RESUMEN
Lysine acetyltransferase 6A (KAT6A) and its paralog KAT6B form stoichiometric complexes with bromodomain- and PHD finger-containing protein 1 (BRPF1) for acetylation of histone H3 at lysine 23 (H3K23). We report that these complexes also catalyze H3K23 propionylation in vitro and in vivo. Immunofluorescence microscopy and ATAC-See revealed the association of this modification with active chromatin. Brpf1 deletion obliterates the acylation in mouse embryos and fibroblasts. Moreover, we identify BRPF1 variants in 12 previously unidentified cases of syndromic intellectual disability and demonstrate that these cases and known BRPF1 variants impair H3K23 propionylation. Cardiac anomalies are present in a subset of the cases. H3K23 acylation is also impaired by cancer-derived somatic BRPF1 mutations. Valproate, vorinostat, propionate and butyrate promote H3K23 acylation. These results reveal the dual functionality of BRPF1-KAT6 complexes, shed light on mechanisms underlying related developmental disorders and various cancers, and suggest mutation-based therapy for medical conditions with deficient histone acylation.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas de Unión al ADN/metabolismo , Histona Acetiltransferasas/metabolismo , Histonas/metabolismo , Neoplasias/etiología , Neoplasias/metabolismo , Trastornos del Neurodesarrollo/etiología , Trastornos del Neurodesarrollo/metabolismo , Acetilación , Proteínas Adaptadoras Transductoras de Señales/genética , Secuencia de Aminoácidos , Animales , Encéfalo/anomalías , Encéfalo/diagnóstico por imagen , Línea Celular , Análisis Mutacional de ADN , Proteínas de Unión al ADN/genética , Susceptibilidad a Enfermedades , Predisposición Genética a la Enfermedad , Histona Acetiltransferasas/genética , Humanos , Imagen por Resonancia Magnética , Ratones , Ratones Noqueados , Modelos Biológicos , Complejos Multiproteicos/metabolismo , Mutación , Neoplasias/diagnóstico , Trastornos del Neurodesarrollo/diagnóstico , Fenotipo , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Procesamiento Proteico-Postraduccional , SíndromeRESUMEN
INTRODUCTION: It is well established that work stress is a major economic burden not only in lost work productivity but also in increased health care utilization and costs. However, there is little research into effective treatment models for work stress. OBJECTIVE: To retrospectively examine the effectiveness of a psychiatric pilot quality improvement program in improving the return-to-work rate in patients in a health maintenance organization who had work stress and took medical leave from work. METHODS: A health maintenance organization's Department of Psychiatry developed a pilot quality improvement program that reviewed a new program of group psychotherapy and specialty mental health treatment targeting patients who self-identified as having work stress and who requested medical leave from work. The retrospective data were collected from the electronic medical record. RESULTS: Of the 166 patients who participated in the Work Recovery Group program, 141 (85%) returned to work and did not have any days off after the Work Recovery Group within the 11-month analysis. Involvement in the group also was associated with improvement in self-reported symptom severity, with a 4.5-point decrease in the average score on the Adult Outcomes Questionnaire about depression and anxiety. DISCUSSION: This is the first known treatment program from a health maintenance organization to provide data on return-to-work outcomes. By providing specialty mental health treatment and getting patients back to work more quickly, this program has potential to reduce mental health service utilization. These results show promise for program expansion and have broader implications for health care organizations and employers.
Asunto(s)
Absentismo , Estrés Laboral/psicología , Estrés Laboral/terapia , Psicoterapia de Grupo/métodos , Reinserción al Trabajo/psicología , Lugar de Trabajo/psicología , Femenino , Sistemas Prepagos de Salud , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Estudios Retrospectivos , Reinserción al Trabajo/estadística & datos numéricos , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
BACKGROUND/OBJECTIVE: Alcohol is a teratogen. Fetal alcohol spectrum disorders (FASDs) affect about 1% of live births, causing severe impairment. Individuals affected by FASDs are overrepresented in psychiatric settings. This study reports on the education and experience of psychiatry trainees in approaching FASDs. METHOD: Data were collected from psychiatry trainees throughout the country by use of a web-based questionnaire. RESULTS: A representative sample (N=308) of psychiatry trainees responded; 19% rate their education on FASDs as "good" or "excellent," and 89% report that they would like more education on FASDs: 6%, 15%, and 30%, endorsed the statement "It is safe to drink some alcohol" during the 1st, 2nd, and 3rd trimesters, respectively. Only 31% correctly report that individuals with an FASD are at equal risk for adverse outcomes as individuals with full-blown fetal alcohol syndrome. CONCLUSIONS: results reveal that training on FASDs is inadequate. Psychiatry trainees poorly understand the importance of abstinence throughout pregnancy. Trainees who report receiving supervision specifically addressing FASDs also report making the diagnosis much more frequently, suggesting that supervision in clinical settings is effective teaching. Results reveal that FASDs are underrecognized, resulting in missed opportunities for prevention and intervention.
