Mechanisms of Tail-Anchored Membrane Protein Targeting and Insertion.

Proper localization of membrane proteins is essential for the function of biological membranes and for the establishment of organelle identity within a cell. Molecular machineries that mediate membrane protein biogenesis need to not only achieve a high degree of efficiency and accuracy, but also prevent off-pathway aggregation events that can be detrimental to cells. The posttranslational targeting of tail-anchored proteins (TAs) provides tractable model systems to probe these fundamental issues. Recent advances in understanding TA-targeting pathways reveal sophisticated molecular machineries that drive and regulate these processes. These findings also suggest how an interconnected network of targeting factors, cochaperones, and quality control machineries together ensures robust membrane protein biogenesis.

NOS2 and S-nitrosothiol signaling induces DNA hypomethylation and LINE-1 retrotransposon expression.

Inducible nitric oxide synthase (NOS2) produces high local concentrations of nitric oxide (NO), and its expression is associated with inflammation, cellular stress signals, and cellular transformation. Additionally, NOS2 expression results in aggressive cancer cell phenotypes and is correlated with poor outcomes in patients with breast cancer. DNA hypomethylation, especially of noncoding repeat elements, is an early event in carcinogenesis and is a common feature of cancer cells. In addition to altered gene expression, DNA hypomethylation results in genomic instability via retrotransposon activation. Here, we show that NOS2 expression and associated NO signaling results in substantial DNA hypomethylation in human cell lines by inducing the degradation of DNA (cytosine-5)­methyltransferase 1 (DNMT1) protein. Similarly, NOS2 expression levels were correlated with decreased DNA methylation in human breast tumors. NOS2 expression and NO signaling also resulted in long interspersed noncoding element 1 (LINE-1) retrotransposon hypomethylation, expression, and DNA damage. DNMT1 degradation was mediated by an NO/p38-MAPK/lysine acetyltransferase 5­dependent mechanism. Furthermore, we show that this mechanism is required for NO-mediated epithelial transformation. Therefore, we conclude that NOS2 and NO signaling results in DNA damage and malignant cellular transformation via an epigenetic mechanism.

Orientation-Guided Immobilization of Probe DNA on swCNT-FET for Enhancing Sensitivity of EcoRV Detection.

We present a novel approach that integrates electrical measurements with molecular dynamics (MD) simulations to assess the activity of type-II restriction endonucleases, specifically EcoRV. Our approach employs a single-walled carbon nanotube field-effect transistor (swCNT-FET) functionalized with the EcoRV substrate DNA, enabling the detection of enzymatic cleavage events. Notably, we leveraged the methylene blue (MB) tag as an "orientation guide" to immobilize the EcoRV substrate DNA in a specific direction, thereby enhancing the proximity of the DNA cleavage reaction to the swCNT surface and consequently improving the sensitivity in EcoRV detection. We conducted computational modeling to compare the conformations and electrostatic potential (ESP) of MB-tagged DNA with its MB-free counterpart, providing strong support for our electrical measurements. Both conformational and ESP simulations exhibited robust agreement with our experimental data. The inhibitory efficacy of the EcoRV inhibitor aurintricarboxylic acid (ATA) was also evaluated, and the selectivity of the sensing device was examined.

Particulate matter exposure during pregnancy increases risk of childhood asthma: modified by gender and NRF2 genotype.

BACKGROUND: Exposure to particulate matter (PM) has been known to develop asthma in children and the oxidative stress-related mechanisms are suggested. For the development of asthma, not only the exposure dose but also the critical window and the risk modifying factors should be evaluated. OBJECTIVE: We investigated whether prenatal exposure to PM10 increases the risk of childhood asthma and evaluated the modifying factors, such as gender and reactive oxidative stress-related gene. METHODS: A general population-based birth cohort, the Panel Study of Korean Children (PSKC), including 1572 mother-baby dyads was analyzed. Children were defined to have asthma at age 7 when a parent reported physician-diagnosed asthma. Exposure to PM10 during pregnancy was estimated by land-use regression models based on national monitoring system. TaqMan method was used for genotyping nuclear factor, erythroid 2-related factor, NRF2 (rs6726395). A logistic Bayesian distributed lag interaction model (BDLIM) was used to evaluate the associations between prenatal PM10 exposure and childhood asthma by gender and NRF2. RESULTS: Exposure to PM10 during pregnancy was associated with the development of asthma (aOR 1.03, 95% CI 1.001.06). Stratifying by gender and NRF2 genotype, exposure to PM10 during 26-28 weeks gestation increased the risk of childhood asthma, especially in boys with NRF2 GG genotype. CONCLUSIONS: A critical window for PM10 exposure on the development of childhood asthma was during 26-28 weeks of gestation, and this was modified by gender and NRF2 genotype.

The association between MTHFR polymorphism, dietary methyl donors, and childhood asthma and atopy.

BACKGROUND: Studies investigating the genetic association of the C677T methylenetetrahydrofolate reductase (MTHFR) genotype and dietary methyl donors with asthma and atopy are limited, and have variable results. OBJECTIVE: To investigate the effect of dietary methyl donor intake on the risk of childhood asthma and atopy, based on the C677T polymorphism in the MTHFR gene. METHODS: This cross-sectional study included 2,333 elementary school children aged 6-8 years across Korea during 2005 and 2006, as part of the first Children's Health and Environmental Research survey. Genotyping for the MTHFR (rs1801133) polymorphism was performed using the TaqMan assay. Multivariable-adjusted logistic regression analysis was performed to determine a descriptive association between the dietary methyl donor intake, MTHFR polymorphism, and childhood asthma and atopy. RESULTS: Intake of dietary methyl donors like folates was significantly associated with a decreased risk of the wheezing symptom, in the past 12 months, and "ever asthma" diagnosis, respectively. Vitamin B6 intake was also associated with a decreased atopy risk. The T allele of the MTHFR (rs1801133) gene was significantly associated with a decreased risk of atopy. Increased intakes of folate, vitamin B2, and vitamin B6 were protective factors against atopy, especially in children with the T allele on the MTHFR gene, compared to those with lower intakes and the CC genotype. CONCLUSIONS: High intakes of dietary methyl donors were associated with reduced risk of atopy and asthma symptoms. These may have additive effects related to the susceptibility alleles of the MTHFR gene. The clinical implications require evaluation.

J-domain proteins promote client relay from Hsp70 during tail-anchored membrane protein targeting.

J-domain proteins (JDPs) play essential roles in Hsp70 function by assisting Hsp70 in client trapping and regulating the Hsp70 ATPase cycle. Here, we report that JDPs can further enhance the targeting competence of Hsp70-bound client proteins during tail-anchored protein (TA) biogenesis. In the guided-entry-of-tail-anchored protein pathway in yeast, nascent TAs are captured by cytosolic Hsp70 and sequentially relayed to downstream chaperones, Sgt2 and Get3, for delivery to the ER. We found that two JDPs, Ydj1 and Sis1, function in parallel to support TA targeting to the ER in vivo. Biochemical analyses showed that, while Ydj1 and Sis1 differ in their ability to assist Hsp70 in TA trapping, both JDPs enhance the transfer of Hsp70-bound TAs to Sgt2. The ability of the JDPs to regulate the ATPase cycle of Hsp70 is essential for enhancing the transfer competence of Hsp70-bound TAs in vitro and for supporting TA insertion in vivo. These results demonstrate a role of JDPs in regulating the conformation of Hsp70-bound clients during membrane protein biogenesis.

Substrate relay in an Hsp70-cochaperone cascade safeguards tail-anchored membrane protein targeting.

Membrane proteins are aggregation-prone in aqueous environments, and their biogenesis poses acute challenges to cellular protein homeostasis. How the chaperone network effectively protects integral membrane proteins during their post-translational targeting is not well understood. Here, biochemical reconstitutions showed that the yeast cytosolic Hsp70 is responsible for capturing newly synthesized tail-anchored membrane proteins (TAs) in the soluble form. Moreover, direct interaction of Hsp70 with the cochaperone Sgt2 initiates a sequential series of TA relays to the dedicated TA targeting factor Get3. In contrast to direct loading of TAs to downstream chaperones, stepwise substrate loading via Hsp70 maintains the solubility and targeting competence of TAs, ensuring their efficient delivery to the endoplasmic reticulum (ER). Inactivation of cytosolic Hsp70 severely impairs TA translocation in vivo Our results demonstrate a new role of cytosolic Hsp70 in directly assisting the targeting of an essential class of integral membrane proteins and provide a paradigm for how "substrate funneling" through a chaperone cascade preserves the conformational quality of nascent membrane proteins during their biogenesis.

Food allergy in early childhood increases the risk of oral allergy syndrome in schoolchildren: A birth cohort study.

BACKGROUND: The level of pollen in Korea has increased over recent decades. Research suggests that oral allergy syndrome (OAS) may be more frequent in childhood than previously recognized. We aimed to investigate the prevalence and characteristics of OAS in children aged 6-10 years from a general-population-based birth cohort. METHODS: We analyzed 930 children from the cohort for childhood origin of asthma and allergic diseases (COCOA). Allergic diseases were diagnosed annually by pediatric allergists. The skin prick tests were performed with 14 common inhalant allergens and four food allergens for the general population of children aged 3 and 7 years. RESULTS: Of the 930 eligible children, 44 (4.7%) aged 6-10 years were diagnosed with OAS. The mean age at onset was 6.74 years. OAS prevalence was 7.2% among children with allergic rhinitis (AR) and 19.1% among those with pollinosis, depending on comorbidity. OAS was more prevalent in schoolchildren with atopic dermatitis, food allergy, and sensitization to food allergens and grass pollen in early childhood. In schoolchildren with AR, only a history of food allergy until the age of 3 years increased the risk of OAS (aOR 2.971, 95% CI: 1.159-7.615). CONCLUSION: Food allergy and food sensitization in early childhood were associated with OAS in schoolchildren with AR. Further study is required to elucidate the mechanism by which food allergy in early childhood affects the development of OAS.

A method for early diagnosis of lung cancer from tumor originated DNA fragments using plasma cfDNA methylome and fragmentome profiles.

Early detection is critical for minimizing mortality from cancer. Plasma cell-free DNA (cfDNA) contains the signatures of tumor DNA, allowing us to quantify the signature and diagnose early-stage tumors. Here, we report a novel tumor fragment quantification method, TOF (Tumor Originated Fragment) for the diagnosis of lung cancer by quantifying and analyzing both the plasma cfDNA methylation patterns and fragmentomic signatures. TOF utilizes the amount of ctDNA predicted from the methylation density information of each cfDNA read mapped on 6243 lung-tumor-specific CpG markers. The 6243 tumor-specific markers were derived from lung tumor tissues by comparing them with corresponding normal tissues and healthy blood from public methylation data. TOF also utilizes two cfDNA fragmentomic signatures: 1) the short fragment ratio, and 2) the 5' end-motif profile. We used 298 plasma samples to analyze cfDNA signatures using enzymatic methyl-sequencing data from 201 lung cancer patients and 97 healthy controls. The TOF score showed 0.98 of the area under the curve in correctly classifying lung cancer from normal samples. The TOF score resolution was high enough to clearly differentiate even the early-stage non-small cell lung cancer patients from the healthy controls. The same was true for small cell lung cancer patients.

Simply structured polarization-independent high efficiency multilayer dielectric gratings.

A polarization-independent multilayer dielectric diffraction grating with a low aspect ratio and high diffraction efficiency was designed and fabricated. The diffraction grating designed with a grating density of 1200 lines/mm had an aspect ratio of 0.59, mean polarization-independent diffraction efficiency in the Littrow angle of ±2.5∘, and 1030-1080 nm wavelength range of 97.2%. The designed grating was fabricated using ion assisted deposition and reactive ion etching techniques. The mean polarization-independent diffraction efficiency of the fabricated grating was 96.1%, and its standard deviation was 0.68%. The fabricated diffraction grating was irradiated with a 1064 nm cw laser, with a power density of 30kW/cm2, for 1 min to measure the temperature change before and after the laser application. It was verified that the temperature variation of the diffraction grating without heat treatment was 8.8°C, and the temperature variation after heat treatment at 400°C decreased to 2.3°C.

Mid-pregnancy PM2.5 exposure affects sex-specific growth trajectories via ARRDC3 methylation.

Prenatal particulate matter <2.5 µm (PM2.5) is associated with adverse birth growth. However, the longitudinal growth impacts have been little studied, and no mechanistic relationships have been described. We investigated the association between prenatal PM2.5 exposure and growth trajectories, and the possible role of epigenetics. We enrolled 1313 neonates with PM2.5 data measured by ordinary kriging from the COhort for Childhood Origin of Asthma and allergic diseases, followed up at 1, 3, and 5 years to evaluate growth. Differential DNA methylation and pyrosequencing of cord blood leukocytes was evaluated according to the prenatal PM2.5 levels and birth weight (BW). PM2.5 exposure during the second trimester (T2) caused the lowest BW in both sexes, further adjusted for indoor PM2.5 levels [female, aOR 1.39 (95% CI 1.05-1.83); male, aOR 1.36 (95% CI 1.04-1.79)]. Bayesian distributed lag models with indoor PM2.5 adjustments revealed a sensitive window for BW effects at 10-26 weeks gestation, but only in females. Latent class mixture models indicated that a persistently low weight-for-height percentile trajectory was more prevalent in the highest PM2.5 exposure quartile at T2 in females, compared to a persistently high trajectory (36.5% vs. 20.3%, P = 0.022). Also, in the females only, the high PM2.5 and low BW neonates showed significantly greater ARRDC3 methylation changes. ARRDC3 methylation was also higher only in females with low weight at 5 years of age. Higher fetal PM2.5 exposure during T2 may cause a decreased growth trajectory, especially in females, mediated by ARRDC3 hyper-methylation-associated energy metabolism.

Zero lock-in implementation by phase wrapping/unwrapping in a ring laser gyroscope.

The main factors that limit the performance of ring laser gyroscopes include random walk, quantization noise, and bias stability. The first two factors determine the alignment time for navigation systems, and the bias stability error can result in long-term accuracy. We show that a phase wrapping/unwrapping algorithm, which has been widely used in interferometry fields, can be utilized to remove lock-in and quantization errors by implementing a zero-lock-in ring laser gyroscope. Furthermore, the performance of the ring laser gyroscope with no mechanical dither is described, and mirror dithering, instead of mechanical dithering, is proposed.

Differential Clearance of Aß Species from the Brain by Brain Lymphatic Endothelial Cells in Zebrafish.

The failure of amyloid beta (Aß) clearance is a major cause of Alzheimer's disease, and the brain lymphatic systems play a crucial role in clearing toxic proteins. Recently, brain lymphatic endothelial cells (BLECs), a non-lumenized lymphatic cell in the vertebrate brain, was identified, but Aß clearance via this novel cell is not fully understood. We established an in vivo zebrafish model using fluorescently labeled Aß42 to investigate the role of BLECs in Aß clearance. We discovered the efficient clearance of monomeric Aß42 (mAß42) compared to oligomeric Aß42 (oAß42), which was illustrated by the selective uptake of mAß42 by BLECs and peripheral transport. The genetic depletion, pharmacological inhibition via the blocking of the mannose receptor, or the laser ablation of BLECs resulted in the defective clearance of mAß42. The treatment with an Aß disaggregating agent facilitated the internalization of oAß42 into BLECs and improved the peripheral transport. Our findings reveal a new role of BLECs in the differential clearance of mAß42 from the brain and provide a novel therapeutic strategy based on promoting Aß clearance.

Association between sensitization and allergic diseases in 7-years-old Korean children.

BACKGROUND: Sensitization is associated with the exacerbation, severity, and prognosis of allergic diseases in children. OBJECTIVE: We characterized the association between sensitization patterns and allergic diseases. METHODS: A cohort of 548 children was enrolled from Panel Study of Korean Children (PSKC) study. Skin prick tests (SPTs) for 18 common allergens, blood tests, and methacholine bronchial challenge tests were performed at age 7. The Korean version of International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire was used. RESULTS: The sensitization rate on SPTs was 46.4%. Sensitization to indoor allergens showed an association with symptoms of asthma (adjusted odds ratio [aOR], 2.39; 95% confidence intervals [95% CIs], 1.10-5.23), allergic rhinitis (AR, aOR 2.08, 95% CIs 1.42-3.06), and atopic dermatitis (AD, aOR 2.36, 95% CIs 1.24-4.50) in the preceding 12 months. In contrast, sensitization to outdoor allergens was associated with AR diagnosis only (aOR 2.40, 95% CIs 1.30-4.41). The number of sensitized allergens was associated with a lifetime diagnosis and symptoms in the preceding 12 months of AR and asthma, but not with AD or BHR. A higher degree of sensitization to indoor allergens was associated with symptoms in the preceding 12 months of asthma, AR, AD, and that for outdoor allergens was associated with symptoms in the prior 12 months of asthma and AR. CONCLUSIONS: The sensitization patterns including allergen type, number, and degree of sensitization are helpful for interpreting the association between sensitization and allergic diseases and identifying the pathophysiologies and diverse phenotypes of allergic diseases.

Vegetable dietary pattern may protect mild and persistent allergic rhinitis phenotype depending on genetic risk in school children.

BACKGROUND: The effect of diet on allergic rhinitis (AR), its severity in children, and whether it modifies AR depending on genetic susceptibility are unknown. We investigated the association between dietary patterns and AR in school children and the influence of diet on AR according to a genetic risk score (GRS). METHODS: Totally, 435 7-year-old school children were recruited from the Panel Study on Korean Children. We used dietary patterns (vegetable, sugar, and meat) and dietary inflammatory index (DII) as dietary parameters. AR and its severity were defined by questionnaires about treatment in the previous 12 months and the Allergic Rhinitis and its Impact on Asthma (ARIA) guideline, respectively. A GRS was calculated using 6 single nucleotide polymorphisms for allergic diseases. RESULTS: A vegetable diet containing a lot of anti-inflammatory nutrients and higher vitamin D level in blood were negatively correlated, while DII was positively correlated with triglyceride level and triglyceride/HDL cholesterol. Vegetable diet (aOR, 95% CI = 0.73, 0.58-0.94) and DII (1.13, 1.01-1.28) were associated with AR risk. In particular, a high-vegetable diet resulted in a lower risk of mild and persistent AR (aOR, 95% CI = 0.24, 0.10-0.56) while a high DII represented a higher risk (2.33, 1.06-5.10). The protective effect of vegetable diet on AR appeared only among children with a lower GRS (adjusted P = .018). CONCLUSIONS: A vegetable dietary pattern characterized by high intake of anti-inflammatory nutrients and higher vitamin D level in blood might be associated with a lower risk of mild and persistent AR. This beneficial effect is modified by a genetic factor.

Prenatal PM2.5 exposure and vitamin D-associated early persistent atopic dermatitis via placental methylation.

BACKGROUND: The effects of prenatal particulate matter with an aerodynamic diameter ranging from 0.1 µm to 2.5 µm (PM2.5) and vitamin D on atopic dermatitis (AD) phenotypes have not been evaluated. DNA methylation and cord blood (CB) vitamin D could represent a plausible link between prenatal PM2.5 exposure and AD in an offspring. OBJECTIVE: To determine the critical windows of prenatal PM2.5 exposure on the AD phenotypes, if vitamin D modulated these effects, and if placental DNA methylation mediated these effects on AD in offspring. METHODS: Mother-child pairs were enrolled from the birth cohort of the Cohort for Childhood Origin of Asthma and allergic diseases (COCOA) study. PM2.5 was estimated by land-use regression models, and CB vitamin D was measured by chemiluminescence immunoassay. AD was identified by the parental report of a physician's diagnosis. We defined the following 4 AD phenotypes according to onset age (by the age of 2 years) and persistence (by the age of 3 years): early-onset transient and persistent, late onset, and never. Logistic regression analysis and Bayesian distributed lag interaction model were used. DNA methylation microarray was analyzed using an Infinium Human Methylation EPIC BeadChip (Illumina, San Diego, California) in placenta. RESULTS: PM2.5 exposure during the first trimester of pregnancy, especially during 6 to 7 weeks of gestation, was associated with early-onset persistent AD. This effect increased in children with low CB vitamin D, especially in those with PM2.5 exposure during 3 to 7 weeks of gestation. AHRR (cg16371648), DPP10 (cg19211931), and HLADRB1 (cg10632894) were hypomethylated in children with AD with high PM2.5 and low CB vitamin D. CONCLUSION: Higher PM2.5 during the first trimester of pregnancy and low CB vitamin D affected early-onset persistent AD, and the most sensitive window was 6 to 7 weeks of gestation. Placental DNA methylation mediated this effect.

Identification of Adult Mesodermal Progenitor Cells and Hierarchy in Atherosclerotic Vascular Calcification.

The nature of calcifying progenitor cells remains elusive. In this study, we investigated the developmental hierarchy and dynamics of progenitor cells. In vitro and in vivo reconstitution assays demonstrated that Sca-1+/PDGFRα- cells in the bone marrow (BM) are the ancestors of Sca-1+/PDGFRα+ cells. Cells of CD29 + Sca-1+/PDGFRα- lineage in the BM showed both hematopoietic potential with osteoclastic differentiation ability as well as mesenchymal stem cell-like properties with osteoblastic differentiation potential. Clonally-isolated BM-derived artery-infiltrated Sca-1+/PDGFRα- cells maintained osteoblastic/osteoclastic bipotency but lost hematopoietic activity. In hypercholesterolemic apolipoprotein-E-deficient (Apoe-/-) mice, the mobilization from BM to peripheral circulation, followed by migration into atherosclerotic plaques of Sca-1+/PDGFRα- cells, but not Sca-1+/PDGFRα+ cells, were significantly decreased, and Interleukin-1ß (IL-1ß) and Interleukin-5 (IL-5) mediated this response. Here, we demonstrated that Sca-1+/PDGFRα- cells are mesodermal progenitor cells in adults, and the dynamics of progenitor cells were regulated by atherosclerosis-related humoral factors. These results may contribute to better understanding of vascular homeostasis and assist in the development of novel therapies for atherosclerosis. Stem Cells 2018;36:1075-1096.

Prenatal particulate matter affects new asthma via airway hyperresponsiveness in schoolchildren.

BACKGROUND: The most relevant time of PM10 exposure to affect airway hyperresponsiveness (AHR) and new development of asthma in school-aged children is unclear. The aims of this study were to investigate the most critical time of PM10 exposure to affect AHR and new diagnosis of asthma from AHR in school-aged children. METHODS: Elementary schoolchildren (n = 3570) have been enrolled in a nationwide prospective 4-year follow-up survey in Korea from 2005 to 2006. Individual annual PM10 exposure was estimated by using an ordinary kriging method from the prenatal period to 7 years of age. AHR at 7 years was defined by a methacholine PC20 ≤8 mg/mL. RESULTS: PM10 exposure during pregnancy and at 1 year of age showed significant effects on AHR (aOR: 1.694, 95% CI: 1.298-2.209; and aOR: 1.750, 95% CI: 1.343-2.282, respectively). PM10 exposure during pregnancy was associated with the risk of a new diagnosis of asthma (aOR: 2.056, 95% CI: 1.240-3.409), with the highest risk in children with AHR at age 7 (aOR: 6.080, 95% CI: 2.150-17.195). PM10 exposure in the second trimester was associated with the highest risk of a new diagnosis of asthma in children with AHR at age 7 (aOR: 4.136, 95% CI: 1.657-10.326). CONCLUSIONS: Prenatal PM10 exposure in the second trimester is associated with an increased risk of a new diagnosis of asthma in school-aged children with AHR at 7 years. This study suggests that PM10 exposure during a specific trimester in utero may affect the onset of childhood asthma via AHR.

Early-life exposure to humidifier disinfectant determines the prognosis of lung function in children.

BACKGROUND: Use of humidifier disinfectants (HD) at home leads to chemical airborne exposure, causing HD associated lung injury (HDLI) with high mortality. However, the lung function in children diagnosed with HDLI is not well studied. We investigated the effect of HD exposure on lung function, prognosis, and exposure characteristics associated with the lung function phenotype in children. METHODS: Eighty-one children diagnosed with HDLI in a nationwide cohort were tested for spirometry and diffusing capacity of the lung for carbon monoxide (DLco) from July 2013 and followed up with at five time points over 2 years. The results were compared with 122 children without HD exposure as controls. Home investigation and questionnaire analysis were conducted to assess HD inhalation exposure. RESULTS: HDLI survivor's mean percent of predicted forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and corrected DLco were significantly lower compared with the control group. On longitudinal assessment, FVC was within the normal range, but flattened, and spirometry showed a predominantly restrictive pattern. Corrected DLco did not normalize above 80% despite increasing age. The persistently low phenotype of lung function was associated with initial exposure age, especially less than 12 months of age. Higher density HD exposure during sleep and close distance between the bed and the humidifier were significantly associated with persistently low corrected DLco. CONCLUSIONS: HD exposure affects prolonged decrement in lung function, especially DLco, particularly among children who are exposed within the first year of life. These results suggested that early-life HD exposure determines long-term prognosis of lung function in children.

Clinical phenotypes of bronchial hyperresponsiveness in school-aged children.

BACKGROUND: Bronchial hyperresponsiveness (BHR), one of the key features of asthma, has a diverse natural course in school-aged children, but studies on BHR phenotypes are lacking. OBJECTIVE: To classify BHR phenotypes according to onset age and persistence in children and investigate the characteristics and factors associated with each phenotype in a longitudinal study. METHODS: This study analyzed 1,305 elementary school children from the Children's Health and Environmental Research (CHEER) study, a 4-year, prospective, follow-up study with 2-year intervals starting at a mean age of 7years. Total serum IgE levels and blood eosinophil counts were measured, and allergy workup, including methacholine challenge tests with the International Study of Asthma and Allergies in Childhood questionnaire, was performed at each survey. RESULTS: The 4 BHR phenotypes were classified as non-BHR (n = 942 [72.2%]), early-onset transient BHR (n = 201 [15.4%]), late-onset BHR (n = 87 [6.7%]), and early-onset persistent BHR (n = 75 [5.7%]). Early-onset persistent BHR is characterized by an increased eosinophil count, total serum IgE level, sensitization rate, decreased lung function, and increased risk of newly diagnosed asthma during follow-up (adjusted odds ratio, 3.89; 95% confidence interval, 1.70-8.88). The 2 early-onset phenotypes were associated with peripheral airway dysfunction. The late-onset BHR phenotype was related to increased risks of allergic rhinitis symptoms at baseline and later sensitization against inhalant allergens. CONCLUSION: The early-onset persistent BHR phenotype in school-aged children is associated with high atopic burden and increased risk of newly diagnosed asthma, whereas the late-onset BHR phenotype related with later sensitization and allergic rhinitis symptoms. Diverse BHR phenotypes in children have specific characteristics that require targeted follow-ups.