TASK DEFINITION: In this task, you are given a passage which has a question and the context. You have to generate an answer to the question based on the information present in the context.
PROBLEM: Context: Diabetic cardiomyopathy (DCM) is associated with suppressed autophagy and augmented apoptosis in the heart although the interplay between the two remains elusive. The ability of mammalian sterile 20-like kinase 1 to regulate both autophagy and apoptosis prompted us to investigate it as a possible candidate in the progression of DCM.', 'Wild-type, Mst1 (also known as Stk4) transgenic and Mst1-knockout mice were challenged with streptozotocin to induce experimental diabetes. In addition, cultured neonatal mouse cardiomyocytes were subjected to simulated diabetes to probe mechanisms.', 'Mst1 knockout alleviated while Mst1 overexpression aggravated cardiac dysfunction in diabetes. Diabetic Mst1 transgenic mice exhibited decreased LC3 expression and enhanced protein aggregation. In contrast, typical autophagosomes were observed in diabetic Mst1-knockout mice with increased LC3 expression and reduced protein aggregation. Mst1 downregulation promoted autophagic flux as demonstrated by increased LC3-II and decreased p62 expression in the presence of bafilomycin A1. Furthermore, Mst1 overexpression increased, while Mst1 knockout decreased, cardiomyocyte apoptosis both in vivo and in vitro. Co-immunoprecipitation assays showed that Mst1 overexpression promoted Beclin1 binding to B cell lymphoma 2 (Bcl-2) and induced dissociation of Bcl-2 from Bax in diabetic mice. Conversely, Mst1 knockout disrupted the Beclin1-Bcl-2 complex and enhanced the interaction between Bcl-2 and Bax.\Question: Does mST1 coordinately regulate autophagy and apoptosis in diabetic cardiomyopathy in mice?

SOLUTION: Mst1 knockout restores autophagy and protects against apoptosis in cardiomyocytes, en route to the rescue against DCM.

PROBLEM: Context: The purpose of the present study was to investigate the potential signal mechanism of tissue factor (TF)\xa0in the regulation of the expression of vascular endothelial growth factor (VEGF) in human retinal pigment epithelial (ARPE-19) cells.', 'An in vitro RPE cell chemical hypoxia model was established by adding cobalt chloride (CoCl2) in the culture medium. The irritative concentration of CoCl2 was determined with a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay kit. VEGF production in ARPE-19 cells was measured with enzyme-linked immunosorbent assay (ELISA) and western blotting. The Wnt signaling pathway-associated molecules, including phospho-glycogen synthase kinase 3β (p-GSK3β), GSK3β, p-β-catenin and β-catenin, were detected with western blotting. pEGFP-N3-hTF was constructed and verified with digestion of the restriction enzyme and sequencing analysis. Human TF overexpression and silencing plasmids were transfected into the ARPE-19 cells to clarify the causal relationship between TF and VEGF expression. The Transwell coculture system of ARPE-19 cells and RF/6A rhesus macaque choroid-retinal endothelial cells was performed to evaluate cell invasion and tube formation ability.', 'Our anoxic model of ARPE-19 cells showed that TF expression was upregulated in accordance with variations in hypoxia-inducible factor 1-alpha (HIF-1α) and VEGF levels. Silencing and overexpression of TF decreased and increased VEGF expression, respectively. The Wnt/β-catenin signaling pathway played an important role in this effect. Results from the ARPE-19 cell and RF/6A cell coculture system showed that the enhancement of TF expression in the ARPE-19 cells led to significantly faster invasion and stronger tube-forming ability of the RF/6A cells, while siRNA-mediated TF silencing caused the opposite effects. Pharmacological disruption of Wnt signaling IWR-1-endo inhibited the effects compared to the TF-overexpressing group, indicating the importance of the Wnt/β-catenin signaling pathway in the process of TF-induced VEGF expression and angiogenesis.\Question: Does tissue factor induce VEGF expression via activation of the Wnt/β-catenin signaling pathway in ARPE-19 cells?

SOLUTION: Involvement of the activation of the Wnt/β-catenin signaling pathway is an important mediator for TF-induced VEGF production during the process of angiogenesis. Thus, our findings may ascertain the molecular regulation of TF in neovessel formation and show significant therapeutic implications.

PROBLEM: Context: Ehlers Danlos Syndrome is a rare form of inherited connective tissue disorder, which primarily affects skin, joints, muscle, and blood cells. The current study aimed at finding the mutation that causing EDS type VII C also known as "Dermatosparaxis" in this family.', 'Through systematic data querying of the electronic medical records (EMRs) of over 80,000 individuals, we recently identified an EDS family that indicate an autosomal dominant inheritance. The family was consented for genomic analysis of their de-identified data. After a negative screen for known mutations, we performed whole genome sequencing on the male proband, his affected father, and unaffected mother. We filtered the list of non-synonymous variants that are common between the affected individuals.', 'The analysis of non-synonymous variants lead to identifying a novel mutation in the ADAMTSL2 (p. Gly421Ser) gene in the affected individuals. Sanger sequencing confirmed the mutation.\Question: Does systematic data-querying of large pediatric biorepository identify novel Ehlers-Danlos Syndrome variant?

SOLUTION:
Our work is significant not only because it sheds new light on the pathophysiology of EDS for the affected family and the field at large, but also because it demonstrates the utility of unbiased large-scale clinical recruitment in deciphering the genetic etiology of rare mendelian diseases. With unbiased large-scale clinical recruitment we strive to sequence as many rare mendelian diseases as possible, and this work in EDS serves as a successful proof of concept to that effect.