Yra1-bound RNA–DNA hybrids cause orientation-independent transcription– replication collisions and telomere instability

R loops are an important source of genome instability, largely due to their negative impact on replication progression. Yra1/ALY is an abundant RNA-binding factor conserved from yeast to humans and required for mRNA export, but its excess causes lethality and genome instability. Here, we show that, in addition to ssDNA and ssRNA, Yra1 binds RNA–DNA hybrids in vitro and, when artificially overexpressed, can be recruited to chromatin in an RNA– DNA hybrid-dependent manner, stabilizing R loops and converting them into replication obstacles in vivo. Importantly, an excess of Yra1 increases R-loop-mediated genome instability caused by transcription–replication collisions regardless of whether they are codirectional or head-on. It also induces telomere shortening in telomerase-negative cells and accelerates senescence, consistent with a defect in telomere replication. Our results indicate that RNA–DNA hybrids form transiently in cells regardless of replication and, after stabilization by excess Yra1, compromise genome integrity, in agreement with a two-step model of R-loop-mediated genome instability. This work opens new perspectives to understand transcription-associated genome instability in repair-deficient cells, including tumoral cells.European Research Council ERC2014 AdG669898 TARLOOPMinisterio de Economía y Competitividad BFU2016-75058-PJunta de Andalucía PA12- BIO123

Enfoque procomún del Trabajo Social

El enfoque procomún del Trabajo Social nace de la Oportunidad d e poner en valor: 1) procesos gestionados por los afectados en régimen colaborativo, horizontal y abierto, y 2) procesos en donde se trabaja a partir de lo experiencial, con o sin expertos. Dado que esta orientación toma en serio la hipótesis de que no hay soluciones ndividuales, sino colectivas, también apuesta por una consideración del trabajo social que tiene más que ver con la tarea de cuidar ciudades que con la de cuidar personas

Endoperiodontal lesions: diagnosis first, then treatment and not always tooth extraction: a cross-sectional survey in Spain and a proposal of a clinical treatment protocol

Background: Endoperiodontal lesion (EPL) is defined as a pathological communication between pulpal and periodontal tissues. Currently, accurate diagnosis and treatment of this pathology are challenging. This study aims to identify the different endoperiodontal therapies to propose a clinical protocol to simplify and unify the criteria for EPL treatment. Material and Methods: Observational cross-sectional study through an electronic survey. This study matches STROBE guidelines. The anonymous questionnaire contained open-ended and close-ended questions and was distributed to dentistry professors of the UPV/EHU and different professionals from Spanish associations and scientific societies. The data collected were analyzed using descriptive and analytical statistics. Results: A total of 128 responses were obtained, of which 120 were active professionals or had not been so for less than 5 years. The majority of professionals were women (65.6%) and from the Basque Country (63.9%). A total of 86.6% reported having complementary studies to a degree or a bachelor’s degree. The treatments performed by these professionals were similar to those reported in the literature, which started with root canal treatment when there was an endodontic origin (91.5%), and with basic periodontal treatment when periodontal (51.3%). Conclusions: Considering the current scientific evidence and the clinical practice of professionals in the treatment of EPL, we designed a clinical protocol. This protocol needs validation in larger populations and with longer follow-ups

Más allá del aula: la implicación de estudiantes y alumni en procesos de investigación científico-divulgativa, expresión artístico-conceptual e intervención micro social

Este proyecto continúa el que, con el mismo título y objetivos, se concedió el año pasado, y que ha tenido un elevado éxito de participación entre estudiantes y egresados de la UCM y de otras universidades españolas. Mi experiencia en los 13 años de docencia en cuatro universidades, tanto de titularidad pública como privada, me han mostrado que los estudiantes suelen responder de forma positiva a las sugerencias de profundización reflexiva y crítica, y a la apertura al cuestionamiento de las ideas y creencias heredadas; rasgos básicos de la búsqueda del conocimiento y de la actividad universitaria. Sin embargo, hay tres condiciones para que eso ocurra: (a) primero, hace falta que el profesorado motive, incentive y acompañe a los estudiantes con esas inquietudes durante el curso para que puedan ejercerlas allí donde ellos no podrían por sí solos; (b) segundo, suele ocurrir que esos estudiantes (igual que los demás) cuando se gradúan, pierden el contacto con la universidad y, al ingresar en el mundo laboral, pierden esas inquietudes más intelectuales que les motivaban durante sus años de estudiantes, debido a la lejanía de profesor y lugares donde poder continuarlas; (c) tercero, hay que saber comprender que cada estudiante manifiesta esas inquietudes reflexivas y críticas de formas distintas: especialmente yo he detectado tres dimensiones: (c.1) la más clásica académica, a través de la escritura, el gusto por los debates, seminarios, interés en publicar, etc. (c.2.) otra más de intervención social, pero en el caso de los universitarios, es una intervención social guiada a la vez por motivos prácticos e intelectuales; suelen ser estudiantes que no expresan sus reflexiones intelectuales a través de los medios académicos tradicionales, sino con acciones más prácticas; (c.3) hay finalmente otros alumnos para los que lo intelectual-reflexivo y el mundo de las ideas cobra vida expresiva a través del arte: sea la narrativa, la pintura, escritura, montajes, cortos, etc.; igual que en el caso anterior, estos alumnos conciben lo intelectual como algo que se manifiesta en lo práctico, pero en vez de en la transformación social, en el arte

Role of proinflammatory mutations in peri‑implantitis: systematic review and meta‑analysis

PURPOSE: To perform a systematic review and meta-analysis on the presence of inflammatory polymorphisms in patients with peri-implantitis (PI). PI is the main complication associated to dental implant therapy. Although its main risk factors are history of periodontitis, poor plaque control and lack of regular maintenance, genetic susceptibility could also be a determinant factor for its appearance. Single nucleotide polymorphisms (SNP) are small mutations of the DNA that alter the osseointegration of implants. Inflammatory proteins participate in both destruction of the extracellular matrix and reabsorption of the alveolar bone. METHODS: A bibliographical research was made in PubMed, Scopus and Web of Science (keywords: "single nucleotide polymorphism", "polymorphism", "periimplantitis", "SNP" and "implant failure"). RESULTS: There is a statistically significant association of peri-implant bone loss with the homozygotic model of IL-1beta (-511) (OR: 2.255; IC: 1.040-4.889). CONCLUSIONS: Associations between inflammatory polymorphisms and PI must be taken with caution due to the heterogeneous methodological design, sample size and diagnostic criteria of the studies. Thus, more well-designed studies are needed that analyze the relationship between these and more SNP and PI

Periodontal health in a population with Parkinson's disease in Spain: a cross-sectional study.

Background: The aim of this research is to evaluate the periodontal health of patients with Parkinson Disease (PD) in a Spanish cohort. Material and Methods: A cross-sectional study was performed on 104 patients with PD (mean age: 66.19+9.3 years) and 106 controls (mean age: 59.26+14.11 years). A pre-designed clinical protocol was implemented, which included a standardized epidemiological index for periodontal disease (CPITN), clinical attachment loss (CAL), tooth-loss, full mouth plaque index (FMPI), and oral hygienic habits. Univariate descriptions and comparative analysis were performed. Results: The majority of PD patients presented good oral hygienic habits. There were no significant differences in relation to CPITN, periodontitis, gingival recessions and tooth loss. However, moderate/severe CAL (p=0.027) and FMPI (p=0.003) was higher in the PD group. Conclusions: There were no differences on periodontitis and tooth loss between both groups. The higher number of advanced CAL and presence of biofilm in the PD group could be related to the difficulties to perform an effective tooth brushing due to this neurological disorder.This research was not supported by any specific agency in the public, commercial, or not-for-profit sectors

Facts and controversies regarding oral health in Parkinson's disease: A case-control study in Spanish patients.

Background: Parkinson's disease (PD) is one of the leading neurological disorders, affecting more than 6 million people worldwide. These patients present motor and non-motor symptoms, including oral pathology. The objective of this research is to determine the oral health of patients diagnosed with PD, in order to stablish a specific preventive oral health programme. Material and methods: Case-control study on 104 PD and 106 control patients. The pre-designed clinical protocol included a complete oral examination on general aspects, standardised epidemiological index for caries, periodontal disease and edentulism, analysis of oral hygiene, presence of mucous/ salivary/ functional disorder, and dental treatments. Results: A higher number of PD patients consumed daily sweets (p<0.004) and antidepressant drugs (p<0.004). Patients with PD practised less interdental hygiene (p<0.023). The mean plaque index was higher in PD (p<0.003). Drooling (p<0.001), xerostomia (p<0.001), hyposialia (p<0.001), dysphagia (p<0.001), hypogeusia/dysgeusia (p<0.025) and chewing difficulty (p<0.006) were more common in PD. Conclusions: Oral disorders are frequent in PD. A good knowledge of these alterations will allow us design a specific preventive protocol. Some oral alterations may be a sign of diagnostic alert or progression of PD.This research was not supported by any specific agency in the public, commercial, or not-for-profit sectors

Targeting the TWEAK–Fn14 pathway prevents dysfunction in cardiac calcium handling after acute kidney injury

Heart and kidney have a closely interrelated pathophysiology. Acute kidney injury (AKI) is associated with significantly increased rates of cardiovascular events, a relationship defined as cardiorenal syndrome type 3 (CRS3). The underlying mechanisms that trigger heart disease remain, however, unknown, particularly concerning the clinical impact of AKI on cardiac outcomes and overall mortality. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14) are independently involved in the pathogenesis of both heart and kidney failure, and recent studies have proposed TWEAK as a possible therapeutic target; however, its specific role in cardiac damage associated with CRS3 remains to be clarified. Firstly, we demonstrated in a retrospective longitudinal clinical study that soluble TWEAK plasma levels were a predictive biomarker of mortality in patients with AKI. Furthermore, the exogenous application of TWEAK to native ventricular cardiomyocytes induced relevant calcium (Ca2+) handling alterations. Next, we investigated the role of the TWEAK–Fn14 axis in cardiomyocyte function following renal ischaemia–reperfusion (I/R) injury in mice. We observed that TWEAK–Fn14 signalling was activated in the hearts of AKI mice. Mice also showed significantly altered intra-cardiomyocyte Ca2+ handling and arrhythmogenic Ca2+ events through an impairment in sarcoplasmic reticulum Ca2+-adenosine triphosphatase 2a pump (SERCA2a) and ryanodine receptor (RyR2) function. Administration of anti-TWEAK antibody after reperfusion significantly improved alterations in Ca2+ cycling and arrhythmogenic events and prevented SERCA2a and RyR2 modifications. In conclusion, this study establishes the relevance of the TWEAK–Fn14 pathway in cardiac dysfunction linked to CRS3, both as a predictor of mortality in patients with AKI and as a Ca2+ mishandling inducer in cardiomyocytes, and highlights the cardioprotective benefits of TWEAK targeting in CRS3This work was mainly supported by projects from the Instituto de Salud Carlos III (ISCIII) (PI20/00763, PI20/01482, CPII20/00022, FI18/00261, FI21/00212, CD19/00029, IFEQ21/00012, PI19/00588, PI22/00469) and co-funded by the European Union, Ministerio de Universidades (FPU20/03005), Ministerio de Ciencia e Innovaci on (RYR2019-026916-I), the Education and Research Council of Madrid (PEJ-2021- AI/SAL-21426), Biomedicine Network Comunidad de Madrid (P2022/BMD-7223 CIFRA_COR-CM), Spanish Network in Inflammasoma and Pyroptosis in Chronic Disease and Cancer (RED2022-134511-T), and the Spanish Society of Nephrology SEN/SENEFRO Foundatio

Endocannabinoid levels in peripheral blood mononuclear cells of multiple sclerosis patients treated with dimethyl fumarate.

The endocannabinoid system (ECS), a signalling network with immunomodulatory properties, is a potential therapeutic target in multiple sclerosis (MS). Dimethyl fumarate (DMF) is an approved drug for MS whose mechanism of action has not been fully elucidated; the possibility exists that its therapeutic effects could imply the ECS. With the aim of studying if DMF can modulate the ECS, the endocannabinoids 2-arachidonoylglycerol (2-AG), anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) were determined by liquid chromatography-mass spectrometry in peripheral blood mononuclear cells from 21 healthy donors (HD) and 32 MS patients at baseline and after 12 and 24 months of DMF treatment. MS patients presented lower levels of 2-AG and PEA compared to HD. 2-AG increased at 24 months, reaching HD levels. AEA and PEA remained stable at 12 and 24 months. OEA increased at 12 months and returned to initial levels at 24 months. Patients who achieved no evidence of disease activity (NEDA3) presented the same modulation over time as EDA3 patients. PEA was modulated differentially between females and males. Our results show that the ECS is dysregulated in MS patients. The increase in 2-AG and OEA during DMF treatment suggests a possible role of DMF in ECS modulation.post-print1392 K