group Plataforma de Interface à Ciência (Platform of Professionals at the Interface of Science), an informal nationwide network in Portugal that brings together professionals involved in a large scope of activities related to research management, knowledge transfer and science communication. Due to the wide scope of functions and profiles of these professionals, they are not publicly nor institutionally recognised as part of the same professional group, which raises barriers for their recognition as relevant players in the research & innovation ecosystem and full achievement of their potential. We take stock of the several definitions of their roles found in the literature and conclude on the need for an inclusive approach to consider these roles as a profession. We propose the designation of Professionals at the Interface of Science (PIoS) to name this wide group of professionals that sits at the interface at all scientific disciplines.This work was supported by European Commission: [EnvMetaGen (grant agreement no 668981)]; Fundação para a Ciência e a Tecnologia: [Grant Number LISBOA-01-0145- FEDER-007654,LISBOA-01-0145-FEDER-007660,POCI-01-0145- FEDER-007274,POCI-01-0145-FEDER-007746,UID/Multi/04423/2013,UID/QUI/50006/2013, UID/IC/4255/2013]; COMPETE2020 – Programa Operacional Competitividade e Internacionalização (POCI): [Grant Number LISBOA-01-0145-FEDER-007654, LISBOA-01-0145-FEDER-007660,POCI-01-0145-FEDER-007274, POCI-01-0145-FEDER-007746,UID/Multi/04423/2013].info:eu-repo/semantics/publishedVersio

Table2_Expanding the phenotype of THRB: a range of macular dystrophies as the major clinical manifestations in patients with a dominant splicing variant.PDF

Supplementary Table 2 Different THRB in vivo and in vitro knock-out and knockdown models and its phenotypic effect.Inherited retinal dystrophies (IRDs) are a clinically and genetically heterogeneous group of disorders that often severely impair vision. Some patients manifest poor central vision as the first symptom due to cone-dysfunction, which is consistent with cone dystrophy (COD), Stargardt disease (STGD), or macular dystrophy (MD) among others. Here, we aimed to identify the genetic cause of autosomal dominant COD in one family. WGS was performed in 3 affected and 1 unaffected individual using the TruSeq Nano DNA library kit and the NovaSeq 6,000 platform (Illumina). Data analysis identified a novel spliceogenic variant (c.283 + 1G>A) in the thyroid hormone receptor beta gene (THRB) as the candidate disease-associated variant. Further genetic analysis revealed the presence of the same heterozygous variant segregating in two additional unrelated dominant pedigrees including 9 affected individuals with a diagnosis of COD (1), STGD (4), MD (3) and unclear phenotype (1). THRB has been previously reported as a causal gene for autosomal dominant and recessive thyroid hormone resistance syndrome beta (RTHβ); however, none of the IRD patients exhibited RTHβ. Genotype-phenotype correlations showed that RTHβ can be caused by both truncating and missense variants, which are mainly located at the 3′ (C-terminal/ligand-binding) region, which is common to both THRB isoforms (TRβ1 and TRβ2). In contrast, the c.283 + 1G>A variant is predicted to disrupt a splice site in the 5′-region of the gene that encodes the N-terminal domain of the TRβ1 isoform protein, leaving the TRβ2 isoform intact, which would explain the phenotypic variability observed between RTHβ and IRD patients. Interestingly, although monochromacy or cone response alterations have already been described in a few RTHβ patients, herein we report the first genetic association between a pathogenic variant in THRB and non-syndromic IRDs. We thereby expand the phenotype of THRB pathogenic variants including COD, STGD, or MD as the main clinical manifestation, which also reflects the extraordinary complexity of retinal functions mediated by the different THRB isoforms.Peer reviewe

Expanding the phenotype of THRB: a range of macular dystrophies as the major clinical manifestations in patients with a dominant splicing variant

© 2023 Fernández-Suárez, González-del Pozo, García-Núñez, Méndez-Vidal, Martín-Sánchez, Mejías-Carrasco, Ramos-Jiménez, Morillo-Sánchez, Rodríguez-de la Rúa, Borrego and Antiñolo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Inherited retinal dystrophies (IRDs) are a clinically and genetically heterogeneous group of disorders that often severely impair vision. Some patients manifest poor central vision as the first symptom due to cone-dysfunction, which is consistent with cone dystrophy (COD), Stargardt disease (STGD), or macular dystrophy (MD) among others. Here, we aimed to identify the genetic cause of autosomal dominant COD in one family. WGS was performed in 3 affected and 1 unaffected individual using the TruSeq Nano DNA library kit and the NovaSeq 6,000 platform (Illumina). Data analysis identified a novel spliceogenic variant (c.283 + 1G>A) in the thyroid hormone receptor beta gene (THRB) as the candidate disease-associated variant. Further genetic analysis revealed the presence of the same heterozygous variant segregating in two additional unrelated dominant pedigrees including 9 affected individuals with a diagnosis of COD (1), STGD (4), MD (3) and unclear phenotype (1). THRB has been previously reported as a causal gene for autosomal dominant and recessive thyroid hormone resistance syndrome beta (RTHβ); however, none of the IRD patients exhibited RTHβ. Genotype-phenotype correlations showed that RTHβ can be caused by both truncating and missense variants, which are mainly located at the 3′ (C-terminal/ligand-binding) region, which is common to both THRB isoforms (TRβ1 and TRβ2). In contrast, the c.283 + 1G>A variant is predicted to disrupt a splice site in the 5′-region of the gene that encodes the N-terminal domain of the TRβ1 isoform protein, leaving the TRβ2 isoform intact, which would explain the phenotypic variability observed between RTHβ and IRD patients. Interestingly, although monochromacy or cone response alterations have already been described in a few RTHβ patients, herein we report the first genetic association between a pathogenic variant in THRB and non-syndromic IRDs. We thereby expand the phenotype of THRB pathogenic variants including COD, STGD, or MD as the main clinical manifestation, which also reflects the extraordinary complexity of retinal functions mediated by the different THRB isoforms.This work was supported by the Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Science and Innovation, Spain and co-funded by ERDF (“A way to make Europe”) [PI21-00244]; The strategic plan for the Precision Medicine Infrastructure associated with Science and Technology - IMPaCT [IMP-0009], Regional Ministry of Health and Families of the Autonomous Government of Andalusia [PEER-0501-2019] and the Foundation Isabel Gemio/Foundation Cajasol [FGEMIO-2019-01]. EF-S is supported by fellowship FI19/00091 from ISCIII (ESF, “Investing in your future”). MM-S [RH-0049-2021] are supported by a fellowship funded by the Regional Ministry of Health and Families of the Autonomous Government of Andalusia.Peer reviewe

Image1_Expanding the phenotype of THRB: a range of macular dystrophies as the major clinical manifestations in patients with a dominant splicing variant.PDF

Supplementary figure S1. Schematic representation of the hypothetical consequences of the THRB variant. In silico prediction of the effect of the spliceogenic variant identified in TRβ1 isoform (NM_001354712.2: c.283+1G>A) showed two scenarios. (A), The skipping of exon 5 disrupts the A/B domain, leaving a protein of 374 amino acids with a secondary structure different from the wild-type protein. The DNAbinding domain (DBD), hinge domain and ligand-binding domain (LBD) are not affected. (B), The skipping of exons 5 and 6 results in a premature codon stop that produces only a small peptide. The 3D models of the proteins were generated using the IntFOLD and PEP-FOLD4 online servers.Inherited retinal dystrophies (IRDs) are a clinically and genetically heterogeneous group of disorders that often severely impair vision. Some patients manifest poor central vision as the first symptom due to cone-dysfunction, which is consistent with cone dystrophy (COD), Stargardt disease (STGD), or macular dystrophy (MD) among others. Here, we aimed to identify the genetic cause of autosomal dominant COD in one family. WGS was performed in 3 affected and 1 unaffected individual using the TruSeq Nano DNA library kit and the NovaSeq 6,000 platform (Illumina). Data analysis identified a novel spliceogenic variant (c.283 + 1G>A) in the thyroid hormone receptor beta gene (THRB) as the candidate disease-associated variant. Further genetic analysis revealed the presence of the same heterozygous variant segregating in two additional unrelated dominant pedigrees including 9 affected individuals with a diagnosis of COD (1), STGD (4), MD (3) and unclear phenotype (1). THRB has been previously reported as a causal gene for autosomal dominant and recessive thyroid hormone resistance syndrome beta (RTHβ); however, none of the IRD patients exhibited RTHβ. Genotype-phenotype correlations showed that RTHβ can be caused by both truncating and missense variants, which are mainly located at the 3′ (C-terminal/ligand-binding) region, which is common to both THRB isoforms (TRβ1 and TRβ2). In contrast, the c.283 + 1G>A variant is predicted to disrupt a splice site in the 5′-region of the gene that encodes the N-terminal domain of the TRβ1 isoform protein, leaving the TRβ2 isoform intact, which would explain the phenotypic variability observed between RTHβ and IRD patients. Interestingly, although monochromacy or cone response alterations have already been described in a few RTHβ patients, herein we report the first genetic association between a pathogenic variant in THRB and non-syndromic IRDs. We thereby expand the phenotype of THRB pathogenic variants including COD, STGD, or MD as the main clinical manifestation, which also reflects the extraordinary complexity of retinal functions mediated by the different THRB isoforms.Peer reviewe

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research