Yoon-Jeong Kim

Genome-wide methylation profiling of the bronchial mucosa of asthmatics: relationship to atopy.

BackgroundAsthma is a common respiratory disease that is characterized by bronchial hyperresponsiveness and airway obstruction due to chronic airway inflammation. Atopic asthma is a typical IgE-mediated disease in which the enhanced production of IgE is driven by the activation of Th2 cells, which release a distinct pattern of cytokines, including interleukin 4 (IL4) and IL3, in response to specific antigen presentation. To evaluate the methylation status of the whole genomes of bronchial mucosa tissues from subjects who lacked or had sensitization to Dermatophagoides farina (Df) and Dermatophagoides pteronyssinus (Dp).MethodsThe genome-wide DNA methylation levels in the bronchial mucosa tissues of atopic asthmatics (N = 10), non-atopic asthmatics (N = 7), and normal controls (N = 7) were examined using microarrays.ResultsIn the bronchial mucosa of atopic asthmatics, hypermethylation was detected at 6 loci in 6 genes, while hypomethylation was detected at 49 loci in 48 genes compared to those of non-atopic asthmatics. Genes that were assigned the ontologies of multicellular organismal process, response to organic substance, hormone metabolic process, and growth factor receptor binding were hypomethylated. The methylation levels in the mucosa of asthmatics and normal controls were similar.ConclusionsThe bronchial mucosa of asthmatics who are atopic to Df or Dp have characteristic methylation patterns for 52 genes. The genes and pathways identified in the present study may be associated with the presence of atopy in asthmatics and therefore represent attractive targets for future research.

Age-dependent increases in tau phosphorylation in the brains of type 2 diabetic rats correlate with a reduced expression of p62

Aging increases the co-incidence of Alzheimers disease (AD) and type 2 diabetes (T2DM). However, the critical factors that contribute to the age-related increase in AD-T2DM comorbidity have yet to be clarified. In this study, aging effects and their relationship to AD-related pathology and T2DM as well as the underlying mechanisms of this process were investigated using obese rats with chronic T2DM. Tau pathology and its associated signaling pathways in the brain were compared between Otsuka Long-Evans Tokushima Fatty (OLETF) rats and corresponding non-diabetic controls at various ages. Tau phosphorylation at AD-related epitopes, including Thr212, Thr231, Ser262, and Ser396, increased with age in the soluble brain extracts of chronic OLETF rats and were accompanied by synaptic protein loss. There was also a marked age-dependent accumulation of polyubiquitinated substances in diabetic rats. Accordingly, tau proteins were highly polyubiquitinated in aged OLETF rats and a strong degree of co-localization existed between p-tau and ubiquitin in these neurons. In addition, the mRNA and protein levels of p62, a known cargo molecule that transports polyubiquitinated tau to proteasomal and autophagic degradation systems, decreased robustly with age in OLETF rats and there was an inverse correlation between protein levels of p62 and p-tau. The impaired degradation of polyubiquitinated p-tau due to age- and T2DM-dependent decreases in p62 transcription is a primary mechanism underlying increased AD-like pathology in a T2DM rat model as age increases. These results provide novel insight into the mechanisms supporting the age-related increase in AD-T2DM comorbidity.

A Highly Sensitive and Specific Genetic Marker to Diagnose Aspirin-Exacerbated Respiratory Disease Using a Genome-Wide Association Study

The aim of the present study was to develop a diagnostic set of single-nucleotide polymorphisms (SNPs) for discriminating aspirin-exacerbated respiratory disease (AERD) from aspirin-tolerant asthma (ATA) using the genome-wide association study (GWAS) data; the GWAS data were filtered according to p-values and odds ratios (ORs) using PLINK software, and the 10 candidate SNPs most closely associated with AERD were selected, based on 100 AERD and 100 ATA subjects. Using multiple logistic regression and receiver-operating characteristic (ROC) curve analysis, eight SNPs were chosen as the best model for distinguishing between AERD and ATA. The relative risk for AERD in each subject was calculated based on the relative risk of each of the eight SNPs. Ten of the original 109,365 SNPs highly associated (filtered with p<0.001 and ORs) with the risk for AERD were selected. A combination model of the eight SNPs among the 10 SNPs showed the highest area under the ROC curve of 0.9. The overall relative risk for AERD based on the eight SNPs was significantly different between the AERD and ATA groups (p=2.802E-21), and the sensitivity and specificity were 78% and 88%, respectively. The candidate set of eight SNPs may be useful in predicting the risk for AERD.

The relationship between cognitive performance and insulin resistance in non‐diabetic patients with mild cognitive impairment

Insulin resistance (IR) is a distinct and early feature of type 2 diabetes mellitus and metabolic syndrome. IR is thought to play a vital role in cognitive impairment. We conducted this study to understand the early characteristics of cognitive dysfunctions attributable to IR.

Genetic effect of single-nucleotide polymorphisms in the PPARGC1B gene on airway hyperreactivity in asthmatic patients.

Background Peroxisome proliferator‐activated receptor gamma coactivator 1 beta (PPARGC1B) is a co‐activator for intracellular receptors such as the estrogen receptor, PPAR, and glucocorticoid receptor, which are involved in asthma development.

Asp664 cleavage of amyloid precursor protein induces tau phosphorylation by decreasing protein phosphatase 2A activity.

Caspase cleavage of amyloid precursor protein (APP) has been reported to be important in amyloid beta protein (Aβ)‐mediated neurotoxicity. However, the underlying mechanisms are not clearly understood. In this study, we explored the effect of caspase cleavage of APP on tau phosphorylation in relation to Aβ. We found that Asp664 cleavage of APP increased tau phosphorylation at Thr212 and Ser262 in N2A cells and primary cultured hippocampal neurons. Compared with wild‐type APP, protein phosphatase 2A (PP2A) activity was significantly increased when Asp664 cleavage was blocked by the D664A point mutation. Furthermore, we found that over‐expression of C31 reduced PP2A activity. C31 binds directly to the PP2A catalytic subunit, through the asparagine, proline, threonine, tyrosine (NPTY) motif, which is essential for C31‐induced tau hyperphosphorylation. However, it appears that the other fragment produced by Asp664 cleavage, Jcasp, modulates neither PP2A activity nor tau hyperphosphorylation. Asp664 cleavage and accompanying tau hyperphosphorylation were remarkably diminished by blockage of Aβ production using a γ‐secretase inhibitor. Taken together, our results suggest that Asp664 cleavage of APP leads to tau hyperphosphorylation at specific epitopes by modulating PP2A activity as a downstream of Aβ. Direct binding of C31 to PP2A through the C31‐NPTY domain was identified as a mechanism underlying this effect.

A genetic screen of the mutations in the Korean patients with early-onset Alzheimer’s disease

Early-onset Alzheimer’s disease (EOAD) has distinct clinical characteristics in comparison to late-onset Alzheimer’s disease (LOAD). The genetic contribution is suggested to be more potent in EOAD. However, the frequency of causative mutations in EOAD could be variable depending on studies. Moreover, no mutation screening study has been performed yet employing large population in Korea. Previously, we reported that the rate of family history of dementia in EOAD patients was 18.7% in a nationwide hospital-based cohort study, the Clinical Research Center for Dementia of South Korea (CREDOS) study. This rate is much lower than in other countries and is even comparable to the frequency of LOAD patients in our country. To understand the genetic characteristics of EOAD in Korea, we screened the common Alzheimer’s disease (AD) mutations in the consecutive EOAD subjects from the CREDOS study from April 2012 to February 2014. We checked the sequence of APP (exons 16–17), PSEN1 (exons 3–12), and PSEN2 (exons 3–12) genes. We identified different causative or probable pathogenic AD mutations, PSEN1 T116I, PSEN1 L226F, and PSEN2 V214L, employing 24 EOAD subjects with a family history and 80 without a family history of dementia. PSEN1 T116I case demonstrated autosomal dominant trait of inheritance, with at least 11 affected individuals over 2 generations. However, there was no family history of dementia within first-degree relation in PSEN1 L226F and PSEN2 V214L cases. Approximately, 55.7% of the EOAD subjects had APOE ε4 allele, while none of the mutation-carrying subjects had the allele. The frequency of genetic mutation in this study is lower compared to the studies from other countries. The study design that was based on nationwide cohort, which minimizes selection bias, is thought to be one of the contributors to the lower frequency of genetic mutation. However, the possibility of the greater likeliness of earlier onset of sporadic AD in Korea cannot be excluded. We suggest early AD onset and not carrying APOE ε4 allele are more reliable factors for predicting an induced genetic mutation than the presence of the family history in Korean EOAD population.

Stable Logic Operation of Fiber-Based Single-Walled Carbon Nanotube Transistor Circuits Toward Thread-Like CMOS Circuitry

A fiber-based single-walled carbon nanotube (SWCNT) thin-film-transistor (TFT) has been proposed. We designed complementary SWCNT TFT circuit based on SPICE simulations, with device parameters extracted from the fabricated fiber-based SWCNT TFTs, such as threshold voltage, contact resistance, and off-/gate-leakage current. We fabricated the SWCNTs CMOS inverter circuits using the selective passivation and n-doping processes on a fiber substrate. By comparing the simulation and experimental results, we could enhance the circuit’s performance by tuning the threshold voltage between p-type and n-type TFTs, reducing the source/drain contact resistance and off current level, and maintaining a low output capacitance of the TFTs. Importantly, it was found that the voltage gain, output swing range, and frequency response of the fiber-based inverter circuits can be dramatically improved.

Particle stimulation dephosphorylates glutathione S-transferase pi 1 of epithelial cells

Environmental pollutant exposure is associated with adverse respiratory outcomes. The phosphorylation of enzymes activates or deactivates many cellular processes and is related to the development of lung diseases such as asthma and chronic obstructive pulmonary disease. However, little is known about protein phosphorylation of bronchial epithelial cells in response to airborne particulates. Herein, we screened differentially phosphorylated proteins in TiO₂-treated epithelial cells and validated the change in GSTP1 protein phosphorylation. Two-dimensional electrophoresis was adopted for differential display proteomics of TiO₂-treated BEAS-2B cell lysates. Phosphoproteins were screened using Pro-Q® Diamond phosphoprotein gel stain and identified by MALDI-TOF/TOF analysis. Immunoprecipitation and immunoblotting were performed for quantitative measurement of GSTP1 phosphorylation in cell lysates. Normalized relative intensities of nine phosphorylated proteins increased after TiO₂ treatment, whereas those of 12 proteins decreased in the BEAS-2B cell lysates. From gene ontology and pathway analysis, proteins involved in signal transduction were commonly identified, followed by cytoskeletal proteins, proteins from oxidation and antioxidation pathways, proteins catalyzing reductions, and those involved in cellular process, transport, and modification. Immunoblotting with anti-GSTP1 antibody demonstrated no change in GSTP1 protein levels in the lysates of BEAS-2B cells after treatment with TiO₂ particles; blotting with anti-phosphoserine and anti-phosphotyrosine antibodies showed dose-dependent decreases in phosphoserine and phosphotyrosine proteins. Stimulation with particulates phosphorylated and dephosphorylated several proteins in epithelial cells, and serine and tyrosine protein phosphorylation of GSTP1 decreased. These data indicate that airborne particles affect the pattern of phosphorylation of proteins involved in defense or apoptosis of respiratory epithelium.