RESUMEN
The ever-growing compendium of genetic variants associated with human pathologies demands new methods to study genotype-phenotype relationships in complex tissues in a high-throughput manner1,2. Here we introduce adeno-associated virus (AAV)-mediated direct in vivo single-cell CRISPR screening, termed AAV-Perturb-seq, a tuneable and broadly applicable method for transcriptional linkage analysis as well as high-throughput and high-resolution phenotyping of genetic perturbations in vivo. We applied AAV-Perturb-seq using gene editing and transcriptional inhibition to systematically dissect the phenotypic landscape underlying 22q11.2 deletion syndrome3,4 genes in the adult mouse brain prefrontal cortex. We identified three 22q11.2-linked genes involved in known and previously undescribed pathways orchestrating neuronal functions in vivo that explain approximately 40% of the transcriptional changes observed in a 22q11.2-deletion mouse model. Our findings suggest that the 22q11.2-deletion syndrome transcriptional phenotype found in mature neurons may in part be due to the broad dysregulation of a class of genes associated with disease susceptibility that are important for dysfunctional RNA processing and synaptic function. Our study establishes a flexible and scalable direct in vivo method to facilitate causal understanding of biological and disease mechanisms with potential applications to identify genetic interventions and therapeutic targets for treating disease.
Asunto(s)
Sistemas CRISPR-Cas , Dependovirus , Edición Génica , Estudios de Asociación Genética , Análisis de la Célula Individual , Transcripción Genética , Animales , Humanos , Ratones , Dependovirus/genética , Estudios de Asociación Genética/métodos , Neuronas/metabolismo , Fenotipo , Corteza Prefrontal/metabolismo , Transcripción Genética/genética , Análisis de la Célula Individual/métodos , Sistemas CRISPR-Cas/genética , Síndrome de DiGeorge/tratamiento farmacológico , Síndrome de DiGeorge/genética , Modelos Animales de Enfermedad , Procesamiento Postranscripcional del ARN , Sinapsis/patología , Predisposición Genética a la EnfermedadRESUMEN
This study examined the effects of using a multidisciplinary, integrated, whole-person, team advocate approach to educate and empower participants with multiple chronic illnesses and coordinate, monitor, and support their health care process. Individuals (N = 39) from Midwest hospitals participated and completed self-report instruments. Changes in participants' functioning were also measured with diagnostic measures completed by the team advocates. The results indicate that the participants' perceptions of physical functioning, physical well-being, control, self-efficacy, and life satisfaction increased. Additionally, health-related behavior changes were reported, and short-term costs were significantly lower than projected costs. Finally, the participants rated their health care services in the program as more effective than previous health care services.
Asunto(s)
Enfermedad Crónica/terapia , Prestación Integrada de Atención de Salud , Servicios de Salud/normas , Estado de Salud , Comunicación Interdisciplinaria , Grupo de Atención al Paciente , Calidad de la Atención de Salud , Adolescente , Adulto , Anciano , Actitud , Niño , Femenino , Humanos , Control Interno-Externo , Masculino , Persona de Mediana Edad , Autoeficacia , Encuestas y CuestionariosRESUMEN
Este estudo propöe-se a discutir teoricamente a percepçäo da comunidade acerca da assistência ao doente mental prestada na Nossa Casa em Säo Lourenço do Sul/RS, considerando os aspectos éticos que esta proposta suscita. Para isto realizou-se uma discussäo teórica sobre a desinstitucionalizaçäo do doente mental e a análise qualitativa de quatro entrevistas que procuraram apreender a percepçäo da comunidade em relaçäo ao doente mental, aos modelos tradicionais de assistência psiquiátrica e aos serviços alternativos como a Nossa Casa. A seguir procurou-se resgatar nestas reflexöes a dimensäo ética deste processo em construçäo.
