Multimerization of HIF enhances transcription of target genes containing the hypoxia ancillary sequence.

Transcriptional activity of the hypoxia inducible factor (HIF) relies on the formation of a heterodimer composed of an oxygen-regulated α-subunit and a stably expressed ß-subunit. Heterodimeric HIF activates expression by binding to RCGTG motifs within promoters of hypoxia-activated genes. Some hypoxia targets also possess an adjacent HIF ancillary sequence (HAS) reported to increase transcription but whose function remains obscure. Here, we investigate the contribution of the HAS element to the hypoxia response and its mechanism of action, using the HAS-containing prolyl 4-hydroxylase subunit α1 (P4HA1) as a gene model in NIH/3T3 mouse embryonic fibroblasts and HEK293 human embryonic kidney cells. Our HIF overexpression experiments demonstrate that the HAS motif is essential for full induction by hypoxia and that the presence of the tandem HAS/HIF, as opposed to HIF-only sequences, provides HIF proteins with the capacity to form complexes of stoichiometry beyond the classical heterodimer, likely tetramers, to cooperatively potentiate hypoxia-induced transcription. We also provide evidence of the crucial role played by the Fα helix of the PAS-B domain of the HIF1ß subunit to support the interaction between heterodimers. Functional analysis showed that human genes containing the HAS/HIF motifs are better responders to hypoxia, and their promoters are enriched for specific transcription factor binding sites. Gene ontology enrichment revealed a predominance of HAS/HIF in genes primarily related to tissue formation and development. Our findings add an extra level of regulation of the hypoxia/HIF signaling through multimerization of HIF proteins on regulatory elements containing the HAS/HIF motifs.

Spanish validation of the Type D personality scale (DS14) / Validación española de la "Escala de personalidad tipo D" (DS14)

Type D personality, which encompasses two dimensions, Negative Affectivity (NA) and Social Inhibition (SI), has been identified as a risk factor for cardiovascular disease, and its link to other conditions has become a focus of research in recent years. The main study objectives were to assess the psychometric properties behind the Type D Personality Scale (DS14) in the Spanish population and to evaluate type D personality presence taking into account sociodemographic as well as clinical variables. A total of 1257 subjects (41.1% men and 58.9% women) participated in this study. Ages ranged from 18 to 80 years. The Spanish version of the DS14 and a sociodemographic questionnaire were administered. Cronbach's alpha coefficients for the DS14 subscales were .84 (NA) and .81 (SI). The original scale’s factor structure was replicated. Type D personality presence was 29.7% in the total sample and 56.5% in patients presenting both hypertension and heart disease. The Spanish version of the DS14 shows high internal consistency and adequate evidence of internal and external validity when assessing type D personality

La personalidad tipo D integrada por dos dimensiones, Afectividad negativa (AN) e Inhibición social (IS) ha sido identificada como un factor de riesgo cardiovascular y, en los últimos años, se está investigando su asociación con otras enfermedades. El objetivo de este estudio es examinar las propiedades psicométricas de la "Escala de personalidad tipo D" (DS14) y su presencia en población española teniendo en cuenta características sociodemográficas y clínicas. La muestra participante fue de 1257 sujetos (41,1% varones), de entre 18 y 80 años de edad. El coeficiente de fiabilidad para las dos subescalas de la DS14 fue de 0,84 (AN) y 0,81 (IS). Se replicó la estructura factorial de la escala en su versión original. La presencia de personalidad tipo D fue de 29,7% en el total de la muestra y de 56,5% en pacientes que presentaban conjuntamente hipertensión y patología cardiaca. La versión española de la DS14 tiene una alta consistencia interna y muestra evidencias adecuadas de validez interna y externa