RESUMO
With the COVID-19 pandemic, emergency rooms are faced with major challenges because they act as the interface between outpatient and inpatient care. The dynamics of the pandemic forced emergency care at the University Hospital Münster to extensively adjust their processes, which had to be carried out in the shortest time possible. This included the establishment of an outpatient coronavirus test center and a medical student-operated telephone hotline. Inside the hospital, new isolation capacities in the emergency room and a dedicated COVID-19 ward were set up. The patient flow was reorganized using flow diagrams for both the outpatient and inpatient areas. The general and special emergency management was optimized for the efficient treatment of COVID-19-positive patients and the staff were trained in the use of protective equipment. This report of our experience is intended to support other emergency departments in their preparation for the COVID-19 pandemic.
Assuntos
Betacoronavirus , Infecções por Coronavirus , Serviços Médicos de Emergência , Serviço Hospitalar de Emergência , Pandemias , Isolamento de Pacientes , Pneumonia Viral , COVID-19 , Infecções por Coronavirus/epidemiologia , Humanos , Pneumonia Viral/epidemiologia , SARS-CoV-2 , TriagemRESUMO
The Hippo pathway fulfills a crucial function in controlling the balance between proliferation, differentiation and apoptosis in cells. Recent studies showed that G protein-coupled receptors (GPCRs) serve as upstream regulators of Hippo signaling, that either activate or inactivate the Hippo pathway via the large tumor suppressor kinase (LATS) and its substrate, the co-transcription factor Yes-associated protein (YAP). In this study, we focused on the Angiotensin II type 1 receptor (AT1R), which belongs to the GPCR family and has an essential role in the control of blood pressure and water homeostasis. We found that Angiotensin II (Ang II) inactivates the pathway by decreasing the activity of LATS kinase; therefore, leading to an enhanced nuclear shuttling of unphosphorylated YAP in HEK293T cells. This shuttling of YAP is actin-dependent as disruption of the actin cytoskeleton inhibited dephosphorylation of LATS and YAP. Interestingly, in contrast to HEK293T cells, podocytes, which are a crucial component of the glomerular filtration barrier, display a predominant nuclear YAP localization in vivo and in vitro. Moreover, stimulation with Ang II did not alter Hippo pathway activity in podocytes, which show a deactivated pathway. Reactivation of the LATS kinase activity in podocytes resulted in an increased cytoplasmic YAP localization accompanied by a strong induction of apoptosis. Thus, our work indicates that the control of LATS activation and subsequent YAP localization is important for podocyte homeostasis and survival.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Fosfoproteínas/genética , Podócitos/metabolismo , Proteínas Serina-Treonina Quinases/genética , Citoesqueleto de Actina/química , Citoesqueleto de Actina/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Angiotensina II/farmacologia , Animais , Apoptose/genética , Linhagem Celular Transformada , Sobrevivência Celular , Regulação da Expressão Gênica , Células HEK293 , Via de Sinalização Hippo , Homeostase , Humanos , Camundongos , Camundongos Transgênicos , Especificidade de Órgãos , Fosfoproteínas/metabolismo , Fosforilação , Podócitos/citologia , Cultura Primária de Células , Proteínas Serina-Treonina Quinases/metabolismo , Transporte Proteico , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Transdução de Sinais , Fatores de Transcrição , Proteínas de Sinalização YAPRESUMO
The human KIBRA gene has been linked to human cognition through a lead intronic single-nucleotide polymorphism (SNP; rs17070145) that is associated with episodic memory performance and the risk to develop Alzheimer's disease. However, it remains unknown how this relates to the function of the KIBRA protein. Here, we identified two common missense SNPs (rs3822660G/T [M734I], rs3822659T/G [S735A]) in exon 15 of the human KIBRA gene to affect cognitive performance, and to be in almost complete linkage disequilibrium with rs17070145. The identified SNPs encode variants of the KIBRA C2 domain with distinct Ca(2+) dependent binding preferences for monophosphorylated phosphatidylinositols likely due to differences in the dynamics and folding of the lipid-binding pocket. Our results further implicate the KIBRA protein in higher brain function and provide direction to the cellular pathways involved.