A genome-wide Asian genetic map and ethnic comparison: The GENDISCAN study

<p>Abstract</p> <p>Background</p> <p>Genetic maps provide specific positions of genetic markers, which are required for performing genetic studies. Linkage analyses of Asian families have been performed with Caucasian genetic maps, since appropriate genetic maps of Asians were not available. Different ethnic groups may have different recombination rates as a result of genomic variations, which would generate misspecification of the genetic map and reduce the power of linkage analyses.</p> <p>Results</p> <p>We constructed the genetic map of a Mongolian population in Asia with CRIMAP software. This new map, called the GENDISCAN map, is based on genotype data collected from 1026 individuals of 73 large Mongolian families, and includes 1790 total and 1500 observable meioses. The GENDISCAN map provides sex-averaged and sex-specific genetic positions of 1039 microsatellite markers in Kosambi centimorgans (cM) with physical positions. We also determined 95% confidence intervals of genetic distances of the adjacent marker intervals.</p> <p>Genetic lengths of the whole genome, chromosomes and adjacent marker intervals are compared with those of Rutgers Map v.2, which was constructed based on Caucasian populations (Centre d'Etudes du Polymorphisme Humain (CEPH) and Icelandic families) by mapping methods identical to those of the GENDISCAN map, CRIMAP software and the Kosambi map function. Mongolians showed approximately 1.9 fewer recombinations per meiosis than Caucasians. As a result, genetic lengths of the whole genome and chromosomes of the GENDISCAN map are shorter than those of Rutgers Map v.2. Thirty-eight marker intervals differed significantly between the Mongolian and Caucasian genetic maps.</p> <p>Conclusion</p> <p>The new GENDISCAN map is applicable to the genetic study of Asian populations. Differences in the genetic distances between the GENDISCAN and Caucasian maps could facilitate elucidation of genomic variations between different ethnic groups.</p

A transcriptomic analysis of serial-cultured, tonsil-derived mesenchymal stem cells reveals decreased integrin α3 protein as a potential biomarker of senescent cells

Abstract Background Mesenchymal stem cells (MSCs) have been widely used for stem cell therapy, and serial passage of stem cells is often required to obtain sufficient cell numbers for practical applications in regenerative medicine. A long-term serial cell expansion can potentially induce replicative senescence, which leads to a progressive decline in stem cell function and stemness, losing multipotent characteristics. To improve the therapeutic efficiency of stem cell therapy, it would be important to identify specific biomarkers for senescent cells. Methods Tonsil-derived mesenchymal stem cells (TMSCs) with 20–25 passages were designated as culture-aged TMSCs, and their mesodermal differentiation potentials as well as markers of senescence and stemness were compared with the control TMSCs passaged up to 8 times at the most (designated as young). A whole-genome analysis was used to identify novel regulatory factors that distinguish between the culture-aged and control TMSCs. The identified markers of replicative senescence were validated using Western blot analyses. Results The culture-aged TMSCs showed longer doubling time compared to control TMSCs and had higher expression of senescence-associated (SA)-β-gal staining but lower expression of the stemness protein markers, including Nanog, Oct4, and Sox2 with decreased adipogenic, osteogenic, and chondrogenic differentiation potentials. Microarray analyses identified a total of 18,614 differentially expressed genes between the culture-aged and control TMSCs. The differentially expressed genes were classified into the Gene Ontology categories of cellular component (CC), functional component (FC), and biological process (BP) using KEGG (Kyoto encyclopedia of genes and genomes) pathway analysis. This analysis revealed that those genes associated with CC and BP showed the most significant difference between the culture-aged and control TMSCs. The genes related to extracellular matrix-receptor interactions were also shown to be significantly different (p < 0.001). We also found that culture-aged TMSCs had decreased expressions of integrin α3 (ITGA3) and phosphorylated AKT protein (p-AKT-Ser473) compared to the control TMSCs. Conclusions Our data suggest that activation of ECM-receptor signaling, specifically involved with integrin family-mediated activation of the intracellular cell survival-signaling molecule AKT, can regulate stem cell senescence in TMSCs. Among these identified factors, ITGA3 was found to be a representative biomarker of the senescent TMSCs. Exclusion of the TMSCs with the senescent TMSC markers in this study could potentially increase the therapeutic efficacy of TMSCs in clinical applications

Cough persistence in adults with chronic cough: a 4-year retrospective cohort study

BackgroundThere is very limited evidence regarding long-term prognosis of chronic cough. We examined longitudinal outcomes among patients with chronic cough, and explored predictors of cough persistence.MethodsA retrospective cohort was constructed of adults who had newly visited a specialist cough clinic in 2012–2013. All had undergone systematic investigation for chronic cough. The Hull Airway Reflux Questionnaire (HARQ) was administered to assess reflux cough symptoms. A follow-up survey was conducted in 2016–2017 to assess cough persistence.ResultsFrom 418 candidates, 323 participated in the follow-up study; main analyses focused on patients with chronic persistent cough (n=64; 19.8%) and remitted cough (n=193; 59.8%). Compared with remitted cough, chronic persistent cough group had more family history of chronic cough (17.2% vs. 4.7%, p=0.001) and cold air-sensitive cough (62.5% vs. 44.6%, p=0.013). The total HARQ score did not differ; however, two items (cough with eating and cough with certain foods) scored significantly higher in chronic persistent cough. In multivariate analyses, a family history of chronic cough (adjusted odds ratio 4.27 [95% confidence interval 1.35-9.89]), cold air-sensitive cough (2.01 [1.09-3.73]), and cough with eating (1.22 [1.02–1.45]) were associated with chronic persistent cough at 4 years.Conclusions Cough persists in about 20% of patients after 4 years following systematic assessment and treatments. Several cough characteristics, such as family history, cold air-sensitivity, or reflux cough, may be associated with cough persistence. Larger cohort studies are warranted to further understand long-term prognosis and confirm predictors of persistence in patients with chronic cough

Cystamine induces AIF-mediated apoptosis through glutathione depletion

AbstractCystamine and its reduced form cysteamine showed protective effects in various models of neurodegenerative disease, including Huntington's disease and Parkinson's disease. Other lines of evidence demonstrated the cytotoxic effect of cysteamine on duodenal mucosa leading to ulcer development. However, the mechanism for cystamine cytotoxicity remains poorly understood. Here, we report a new pathway in which cystamine induces apoptosis by targeting apoptosis-inducing factor (AIF). By screening of various cell lines, we observed that cystamine and cysteamine induce cell death in a cell type-specific manner. Comparison between cystamine-sensitive and cystamine-resistant cell lines revealed that cystamine cytotoxicity is not associated with unfolded protein response, reactive oxygen species generation and transglutaminase or caspase activity; rather, it is associated with the ability of cystamine to trigger AIF nuclear translocation. In cystamine-sensitive cells, cystamine suppresses the levels of intracellular glutathione by inhibiting γ-glutamylcysteine synthetase expression that triggers AIF translocation. Conversely, glutathione supplementation completely prevents cystamine-induced AIF translocation and apoptosis. In rats, cysteamine administration induces glutathione depletion and AIF translocation leading to apoptosis of duodenal epithelium. These results indicate that AIF translocation through glutathione depletion is the molecular mechanism of cystamine toxicity, and provide important implications for cystamine in the neurodegenerative disease therapeutics as well as in the regulation of AIF-mediated cell death

Association between diet and gallstones of cholesterol and pigment among patients with cholecystectomy: a case-control study in Korea

Background: The prevalence of cholesterol gallstones is high in Western populations, while pigment gallstones are common in Asian populations. Dietary factors are suggested to be associated with gallstone risk, but their relationship with gallstone type has not been evaluated. This study investigated the association between diet and risk of cholesterol gallstone or pigment gallstone in a Korean population whose dietary pattern and type of gallstone were changed during the last 30 years. Methods: Patients with cholesterol (n = 40) and pigment (n = 59) gallstones were recruited after laparoscopic cholecystectomy and were compared with those of age- and sex-matched controls without gallstones (n = 99). Dietary intakes were assessed by trained dietitians using a semi-quantitative food frequency questionnaire. Multinomial logistic regression analysis was performed to calculate odds ratios and 95% confidence intervals to examine the associations between diet and risk for type of gallstones adjusted by potential confounders. Results: Patients with cholesterol gallstone consumed more lipid, animal lipid, beef, pork, and fried food than those with pigment gallstones and control, while patients with pigment gallstone consumed more carbohydrate and noodles than patients with cholesterol gallstone and control. In multinomial logistic regression analysis using control as reference group, dietary pattern with high consumption of beef, pork, and fried food was associated with risk of cholesterol gallstones, while there was no association between the risk of pigment gallstone and dietary pattern. In addition, control consumed more alcohol than patients with cholesterol and pigment gallstones. Conclusions: The present study suggested consumption of fat from meat and fried foods increased the risk of cholesterol gallstone, and intake of carbohydrate from noodles increased the risk of pigment gallstone

Could Fractional Exhaled Nitric Oxide Test be Useful in Predicting Inhaled Corticosteroid Responsiveness in Chronic Cough? A Systematic Review

© 2016 Background Fractional exhaled nitric oxide (FENO) is a safe and convenient test for assessing T H 2 airway inflammation, which is potentially useful in the management of patients with chronic cough. Objective To summarize the current evidence on the diagnostic usefulness of FENO for predicting inhaled corticosteroid (ICS) responsiveness in patients with chronic cough. Methods A systematic literature review was conducted to identify articles published in peer-reviewed journals up to February 2015, without language restriction. We included studies that reported the usefulness of FENO (index test) for predicting ICS responsiveness (reference standard) in patients with chronic cough (target condition). The data were extracted to construct a 2 × 2 accuracy table. Study quality was assessed with Quality Assessment of Diagnostic Accuracy Studies 2. Results We identified 5 original studies (2 prospective and 3 retrospective studies). We identified considerable heterogeneities in study design and outcome definitions, and thus were unable to perform a meta-analysis. The proportion of ICS responders ranged from 44% to 59%. Sensitivity and specificity ranged from 53% to 90%, and from 63% to 97%, respectively. The reported area under the curve ranged from abou t 0.60 to 0.87; however, studies with a prospective design and a lower prevalence of asthma had lower area under the curve values. None measured placebo effects or objective cough frequency. Conclusions We did not find strong evidence to support the use of FENO tests for predicting ICS responsiveness in chronic cough. Further studies need to have a randomized, placebo-controlled design, and should use validated measurement tools for cough. Standardization would facilitate the development of clinical evidence

Donepezil Regulates LPS and Aβ-Stimulated Neuroinflammation through MAPK/NLRP3 Inflammasome/STAT3 Signaling

The acetylcholinesterase inhibitors donepezil and rivastigmine have been used as therapeutic drugs for Alzheimer’s disease (AD), but their effects on LPS-and Aβ-induced neuroinflam-matory responses and the underlying molecular pathways have not been studied in detail in vitro and in vivo. In the present study, we found that 10 or 50 μM donepezil significantly decreased the LPS-induced increases in the mRNA levels of a number of proinflammatory cytokines in BV2 mi-croglial cells, whereas 50 μM rivastigmine significantly diminished only LPS-stimulated IL-6 mRNA levels. In subsequent experiments in primary astrocytes, donepezil suppressed only LPS-stimulated iNOS mRNA levels. To identify the molecular mechanisms by which donepezil regulates LPS-induced neuroinflammation, we examined whether donepezil alters LPS-stimulated proin-flammatory responses by modulating LPS-induced downstream signaling and the NLRP3 inflam-masome. Importantly, we found that donepezil suppressed LPS-induced AKT/MAPK signaling, the NLRP3 inflammasome, and transcription factor NF-kB/STAT3 phosphorylation to reduce neuroin-flammatory responses. In LPS-treated wild-type mice, a model of neuroinflammatory disease, donepezil significantly attenuated LPS-induced microglial activation, microglial density/morphol-ogy, and proinflammatory cytokine COX-2 and IL-6 levels. In a mouse model of AD (5xFAD mice), donepezil significantly reduced Aβ-induced microglial and astrocytic activation, density, and mor-phology. Taken together, our findings indicate that donepezil significantly downregulates LPS-and Aβ-evoked neuroinflammatory responses in vitro and in vivo and may be a therapeutic agent for neuroinflammation-associated diseases such as AD. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.1

Imidazole propionate ameliorates atopic dermatitis-like skin lesions by inhibiting mitochondrial ROS and mTORC2

BackgroundImidazole propionate (IMP) is a histidine metabolite produced by some gut microorganisms in the human colon. Increased levels of IMP are associated with intestinal inflammation and the development and progression of cardiovascular disease and diabetes. However, the anti-inflammatory activity of IMP has not been investigated. This study aimed to elucidate the role of IMP in treating atopic dermatitis (AD). MethodsTo understand how IMP mediates immunosuppression in AD, IMP was intraperitoneally injected into a Dermatophagoides farinae extract (DFE)/1-chloro-2,4 dinitrochlorobenzene (DNCB)-induced AD-like skin lesions mouse model. We also characterized the anti-inflammatory mechanism of IMP by inducing an AD response in keratinocytes through TNF-α/IFN-γ or IL-4 stimulation. ResultsContrary to the prevailing view that IMP is an unhealthy microbial metabolite, we found that IMP-treated AD-like skin lesions mice showed significant improvement in their clinical symptoms, including ear thickness, epidermal and dermal thickness, and IgE levels. Furthermore, IMP antagonized the expansion of myeloid (neutrophils, macrophages, eosinophils, and mast cells) and Th cells (Th1, Th2, and Th17) in mouse skin and prevented mitochondrial reactive oxygen species production by inhibiting mitochondrial energy production. Interestingly, we found that IMP inhibited AD by reducing glucose uptake in cells to suppress proinflammatory cytokines and chemokines in an AD-like in vitro model, sequentially downregulating the PI3K and mTORC2 signaling pathways centered on Akt, and upregulating DDIT4 and AMPK. DiscussionOur results suggest that IMP exerts anti-inflammatory effects through the metabolic reprogramming of skin inflammation, making it a promising therapeutic candidate for AD and related skin diseases

Corrigendum: Behavioral and Neuroimaging Evidence for Facial Emotion Recognition in Elderly Korean Adults with Mild Cognitive Impairment, Alzheimer's Disease, and Frontotemporal Dementia

Background: Facial emotion recognition (FER) is impaired in individuals with frontotemporal dementia (FTD) and Alzheimer’s disease (AD) when compared to healthy older adults. Since deficits in emotion recognition are closely related to caregiver burden or social interactions, researchers have fundamental interest in FER performance in patients with dementia.Purpose: The purpose of this study was to identify the performance profiles of six facial emotions (i.e., fear, anger, disgust, sadness, surprise, and happiness) and neutral faces measured among Korean healthy control (HCs), and those with mild cognitive impairment (MCI), AD, and FTD. Additionally, the neuroanatomical correlates of facial emotions were investigated.Methods: A total of 110 (33 HC, 32 MCI, 32 AD, 13 FTD) older adult participants were recruited from two different medical centers in metropolitan areas of South Korea. These individuals underwent an FER test that was used to assess the recognition of emotions or absence of emotion (neutral) in 35 facial stimuli. Repeated measures two-way analyses of variance were used to examine the distinct profiles of emotional recognition among the four groups. We also performed brain imaging and voxel-based morphometry (VBM) on the participants to examine the associations between FER scores and gray matter volume.Results: The mean score of negative emotion recognition (i.e., fear, anger, disgust, and sadness) clearly discriminated FTD participants from individuals with MCI and AD and HC [F(3,106) = 10.829, p 2 = 0.235], whereas the mean score of positive emotion recognition (i.e., surprise and happiness) did not. A VBM analysis showed negative emotions were correlated with gray matter volume of anterior temporal regions, whereas positive emotions were related to gray matter volume of fronto-parietal regions.Conclusion: Impairment of negative FER in patients with FTD is cross-cultural. The discrete neural correlates of FER indicate that emotional recognition processing is a multi-modal system in the brain. Focusing on the negative emotion recognition is a more effective way to discriminate healthy aging, MCI, and AD from FTD in older Korean adults.</p