Development and evaluation of a novel dietary bisphenol A (BPA) exposure risk tool

Background: Exposure to endocrine disrupting chemicals such as bisphenol A (BPA) is primarily from the diet through canned foods. Characterizing dietary exposures can be conducted through biomonitoring and dietary surveys; however, these methods can be time-consuming and challenging to implement. Methods: We developed a novel dietary exposure risk questionnaire to evaluate BPA exposure and compared these results to 24-hr dietary recall data from participants (n = 404) of the Diet Intervention Examining The Factors Interacting with Treatment Success (DIETFITS) study, a dietary clinical trial, to validate questionnaire responses. High BPA exposure foods were identified from the dietary recalls and used to estimate BPA exposure. Linear regression models estimated the association between exposure to BPA and questionnaire responses. A composite risk score was developed to summarize questionnaire responses. Results: In questionnaire data, 65% of participants ate canned food every week. A composite exposure score validated that the dietary exposure risk questionnaire captured increasing BPA exposure. In the linear regression models, utilizing questionnaire responses vs. 24-hr dietary recall data, participants eating canned foods 1–2 times/week (vs. never) consumed 0.78 more servings (p \u3c 0.001) of high BPA exposure foods, and those eating canned foods 3+ times/week (vs. never) consumed 0.89 more servings (p = 0.013) of high BPA exposure foods. Participants eating 3+ packaged items/day (vs. never) consumed 62.65 more total grams of high BPA exposure food (p = 0.036). Conclusions: Dietary exposure risk questionnaires may provide an efficient alternative approach to 24-hour dietary recalls to quantify dietary BPA exposure with low participant burden. Trial registration: The trial was prospectively registered at clinicaltrials.gov as NCT01826591 on April 8, 2013

Circadian control of interferon-sensitive gene expression in murine skin.

The circadian clock coordinates a variety of immune responses with signals from the external environment to promote survival. We investigated the potential reciprocal relationship between the circadian clock and skin inflammation. We treated mice topically with the Toll-like receptor 7 (TLR7) agonist imiquimod (IMQ) to activate IFN-sensitive gene (ISG) pathways and induce psoriasiform inflammation. IMQ transiently altered core clock gene expression, an effect mirrored in human patient psoriatic lesions. In mouse skin 1 d after IMQ treatment, ISGs, including the key ISG transcription factor IFN regulatory factor 7 (Irf7), were more highly induced after treatment during the day than the night. Nuclear localization of phosphorylated-IRF7 was most prominently time-of-day dependent in epidermal leukocytes, suggesting that these cell types play an important role in the diurnal ISG response to IMQ. Mice lacking Bmal1 systemically had exacerbated and arrhythmic ISG/Irf7 expression after IMQ. Furthermore, daytime-restricted feeding, which affects the phase of the skin circadian clock, reverses the diurnal rhythm of IMQ-induced ISG expression in the skin. These results suggest a role for the circadian clock, driven by BMAL1, as a negative regulator of the ISG response, and highlight the finding that feeding time can modulate the skin immune response. Since the IFN response is essential for the antiviral and antitumor effects of TLR activation, these findings are consistent with the time-of-day-dependent variability in the ability to fight microbial pathogens and tumor initiation and offer support for the use of chronotherapy for their treatment

Three Highly Conserved Proteins Catalyze the Conversion of UDP-N-Acetyl-D-Glucosamine to Precursors for the Biosynthesis of O antigen in Pseudomonas aeruginosa O11 and Capsule in Staphylococcus aureus Type 5 - Implications for the UDP-N-Acetyl-L-Fucosamine Biosynthetic Pathway*

N-Acetyl-l-fucosamine is a constituent of surface polysaccharide structures of Pseudomonas aeruginosa and Staphylococcus aureus. The three P. aeruginosa enzymes WbjB, WbjC, and WbjD, as well as the S. aureus homologs Cap5E, Cap5F, and Cap5G, involved in the biosynthesis of N-acetyl-l-fucosamine have been overexpressed and purified to near homogeneity. Capillary electrophoresis (CE), mass spectroscopy (MS), and nuclear magnetic resonance spectroscopy have been used to elucidate the biosynthesis pathway, which proceeds in five reaction steps. WbjB/Cap5E catalyzed 4,6-dehydration of UDP-N-acetyl-d-glucosamine and 3- and 5-epimerization to yield a mixture of three keto-deoxy-sugars. The third intermediate compound was subsequently reduced at C-4 to UDP-2-acetamido-2,6-dideoxy-l-talose by WbjC/Cap5F. Incubation of UDP-2-acetamido-2,6-dideoxy-l-talose (UDP-TalNAc) with WbjD/Cap5G resulted in a new peak separable by CE that demonstrated identical mass and fragmentation patterns by CE-MS/MS to UDP-TalNAc. These results are consistent with WbjD/Cap5G-mediated 2-epimerization of UDP-TalNAc to UDP-FucNAc. A nonpolar gene knockout of wbjB, the first of the genes associated with this pathway, was constructed in P. aeruginosa serotype O11 strain PA103. The corresponding mutant produced rough lipopolysaccharide devoid of B-band O antigen. This lipopolysaccharide deficiency could be complemented with P. aeruginosa wbjB or with the S. aureus homolog cap5E. Insertional inactivation of either the cap5G or cap5F genes abolished capsule polysaccharide production in the S. aureus strain Newman. Providing the appropriate gene in trans, thereby complementing these mutants, fully restored the capsular polysaccharide phenotype

A combined strategy for quantitative trait loci detection by genome-wide association

We applied a range of genome-wide association (GWA) methods to map quantitative trait loci (QTL) in the simulated dataset provided by the 12th QTLMAS workshop in order to derive an effective strategy.A variance component linkage analysis revealed QTLs but with low resolution. Three single-marker based GWA methods were then applied: Transmission Disequilibrium Test and single marker regression, fitting an additive model or a genotype model, on phenotypes pre-corrected for pedigree and fixed effects. These methods detected QTL positions with high concordance to each other and with greater refinement of the linkage signals. Further multiple-marker and haplotype analyses confirmed the results with higher significance. Two-locus interaction analysis detected two epistatic pairs of markers that were not significant by marginal effects. Overall, using stringent Bonferroni thresholds we identified 9 additive QTL and 2 epistatic interactions, which together explained about 12.3% of the corrected phenotypic variance.The combination of methods that are robust against population stratification, like QTDT, with flexible linear models that take account of the family structure provided consistent results. Extensive simulations are still required to determine appropriate thresholds for more advanced model including epistasis

The Widespread Multidrug-Resistant Serotype O12 <i>Pseudomonas aeruginosa</i> Clone Emerged through Concomitant Horizontal Transfer of Serotype Antigen and Antibiotic Resistance Gene Clusters

The O-specific antigen (OSA) in Pseudomonas aeruginosa lipopolysaccharide is highly varied by sugar identity, side chains, and bond between O-repeats. These differences classified P. aeruginosa into 20 distinct serotypes. In the past few decades, O12 has emerged as the predominant serotype in clinical settings and outbreaks. These serotype O12 isolates exhibit high levels of resistance to various classes of antibiotics. Here, we explore how the P. aeruginosa OSA biosynthesis gene clusters evolve in the population by investigating the association between the phylogenetic relationships among 83 P. aeruginosa strains and their serotypes. While most serotypes were closely linked to the core genome phylogeny, we observed horizontal exchange of OSA biosynthesis genes among phylogenetically distinct P. aeruginosa strains. Specifically, we identified a “serotype island” ranging from 62 kb to 185 kb containing the P. aeruginosa O12 OSA gene cluster, an antibiotic resistance determinant (gyrA(C248T)), and other genes that have been transferred between P. aeruginosa strains with distinct core genome architectures. We showed that these genes were likely acquired from an O12 serotype strain that is closely related to P. aeruginosa PA7. Acquisition and recombination of the “serotype island” resulted in displacement of the native OSA gene cluster and expression of the O12 serotype in the recipients. Serotype switching by recombination has apparently occurred multiple times involving bacteria of various genomic backgrounds. In conclusion, serotype switching in combination with acquisition of an antibiotic resistance determinant most likely contributed to the dissemination of the O12 serotype in clinical settings

Effect of Treatment, during Primary Infection, on Establishment and Clearance of Cellular Reservoirs of HIV-1

Patients in whom virologic suppression is achieved with highly active antiretroviral therapy (HAART) retain long-lived cellular reservoirs of human immunodeficiency virus type 1 (HIV-1); this retention is an obstacle to sustained control of infection. To assess the impact that initiating treatment during primary HIV-1 infection has on this cell population, we analyzed the decay kinetics of HIV-1 DNA and of infectivity associated with cells activated ex vivo in 27 patients who initiated therapy before or <6 months after seroconversion and in whom viremia was suppressed to <50 copies/mL. The clearance rates of cellular reservoirs could not be distinguished by these techniques (median half-life, 20 weeks) during the first year of HAART. The clearance of HIV-1 DNA slowed significantly during the subsequent 3 years of treatment (median half-life, 70 weeks), consistent with heterogeneous cellular reservoirs being present. Total cell-associated infectivity (CAI) after 1 year of treatment was undetectable (<0.07 infectious units/million cells [IUPM]) in most patients initiating treatment during primary infection either before (9/9) or <6 months after (6/8) seroconversion. In contrast, all 17 control patients who initiated HAART during chronic infection retained detectable CAI after 3-6 years of treatment (median reservoir size, 1.1 IUPM; P<.0005). These results suggest that treatment <6 months after seroconversion may facilitate long-term control of cellular reservoirs that maintain HIV-1 infection during treatmen

Prevalence, incidence, and progression of myopia of school children

PURPOSE. To determine the prevalence, incidence, and progression of myopia of Chinese children in Hong Kong. METHODS. A cross-sectional survey was initially conducted. A longitudinal follow-up study was then conducted 12 months later. RESULTS. A total of 7560 children of mean age 9.33 (95% confidence interval [CI] ϭ 9.11-9.45; range, 5-16) participated in the study. Mean spherical equivalent refraction (SER) was Ϫ0.33 D (SD ϭ 11.56; range, Ϫ13.13 to ϩ14.25 D). Myopia (SER Յ Ϫ0.50 D) was the most common refractive error and was found in 36.71% Ϯ 2.87% (SD) of children. Prevalence of myopia correlated positively with older age. Children aged 11 years were almost 15 times more likely to have myopia than were children younger than 7 years (Odds ratio [OR] ϭ 14.81; 95% CI ϭ 14.17-15.48). Incidence of myopia was 144.1 Ϯ 2.31 (SD) per 1000 primary school children per annum. Increasing age was correlated with increased incidence of myopia, with highest risk in children ages 11 years (OR ϭ 2.27; 95% CI ϭ 2.11-2.44). The average annual change in SER for children with myopia (SER Յ Ϫ0.50 D) was Ϫ0.63 D (SD ϭ 3.44) compared with Ϫ0.29 D (SD ϭ 2.96) for those who were not myopic at the beginning of the study (P Ͻ 0.001). CONCLUSIONS. The results show that the prevalence and progression of myopia in Hong Kong children was much higher than those previously reported in Western countries. The longterm socioeconomic impact of these findings warrants further studies. (Invest Ophthalmol Vis Sci

Immunofluorescence Assay for Serologic Diagnosis of SARS

We evaluated a virus-infected cell-based indirect immunofluorescence assay for detecting anti–severe acute respiratory syndrome-associated coronavirus (SARS-CoV) immunoglobulin (Ig) G antibody. All confirmed SARS cases demonstrated seroconversion or fourfold rise in IgG antibody titer; no control was positive. Sensitivity and specificity of this assay were both 100%. Immunofluorescence assay can ascertain the status of SARS-CoV infection

Multi-Messenger Gravitational Wave Searches with Pulsar Timing Arrays: Application to 3C66B Using the NANOGrav 11-year Data Set

When galaxies merge, the supermassive black holes in their centers may form binaries and, during the process of merger, emit low-frequency gravitational radiation in the process. In this paper we consider the galaxy 3C66B, which was used as the target of the first multi-messenger search for gravitational waves. Due to the observed periodicities present in the photometric and astrometric data of the source of the source, it has been theorized to contain a supermassive black hole binary. Its apparent 1.05-year orbital period would place the gravitational wave emission directly in the pulsar timing band. Since the first pulsar timing array study of 3C66B, revised models of the source have been published, and timing array sensitivities and techniques have improved dramatically. With these advances, we further constrain the chirp mass of the potential supermassive black hole binary in 3C66B to less than $(1.65\pm0.02) \times 10^9~{M_\odot}$ using data from the NANOGrav 11-year data set. This upper limit provides a factor of 1.6 improvement over previous limits, and a factor of 4.3 over the first search done. Nevertheless, the most recent orbital model for the source is still consistent with our limit from pulsar timing array data. In addition, we are able to quantify the improvement made by the inclusion of source properties gleaned from electromagnetic data to `blind' pulsar timing array searches. With these methods, it is apparent that it is not necessary to obtain exact a priori knowledge of the period of a binary to gain meaningful astrophysical inferences.Comment: 14 pages, 6 figures. Accepted by Ap