2023 REVIEW OF THE IMPLEMENTATION OF THE COUNCIL OF EUROPE REFERENCE FRAMEWORK OF COMPETENCES FOR DEMOCRATIC CULTURE (RFCDC)

This report presents the main findings from the first review of the implementation of the Reference Framework of Competences for Democratic Culture (RFCDC). The review process took place between March – December 2023.The main aim of this study was to understand the extent to which the RFCDC has been used in formal education systems of Member States since 2016, including its influence on policies and practices. Moreover, this review was intended as an opportunity for policy learning among Member States. The results have supported the preparation of the Council of Europe Education Strategy 2024-2030 and were fed into the 26th session of the Standing Conference of Ministers of Education of the Council of Europe on 28-29 September 2023. Chapter 1 of the report offers an overview of the conceptual definitions guiding the study and the research design used. Chapter 2 analyses the main findings in the implementation of the RFCDC in the following areas: 1) education policy development; 2) education system; 3) school; 4) addressing current and emerging issues, such violence in schools, violent extremism and radicalisation; climate change; media and informational literacy; ethical implications of artificial intelligence (AI); and education in times of crisis; and 5) main opportunities and challenges related to the integration of the RFCDC in education systems. The concluding chapter (chapter 3) presents policy pointers for improvement with regards to the implementation of the RFCDC in key areas of action, and how to support further Member States in undertaking this task.The findings presented below were drawn from the analysis of evidence collected through:• A literature and document review conducted in English and French.• 2 online surveys: one for the Education Policy Advisors Network (EPAN) members (25 responses received), and one for education stakeholders across levels and sectors of education (42 responses received).• Peer learning workshops with the EPAN Network held in May 2023.• Online focus groups (15 participants in 5 online focus groups).• Individual interviews with EPAN Network members (5)  <br/

Whole Exome Sequencing Reveals the Major Genetic Contributors to Nonsyndromic Tetralogy of Fallot

Rationale: Familial recurrence studies provide strong evidence for a genetic component to the predisposition to sporadic, nonsyndromic Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease phenotype. Rare genetic variants have been identified as important contributors to the risk of congenital heart disease, but relatively small numbers of TOF cases have been studied to date. Objective: We used whole exome sequencing to assess the prevalence of unique, deleterious variants in the largest cohort of nonsyndromic TOF patients reported to date. Methods and Results: Eight hundred twenty-nine TOF patients underwent whole exome sequencing. The presence of unique, deleterious variants was determined; defined by their absence in the Genome Aggregation Database and a scaled combined annotation-dependent depletion score of ≥20. The clustering of variants in 2 genes, NOTCH1 and FLT4, surpassed thresholds for genome-wide significance (assigned as P<5×10−8) after correction for multiple comparisons. NOTCH1 was most frequently found to harbor unique, deleterious variants. Thirty-one changes were observed in 37 probands (4.5%; 95% CI, 3.2%–6.1%) and included 7 loss-of-function variants 22 missense variants and 2 in-frame indels. Sanger sequencing of the unaffected parents of 7 cases identified 5 de novo variants. Three NOTCH1 variants (p.G200R, p.C607Y, and p.N1875S) were subjected to functional evaluation, and 2 showed a reduction in Jagged1-induced NOTCH signaling. FLT4 variants were found in 2.4% (95% CI, 1.6%–3.8%) of TOF patients, with 21 patients harboring 22 unique, deleterious variants. The variants identified were distinct to those that cause the congenital lymphoedema syndrome Milroy disease. In addition to NOTCH1, FLT4 and the well-established TOF gene, TBX1, we identified potential association with variants in several other candidates, including RYR1, ZFPM1, CAMTA2, DLX6, and PCM1. Conclusions: The NOTCH1 locus is the most frequent site of genetic variants predisposing to nonsyndromic TOF, followed by FLT4. Together, variants in these genes are found in almost 7% of TOF patients

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Running head: Endoglin isoforms in myeloid cells

40 p.-7 fig.-1 tab.Endoglin is an auxiliary cell surface receptor for TGF-beta family members. Two different alternatively spliced isoforms, long (L)-endoglin and short (S)-endoglin, have been reported. S-endoglin and L-endoglin proteins vary from each other in their cytoplasmic tails that contain 14 and 47 amino acids, respectively. A critical role for endoglin in vascular development has primarily been studied in endothelial cells. In addition, endoglin expression is upregulated during monocyte-to-macrophage differentiation; however, little is known about its role in this myeloid context. To investigate the function of endoglin in monocytes, stable transfectants expressing the two endoglin isoforms in the promonocytic human cell line U937 were generated. The differential gene expression fingerprinting of these endoglin transfectants using DNA microarrays and further bioinformatics analysis showed a clear alteration in essential biological functions, mainly those related to "Cellular Movement", including cell adhesion and transmigration. Interestingly, these cellular functions are highly dependent on adhesion molecules, including integrins alpha 1 (CD49a, ITGA1 gene), alpha L (CD11a, ITGAL gene), alpha M(CD11b, ITGAM gene) and beta 2 (CD18, ITGB2 gene) and the chemokine receptor CCR2 (CD192, CCR2 gene), which are downregulated in endoglin transfectants. Moreover, activin A (INHBA gene), a TGF-beta superfamily member involved in macrophage polarization, was distinctly affected in each endoglin transfectant, and may contribute to the regulated expression of integrins. These data were confirmed by quantitative PCR, flow cytometry and functional tests. Taken together, these results provide new insight into endoglin function in monocytes.This study has been supported by grants from Ministerio de Economia y Competitividad of Spain (SAF2010-19222 to CB), Genoma España (MEICA to CB), and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER, CB). FJB is a scientific researcher from the CIBERER, an initiative of the Instituto de Salud Carlos III (ISCIII) of Spain supported by FEDER funds.Peer reviewe