Association of maternal ultra-processed food consumption during pregnancy with atopic dermatitis in infancy: Korean Mothers and Children's Environmental Health (MOCEH) study.

BACKGROUND: Maternal diet during pregnancy might influence the development of childhood allergic disorders. There are few studies on the association between processed food intake and infant atopic dermatitis (AD) during pregnancy. The aim of the present study was to investigate the association of ultra-processed food (UPF) intake during pregnancy with infantile AD. METHODS: This study involved 861 pairs of pregnant women and their offspring from the Mothers' and Children's Environmental Health (MOCEH) study, a multi-center birth cohort project conducted in Korea. Dietary intake was estimated using a 24-h recall method at 12-28 weeks gestation. The NOVA classification was used to identify UPF, and UPF intake was calculated as the percentage of total energy consumption and categorized into quartiles. Infantile AD was assessed based on medical history and the criteria of the International Study of Asthma and Allergies in Childhood (ISAAC). Associations were assessed by logistic regression with adjustment for confounding factors. RESULTS: Children born to mothers in the highest quartile of UPF consumption (15.5% or more of the total energy) compared to the lowest quartile (6.8% or less) showed a higher risk of AD within 12 months [odds ratio (OR) = 1.69; 95% confidence interval (CI): 1.07-2.66, P for trend 0.0436]. After adjustment for the confounding factors under study, the association was strengthened; the adjusted OR between extreme quartiles was 2.19 (95% CI: 1.11-4.32, P for trend = 0.0418). This association was maintained even after an additional adjustment based on the Korean Healthy Eating Index (KHEI), an indicator of diet quality. CONCLUSIONS: Higher maternal consumption of UPF during pregnancy was associated with a greater risk of infantile AD within the first year of life.

Associations of mediterranean diet score and age-related macular degeneration in Korean elderly.

BACKGROUND: Previous studies have reported associations between individual nutrients or specific foods and the risk of age-related macular degeneration (AMD). However, the relationship between overall dietary quality, specifically the alternative Mediterranean diet (aMED) score, and AMD remains unclear. Therefore, this study aimed to investigate the association between the aMED score, as an indicator of overall diet quality, and AMD in the Korean population. METHODS: We conducted a cross-sectional analysis using nationally representative samples of older adults aged ≥ 65 years (895 men and 1,191 women) from the Korea National Health and Nutrition Examination Survey (2017-2018). Food intake and the aMED score were estimated using 24-h recall. AMD was diagnosed by an ophthalmologist based on fundus photography. The associations of aMED score tertiles with AMD were determined using odds ratios (ORs) from multivariate logistic regressions. RESULTS: Multiple logistic regression analysis revealed a significantly negative association between the aMED score and AMD (adjusted ORs = 0.58; 95% confidence interval = 0.39-0.88; p-trend = 0.021) in older men after adjusting for confounding factors such as age, body mass index, family monthly income, current smoking, alcohol consumption, physical activity, chronic disease status, and energy intake. Notably, this association was exclusively observed in men, and no significant association was observed between the aMED score and AMD in women (adjusted OR = 0.88; 95% CI = 0.61-1.29; p-trend = 0.691). CONCLUSIONS: This study's findings suggest that a high aMED score may be associated with a reduced risk of AMD in older men. Future studies with larger sample sizes and a prospective or interventional design are required to enhance current understanding regarding the association between diet quality and AMD.

Anti-Diabetic Potential of Sargassum horneri and Ulva australis Extracts In Vitro and In Vivo.

Sargassum horneri (SH) and Ulva australis (UA) are marine waste resources that cause environmental and economic problems when entering or multiplying the coastal waters of Jeju Island. We analyzed their anti-diabetic efficacy to assess their reusability as functional additives. The alpha-glucosidase inhibitory activity of SH and UA extracts was confirmed, and the effect of UA extract was higher than that of SH. After the induction of insulin-resistant HepG2 cells, the effects of the two marine extracts on oxidative stress, intracellular glucose uptake, and glycogen content were compared to the positive control, metformin. Treatment of insulin-resistant HepG2 cells with SH and UA resulted in a concentration-dependent decrease in oxidative stress and increased intracellular glucose uptake and glycogen content. Moreover, SH and UA treatment upregulated the expression of IRS-1, AKT, and GLUT4, which are suppressed in insulin resistance, to a similar degree to metformin, and suppressed the expression of FoxO1, PEPCK involved in gluconeogenesis, and GSK-3ß involved in glycogen metabolism. The oral administration of these extracts to rats with streptozotocin-induced diabetes led to a higher weight gain than that in the diabetic group. Insulin resistance and oral glucose tolerance are alleviated by the regulation of blood glucose. Thus, the SH and UA extracts may be used in the development of therapeutic agents or supplements to improve insulin resistance.

Association of socioeconomic factors and dietary intake with sarcopenic obesity in the Korean older population.

BACKGROUND AND OBJECTIVES: This study investigated the relationship between socioeconomic factors, dietary intake, and sarcopenic obesity among older adults in Korea. METHODS AND STUDY DESIGN: Data from the seventh Korean National Health and Nutrition Examination Survey (2016-2018) were analyzed. The study included 3,690 participants (1,645 men and 2,045 women) aged 65 years and older. Sarcopenic obesity was defined as the coexistence of low muscle strength (handgrip strength <28 kg in men and <18 kg in women) and abdominal obesity (waist circumference >90 cm in men and >85 cm in women). Socioeconomic factors assessed included age, living status, residential area, employment, education, and family income level. Dietary intake was evaluated using the nutrient adequacy ratio and mean adequacy ratio derived from 24-h dietary recall data. Multiple logistic regression was used to identify factors associated with sarcopenic obesity. RESULTS: The prevalence rates of sarcopenic obesity were 6.5% in men and 17.4% in women. Low education levels were significantly associated with a higher prevalence of sarcopenic obesity in women, whereas lower family income levels were associated with an increased risk of sarcopenic obesity in men. In women, a lower mean adequacy ratio was significantly associated with a higher risk of sarcopenic obesity. CONCLUSIONS: Lower family income and education level are associated with a higher prevalence of sarcopenic obesity. Ad-ditionally, overall nutritional adequacy is inversely related to the prevalence of sarcopenic obesity, particularly in women.

Levels of plasma glycan-binding auto-IgG biomarkers improve the accuracy of prostate cancer diagnosis.

Strategies to improve the early diagnosis of prostate cancer will provide opportunities for earlier intervention. The blood-based prostate-specific antigen (PSA) assay is widely used for prostate cancer diagnosis but specificity of the assay is not satisfactory. An algorithm based on serum levels of PSA combined with other serum biomarkers may significantly improve prostate cancer diagnosis. Plasma glycan-binding IgG/IgM studies suggested that glycan patterns differ between normal and tumor cells. We hypothesize that in prostate cancer glycoproteins or glycolipids are secreted from tumor tissues into the blood and induce auto-immunoglobulin (Ig) production. A 24-glycan microarray and a 5-glycan subarray were developed using plasma samples obtained from 35 prostate cancer patients and 54 healthy subjects to identify glycan-binding auto-IgGs. Neu5Acα2-8Neu5Acα2-8Neu5Acα (G81)-binding auto-IgG was higher in prostate cancer samples and, when levels of G81-binding auto-IgG and growth differentiation factor-15 (GDF-15 or NAG-1) were combined with levels of PSA, the prediction rate of prostate cancer increased from 78.2% to 86.2% than with PSA levels alone. The G81 glycan-binding auto-IgG fraction was isolated from plasma samples using G81 glycan-affinity chromatography and identified by N-terminal sequencing of the 50 kDa heavy chain variable region of the IgG. G81 glycan-binding 25 kDa fibroblast growth factor-1 (FGF1) fragment was also identified by N-terminal sequencing. Our results demonstrated that a multiplex diagnostic combining G81 glycan-binding auto-IgG, GDF-15/NAG-1 and PSA (≥ 2.1 ng PSA/ml for cancer) increased the specificity of prostate cancer diagnosis by 8%. The multiplex assessment could improve the early diagnosis of prostate cancer thereby allowing the prompt delivery of prostate cancer treatment.

Anticancer Strategy Targeting Cell Death Regulators: Switching the Mechanism of Anticancer Floxuridine-Induced Cell Death from Necrosis to Apoptosis.

Cell death can be broadly characterized as either necrosis or apoptosis, depending on the morphological and biochemical features of the cell itself. We have previously reported that the treatment of mouse mammary carcinoma FM3A cells with the anticancer drug floxuridine (FUdR) induces necrosis in the original clone F28-7 but apoptosis in the variant F28-7-A. We have identified regulators, including heat shock protein 90, lamin-B1, cytokeratin-19, and activating transcription factor 3, of cell death mechanisms by using comprehensive gene and protein expression analyses and a phenotype-screening approach. We also observed that the individual inhibition or knockdown of the identified regulators in F28-7 results in a shift from necrotic to apoptotic morphology. Furthermore, we investigated microRNA (miRNA, miR) expression profiles in sister cell strains F28-7 and F28-7-A using miRNA microarray analyses. We found that several unique miRNAs, miR-351-5p and miR-743a-3p, were expressed at higher levels in F28-7-A than in F28-7. Higher expression of these miRNAs in F28-7 induced by transfecting miR mimics resulted in a switch in the mode of cell death from necrosis to apoptosis. Our findings suggest that the identified cell death regulators may play key roles in the decision of cell death mechanism: necrosis or apoptosis.

Associations of recommended food score and physical performance in Korean elderly.

BACKGROUND: A single nutrient or dietary pattern has been associated with physical performance. However, little is still known about the association of overall dietary quality with physical performance. This study aimed to investigate the link between the recommended food score (RFS), defined as an indicator of overall diet quality, and physical performance among the Korean elderly aged over 65 years. METHODS: The study subjects consisted of 622 participants (294 men and 328 women) aged over 65 years from the 2014-2015 National Fitness Award project. RESULTS: The mean value of RFS was higher in elderly women (30.7 ± 7.6) than elderly men (29.5 ± 8.8), but the difference was only marginally significant (P = 0.065). In elderly women, multiple regression linear models, adjusted for potential confounders, showed that RFS was positively related to absolute hand grip strength (kg) (ß = 0.066, 95% CI = 0.010 to 0.122) and relative hand grip strength (%) (ß =0.109, 95% CI = 0.016 to 0.201); other physical performance indicators did not show any association with RFS. In elderly men, none of the physical performance indexes were associated with RFS. CONCLUSIONS: These results suggest that a better overall diet quality may be associated with improved grip strength among elderly women in Korea.

Association of recommended food score with depression, anxiety, and quality of life in Korean adults: the 2014-2015 National Fitness Award Project.

BACKGROUND: A healthy diet is a key determinant of an individual's health status and is closely related to mental health and quality of life (QoL); however, the exact nature of the relationship is unknown. This study hypothesized that a higher diet quality score is associated with a lower observance of symptoms of depression and anxiety and a higher QoL. METHODS: This study evaluated 1,295 adults (521 men; 774 women) aged 19-64 years, who participated in the 2014-2015 National Fitness Award Project. Diet quality was measured by the recommended food score (RFS), and mental health and QoL were assessed by the beck depression inventory (BDI), beck anxiety inventory (BAI), and the World Health Organization QoL-Brief (WHOQoL-BREF). RESULTS: After adjusting for covariates, the individuals with depression had a significantly lower RFS value compared to those without depression, and the group with a QoL score above the median had a higher RFS value than the group with a QoL score below the median. These trends occurred in both men and women. Subjects in the highest tertile of RFS showed a lower odds of depression (OR = 0.51, 95% CI = 0.32-0.81, p-trend = 0.0043) and a QoL score below the median (OR = 0.40, 95% CI = 0.30-0.54, p-trend < 0.0001) compared with those in the lowest tertile. The RFS was not associated with anxiety. CONCLUSIONS: Our data suggest that higher diet quality may be associated with lower depressive symptoms and a better QoL in Korean adults.

Association between lutein intake and lutein concentrations in human milk samples from lactating mothers in South Korea.

PURPOSE: This study aimed to determine the lutein content of breast milk and its association with maternal lutein intake among lactating mothers in South Korea. METHODS: Milk samples were obtained from 98 healthy lactating women (mean age; 32.5 ± 3.5 years). Dietary intake data were collected by a food record method for three consecutive days. Maternal lutein intake was estimated by using the lutein database. Lutein concentrations in human milk were analyzed using a high-performance liquid chromatography-ultraviolet detection method. RESULTS: The mean values of the daily lutein intakes and breast milk lutein concentrations in lactating mothers were 4.70 ± 3.11 mg/day (median 3.87) and 3.50 ± 3.71 µg/dl (median 2.45), respectively. Breast milk lutein concentrations were positively associated with the dietary lutein intake of lactating mothers after adjustment for lactating women's age, BMI, dietary energy intake, type of breastfeeding, and infants' age (ß = 0.3629, P = 0.0056). CONCLUSIONS: Considering that lutein in milk can be associated with dietary lutein intake, knowledge about infant requirement is needed to define the adequate lutein levels in human milk.

Association of maternal omega-6 fatty acid intake with infant birth outcomes: Korean Mothers and Children's Environmental Health (MOCEH).

BACKGROUND: Maternal fatty acids (FAs) intake has an effect on birth weight, birth length, and gestational age, as fetal development is entirely dependent on the maternal essential FA supply. This study aimed to identify the association between the maternal intake of FAs and birth outcomes among pregnant women who participated in the Mothers and Children's Environmental Health (MOCEH) prospective cohort study in South Korea. METHODS: A total of 1407 pregnant women, aged 30.2 ± 3.7 years, at 12 to 28 weeks' gestation were recruited between August 2006 and December 2010. Their dietary intake during pregnancy was investigated by the 1-day 24-h dietary recall method. The pregnancy outcome data-namely infant's gestational age, birth weight, and birth length-were analyzed for their associations with their mothers' intake of FAs. RESULTS: When adjusted for confounding factors, multiple regression analysis revealed adverse effects on birth weight (P = 0.031) and birth length (P = 0.025) with high maternal intake of omega-6 FAs. In the multiple logistic regression analysis, the odds ratio (OR) for the risk of being below the 10th percentile for birth weight was higher in the highest quintile (Q5) compared to the lowest quintile (Q1) of omega-6 FA intake levels (OR = 2.444; 95% CI = 1.038-5.751; P for trend = 0.010). Also, the OR for being above the 90th percentile of birth length was lower in the highest quintile (Q5) compared to that in the lowest quintile (Q1) of omega-6 FA intake (OR = 0.432; 95% CI = 0.211-0.884; P for trend = 0.020). However, the maternal intake of omega-3 FAs was not related to gestational age, birth weight, or birth length. CONCLUSIONS: A high maternal omega-6 FA intake was negatively associated with birth weight and birth length.

Maternal fruit and vegetable or vitamin C consumption during pregnancy is associated with fetal growth and infant growth up to 6 months: results from the Korean Mothers and Children's Environmental Health (MOCEH) cohort study.

BACKGROUND: Based on data obtained from pregnant women who participated in the Mothers and Children's Environmental Health (MOCEH) study in South Korea, we aimed to determine whether maternal intake of fruits and vegetables or vitamin C is associated with fetal and infant growth. METHODS: A total of 1138 Korean pregnant women at 12-28 weeks gestation with their infants were recruited as study participants for the MOCEH. Intake of fruits and vegetables or vitamin C during pregnancy was assessed by a 1-day 24-h recall method. Fetal biometry was determined by ultrasonography at late pregnancy. Infant weight and length were measured at birth and 6 months. RESULTS: A multiple regression analysis after adjusting for covariates showed that maternal intake of fruits and vegetables was positively associated with the biparietal diameter of the fetus and infant's weight from birth to 6 months. Also, maternal vitamin C intake was positively associated with the abdominal circumference of the fetus and infant birth length. In addition, there was a significant inverse relationship between consumption of fruits and vegetables (below the median compared to above the median of ≥519 g/d) and the risk of low growth (<25th percentile) of biparietal diameter (odds ratio (OR): 2.220; 95% confidence interval (CI): 1.153-4.274) and birth weight (OR: 1.434; 95% CI: 1.001-2.056). A significant inverse relationship also existed between vitamin C consumption (below vs above the estimated average requirement (EAR) of ≥85 mg/d) and the risk of low growth (<25th percentile) of birth weight (OR: 1.470; 95% CI: 1.011-2.139), weight from birth to 6 months (OR: 1.520; 95% CI: 1.066-2.165), and length at birth (OR: 1.579; 95% CI: 1.104-2.258). CONCLUSIONS: An increased intake of fruits and vegetables or vitamin C at mid-pregnancy is associated with increased fetal growth and infant growth up to 6 months of age.

Role of the uridine/cytidine kinase 2 mutation in cellular sensitiveness toward 3'-ethynylcytidine treatment of human cancer cells.

A nucleosidic medicine, 1-(3-C-ethynyl-ß-D-ribo-pentofuranosyl)cytosine [3'-ethynylcytidine (ECyd)], is a potent inhibitor of RNA polymerase I and shows anticancer activity to various human solid tumors in vitro and in vivo. ECyd is phosphorylated to 3'-ethyntlcytidine 5'-monophosphate by uridine/cytidine kinase 2 (UCK2) and subsequently further to diphosphate and triphosphate (3'-ethyntlcytidine 5'-diphosphate, 3'-ethyntlcytidine 5'-triphosphate). 3'-Ethyntlcytidine 5'-triphosphate is an active metabolite that can inhibit RNA polymerase I competitively, causing cancer cell death. Here, to identify the UCK2 mutation for detecting responder or nonresponder to ECyd, we investigated the relationship between point mutation of the UCK2 gene and response to ECyd in various human solid tumors. We identified several functional point mutations including the splice-site mutation of the UCK2 gene IVS5+5 G>A. In addition, we found that the IVS5+5 G>A variant generates an aberrant mRNA transcript, namely, truncated mRNA was produced and normal mRNA levels were markedly decreased in the ECyd-resistant cancer cell line HT1080. We concluded that these findings strongly suggest that the IVS5+5 G>A variant would affect the expression level of the UCK2 transcript, resulting in decreased sensitivity to ECyd.

Breast milk fatty acid composition and fatty acid intake of lactating mothers in South Korea.

The aim of this study was to determine the fatty acid (FA) composition of breast milk, and its association with mothers' FA intake. Milk samples were obtained from 238 healthy lactating women who volunteered to participate in the Human Milk Micronutrients Analysis Research. Dietary intake during lactation was assessed using a 3-d food record, and fat content and FA composition of the breast milk samples were analysed by IR spectrometry using MilkoScan FT2 and GC flame ionisation detector, respectively. The fat content was 3·31 (sd 1·41) g/100 ml breast milk. The concentrations of arachidonic acid (20 : 4 n-6), EPA (20 : 5 n-3) and DHA (22 : 6 n-3) in breast milk were 0·48 (sd 0·13), 0·15 (sd 0·12) and 0·67 (sd 0·47) % of total FA, respectively. Fat content and FA composition of breast milk were associated with maternal age, BMI, supplement use and infant age. Dietary intakes of EPA, DHA, n-3 FA, n-6 FA, SFA and PUFA were positively correlated with the corresponding FA in the milk samples. FA levels in breast milk and maternal diet are highly correlated. Further studies are warranted to explore factors that may be associated with changes in FA composition in human milk.

Associations between fruit and vegetable, and antioxidant nutrient intake and age-related macular degeneration by smoking status in elderly Korean men.

BACKGROUND: Age-related macular degeneration (AMD) is one of the major causes of irreversible blindness. The objective of this study was to determine whether there is any relationship between dietary intake of fruits and vegetables (F&V) and antioxidant nutrients including carotenoids and AMD according to smoking status in elderly men. METHODS: We performed a cross-sectional analysis using nationally representative samples of elderly aged ≥ 65 years (n = 1414) from the Korea National Health and Nutrition Examination Survey (KNHANES, 2010-2012). RESULTS: The current smokers consumed less food in total, and, in particular, less cereals/potatoes/sugar products, fruits and vegetables than the nonsmokers and former smokers (p < 0.05). Intake of energy, thiamin, vitamin C, vitamin A, and ß-carotene were significantly lower in the current smokers than in the nonsmokers and the former smokers. For current smokers, the ORs of the highest tertile compared with the lowest tertile were 0.36 (95% CI: 0.14-0.96, p for trend = 0.0576) for F&V, 0.32 (95% CI: 0.12-0.85, p for trend = 0.0561) for vitamin C, 0.23 (95% CI: 0.08-0.67, p for trend = 0.0038) for α-carotene, 0.13 (95% CI: 0.04-0.46, p for trend = 0.0003) for ß-carotene after adjusting for confounding factors. In contrast, there was no association between antioxidant nutrient intake and AMD among the nonsmokers and former smokers. CONCLUSIONS: These results suggest that increased consumption of fruits and vegetables containing antioxidant components such as vitamin C, α-carotene, and ß-carotene may have a protective effect on AMD. These effects may be more evident among current smokers.

Association between maternal intake of n-6 to n-3 fatty acid ratio during pregnancy and infant neurodevelopment at 6 months of age: results of the MOCEH cohort study.

BACKGROUND & AIMS: Long-chain polyunsaturated fatty acids (LC-PUFAs) are essential for infant neurodevelopment. The nutritional adequacy of dietary LC-PUFAs depends not only on the LC-PUFAs intake but also on the n-6 to n-3 fatty acid ratio (n-6/n-3 PUFAs). This study aimed to identify the association between the maternal dietary n-6/n-3 PUFAs and motor and cognitive development of infants at 6 months of age. METHODS: We used data from 960 participants in the Mothers and Children's Environmental Health (MOCEH) study, which is a multi-center prospective cohort study. Dietary intake of pregnant women was assessed by a one-day 24-h recall method. Food consumption of infants was estimated based on the volume of breast milk and weaning foods. The duration of each feed was used to estimate the likely volume of milk consumed. Dietary intake of infants at 6 months was also assessed by a 24-h recall method. Cognitive and motor development of infants at 6 months of age was assessed by the Korean Bayley scales of infant development edition II (BSID-II) including the mental developmental index (MDI) and the psychomotor developmental index (PDI). RESULTS: Maternal intakes of n-6/n-3 PUFAs and linoleic acid (LA)-to-α-linolenic acid (ALA) ratio (LA/ALA) were 9.7 ± 6.3 and 11.12 ± 6.9, respectively. Multiple regression analysis, after adjusting for covariates, showed that n-6/n-3 PUFAs was negatively associated with both the MDI (ß = -0.1674, P = 0.0291) and PDI (ß = -0.1947, P = 0.0380) at 6 months of age. These inverse associations were also observed between LA/ALA and both the MDI and PDI (MDI; ß = -0.1567; P = 0.0310, PDI; ß = -0.1855; P = 0.0367). Multiple logistic regression analysis, with the covariates, showed that infants whose mother's LA/ALA were ranked in the 2nd, 3rd, and 4th quartile were at approximately twice the risk with more than twice the risk of delayed performance on the PDI compared to the lowest quartile (1st vs. 2nd; OR = 2.965; 95% CI = 1.376 - 6.390, 1st vs. 3rd; OR = 3.047; 95% CI = 1.374 - 6.756 and 1st vs. 4th; OR = 2.551; 95% CI = 1.160 - 5.607). CONCLUSIONS: Both the maternal dietary n-6/n-3 PUFAs and LA/ALA intake were significantly associated with the mental and psychomotor development of infants at 6 months of age. Thus, maintaining low n-6/n-3 PUFAs and LA/ALA is encouraged for women during pregnancy.

WrpA Is an Atypical Flavodoxin Family Protein under Regulatory Control of the Brucella abortus General Stress Response System.

UNLABELLED: The general stress response (GSR) system of the intracellular pathogen Brucella abortus controls the transcription of approximately 100 genes in response to a range of stress cues. The core genetic regulatory components of the GSR are required for B. abortus survival under nonoptimal growth conditions in vitro and for maintenance of chronic infection in an in vivo mouse model. The functions of the majority of the genes in the GSR transcriptional regulon remain undefined. bab1_1070 is among the most highly regulated genes in this regulon: its transcription is activated 20- to 30-fold by the GSR system under oxidative conditions in vitro. We have solved crystal structures of Bab1_1070 and demonstrate that it forms a homotetrameric complex that resembles those of WrbA-type NADH:quinone oxidoreductases, which are members of the flavodoxin protein family. However, B. abortus WrbA-related protein (WrpA) does not bind flavin cofactors with a high affinity and does not function as an NADH:quinone oxidoreductase in vitro. Soaking crystals with flavin mononucleotide (FMN) revealed a likely low-affinity binding site adjacent to the canonical WrbA flavin binding site. Deletion of wrpA (ΔwrpA) does not compromise cell survival under acute oxidative stress in vitro or attenuate infection in cell-based or mouse models. However, a ΔwrpA strain does elicit increased splenomegaly in a mouse model, suggesting that WrpA modulates B. abortus interaction with its mammalian host. Despite high structural homology with canonical WrbA proteins, we propose that B. abortus WrpA represents a functionally distinct member of the diverse flavodoxin family. IMPORTANCE: Brucella abortus is an etiological agent of brucellosis, which is among the most common zoonotic diseases worldwide. The general stress response (GSR) regulatory system of B. abortus controls the transcription of approximately 100 genes and is required for maintenance of chronic infection in a murine model; the majority of GSR-regulated genes remain uncharacterized. We present in vitro and in vivo functional and structural analyses of WrpA, whose expression is strongly induced by GSR under oxidative conditions. Though WrpA is structurally related to NADH:quinone oxidoreductases, it does not bind redox cofactors in solution, nor does it exhibit oxidoreductase activity in vitro. However, WrpA does affect spleen inflammation in a murine infection model. Our data provide evidence that WrpA forms a new functional class of WrbA/flavodoxin family proteins.

Differential BPA levels in sewage wastewater effluents from metro Detroit communities.

The endocrine disruptor Bisphenol A (BPA) is ubiquitous in both aquatic and surface sediment environments because it is continuously released into sewage wastewater effluent. The measurement of BPA at wastewater treatment plants is rarely performed even though the United States Environmental Protection Agency (EPA) states that current levels of environmental BPA could be a threat to aquatic organisms. Therefore, the aims of this study were to measure BPA levels in sewage wastewater at different collection points over a 1-year period and to compare the levels of BPA to 8-isoprostane, a human derived fatty acid, found in sewage wastewater. We analyzed pre-treated sewage samples collected from three source points located in different communities in the metropolitan Detroit area provided by the Detroit Water and Sewerage Department. Human urine samples were also used in the study. BPA and 8-isoprostane were measured using ELISA kits from Detroit R&D, Inc. BPA levels from the same collection point oscillated more than 10-fold over 1 year. Also, BPA levels fluctuated differentially at each collection point. Highly fluctuating BPA values were confirmed by LC/MS/MS. The concentration of BPA in sewage wastewater was ~100-fold higher than the concentration of 8-isoprostane, while urinary concentration was ~20-fold higher. Thus, BPA levels discharged into the sewage network vary among communities, and differences are also observed within communities over time. The difference in BPA and 8-isoprostane levels suggest that most of the BPA discharged to sewage wastewater might be derived from industries rather than from human urine. Therefore, the continuous monitoring of BPA could account for a better regulation of BPA release into a sewage network.

The Brucella abortus virulence regulator, LovhK, is a sensor kinase in the general stress response signalling pathway.

In the intracellular pathogen Brucella abortus, the general stress response (GSR) signalling system determines survival under acute stress conditions in vitro, and is required for long-term residence in a mammalian host. To date, the identity of the Brucella sensor kinase(s) that function to perceive stress and directly activate GSR signalling have remained undefined. We demonstrate that the flavin-binding sensor histidine kinase, LovhK (bab2_0652), functions as a primary B. abortus GSR sensor. LovhK rapidly and specifically phosphorylates the central GSR regulator, PhyR, and activates transcription of a set of genes that closely overlaps the known B. abortus GSR regulon. Deletion of lovhK severely compromises cell survival under defined oxidative and acid stress conditions. We further show that lovhK is required for cell survival during the early phase of mammalian cell infection and for establishment of long-term residence in a mouse infection model. Finally, we present evidence that particular regions of primary structure within the two N-terminal PAS domains of LovhK have distinct sensory roles under specific environmental conditions. This study elucidates new molecular components of a conserved signalling pathway that regulates B. abortus stress physiology and infection biology.

Improvement of Oral Bioavailability of N-251, a Novel Antimalarial Drug, by Increasing Lymphatic Transport with Long-Chain Fatty Acid-Based Self-Nanoemulsifying Drug Delivery System.

PURPOSE: The objective of this study was to improve the absorption behavior of N-251, a novel antimalarial drug, by preparing an appropriate self-nanoemulsifying drug delivery system (SNEDDS). METHODS: Two different types of SNEDDS formulations, medium-chain fatty acid-based SNEDDS (MC-SNEDDS) and long-chain fatty acid-based SNEDDS (LC-SNEDDS), were prepared based on pseudo-ternary phase diagram, and examined for their in vivo oral absorption behavior in rats. RESULTS: Oral dosing of MC-SNEDDS formulations significantly improved the bioavailability (BA) of N-251 compared with N-251 powders. However, its high hepatic extraction limited the BA of N-251 to only 0.49 for MC-SNEDDS B, the best formulation of MC-SNEDDS. LC-SNEDDS formulations, especially LC-SNEDDS F provided the highest BA, 0.65, and successfully attenuated the inter-individual difference in the absorption behavior. Furthermore, it was confirmed that lymphatic transport of N-251 for LC-SNEDDS F was significantly increased up to around 3.19 times larger than that for MC-SNEDDS B. Simulation study suggested that 20 to 39% of N-251 uptaken by the small intestine would be delivered to lymphatic system after oral administration of LC-SNEDDS F. CONCLUSIONS: SNEDDS formulations significantly improved the absorption behavior of N-251 and long-chain fatty acid-based lipid further improved it by avoiding the hepatic first-pass elimination.

The Brucella abortus general stress response system regulates chronic mammalian infection and is controlled by phosphorylation and proteolysis.

BACKGROUND: Virulence of pathogenic bacteria is often determined by their ability to adapt to stress. RESULTS: The Brucella abortus general stress response (GSR) system is required for chronic mammalian infection and is regulated by phosphorylation and proteolysis. CONCLUSION: The B. abortus GSR signaling pathway has multiple layers of post-translational control and is a determinant of chronic infection. SIGNIFICANCE: This study provides new, molecular level insight into chronic Brucella infection. Brucella spp. are adept at establishing a chronic infection in mammals. We demonstrate that core components of the α-proteobacterial general stress response (GSR) system, PhyR and σ(E1), are required for Brucella abortus stress survival in vitro and maintenance of chronic murine infection in vivo. ΔphyR and ΔrpoE1 null mutants exhibit decreased survival under acute oxidative and acid stress but are not defective in infection of primary murine macrophages or in initial colonization of BALB/c mouse spleens. However, ΔphyR and ΔrpoE1 mutants are attenuated in spleens beginning 1 month postinfection. Thus, the B. abortus GSR system is dispensable for colonization but is required to maintain chronic infection. A genome-scale analysis of the B. abortus GSR regulon identified stress response genes previously linked to virulence and genes that affect immunomodulatory components of the cell envelope. These data support a model in which the GSR system affects both stress survival and the interface between B. abortus and the host immune system. We further demonstrate that PhyR proteolysis is a unique feature of GSR control in B. abortus. Proteolysis of PhyR provides a mechanism to avoid spurious PhyR protein interactions that inappropriately activate GSR-dependent transcription. We conclude that the B. abortus GSR system regulates acute stress adaptation and long term survival within a mammalian host and that PhyR proteolysis is a novel regulatory feature in B. abortus that ensures proper control of GSR transcription.