Impact of Acetate in Reduction of Perchlorate by Mixed Microbial Culture under the Influence of Nitrate and Sulfate.

The biological reduction of slow degradation contaminants such as perchlorate (ClO4-) is considered to be a promising water treatment technology. The process is based on the ability of a specific mixed microbial culture to use perchlorate as an electron acceptor in the absence of oxygen. In this study, batch experiments were conducted to investigate the effect of nitrate on perchlorate reduction, the kinetic parameters of the Monod equation and the optimal ratio of acetate to perchlorate for the perchlorate reducing bacterial consortium. The results of this study suggest that acclimated microbial cultures can be applied to treat wastewater containing high concentrations of perchlorate. Reactor experiments were carried out with different hydraulic retention times (HRTs) to determine the optimal operating conditions. A fixed optimal HRT and the effect of nitrate on perchlorate reduction were investigated with various concentrations of the electron donor. The results showed that perchlorate reduction occurred after nitrate removal. Moreover, the presence of sulfate in wastewater had no effect on the perchlorate reduction. However, it had little effect on biomass concentration in the presence of nitrate during exposure to a mixed microbial culture, considering the nitrate as the inhibitor of perchlorate reduction by reducing the degradation rate. The batch scale experiment results illustrated that for efficient operation of perchlorate reduction, the optimal acetate to perchlorate ratio of 1.4:1.0 would be enough. Moreover, these experiments found the following results: the kinetic parameters equivalent to Y = 0.281 mg biomass/mg perchlorate, Ks = 37.619 mg/L and qmax = 0.042 mg perchlorate/mg biomass/h. In addition, anoxic-aerobic experimental reactor results verify the optimal HRT of 6 h for continuous application. Furthermore, it also illustrated that using 600 mg/L of acetate as a carbon source is responsible for 100% of nitrate reduction with less than 50% of the perchlorate reduction, whereas at 1000 mg/L acetate, approximately 100% reduction was recorded.

CRISPR/Cas9-Mediated Knockout of DGK Improves Antitumor Activities of Human T Cells.

The efficacy of T-cell therapy is inhibited by various tumor-associated immunosuppressive ligands and soluble factors. Such inhibitory signals turn specific T-cell signaling pathways on or off, impeding the anticancer functions of T cells. Many studies have focused on PD-1 or CTLA-4 blockade to invigorate T-cell functions through CD28/B7 signaling, but obtaining robust clinical outcomes remains challenging. In this study, we use CRISPR/Cas9 to potentiate T-cell function by increasing CD3 signaling via knockout of diacylglycerol kinase (DGK), an enzyme that metabolizes diacylglycerol to phosphatidic acid. Knockout of DGK augmented the effector functions of CAR-T cells in vitro via increased TCR signaling. DGK knockout from CAR-T cells rendered them resistant to soluble immunosuppressive factors such as TGFß and prostaglandin E2 and sustained effector functions under conditions of repeated tumor stimulation. Moreover, DGK knockout caused significant regression of U87MGvIII glioblastoma tumors through enhanced effector functions in a xenograft mouse model. Collectively, our study shows that knockout of DGK effectively enhances the effector functions of CAR-T cells, suggesting that CRISPR/Cas9-mediated knockout of DGK could be applicable as part of a multifaceted clinical strategy to treat solid cancers.Significance: This novel study demonstrates efficient ablation of diacylglycerol kinase in human CAR-T cells that leads to improved antitumor immunity and may have significant impact in human cancer immunotherapy. Cancer Res; 78(16); 4692-703. ©2018 AACR.

Interaction between 25-hydroxyvitamin D and variants at 17q12-21 on respiratory infections.

OBJECTIVES: 25-hydroxyvitamin D (25[OH]D) deficiency and genetic variants at the 17q12-21 locus are independent risk factors for respiratory tract infections (RTIs). We aimed to investigate whether the effect of 25(OH)D at birth and 1 year of age and the polymorphism at the 17q12-21 locus, or interactions between these two factors, increase susceptibility to RTIs in the first year of life. METHODS: We tested cord-blood (CB) 25(OH)D at birth and 1 year of age and genotypes of a variant at the 17q12-21 locus for associations with RTIs, particularly lower respiratory tract infections (LRTIs), and determined whether there exist interactions between 25(OH)D and 17q12-21 genotypes in a birth cohort of 473 infants. RESULTS: The levels of CB 25(OH)D inversely associate with development of RTIs and LRTIs during the first year of life. There exists an inverse association of 25(OH)D at birth, but not at 1 year, with the risk of acquiring LRTIs in early infancy (adjusted odds ratio [aOR], 2.37; 95% confidence interval [CI]: 1.23-4.60; P = 0.010 and aOR, 0.50; 95%CI: 0.23-1.12; P = 0.094). We have also found a significant interaction between CB 25(OH)D and a variant at the 17q12-21 locus with respect to the development of early LRTIs, such that associations between a variant at the 17q12-21 locus and LRTIs are restricted to infants with low CB 25(OH)D concentrations (P for interaction = 0.013). In addition, when infants with a variant at the 17q12-21 locus had been exposed to chronic 25(OH)D deficiency over the first year, their risk of LRTIs was increased. CONCLUSION: CB 25(OH)D deficiency during fetal life contribute to the development of LRTIs in genetically susceptible infants. Pediatr Pulmonol. 2016; 51:958-967. © 2016 Wiley Periodicals, Inc.

Phase transitions via selective elemental vacancy engineering in complex oxide thin films.

Defect engineering has brought about a unique level of control for Si-based semiconductors, leading to the optimization of various opto-electronic properties and devices. With regard to perovskite transition metal oxides, O vacancies have been a key ingredient in defect engineering, as they play a central role in determining the crystal field and consequent electronic structure, leading to important electronic and magnetic phase transitions. Therefore, experimental approaches toward understanding the role of defects in complex oxides have been largely limited to controlling O vacancies. In this study, we report on the selective formation of different types of elemental vacancies and their individual roles in determining the atomic and electronic structures of perovskite SrTiO3 (STO) homoepitaxial thin films fabricated by pulsed laser epitaxy. Structural and electronic transitions have been achieved via selective control of the Sr and O vacancy concentrations, respectively, indicating a decoupling between the two phase transitions. In particular, O vacancies were responsible for metal-insulator transitions, but did not influence the Sr vacancy induced cubic-to-tetragonal structural transition in epitaxial STO thin film. The independent control of multiple phase transitions in complex oxides by exploiting selective vacancy engineering opens up an unprecedented opportunity toward understanding and customizing complex oxide thin films.

Prenatal maternal distress affects atopic dermatitis in offspring mediated by oxidative stress.

BACKGROUND: Recent evidence suggests that prenatal maternal distress increases the risk of allergic diseases in offspring. However, the effect of prenatal maternal depression and anxiety on atopic dermatitis (AD) risk remains poorly understood. OBJECTIVE: We investigated whether prenatal maternal distress is associated with AD risk in offspring and whether the mechanism is mediated by reactive oxygen species. METHODS: Two general population-based birth cohorts formed the study. One cohort (Cohort for Childhood Origin of Asthma and Allergic Diseases [COCOA]) consisted of 973 mother-baby dyads, and the other (Panel Study on Korean Children [PSKC]) consisted of 1531 mother-baby dyads. The association between prenatal distress and AD was assessed by using Cox proportional hazards and logistic regression models. In COCOA placental 11ß-hydroxysteroid dehydrogenase type 2 and glutathione levels and serum IgE levels in 1-year-old children were measured. RESULTS: In COCOA and PSKC AD occurred in 30.6% (lifetime prevalence) and 11.6% (1 year prevalence) of offspring, respectively. Prenatal maternal distress increased the risk of AD in offspring, both in COCOA (hazard ratio for depression, 1.31 [95% CI, 1.02-1.69]; hazard ratio for anxiety, 1.41 [95% CI, 1.06-1.89]) and PSKC (odds ratio for distress, 1.85 [95% CI, 1.06-3.25]). In COCOA both prenatal maternal depression and anxiety scores were positively related to the predicted probability of AD (P < .001 in both). Prenatal distress decreased placental glutathione to glutathione disulfide ratios (P = .037) and, especially in those who later had AD, decreased placental 11ß-hydroxysteroid dehydrogenase type 2 levels (P = .010) and increased IgE levels at 1 year of age (P = .005). CONCLUSION: Prenatal maternal depression and anxiety promote risk of AD in offspring. Maternal distress increases the predicted probability of AD. The mechanism might involve chronic stress, abnormal steroid levels, and reactive oxygen species.

Association Between Antibiotic Exposure, Bronchiolitis, and TLR4 (rs1927911) Polymorphisms in Childhood Asthma.

PURPOSE: The complex interplay between environmental and genetic factors plays an important role in the development of asthma. Several studies have yielded conflicting results regarding the 2 asthma-related risk factors: antibiotic usage during infancy and/or a history of bronchiolitis during early life and the development of asthma. In addition to these risk factors, we also explored the effects of Toll-like receptor 4 (TLR4) polymorphism on the development of childhood asthma. METHODS: This cross-sectional study involved 7,389 middle school students who were from 8 areas of Seoul, Korea, and completed the International Study of Asthma and Allergies in Childhood questionnaire. The TLR4 polymorphism rs1927911 was genotyped in 1,395 middle school students from two areas using the TaqMan assay. RESULTS: Bronchiolitis in the first 2 years of life, antibiotic exposure during the first year of life, and parental history of asthma were independent risk factors for the development of asthma. When combined, antibiotic use and a history of bronchiolitis increased the risk of asthma (adjusted odds ratio [aOR]: 4.64, 95% confidence interval [CI]: 3.09-6.97, P value for interaction=0.02). In subjects with CC genotype of TLR4, antibiotic exposure and a history of bronchiolitis during infancy, the risk of asthma was increased, compared to subjects without these risk factors (aOR: 5.72, 95% CI: 1.74-18.87). CONCLUSIONS: Early-life antibiotic exposures and a history of bronchiolitis are risk factors for asthma in young adolescents. Polymorphisms of TLR4 modified the influence of these environmental factors. Reducing antibiotic exposure and preventing bronchiolitis during infancy may prevent the development of asthma, especially in genetically susceptible subjects.

The effect of perinatal anxiety on bronchiolitis is influenced by polymorphisms in ROS-related genes.

BACKGROUND: Exposure to perinatal anxiety affects disease susceptibility in offspring but studies on the association between perinatal anxiety and gene polymorphisms are lacking. This study aimed to elucidate the interaction between perinatal anxiety and polymorphisms in antioxidant defense and innate immunity genes on the development of respiratory tract infections (RTIs) during early infancy. METHODS: Trait anxiety levels in 440 women were assessed by the State-Trait Anxiety Inventory during late gestation. The occurrence of RTIs, including bronchiolitis, during the first year of life was assessed by parent-reported doctor diagnosis. Polymorphisms in glutathione S-transferase P-1 (GSTP1, rs1695) and CD14 (rs2569190) were genotyped using the TaqMan assay. Copy number variations of GSTT1 were measured by real-time polymerase chain reaction. RESULTS: Exposure to high levels of perinatal anxiety increased the risk of bronchiolitis in the first year of life (adjusted odds ratio [aOR], 1.30; 95% confidence interval [CI]: 1.00-1.80), in particular among children with the AG + GG genotype of GSTP1 or the GSTT1 null genotype (aOR 3.36 and 2.79). In infants with the TC + CC genotype of CD14, high levels of perinatal anxiety were associated with an increased risk of upper RTI, lower RTI, and bronchiolitis (aOR 2.51, 4.60, and 4.31, respectively). CONCLUSIONS: Perinatal maternal anxiety levels affect the occurrence of bronchiolitis in offspring. The effect of perinatal anxiety on the occurrence of bronchiolitis during infancy was influenced by genetic polymorphisms in antioxidant defense and innate immunity genes.

Effect of antibiotic use and mold exposure in infancy on allergic rhinitis in susceptible adolescents.

BACKGROUND: Antibiotic use in infancy induces alteration in intestinal microbiota and is associated with the development of allergic diseases. Mold exposure is also associated with allergic diseases. Genetic susceptibility may interact with specific environmental factors in allergic disease development. OBJECTIVE: To investigate independent and combined effects of antibiotic use and mold exposure in infancy on the risk of allergic rhinitis (AR) in adolescents. METHODS: Data on AR and environmental factors were collected using the International Study of Asthma and Allergies in Childhood questionnaire from 7,389 adolescents from Seoul, Korea. TaqMan genotyping was performed for interleukin 13 (IL-13) (rs20541) and Toll-like receptor 4 (rs1927911) polymorphisms in 1,395 adolescents. RESULTS: Age, parental history of AR, antibiotic use in infancy, and pet ownership during pregnancy or infancy were associated with an increased risk of current AR (diagnosis of AR and symptoms of AR within the preceding 12 months). Having older siblings was a protective effect. The adjusted odds ratio (aOR) for current AR for combined antibiotic use and mold exposure in infancy was 1.45 (95% confidence interval [CI], 1.01-2.09). For each factor separately, aORs were 1.25 (95% CI, 1.04-1.50) and 0.99 (95% CI, 0.75-1.31), respectively. Antibiotic and mold exposure in infancy, GA or AA genotypes of IL-13 (rs20541) (aOR 4.53; 95% CI, 1.66-12.38; P for interaction = .05), and CT+TT genotype of Toll-like receptor 4 (rs1927911) (aOR, 3.20; 95% CI, 1.24-8.26; P for interaction = .18) increased the risk of current AR. CONCLUSION: Antibiotic use and mold exposure in infancy have additive effects on the risk of current AR in genetically susceptible adolescents. Gene-environment interactions between IL-13 (rs20541) and antibiotics or mold may play a role in AR.

Association between recent acetaminophen use and asthma: modification by polymorphism at TLR4.

The risk of asthma has been increasing in parallel with use of acetaminophen, which is a potential source of oxidative stress. Toll-like receptor 4 (TLR4) plays a critical role not only in innate immunity, but also in mediating reactive oxygen species induced inflammation. Therefore, we investigated associations between acetaminophen usage and TLR4 polymorphism on asthma and bronchial hyperresponsiveness (BHR). The number of 2,428 elementary school children in Seoul and Jeongeup cities was recruited. Subjects who used acetaminophen with a family history of asthma had an increased risk of both asthma diagnosis ever and current asthma. Individuals with CT+TT genotypes at the TLR4 polymorphism, in combination with acetaminophen usage, also demonstrated an increased risk of asthma diagnosis ever (aOR, 2.08; 95% confidence interval [CI], 1.10-3.92). Family history of asthma and acetaminophen usage were risk factors for BHR. Although TLR4 was not an independent risk factor for BHR, individuals with CT+TT genotypes at the TLR4 polymorphism had an increased risk of BHR when combined with acetaminophen usage (aOR, 1.74; 95% CI, 1.03-2.94). In conclusion, acetaminophen usage may be associated with asthma and BHR in genetically susceptible subjects. This effect may be modified by polymorphism at TLR4.

Bacillus Calmette-Guérin Suppresses Asthmatic Responses via CD4(+)CD25(+) Regulatory T Cells and Dendritic Cells.

PURPOSE: Bacillus Calmette-Guérin (BCG) is known to suppress the asthmatic responses in a murine model of asthma and to induce dendritic cells (DCs) maturation. Mature DCs play a crucial role in the differentiation of regulatory T cells (Tregs), which are known to regulate allergic inflammatory responses. To investigate whether BCG regulates Tregs in a DCs-mediated manner, we analyzed in a murine model of asthma. METHODS: BALB/c mice were injected intraperitoneally with BCG or intravenously with BCG-stimulated DCs and then sensitized and challenged with ovalbumin (OVA). Mice were analysed for bronchial hyperresponsiveness (BHR), the influx of inflammatory cells in the bronchoalveolar lavage (BAL) fluid, and histopathological changes in the lung. To identify the mechanisms, IgE, IgG1 and IgG2a in the serum were analysed and the CD25+ Tregs in the mice were depleted with anti-CD25 monoclonal antibody (mAb). RESULTS: BCG and the transfer of BCG-stimulated DCs both suppressed all aspects of the asthmatic responses, namely, BHR, the production of total IgE and OVA-specific IgE and IgGs, and pulmonary eosinophilic inflammation. Anti-CD25mAb treatment reversed these effects. CONCLUSIONS: BCG can attenuate the allergic inflammation in a mouse model of asthma by a Tregs-related mechanism that is mediated by DCs.

A novel synthetic mycolic Acid inhibits bronchial hyperresponsiveness and allergic inflammation in a mouse model of asthma.

PURPOSE: Recognition of microbes is important to trigger the innate immune system. Mycolic acid (MA) is a component of the cell walls of mycobacteria such as Mycobacterium bovis Bacillus Calmette-Guerin. MA has immunogenic properties, which may modulate the innate and adaptive immune response. This study aimed to investigate whether a novel synthetic MA (sMA) inhibits allergic inflammatory responses in a mouse model of asthma. METHODS: BALB/c mice were injected intraperitoneally with sMA followed by sensitization and challenge with ovalbumin (OVA). Mice were examined for bronchial hyperresponsiveness (BHR), the influx of inflammatory cells into the lung tissues, histopathological changes in the lungs and CD4(+)CD25(+)Foxp3(+) T cells in the spleen, and examined the response after the depleting regulatory T cells (Tregs) with an anti-CD25mAb. RESULTS: Treatment of mice with sMA suppressed the asthmatic response, including BHR, bronchoalveolar inflammation, and pulmonary eosinophilic inflammation. Anti-CD25mAb treatment abrogated the suppressive effects of sMA in this mouse model of asthma and totally depleted CD4(+)CD25(+)Foxp3(+) T cells in the spleen. CONCLUSIONS: sMA attenuated allergic inflammation in a mouse model of asthma, which might be related with CD4(+)CD25(+)Foxp3(+) T cell.

Mutations in the Filaggrin are Predisposing Factor in Korean Children With Atopic Dermatitis.

PURPOSE: Filaggrin (FLG) is a key protein that facilitates the terminal differentiation of the epidermis and the formation of the skin barrier. Recent studies showed that atopic dermatitis (AD) associates closely with loss-of-function mutations in the FLG gene. Asian and European populations differ in the frequencies of FLG mutations. Several FLG mutations, including 3321delA, E2422X, K4671X, S2554X, and R501X, occur frequently in Chinese and Japanese populations. The association between three FLG null mutations and AD in Korean children was investigated. METHODS: The FLG mutations in 1,430 children (aged 0-18 years) with AD and 862 control subjects were genotyped by using the TaqMan assay. RESULTS: The FLG null mutation E2422X was not detected in any patients with AD or control subjects. The R501X null mutation was detected in only one child with AD (0.1%). Children with AD had the 3321delA deletion significantly more frequently (2.4%) than the control subjects (0.0%, P<0.001). Children with AD also had a significantly higher combined allele frequency of the three FLG null mutations (2.6%) than the controls (0.0%, P<0.001). The 3321delA null mutation did not associate significantly with AD severity (P=0.842). When the patients with AD were divided into allergic AD and non-allergic AD patient groups, these two groups did not differ in terms of the frequency of 3321delA. CONCLUSIONS: The Korean children had a lower frequency of FLG mutations than European populations. FLG null mutations may be associated with the development of AD in Korean children.

Effect of paracetamol use on the modification of the development of asthma by reactive oxygen species genes.

BACKGROUND: Recent studies have identified an increase in the prevalence of asthma associated with paracetamol use. OBJECTIVE: To identify the relationship among asthma, biomarkers, genes, and paracetamol use in preschool children. METHODS: We undertook a population-based, cross-sectional survey of 933 preschool children. Asthma status was classified according to medical history and asthmatic symptoms. History of paracetamol use in infancy was recorded. Impulse oscillometry, blood tests for eosinophils and total IgE, and genotyping of NAT2, Nrf2, and GSTP1 polymorphisms by TaqMan assay were conducted. RESULT: Paracetamol use in infancy was associated with an increased risk of treatment for asthma within the previous 12 months. Paracetamol use together with a family history of asthma increased the risk of asthma diagnosis ever, current asthma, and treatment for asthma within the previous 12 months. Gene polymorphisms in NAT2 (rs4271002), Nrf2 (rd6726395), and GSTP1 (rd1695) increased the risk of treatment for asthma within the last 12 months. Eosinophils were significantly elevated in the group with paracetamol use and a family history of asthma; however, the serum total IgE level and IOS did not show any significant difference. CONCLUSION: Paracetamol use in infancy was significantly associated with increased risk of asthma. The association is more significant in genetically susceptible children, related to antioxidant genes, and the effect may be mediated by eosinophilic inflammation.

GSDMB/ORMDL3 variants contribute to asthma susceptibility and eosinophil-mediated bronchial hyperresponsiveness.

In 2007, a genome-wide association study identified associations between variants involved in the regulation of ORMDL3 expression and asthma. These observations were subsequently replicated in case-control studies in several ethnic groups. We investigated the possible contribution of GSDMB/ORMDL3 variants to asthma susceptibility and intermediate asthma phenotypes in Korean children. The polymorphisms rs7216389, rs4794820, rs4065275, and rs11650680 were genotyped using the TaqMan assay in 931 asthmatics and 480 normal controls in a case-control study, and in 1907 elementary school children in a general population study. Each subject also underwent peripheral blood analysis of immunoglobulin E levels, eosinophil cationic protein (ECP) levels, and eosinophil percentage. Pulmonary function testing (FEV(1) and MMEF) and a methacholine provocation test (PC(20)) were also performed. The case-control study revealed a significant association between a linkage disequilibrium block, including rs7216389, rs4794820, and rs4065275, and susceptibility to asthma and atopic asthma. The CT and TT genotypes of rs11650680 were associated with lower logECP levels than the CC genotype in asthmatics, while the GA and AA genotypes of rs4794820 were associated with higher logPC(20) values than the GG genotype in atopic asthmatics. The haplotype (CAA) of rs7216389, rs4794820 and rs4065275 was associated with a lower risk of asthma susceptibility and a higher logPC(20). In the general population study, rs11650680 was significantly associated with a diagnosis of asthma. Moreover, the GA and AA genotypes of rs4794820 were associated with higher logPC(20) values and lower eosinophil percentages than the GG genotype in subjects who had been diagnosed with asthma, or showed bronchial hyperresponsiveness (PC(20)≤16). The GSDMB/ORMDL3 gene block, which includes rs7216389, rs4065275, rs4794820, and rs11650680, may be associated with asthma susceptibility in Korean children because it promotes eosinophilic inflammation, which induces bronchial hyperresponsiveness.

Effects of the anti-sepsis drug, (S)-1-(α-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (CKD-712), on mortality, inflammation, and organ injuries in rodent sepsis models.

CKD-712 is a 1-naphthyl analog of higenamine that has been reported to have potent antiinflammatory and thus anti-sepsis effects. The purpose of this study was to investigate the potential of CKD-712 as a medicine for sepsis and to confirm its protective effects on organs in animal sepsis models. Pretreatment with CKD-712 dose-dependently increased survival rate in a lipopolysaccharide-induced sepsis model in mice. Body temperature decrease, an important pre-symptom of septic death, was also prevented by CKD-712. CKD-712 still significantly increased survival rate even when administered one and four hours after lipopolysaccharide injection. Therapeutic efficacy of CKD-712 was also confirmed against sepsis following zymosan-induced endotoxemia and in cecal ligation and puncture surgery in mice. In a disseminated intravascular coagulation model in rats, CKD-712 showed organ-protective effect by reducing serum glutamate-oxaloacetate transaminase, glutamate-pyruvate transferase, blood urea nitrogen, and creatinine levels. CKD-712 also prevented histological damage to the lung and liver. In this same model, CKD-712 showed anti-inflammatory effects through decreases in tumor necrosis factor-α and interleukin-6 in the blood and reduced translocation of nuclear factor-κB to the nuclei of lung cells. CKD-712 administration also diminished infiltration of leukocytes into the lung and liver. Taken together, these results show that CKD-712 has excellent potential as an effective medicine for sepsis.

Acute human immunodeficiency virus syndrome presenting with hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) has been described in patients with advanced stages of human immunodeficiency virus (HIV) infection, but rarely occurs during the seroconversion stage of acute HIV infection. We report a case of acute HIV syndrome that presented with virus-associated HLH. The patient recovered spontaneously without any immunomodulating therapy. This case suggests that acute HIV infection should be included in the differential diagnosis of HLH and indicates that HLH associated with acute HIV infection can have a favorable outcome.