Inhibition of EZH2 Promotes Human Embryonic Stem Cell Differentiation into Mesoderm by Reducing H3K27me3.

Mesoderm derived from human embryonic stem cells (hESCs) is a major source of the mesenchymal stem/stromal cells (MSCs) that can differentiate into osteoblasts and chondrocytes for tissue regeneration. While significant progress has been made in understanding of molecular mechanisms of hESC differentiation into mesodermal cells, little is known about epigenetic factors controlling hESC fate toward mesoderm and MSCs. Identifying potential epigenetic factors that control hESC differentiation will undoubtedly lead to advancements in regenerative medicine. Here, we conducted an epigenome-wide analysis of hESCs and MSCs and uncovered that EZH2 was enriched in hESCs and was downregulated significantly in MSCs. The specific EZH2 inhibitor GSK126 directed hESC differentiation toward mesoderm and generated more MSCs by reducing H3K27me3. Our results provide insights into epigenetic landscapes of hESCs and MSCs and suggest that inhibiting EZH2 promotes mesodermal differentiation of hESCs

Linear Approximations to AC Power Flow in Rectangular Coordinates

This paper explores solutions to linearized powerflow equations with bus-voltage phasors represented in rectangular coordinates. The key idea is to solve for complex-valued perturbations around a nominal voltage profile from a set of linear equations that are obtained by neglecting quadratic terms in the original nonlinear power-flow equations. We prove that for lossless networks, the voltage profile where the real part of the perturbation is suppressed satisfies active-power balance in the original nonlinear system of equations. This result motivates the development of approximate solutions that improve over conventional DC power-flow approximations, since the model includes ZIP loads. For distribution networks that only contain ZIP loads in addition to a slack bus, we recover a linear relationship between the approximate voltage profile and the constant-current component of the loads and the nodal active and reactive-power injections

Patient derived endothelial progenitor cells as a potential ex vivo model of vascular health and disease

Introduction: Ischaemic heart disease (IHD) is the leading cause of death in Australia. Its onset is due to abnormal pathology such as blockages or narrowing in the arteries resulting in poor perfusion. This is usually caused by atherosclerotic plaque development and can result in a myocardial infarction (MI). Through exploration of molecular pathways, we hope to identify novel biomarkers and/or therapies for cardiovascular disease (CVD). I have approached this by utilising patient-derived EPCs from the BioHEART study for molecular and functional characterisation. Aims: 1. To develop methodology to isolate EPCs from participants in the BioHEART study. 2. To functionally characterise EPCs and compare them to standard vascular endothelial cells. 3. To collate molecular and functional data from EPCs with participant coronary artery disease (CAD) and CVD risk profile. Methods: Patients were recruited to the BioHEART study at North Shore Private Hospital, and data was collected on age, sex, medication and cardiovascular risk factors. Blood samples were collected in heparin-coated vacuettes and peripheral blood mononuclear cells were extracted via Ficoll gradient centrifugation and cultured in 0.1% gelatin-coasted flasks in endothelial cell growth medium. Following the emergence of EPCs, cells were passaged 3 times and cryopreserved. Cells were stained with fluorescent tagged antibodies and surface marker expression was detected through flow cytometry. Angiogenesis was assessed by migration and tubule formation assays. Redox signalling was assessed by superoxide generation in live cells and expression of reactive oxygen species (ROS) and other proteins by immunoblotting. Results: The spontaneous development of EPCs was assessed in BioHEART participants. Body mass index (BMI) of participants affected the capacity for EPCs to develop in culture. Samples where EPCs spontaneously appeared came from patients with BMI of 25.9 ± 0.3, (n=215) whereas samples where EPCs failed to grow were from patients with BMI 30.6 ± 0.4, (n=728; p<0.0001). Having a BMI ≥ 30, diabetes and taking beta-blockers negatively affected growth, while taking statins positively contributed to growth. EPCs had an expression and functional profile similar to human umbilical vein endothelial cells (HuVECs). NADPH oxidase (Nox)-2 protein expression was increased two-fold in EPCs of participants that were classified to have CVD based on their coronary calcification measure by computer tomography (n=13-14, p<0.05). Interestingly, I observed disparity in between EPCs extracted from males and females. In females with CVD there was elevated eNOS expression in comparison to EPCs from healthy females, but this was not evident in male EPCs. This correlated with increased tubule formation in females with CVD but not males. However, I found that migration of EPCs were not affected by CVD in females, yet slightly accelerated in males. These functional changes in capacity for angiogenesis were seemingly not caused by the common angiogenesis signalling pathways, as expression and phosphorylation of AKT and ERK were not altered in EPCs from CVD patients. Conclusion: Patient-derived EPCs have characteristics similar to vascular endothelial cells and are a robust source of molecular information relevant to CVD. They may be useful in predicting disease and/or developing personalised therapies in the future

Patients without colonoscopic follow-up after abnormal fecal immunochemical tests are often unaware of the abnormal result and report several barriers to colonoscopy.

BackgroundThe fecal immunochemical test (FIT) is the second most commonly used colorectal cancer (CRC) screening modality in the United States; yet, follow-up of abnormal FIT results with diagnostic colonoscopy is underutilized. Our objective was to determine patient-reported barriers to diagnostic colonoscopy following abnormal FIT in an academic healthcare setting.MethodsWe included patients age 50-75 with an abnormal FIT result between 1/1/2015 and 10/31/2017 and no documented follow-up diagnostic colonoscopy. We abstracted demographic data from the electronic health record (EHR). Study personnel conducted telephone surveys with patients to confirm colonoscopy completion and elicit data on notification of FIT results and barriers to colonoscopy. We also provided brief verbal education about diagnostic colonoscopy. We calculated frequencies of demographic data and survey responses and compared survey responses by interest in colonoscopy after education.ResultsWe surveyed 67 patients. Fifty-one were aware of the abnormal FIT result, and a majority learned of the abnormal FIT result by direct communication with providers (19, 37.3%) or EHR messaging (11, 21.6%). Overall, fifty-three patients (79.1%) confirmed lack of colonoscopy, citing provider-related (19, 35.8%), patient-related (16, 30.2%), system-related (1, 1.9%), or multifactorial (17, 32.1%) reasons. Lack of knowledge of FIT result (14, 26.4%) was most common. After brief education, 20 (37.7%) patients requested colonoscopy.ConclusionPatients with an abnormal FIT reported various multi-level barriers to diagnostic colonoscopy after abnormal FIT, including knowledge of FIT results. When provided with brief education, participants expressed interest in diagnostic colonoscopy. Future efforts will evaluate interventions to improve colonoscopy follow-up

A new familial form of a late-onset, persistent hyperinsulinemic hypoglycemia of infancy caused by a novel mutation in KCNJ11.

The ATP-sensitive potassium channel (KATP) functions as a metabo-electric transducer in regulating insulin secretion from pancreatic β-cells. The pancreatic KATP channel is composed of a pore-forming inwardly-rectifying potassium channel, Kir6.2, and a regulatory subunit, sulphonylurea receptor 1 (SUR1). Loss-of-function mutations in either subunit often lead to the development of persistent hyperinsulinemic hypoglycemia of infancy (PHHI). PHHI is a rare genetic disease and most patients present with immediate onset within the first few days after birth. In this study, we report an unusual form of PHHI, in which the index patient developed hyperinsulinemic hypoglycemia after 1 year of age. The patient failed to respond to routine medication for PHHI and underwent a complete pancreatectomy. Genotyping of the index patient and his immediate family members showed that the patient and other family members with hypoglycemic episodes carried a heterozygous novel mutation in KCNJ11 (C83T), which encodes Kir6.2 (A28V). Electrophysiological and cell biological experiments revealed that A28V hKir6.2 is a dominant-negative, loss-of-function mutation and that KATP channels carrying this mutation failed to reach the cell surface. De novo protein structure prediction indicated that this A28V mutation reoriented the ER retention motif located at the C-terminal of the hKir6.2, and this result may explain the trafficking defect caused by this point mutation. Our study is the first report of a novel form of late-onset PHHI that is caused by a dominant mutation in KCNJ11 and exhibits a defect in proper surface expression of Kir6.2

Extracting Three-Dimensional Orientation and Tractography of Myofibers Using Optical Coherence Tomography

Abnormal changes in orientation of myofibers are associated with various cardiac diseases such as arrhythmia, irregular contraction, and cardiomyopathy. To extract fiber information, we present a method of quantifying fiber orientation and reconstructing three-dimensional tractography of myofibers using optical coherence tomography (OCT). A gradient based algorithm was developed to quantify fiber orientation in three dimensions and particle filtering technique was employed to track myofibers. Prior to image processing, three-dimensional image data set were acquired from all cardiac chambers and ventricular septum of swine hearts using OCT system without optical clearing. The algorithm was validated through rotation test and comparison with manual measurements. The experimental results demonstrate that we are able to visualize three-dimensional fiber tractography in myocardium tissues

Quality family meal times in promoting good social adjustment among adolescents

The proportion of families eating together has decreased over the years and few findings exist to examine the importance of family meal time quality and its impact on family members? well being. This study aimed to examine the relationship between the quality of family meal times and adolescents? social adjustment. In this study, the family meal is defined as the meal eaten by a person who lives in a multi-person household which takes place at home. Participants consisted of 120 students (males = 60; females = 60) aged 16-18 years old from Tawau, Sabah. The Family Meal Time Questionnaire, Family Functioning Scale (FFS) and Rosenberg Self-Esteem Scale (RSE) were administered to investigate self-esteem and perception of family functioning as mediating variables for adolescent social adjustment. Results demonstrated quality family meals were significantly related to higher levels of self-esteem (r = .318, p<.01) and better perceptions of one?s family function (r = .650, p<.01). In conclusion, family meal time may promote better adolescent?s mental health

Asian American Coping Attitudes, sources, and Practices: Implications for Indigenous Counseling Strategies

Coping attitudes, sources, and practices were assessed within and across a sample of Asian American college and graduate students from four ethnic groups: Chinese, Korean, Filipino, and Indian (N = 470). We found that Asian Americans tended to endorse coping sources and practices that emphasized talking with familial and social relations rather than professionals such as counselors and doctors. Korean Americans were significantly more likely to cope with problems by engaging in religious activities. Counseling implications are discussed