Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
1.
PLoS Genet ; 14(8): e1007587, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30096149

RESUMO

The basic helix-loop-helix (bHLH) transcription factor ASCL2 plays essential roles in diploid multipotent trophoblast progenitors, intestinal stem cells, follicular T-helper cells, as well as during epidermal development and myogenesis. During early development, Ascl2 expression is regulated by genomic imprinting and only the maternally inherited allele is transcriptionally active in trophoblast. The paternal allele-specific silencing of Ascl2 requires expression of the long non-coding RNA Kcnq1ot1 in cis and the deposition of repressive histone marks. Here we show that Del7AI, a 280-kb deletion allele neighboring Ascl2, interferes with this process in cis and leads to a partial loss of silencing at Ascl2. Genetic rescue experiments show that the low level of Ascl2 expression from the paternal Del7AI allele can rescue the embryonic lethality associated with maternally inherited Ascl2 mutations, in a level-dependent manner. Despite their ability to support development to term, the rescued placentae have a pronounced phenotype characterized by severe hypoplasia of the junctional zone, expansion of the parietal trophoblast giant cell layer, and complete absence of invasive glycogen trophoblast cells. Transcriptome analysis of ectoplacental cones at E7.5 and differentiation assays of Ascl2 mutant trophoblast stem cells show that ASCL2 is required for the emergence or early maintenance of glycogen trophoblast cells during development. Our work identifies a new cis-acting mutation interfering with Kcnq1ot1 silencing function and establishes a novel critical developmental role for the transcription factor ASCL2.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Linhagem da Célula , Glicogênio/metabolismo , Trofoblastos/fisiologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Diferenciação Celular , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Inativação Gênica , Impressão Genômica , Técnicas de Genotipagem , Heterozigoto , Masculino , Camundongos , Placenta/citologia , Gravidez , Análise de Sequência de RNA , Células-Tronco/citologia , Trofoblastos/citologia
2.
BMC Fam Pract ; 16: 25, 2015 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-25884181

RESUMO

BACKGROUND: Recent trends document growth in medical tourism, the private pursuit of medical interventions abroad. Medical tourism introduces challenges to decision-making that impact and are impacted by the physician-patient trust relationship-a relationship on which the foundation of beneficent health care lies. The objective of the study is to examine the views of Canadian family physicians about the roles that trust plays in decision-making about medical tourism, and the impact of medical tourism on the therapeutic relationship. METHODS: We conducted six focus groups with 22 family physicians in the Canadian province of British Columbia. Data were analyzed thematically using deductive and inductive codes that captured key concepts across the narratives of participants. RESULTS: Family physicians indicated that they trust their patients to act as the lead decision-makers about medical tourism, but are conflicted when the information they are managing contradicts the best interests of the patients. They reported that patients distrust local health care systems when they experience insufficiencies in access to care and that this can prompt patients to consider going abroad for care. Trust fractures in the physician-patient relationship can arise from shame, fear and secrecy about medical tourism. CONCLUSIONS: Family physicians face diverse tensions about medical tourism as they must balance their roles in: (1) providing information about medical tourism within a context of information deficits; (2) supporting decision-making while distancing themselves from patients' decisions to engage in medical tourism; and (3) acting both as agents of the patient and of the domestic health care system. These tensions highlight the ongoing need for reliable third-party informational resources about medical tourism and the development of responsive policy.


Assuntos
Atitude do Pessoal de Saúde , Turismo Médico , Relações Médico-Paciente , Médicos de Família , Confiança , Colúmbia Britânica , Tomada de Decisões , Grupos Focais , Humanos
3.
Stem Cell Rev Rep ; 12(4): 438-47, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27286955

RESUMO

Parents and primary caregivers of children with Cerebral Palsy (CP) and Autism Spectrum Disorder (ASD) are faced with difficult treatment choices and management options for their children. The potential of stem cell technologies as an interventional strategy for CP and ASD has gained attention in the last decade. Information about these interventions varies in quality, resulting in a complex landscape for parent decision making for a child's care. Further complicating this landscape are clinics that advertise these interventions as a legitimate treatment for a fee. In this study, we surveyed individuals who considered taking their child with ASD or CP abroad for stem cell interventions on their use of different sources of stem cell related health information and their level of trust in these sources. Participants reported that while the Internet was their most frequent source of information, it was not well-trusted. Rather, information sources trusted most were researchers and the science journals in which they publish, other parents of children with CP and ASD, and healthcare providers. These findings highlight a dichotomy between information-seeking preferences and information-trusted sources. We discuss the challenges of health science communication and present innovative opportunities to increase communication with trusted and reliable sources as part of an integrated multi-pronged approach.


Assuntos
Transtorno do Espectro Autista/terapia , Paralisia Cerebral/terapia , Troca de Informação em Saúde/normas , Sistemas de Informação em Saúde/normas , Transplante de Células-Tronco/métodos , Adulto , Idoso , Tomada de Decisões , Feminino , Troca de Informação em Saúde/estatística & dados numéricos , Sistemas de Informação em Saúde/estatística & dados numéricos , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Disseminação de Informação/métodos , Comportamento de Busca de Informação , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários
4.
Endocrinology ; 151(2): 502-12, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20056832

RESUMO

Insulin enhances the proliferation and survival of pancreatic beta-cells, but its mechanisms remain unclear. We hypothesized that Raf-1, a kinase upstream of both ERK and Bad, might be a critical target of insulin in beta-cells. To test this hypothesis, we treated human and mouse islets as well as MIN6 beta-cells with multiple insulin concentrations and examined putative downstream targets using immunoblotting, immunoprecipitation, quantitative fluorescent imaging, and cell death assays. Low doses of insulin rapidly activated Raf-1 by dephosphorylating serine 259 and phosphorylating serine 338 in human islets, mouse islets, and MIN6 cells. The phosphorylation of ERK by insulin was eliminated by exposure to a Raf inhibitor (GW5074) or transfection with a dominant-negative Raf-1 mutant. Insulin also enhanced the interaction between mitochondrial Raf-1 and Bcl-2 agonist of cell death (Bad), promoting Bad inactivation via its phosphorylation on serine 112. Insulin-stimulated ERK phosphorylation was abrogated by calcium chelation, calcineurin and calmodulin-dependent protein kinase II inhibitors, and Ned-19, a nicotinic acid adenine dinucleotide phosphate receptor (NAADPR) antagonist. Blocking Raf-1 and Ca(2+) signaling resulted in nonadditive beta-cell death. Autocrine insulin signaling partly accounted for the effects of glucose on ERK phosphorylation. Our results demonstrate that Raf-1 is a critical target of insulin in primary beta-cells. Activation of Raf-1 leads to both an ERK-dependent pathway that involves nicotinic acid adenine dinucleotide phosphate-sensitive Ca(2+) stores and Ca(2+)-dependent phosphorylation events, and an ERK-independent pathway that involves Bad inactivation at the mitochondria. Together our findings identify a novel insulin signaling pathway in beta-cells and shed light on insulin's antiapoptotic and mitogenic mechanisms.


Assuntos
Cálcio/fisiologia , Células Secretoras de Insulina/fisiologia , Insulina/fisiologia , Proteínas Proto-Oncogênicas c-raf/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Humanos , Indóis/farmacologia , Insulina/genética , Insulina/farmacologia , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/fisiologia , Fenóis/farmacologia , Fosforilação , Proteínas Proto-Oncogênicas c-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-raf/genética
SELEÇÃO DE REFERÊNCIAS
Detalhe da pesquisa