Mitogen-activated protein kinase (MAPK)-regulated interactions between Osterix and Runx2 are critical for the transcriptional osteogenic program

The transcription factors Runx2 and Osx (Osterix) are required for osteoblast differentiation and bone formation. Runx2 expression occurs at early stages of osteochondroprogenitor determination, followed by Osx induction during osteoblast maturation. We demonstrate that coexpression of Osx and Runx2 leads to cooperative induction of expression of the osteogenic genes Col1a1, Fmod, and Ibsp. Functional interaction of Osx and Runx2 in the regulation of these promoters is mediated by enhancer regions with adjacent Sp1 and Runx2 DNA-binding sites. These enhancers allow formation of a cooperative transcriptional complex, mediated by the binding of Osx and Runx2 to their specific DNA promoter sequences and by the protein-protein interactions between them. We also identified the domains involved in the interaction between Osx and Runx2. These regions contain the amino acids in Osx and Runx2 known to be phosphorylated by p38 and ERK MAPKs. Inhibition of p38 and ERK kinase activities or mutation of their known phosphorylation sites in Osx or Runx2 strongly disrupts their physical interaction and cooperative transcriptional effects. Altogether, our results provide a molecular description of a mechanism for Osx and Runx2 transcriptional cooperation that is subject to further regulation by MAPK-activating signals during osteogenesis

L'Agricultura social a Catalunya. Una doble alternativa: desenvolupament local i ocupació de col·lectius en risc d'exclusió social

A Catalunya, com en molts països de la Unió Europea, hi ha una crisi econòmica i social de les activitats agràries. En aquest context, des del territori han sorgit iniciatives alternatives que busquen aconseguir la sostenibilitat ambiental, social i econòmica de les seves explotacions, com són l'agricultura de proximitat i l'agricultura social (AS). L'AS és un fenomen emergent en el món rural i en el periurbà dels països europeus, però és una pràctica encara incipient a Catalunya. L'AS dóna funcionalitats i significats nous a la pràctica agrícola, més enllà de la funció productiva. En la situació socioeconòmica actual, l'AS sorgeix com una pràctica de baix a dalt (bottom-up) d'innovació social en tant que sorgeix de la societat civil amb la finalitat de crear llocs d'ocupació nous per a les persones en risc d'exclusió social i al mateix temps ajudar al desenvolupament rural. En aquesta aportació es pretén explicar breument les característiques i les possibilitats de l'AS, posant en relleu les formes d'organització col·lectiva com el cooperativisme. La diagnosi s'ha realitzat a partir de la construcció d'una base de dades i entrevistes a promotors i informadors clau. La metodologia qualitativa ha permès fer aquesta diagnosi emprant instruments d'anàlisi com el DAFO i el fluxgrama. L'aplicació d'aquesta metodologia posa en relleu, per una banda, el potencial i la contribució de l'AS en diversos àmbits (dotar de serveis sociosanitarisàrees rurals, desenvolupament local, agricultura ecològica, innovació social, alternatives econòmiques) i, per l'altra, les manques i necessitats del sector que en condicionen el desenvolupament. D'acord amb la influència d'aquests factors s'han dissenyat algunes estratègies per contribuir a la seva difusió i al seu impuls a Catalunya.In Catalonia, as in many countries of the European Union, there is an economic and social crisis in the agricultural field. Some initiatives have arisen in the territory, including local agriculture or social farming (SF), which seek to achieve economic, social and environmental sustainability. SF is an emerging phenomenon in rural and periurban areas in the European countries but it is still a new practice in Catalonia. SF provides new functions and meanings to agricultural practice beyond the scope of production. In the current socio-economic situation, SF is a bottom-up practice of social innovation in civil society aimed to create new employment for people at risk of social exclusion, while helping rural development. This paper seeks to briefly explain the characteristics and potential of SF, highlighting forms of collective organization like cooperatives. The analysis was based on the building of a database and on interviews with key developers and informants. Qualitative methodology has provided a diagnosis using tools such as SWOT analysis and flowcharts. This methodology has highlighted, on the one hand, the potential and contribution of SF in various areas (provision of social services in rural areas, local development, organic farming, social innovation, and economic alternatives) and, on the other, the gaps and needs of the sector that influence its development. Based on the effect of these factors, some strategies have been designed to contribute to the dissemination and promotion of SF in Catalonia.En Cataluña, como en muchos países de la Unión Europea, hay una crisis económica y social de las actividades agrarias. Desde el territorio han surgido iniciativas diversas que buscan conseguir la sostenibilidad ambiental, social y económica de sus explotaciones, como son la agricultura de proximidad o la agricultura social (AS). La AS es un fenómeno emergente en el ámbito rural y en el periurbano de los países europeos, aunque es una práctica incipiente en Cataluña. La AS da nuevas funcionalidades y nuevos significados a la práctica agrícola, más allá de la propia función productiva. En la actual situación socioeconómica, la AS aparece como una práctica de abajo arriba (bottom-up) de innovación social desde la sociedad civil con el fin de crear nueva ocupación para las personas en riesgo de exclusión social y a la vez ayudar al desarrollo rural. En esta aportación se pretende explicar brevemente las características y las posibilidades de la AS, poniendo de relieve las formas de organización colectiva como el cooperativismo. El diagnóstico se ha realizado a partir de la construcción de una base de datos y entrevistas a promotores e informadores clave. La metodología cualitativa ha permitido hacer este diagnóstico empleando instrumentos de análisis como el DAFO y el flujograma. La aplicación de esta metodología pone de relieve, por un lado, el potencial y la contribución de la AS en diversos ámbitos (dotar de servicios sociosanitarios áreas rurales, desarrollo local, agricultura ecológica, innovación social, alternativas económicas) y, por el otro, las carencias y necesidades del sector que condicionan su desarrollo. De acuerdo con la influencia de estos factores se han diseñado algunas estrategias para contribuir a su difusión e impulso en Cataluña

Extracellular calcium promotes bone formation from bone marrow mesenchymal stem cells by amplifying the effects of BMP-2 on SMAD signalling

Understanding the molecular events that regulate osteoblast differentiation is essential for the development of effective approaches to bone regeneration. In this study, we analysed the osteoinductive properties of extracellular calcium in bone marrow-derived mesenchymal stem cell (BM-MSC) differentiation. We cultured BM-MSCs in 3D gelatin scaffolds with Ca2+ and BMP-2 as osteoinductive agents. Early and late osteogenic gene expression and bone regeneration in a calvarial critical-size defect model demonstrate that extracellular Ca2+ enhances the effects of BMP-2 on Osteocalcin, Runx2 and Osterix expression and promotes bone regeneration in vivo. Moreover, we analysed the molecular mechanisms involved and observed an antagonistic effect between Ca2+ and BMP-2 on SMAD1/5, ERK and S6K signalling after 24 hours. More importantly, a cooperative effect between Ca2+ and BMP-2 on the phosphorylation of SMAD1/5, S6, GSK3 and total levels of β-CATENIN was observed at a later differentiation time (10 days). Furthermore, Ca2+ alone favoured the phosphorylation of SMAD1, which correlates with the induction of Bmp2 and Bmp4 gene expression. These data suggest that Ca2+ and BMP-2 cooperate and promote an autocrine/paracrine osteogenic feed-forward loop. On the whole, these results demonstrate the usefulness of calcium-based bone grafts or the addition of exogenous Ca2+ in bone tissue engineering

Spanish Adaptation of the Autism Spectrum Disorders - Diagnosis for Adults (ASD-DA) in Adults with Severe and Profound Intellectual Disability

The Autism Spectrum Disorders - Diagnosis for Adults (ASD-DA) with intellectual disability was designed to quickly provide relevant information to establish a diagnosis of the most common Autism Spectrum Disorders (ASD) (autism, pervasive developmental disorder not otherwise specified and Asperger's syndrome) (Matson et al. 2007a). The ASD-DA was adapted and translated into Spanish and administered to a sample of 156 adults with severe (n = 67, 42.9%) and profound (n = 89, 57.1%) intellectual disability. Seventy-one (45.5%) participants had a diagnosis of intellectual disability and autism spectrum disorder, and the other eighty-five (54.5%) had a diagnosis of intellectual disability without autism spectrum disorder. The reliability scores of the scales implied values in the "good-to-excellent" range (0.78-0.95), and test-retest reliability was obtained with good values for most of the items on the scale. A three-factor structure was replicated via confirmatory factor analysis. Participants with and without ASD showed significant differences in the three ASD-DA scales and in their total scores. Using a receiver operating characteristics (ROC) curve, a score of 21 on the ASD-DA scale showed good specificity (0.97) and sensitivity (0.92) values with respect to DSM-IV-TR criteria

Los Esgrafiados sobre cerámica de Sigarra (Els Prats de Rei, Barcelona)

Se presenta la primera edición conjunta, tras autopsia, de los esgrafiados sobre cerámica hallados en el yacimiento lacetano de Sigarra, bajo el actual municipio de Prats de Rei (l'Anoia, Barcelona)

L'agricultura social, una activitat que retorna a la societat més del que inverteix. Aplicació de mètode del retorn social de les inversions

L'agricultura social (AS), promoguda per institucions públiques o privades, pretén facilitar la inserció laboral de col·lectius en risc d'exclusió social (RES) a través de l'activitat agrària, la transformació dels productes agraris o la relació amb la natura. La metodologia del retorn social de les inversions (SROI) ens permet comptabilitzar els guanys de la societat respecte del conjunt de les aportacions dels agents d'interès, els quals cal identificar. En nou dels deu projectes estudiats, de mitjana, hi ha un retorn social, econòmic i ambiental de prop de tres euros per cada euro utilitzat. Cal mesurar tots els resultats i donar-los valor, incorporant els costos i els beneficis socials, mediambientals i econòmics, i quantificant el canvi que genera l'activitat d'una organització. Hi ha conceptes que no es poden quantificar directament i requereixen que s'empri una variable financera aproximada usada com a indicador o valor de referència. La metodologia SROI inclou elements objectius i subjectius que es garanteixen per un protocol establert per la Guide to social return on investment de l'Oficina del Tercer Sector Social (TSS) de la Gran Bretanya.Social Farming (SF), promoted by public or private institutions, aims to facilitate the access to the labour market of groups at risk of social exclusion (RSE) through agrarian activity, the transformation of farm products, or contact with nature. The Social Return on Investment (SROI) method allows accounting of the return to society based on the overall set of contributions of the stakeholders, who must be identified. On the average, for nine of the ten cases studied here, there is a social, economic and environmental return of approximately €3 on each euro invested. It is necessary to measure and attribute a value to all the results, incorporating social, environmental and economic costs and benefits, and quantifying the change generated by anorganization's activity. There are concepts that can be quantified directly while others need to use a “financial proxy” as an indicator of reference values. The SROI method includes objective and subjective elements that are based on a protocol established by the Guide to Social Return on Investment of the UK's Office of the Third Sector.La agricultura social (AS), promovida por instituciones públicas o privadas, pretende facilitar la inserción laboral de colectivos en riesgo de exclusión social (RES) a través de la actividad agraria, la transformación de los productos agrarios o la relación con la naturaleza. La metodología del retorno social de las inversiones (SROI) nos permite contabilizar cuál es el beneficio de la sociedad en relación con el conjunto de aportaciones de los agentes de interés, que deberán identificarse. En nueve de los diez proyectos estudiados, de promedio, hay un retorno social, económico y ambiental de casi tres euros por cada euro utilizado. Se debe medir y dar un valor a todos los resultados, incorporando los costes y los beneficios sociales, medioambientales y económicos, y cuantificando el cambio que genera la actividad de una organización. Los conceptos que no se pueden cuantificar de forma directa precisan de una variable financiera aproximada usada como indicador o valor de referencia. La metodología SROI incluye elementos objetivos y subjetivos que se garantizan por un protocolo establecido por la Guide to social return on investment de la Oficina del Tercer Sector Social (TSS) de Gran Bretaña

Stable isotopes and diet uncover trophic-niche divergence and ecological diversification processes of endemic reptiles on Socotra Island

Ecological diversification on islands typically results in divergence of ecological niches. As diet is a majorcomponent of species niches, we hypothesize that sister species within island monophyletic groupsdiversify in their dietary preferences. We have examined this hypothesis in two Haemodracon and fourHemidactylus species endemic reptiles of from Socotra Island (Yemen), corresponding to two indepen-dent colonization events. Convergence i.e., similar dietary patterns of phylogenetically unrelated species,was also examined. Trophic niches were studied by the analysis of carbon and nitrogen stable isotopescombined with faecal samples. We collected tail tips (for isotopes) and faecal pellets during two visitsin 2013 and 2014 to Socotra. Specific trophic niche widths inferred from stable isotopes were estimatedfrom ellipse-based metrics, whereas interspecific differences were compared by linear mixed models andexamined in a phylogenetic framework. From faecal samples, diet variation among species was quanti-fied by the Bray-Curtis index. Isotope and dietary interspecific divergence was compared with Manteltests. For both isotopes, models detected interspecific differences between sister species i.e., trophic nichedivergence and also interspecific similarities of distant lineages that use similar microhabitats i.e., ecolog-ical convergence. We did not find any phylogenetic signal neither in the interspecific differences in 13Cnor in 15N isotopic values; thus species phylogenetically more closely related did not have more similarisotopic niches. The Mantel test demonstrated similar interspecific divergence using isotopes and faecalsamples. In a phylogenetic context, trophic-niche interspecific comparisons highlight some mechanismsthat are driving ecological diversification and speciation of Socotra Island

Leveraging Northern European population history : novel low-frequency variants for polycystic ovary syndrome

STUDY QUESTION Can we identify novel variants associated with polycystic ovary syndrome (PCOS) by leveraging the unique population history of Northern Europe? SUMMARY ANSWER We identified three novel genome-wide significant associations with PCOS, with two putative independent causal variants in the checkpoint kinase 2 (CHEK2) gene and a third in myosin X (MYO10). WHAT IS KNOWN ALREADY PCOS is a common, complex disorder with unknown aetiology. While previous genome-wide association studies (GWAS) have mapped several loci associated with PCOS, the analysis of populations with unique population history and genetic makeup has the potential to uncover new low-frequency variants with larger effects. STUDY DESIGN, SIZE, DURATION A population-based case-control GWAS was carried out. PARTICIPANTS/MATERIALS, SETTING, METHODS We identified PCOS cases from national registers by ICD codes (ICD-10 E28.2, ICD-9 256.4, or ICD-8 256.90), and all remaining women were considered controls. We then conducted a three-stage case-control GWAS: in the discovery phase, we had a total of 797 cases and 140 558 controls from the FinnGen study. For validation, we used an independent dataset from the Estonian Biobank, including 2812 cases and 89 230 controls. Finally, we performed a joint meta-analysis of 3609 cases and 229 788 controls from both cohorts. Additionally, we reran the association analyses including BMI as a covariate, with 2169 cases and 160 321 controls from both cohorts. MAIN RESULTS AND THE ROLE OF CHANCE Two out of the three novel genome-wide significant variants associating with PCOS, rs145598156 (P = 3.6x10(-8), odds ratio (OR) = 3.01 [2.02-4.50] minor allele frequency (MAF) = 0.005) and rs182075939 (P = 1.9x10(-16), OR = 1.69 [1.49-1.91], MAF = 0.04), were found to be enriched in the Finnish and Estonian populations and are tightly linked to a deletion c.1100delC (r(2) = 0.95) and a missense I157T (r(2) = 0.83) in CHEK2. The third novel association is a common variant near MYO10 (rs9312937, P = 1.7 x 10(-8), OR = 1.16 [1.10-1.23], MAF = 0.44). We also replicated four previous reported associations near the genes Erb-B2 Receptor Tyrosine Kinase 4 (ERBB4), DENN Domain Containing 1A (DENND1A), FSH Subunit Beta (FSHB) and Zinc Finger And BTB Domain Containing 16 (ZBTB16). When adding BMI as a covariate only one of the novel variants remained genome-wide significant in the meta-analysis (the EstBB lead signal in CHEK2 rs182075939, P = 1.9x10(-16), OR = 1.74 [1.5-2.01]) possibly owing to reduced sample size. LARGE SCALE DATA The age- and BMI-adjusted GWAS meta-analysis summary statistics are available for download from the GWAS Catalog with accession numbers GCST90044902 and GCST90044903. LIMITATIONS, REASONS FOR CAUTION The main limitation was the low prevalence of PCOS in registers; however, the ones with the diagnosis most likely represent the most severe cases. Also, BMI data were not available for all (63% for FinnGen, 76% for EstBB), and the biobank setting limited the accessibility of PCOS phenotypes and laboratory values. WIDER IMPLICATIONS OF THE FINDINGS This study encourages the use of isolated populations to perform genetic association studies for the identification of rare variants contributing to the genetic landscape of complex diseases such as PCOS. STUDY FUNDING/COMPETING INTEREST(S) This work has received funding from the European Union's Horizon 2020 research and innovation programme under the MATER Marie Sklodowska-Curie grant agreement No. 813707 (N.P.-G., T.L., T.P.), the Estonian Research Council grant (PRG687, T.L.), the Academy of Finland grants 315921 (T.P.), 321763 (T.P.), 297338 (J.K.), 307247 (J.K.), 344695 (H.L.), Novo Nordisk Foundation grant NNF17OC0026062 (J.K.), the Sigrid Juselius Foundation project grants (T.L., J.K., T.P.), Finska Lakaresallskapet (H.L.) and Jane and Aatos Erkko Foundation (H.L.). The funders had no role in study design, data collection and analysis, publishing or preparation of the manuscript. The authors declare no conflicts of interest.Peer reviewe

A Genome-Wide Association Study of Attention Function in a Population-Based Sample of Children

BACKGROUND: Attention function filters and selects behaviorally relevant information. This capacity is impaired in some psychiatric disorders and has been proposed as an endophenotype for Attention-Deficit/Hyperactivity Disorder; however, its genetic basis remains largely unknown. This study aimed to identify single nucleotide polymorphism (SNPs) associated with attention function. MATERIALS AND METHODS: The discovery sample included 1655 children (7-12 years) and the replication sample included 546 children (5-8 years). Five attention outcomes were assessed using the computerized Attentional Network Test (ANT): alerting, orienting, executive attention, Hit Reaction time (HRT) and the standard error of HRT (HRTSE). A Genome-wide Association Study was conducted for each outcome. Gene set enrichment analyses were performed to detect biological pathways associated with attention outcomes. Additional neuroimaging analyses were conducted to test neural effects of detected SNPs of interest. RESULTS: Thirteen loci showed suggestive evidence of association with attention function (P<10-5) in the discovery sample. One of them, the rs4321351 located in the PID1 gene, was nominally significant in the replication sample although it did not survive multiple testing correction. Neuroimaging analysis revealed a significant association between this SNP and brain structure and function involving the frontal-basal ganglia circuits. The mTOR signaling and Alzheimer disease-amyloid secretase pathways were significantly enriched for alerting, orienting and HRT respectively (FDR<5%). CONCLUSION: These results suggest for the first time the involvement of the PID1 gene, mTOR signaling and Alzheimer disease-amyloid secretase pathways, in attention function during childhood. These genes and pathways have been proposed to play a role in neuronal plasticity, memory and neurodegenerative disease

Glucose Restriction Promotes Osteocyte Specification by Activating a PGC-1α-Dependent Transcriptional Program.

Osteocytes, the most abundant of bone cells, differentiate while they remain buried within the bonematrix. This encasement limits their access to nutrients and likely affects their differentiation, a pro-cess that remains poorly defined. Here, we show that restriction in glucose supply promotes the oste-ocyte transcriptional program while also being associated with increased mitochondrial DNA levels.Glucose deprivation triggered the activation of the AMPK/PGC-1 pathway. AMPK and SIRT1 activa-tors or PGC-1aoverexpression are sufficient to enhance osteocyte gene expression in IDG-SW3 cells,murine primary osteoblasts, osteocytes, and organotypic/ex vivobone cultures. Conversely, osteo-blasts and osteocytes deficient inPpargc1aandbwere refractory to the effects of glucose restriction.Finally, conditional ablation of both genes in osteoblasts and osteocytes generate osteopenia andreduce osteocytic gene expression in mice. Altogether, we uncovered a role for PGC-1 in the regula-tion of osteocyte gene expression