Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Immunohistochemical, histomorphometric, and gingival crevicular fluid analysis of residual and shallow periodontal pockets in patients with periodontitis Stages III and IV

Issue Online: 15 July 2020 Version of Record online: 16 January 2020 Accepted manuscript online: 20 December 2019 Manuscript accepted: 23 September 2019 Manuscript revised: 07 August 2019 Manuscript received: 21 January 2019Background: To study the differences between shallow and residual periodontal pockets in patients with periodontitis (Stages III and IV) after non-surgical periodontal treatment. Methods: Twenty patients diagnosed of periodontitis who were scheduled for periodontal surgery were included. In each patient, a palatal shallow site (≤3 mm) and a residual site (≥5 mm) were selected and GCF samples were processed by Luminex® analysis to determine the concentrations of interleukins (IL-1β, IL-6, IL-10, and IL-17a). During the periodontal surgery gingival biopsies were collected and processed for histo-morphometric and immunohistochemical evaluation to determine the extent of connective tissue inflammatory infiltrate (CTII) using the following markers (CD4, CD5, CD8, CD14, CD19, Elastase, and Syndecan). Mean differences between shallow and residual pockets samples, as well as correlations between GCF cytokine concentrations, area of CTII, and cellularity of the CTII were calculated. Results: A total of 15 patients were finally included, with analysis of 30 histological specimens and 30 GCF samples. Residual pockets presented significantly higher mean GCF volume, higher mean area of CTII and higher concentrations of IL-1β and IL-6 in GCF than shallow pockets. A significant correlation was detected between IL-10 levels and the CTII area, IL-10 and the percentage of Syndecan, and the area of CTII and the percentages of CD14 and Syndecan. Conclusions: The concentration of GCF cytokines did not correlate with the area of CTII measured histologically. A residual CTII and elevated concentrations of proinflammatory cytokines and cells were present in all sites 2 months after non-surgical treatment. The lack of healthy controls does not allow to establish differences between both groups.Universidad Complutense de Madrid (España)Depto. de Especialidades Clínicas OdontológicasFac. de OdontologíaTRUEpu

Interactions between TGF-beta1 and TGF-beta3 and their role in medial edge epithelium cell death and palatal fusion in vitro

In recent decades, studies have shown that both TGF-b1 and TGF-b3 play an important role in the induction of medial edge epithelium (MEE) cell death and palatal fusion. Many of these experiments involved the addition or blockage of one of these growth factors in wild-type (WT) mouse palate cultures, where both TGF-b1 and TGF-b3 are present. Few studies have addressed the existence of interactions between TGF-b1 and TGF-b3, which could modify their individual roles in MEE cell death during palatal fusion. We carried out several experiments to test this possibility, and to investigate how this could influence TGF-b1 and TGF-b3 actions on MEE cell death and palatal shelf fusion. We double immunolabelled developing mouse palates with anti-TGF-b1 or anti-TGF-b3 antibodies and TUNEL, added rhTGF-b1 or rhTGF-b3 or blocked the TGF-b1 and TGF-b3 action at different concentrations to WT or Tgf-b3 null mutant palate cultures, performed in situ hybridizations with Tgf-b1 or Tgf-b3 riboprobes, and measured the presence of TUNEL-positive midline epithelial seam (MES) cells and MES disappearance (palatal shelf fusion) in the different in vitro conditions. By combining all these experiments, we demonstrate great interaction between TGF-b1 and TGF-b3 in the developing palate and confirm that TGF-b3 has a more active role in MES cell death than TGF-b1, although both are major inductors of MES disappearance. Finally, the co-localization of TGF-b1, but not TGF-b3, with TUNEL in the MES allows us to suggest a possible role for TGF-b1 in MES apoptotic clearance.Ministerio de Sanidad de EspañaComunidad Autónoma de MadridUniversidad ComplutenseDepto. de Anatomía y EmbriologíaFac. de MedicinaTRUEpu

Maxillary growth in a congenital cleft palate canine model for surgical research

We have recently presented the Old Spanish Pointer dog, with a 15-20% spontaneous congenital cleft palate rate, as a unique experimental model of this disease. This study aimed to describe the cleft palate of these dogs for surgical research purposes and to determine whether congenital cleft palate influences maxillofacial growth. Seven newborn Old Spanish Pointer dogs of both sexes, comprising a cleft palate group (n = 4) and a normal palate group (n = 3), were fed using the same technique. Macroscopic photographs and plaster casts from the palate, lateral radiographs and computer tomograms of the skull were taken sequentially over 41 weeks, starting at week 5. The cleft morphology, the size and the tissue characteristics in these dogs resembled the human cleft better than current available animal models. During growth, the cleft width varies. Most of the transverse and longitudinal measures of the palate were statistically lower in the cleft palate group. The cleft palate group showed hypoplasia of the naso-maxillary complex. This model of congenital cleft palate seems suitable for surgical research purposes. A reduced maxillofacial pre- and post-natal development is associated to the congenital cleft palate in the Old Spanish Pointer dog.Ministerio de Sanidad de EspañaOsteology FoundationUniversidad Complutense de MadridBanco SantanderDepto. de Anatomía y EmbriologíaFac. de MedicinaTRUEpu

A new technique for feeding dogs with a congenital cleft palate for surgical research

In humans, cleft palate (CP) is one of the most common malformations. Although surgeons use palatoplasty to close CP defects in children, its consequences for subsequent facial growth have prompted investigations into other novel surgical alternatives. The animal models of CP used to evaluate new surgical treatments are frequently obtained by creating surgically induced clefts in adult dogs. This procedure has been ethically criticized due to its severity and questionable value as an animal model for human CP. Dogs born with a congenital CP would be much better for this purpose, provided they developed CP at a sufficient rate and could be fed. Up until now, feeding these pups carried the risk of aspiration pneumonia, while impeding normal suckling and chewing, and thus compromising orofacial growth. We developed a technique for feeding dog pups with CP from birth to the time of surgery using two old Spanish pointer dog pups bearing a complete CP. This dog strain develops CP in 15-20% of the offspring spontaneously. Custom-made feeding teats and palatal prostheses adapted to the pups' palates were made from thermoplastic plates. This feeding technique allowed lactation, eating and drinking in the pups with CP, with only sporadic rhinitis. To determine whether the use of this palatal prosthesis interferes with palatal growth, the palates of three littermate German shorthaired pointer pups without CP, either wearing or not wearing (controls) the prosthesis, were measured. The results showed that the permanent use of this prosthesis does not impede palatal growth in the pups.Miisterio de Sanidad de EspañaComunidad de MadridDepto. de Anatomía y EmbriologíaFac. de MedicinaTRUEpu

Aumentando la FP : libros vivos

Convocatoria proyectos de innovación de Extremadura 2020/2021Se describe un proyecto llevado a cabo en el IES El Pomar de Jeréz de los Caballeros (Badajoz) que consistió en trabajar la realidad aumentada. La propuesta consistió en dotar a varios libros del aula de características que permitieran trabajar con la realidad aumentada escaneando imágenes o códigos reconocibles para que actuasen como disparadores de contenido. Entre los objetivos del proyecto destacan: motivar a los alumnos a través de un nuevo método de trabajo, mejorar sus resultados y calificaciones, favorecer el uso responsable de las nuevas tecnologías y desarrollar el espíritu emprendedor y la autonomía personalExtremaduraES

Discovering HIV related information by means of association rules and machine learning

Acquired immunodeficiency syndrome (AIDS) is still one of the main health problems worldwide. It is therefore essential to keep making progress in improving the prognosis and quality of life of affected patients. One way to advance along this pathway is to uncover connections between other disorders associated with HIV/AIDS-so that they can be anticipated and possibly mitigated. We propose to achieve this by using Association Rules (ARs). They allow us to represent the dependencies between a number of diseases and other specific diseases. However, classical techniques systematically generate every AR meeting some minimal conditions on data frequency, hence generating a vast amount of uninteresting ARs, which need to be filtered out. The lack of manually annotated ARs has favored unsupervised filtering, even though they produce limited results. In this paper, we propose a semi-supervised system, able to identify relevant ARs among HIV-related diseases with a minimal amount of annotated training data. Our system has been able to extract a good number of relationships between HIV-related diseases that have been previously detected in the literature but are scattered and are often little known. Furthermore, a number of plausible new relationships have shown up which deserve further investigation by qualified medical experts

Novel genes and sex differences in COVID-19 severity.

Here we describe the results of a genome-wide study conducted in 11 939 COVID-19 positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (p < 5x10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (p = 1.3x10-22 and p = 8.1x10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (p = 4.4x10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (p = 2.7x10-8) and ARHGAP33 (p = 1.3x10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, p = 4.1x10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥ 60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided