YAF2 promotes TP53-mediated genotoxic stress response via stabilization of PDCD5

AbstractProgrammed cell death 5 (PDCD5) plays a crucial role in TP53-mediated apoptosis, but the regulatory mechanism of PDCD5 itself during apoptosis remains obscure. We identified YY1-associated factor 2 (YAF2) as a novel PDCD5-interacting protein in a yeast two-hybrid screen for PDCD5-interacting proteins. We found that YY1-associated factor 2 (YAF2) binds to and increases PDCD5 stability by inhibiting the ubiquitin-dependent proteosomal degradation pathway. However, knocking-down of YAF2 diminishes the levels of PDCD5 protein but not the levels of PDCD5 mRNA. Upon genotoxic stress response, YAF2 promotes TP53 activation via association with PDCD5. Strikingly, YAF2 failed to promote TP53 activation in the deletion of PDCD5, whereas restoration of wild-type PDCD5WT efficiently reversed the ineffectiveness of YAF2 on TP53 activation. Conversely, PDCD5 efficiently overcame the knockdown effect of YAF2 on ET-induced TP53 activation. Finally, impaired apoptosis upon PDCD5 ablation was substantially rescued by restoration of PDCD5WT but not YAF2-interacting defective PDCD5E4D nor TP53-interacting defective PDCD5E16D mutant. Our findings uncovered an apoptotic signaling cascade linking YAF2, PDCD5, and TP53 during genotoxic stress responses

Genetic and Metabolic Characterization of Insomnia

Insomnia is reported to chronically affect 10∼15% of the adult population. However, very little is known about the genetics and metabolism of insomnia. Here we surveyed 10,038 Korean subjects whose genotypes have been previously profiled on a genome-wide scale. About 16.5% reported insomnia and displayed distinct metabolic changes reflecting an increase in insulin secretion, a higher risk of diabetes, and disrupted calcium signaling. Insomnia-associated genotypic differences were highly concentrated within genes involved in neural function. The most significant SNPs resided in ROR1 and PLCB1, genes known to be involved in bipolar disorder and schizophrenia, respectively. Putative enhancers, as indicated by the histone mark H3K4me1, were discovered within both genes near the significant SNPs. In neuronal cells, the enhancers were bound by PAX6, a neural transcription factor that is essential for central nervous system development. Open chromatin signatures were found on the enhancers in human pancreas, a tissue where PAX6 is known to play a role in insulin secretion. In PLCB1, CTCF was found to bind downstream of the enhancer and interact with PAX6, suggesting that it can probably inhibit gene activation by PAX6. PLCB4, a circadian gene that is closely located downstream of PLCB1, was identified as a candidate target gene. Hence, dysregulation of ROR1, PLCB1, or PLCB4 by PAX6 and CTCF may be one mechanism that links neural and pancreatic dysfunction not only in insomnia but also in the relevant psychiatric disorders that are accompanied with circadian rhythm disruption and metabolic syndrome

Retrospective Analysis of Peripheral Blood Stem Cell Transplantation for the Treatment of High-Risk Neuroblastoma

Disease relapse after autologous peripheral blood stem cell transplantation (APBSCT) is the main cause of treatment failure in high-risk neuroblastoma (NBL). To reduce relapse, various efforts have been made such as CD34+ selection and double APBSCT. Here the authors reviewed the clinical features and outcomes of high-risk NBL patients and analyzed their survival. The medical records of 36 patients with stage III or IV NBL who underwent APBSCT at Seoul National University Children's Hospital between May 1996 and May 2004 were reviewed. Total 46 APBSCTs were performed in 36 patients. Disease free survival (DFS) and overall survival of all patients were 47.7% and 68.8%, respectively. The patients were allocated to three groups according to the APBSCT type. The DFS of CD34+ non-selected single APBSCT patients (N=13), CD34+ selected single APBSCT patients (N=14), and CD34+ selected double APBSCT patients (N=9) were 55.6%, 40.6%, and 50.0%, respectively, which were not significantly different. Thus the survival was not found to be affected by CD34+ selection or transplantation number. To improve long-term survival, various efforts should be made such as chemotherapy dose intensification, more effective tumor purging, and control of minimal residual disease via the use of differentiating and immune-modulating agents

The effect of non-optimal lipids on the progression of coronary artery calcification in statin-naïve young adults: results from KOICA registry

BackgroundDespite the importance of attaining optimal lipid levels from a young age to secure long-term cardiovascular health, the detailed impact of non-optimal lipid levels in young adults on coronary artery calcification (CAC) is not fully explored. We sought to investigate the risk of CAC progression as per lipid profiles and to demonstrate lipid optimality in young adults.MethodsFrom the KOrea Initiative on Coronary Artery calcification (KOICA) registry that was established in six large volume healthcare centers in Korea, 2,940 statin-naïve participants aged 20–45 years who underwent serial coronary calcium scans for routine health check-ups between 2002 and 2017 were included. The study outcome was CAC progression, which was assessed by the square root method. The risk of CAC progression was analyzed according to the lipid optimality and each lipid parameter.ResultsIn this retrospective cohort (mean age, 41.3 years; men 82.4%), 477 participants (16.2%) had an optimal lipid profile, defined as triglycerides <150 mg/dl, LDL cholesterol <100 mg/dl, and HDL cholesterol >60 mg/dl. During follow-up (median, 39.7 months), CAC progression was observed in 434 participants (14.8%), and more frequent in the non-optimal lipid group (16.5% vs. 5.7%; p < 0.001). Non-optimal lipids independently increased the risk of CAC progression [adjusted hazard ratio (aHR), 1.97; p = 0.025], in a dose-dependent manner. Even in relatively low-risk participants with an initial calcium score of zero (aHR, 2.13; p = 0.014), in their 20 s or 30 s (aHR 2.15; p = 0.041), and without other risk factors (aHR 1.45; p = 0.038), similar results were demonstrable. High triglycerides had the greatest impact on CAC progression in this young adult population.ConclusionNon-optimal lipid levels were significantly associated with the risk of CAC progression in young adults, even at low-risk. Screening and intervention for non-optimal lipid levels, particularly triglycerides, from an early age might be of clinical value

Considerations for physicians using ketamine for sedation of children in emergency departments

Objective Ketamine use in emergency departments (EDs) for procedural sedation and analgesia is becoming increasingly common. However, few studies have examined patient factors related to adverse events associated with ketamine. This study investigated factors for consideration when using ketamine to sedate pediatric ED patients. Methods The study included pediatric patients receiving ketamine for laceration repair in the ED. Before sedation, information was collected about upper respiratory tract infection symptoms, allergy history, and fasting time. Patients received 2 mg/kg ketamine intravenously or 4 mg/kg ketamine intramuscularly. The primary outcomes were adverse events due to ketamine. Results We studied 116 patients aged 8 months to 7 years (2.8±1.5 years). The group with adverse events was significantly younger on average than the group without adverse events (2.5±1.5 vs. 3.1±1.5, P=0.028). Upper respiratory tract infection symptoms were not significant variables affecting ketamine sedation (48.9% vs. 43.7%, P=0.719). There was no significant association between duration of fasting and adverse events (P=0.073 and P=0.897, respectively), or between food type and adverse events (P=0.734). However, the number of attempts to sedate and ketamine dose correlated with adverse events (P<0.001 and P=0.022, respectively). In multiple logistic regression analysis, intravenous injection and ketamine dose were significant factors (odds ratio, 16.77; 95% confidence interval, 1.78 to 498.54; odds ratio, 4.37; 95% confidence interval, 1.59 to 22.9, respectively). Conclusion Emergency medicine physicians should consider injection type and ketamine dose when using ketamine sedation while suturing lacerations

SYNGAS PRODUCTION WITH A DUAL FLUIDIZED BED GASIFIER FOR POLYGENERATION

A pilot scale dual fluidized bed gasification system was developed for polygeneration with biomass. The gasification system is designed for supplying syngas for Fischer Tropsch (F-T) synthesis of bio-diesel and power generation with a syngas engine. Characteristics of biomass steam gasification were investigated in a lab scale bubbling fluidized bed, and hydrodynamics of a dual fluidized bed were investigated in a cold flow model. Based on the results from the lab scale test and cold flow model, a pilot scale dual fluidized bed gasifier was designed. In this paper, the developing process of the gasifier and preliminary results of system operation will be presented

The association of asthma and its subgroups with osteoporosis: a cross-sectional study using KoGES HEXA data

Background A few studies have reported the association between asthma and osteoporosis. We aimed to analyze the association of asthma and its subgroups with osteoporosis in the Korean adult population. Methods We used the health examinee (HEXA) data from the Korean Genome and Epidemiology Study (KoGES) obtained between 2004 and 2016. We included 162,579 participants (n = 3,160 with asthma; n = 159,419 controls) who reported their previous histories of asthma and osteoporosis. The participants were categorized into 3 groups based on asthma management: participants who did not need further treatment due to controlled symptoms (well controlled); participants with ongoing treatment (being treated); participants who were not treated even though they had symptoms (not being treated). Multiple logistic regression analyses were used to calculate the adjusted odds ratios (aORs) with 95% confidence intervals (CIs) for osteoporosis. Subgroup analyses for age and sex were conducted. Results The prevalence of osteoporosis was higher in patients with asthma (13.6%) than in controls (6.8%). In the full-adjusted model, the aORs for osteoporosis were 1.74 (95% CI 1.55–1.94, P < 0.001) in patients with asthma compared to controls. There were consistent findings across the age and sex subgroups. The aORs for osteoporosis were 1.43 (95% CI 1.10–1.86, P = 0.008) in the well-controlled asthma group; 1.55 (95% CI 1.28–1.89, P < 0.001) in the being treated asthma group; and 1.96 (95% CI 1.66–2.31, P < 0.001) in the not being treated asthma group compared to the control group. Conclusion Asthma was associated with osteoporosis in the Korean adult population. Patients with asthma not being treated showed the highest ORs for osteoporosis.This research was funded by National Research Foundation (NRF) of Korea, grant number (NRF-2018-R1D1A1A0-2085328 by Hyo Geun Choi, NRF-2020R1G1A1005390 by Jee Hye Wee). The funding organization did not contribute to the design or conduct of this study, preparation, review, approval, or decision to submit this manuscript for publication

Suppression of STAT3 and HIF-1 Alpha Mediates Anti-Angiogenic Activity of Betulinic Acid in Hypoxic PC-3 Prostate Cancer Cells

Background: Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates various cellular processes such as cell survival, angiogenesis and proliferation. In the present study, we examined that betulinic acid (BA), a triterpene from the bark of white birch, had the inhibitory effects on hypoxia-mediated activation of STAT3 in androgen independent human prostate cancer PC-3 cells. Methodology/Principal Findings: BA inhibited the protein expression and the transcriptional activities of hypoxia-inducible factor-1a (HIF-1a) under hypoxic condition. Consistently, BA blocked hypoxia-induced phosphorylation, DNA binding activity and nuclear accumulation of STAT3. In addition, BA significantly reduced cellular and secreted levels of vascular endothelial growth factor (VEGF), a critical angiogenic factor and a target gene of STAT3 induced under hypoxia. Furthermore, BA prevented in vitro capillary tube formation in human umbilical vein endothelial cells (HUVECs) maintained in conditioned medium of hypoxic PC-3 cells, implying anti-angiogenic activity of BA under hypoxic condition. Of note, chromatin immunoprecipitation (ChiP) assay revealed that BA inhibited binding of HIF-1a and STAT3 to VEGF promoter. Furthermore, silencing STAT3 using siRNA transfection effectively enhanced the reduced VEGF production induced by BA treatment under hypoxia. Conclusions/Significance: Taken together, our results suggest that BA has anti-angiogenic activity by disturbing th

Manumycin from a new Streptomyces strain shows antagonistic effect against methicillin-resistant Staphylococcus aureus (MRSA)/vancomycin-resistant enterococci (VRE) strains from Korean Hospitals

An antimicrobial compound, highly effective against multidrug-resistant (MDR) bacteria, purified from a Streptomyces strain was identified as manumycin. The minimal inhibitory concentrations (MICs) of manumycin against 8 different strains of methicillin-resistant Staphylococcus aureus (MRSA) were ranged 2 to 32 μg/ml. Similarly, MICs of manumycin against 4 vancomycin-resistant enterococci (VRE) strains were ranged 8 to 32 μg/ml while it remained ineffective against 4 other VRE strains. Compared to vancomycin, manumycin provided slightly weaker activity against MRSA strains but stronger activity against 4 VRE strains. This is the first report of antagonistic effect of manumycin against MDR pathogens.Keywords: Manumycin, methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE)African Journal of Biotechnology Vol. 12(17), pp. 2249-225