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Abstract Recent findings have shown an inverse association between circulating C15:0/C17:0 fatty acids with disease risk, therefore, their origin needs to be determined to understanding their role in these pathologies. Through combinations of both animal and human intervention studies, we comprehensively investigated all possible contributions of these fatty acids from the gut-microbiota, the diet, and novel endogenous biosynthesis. Investigations included an intestinal germ-free study and a C15:0/C17:0 diet dose response study. Endogenous production was assessed through: a stearic acid infusion, phytol supplementation, and a Hacl1−/− mouse model. Two human dietary intervention studies were used to translate the results. Finally, a study comparing baseline C15:0/C17:0 with the prognosis of glucose intolerance. We found that circulating C15:0/C17:0 levels were not influenced by the gut-microbiota. The dose response study showed C15:0 had a linear response, however C17:0 was not directly correlated. The phytol supplementation only decreased C17:0. Stearic acid infusion only increased C17:0. Hacl1−/− only decreased C17:0. The glucose intolerance study showed only C17:0 correlated with prognosis. To summarise, circulating C15:0 and C17:0 are independently derived; C15:0 correlates directly with dietary intake, while C17:0 is substantially biosynthesized, therefore, they are not homologous in the aetiology of metabolic disease. Our findings emphasize the importance of the biosynthesis of C17:0 and recognizing its link with metabolic disease.
Abstract Introduction: Phthalate exposure may reduce intellectual development in young children. In 2011, numerous Taiwanese children had been reported to have consumed phthalate-tainted products. We investigated the effects of phthalate exposure on the intellectual development of these children after the 2011 Taiwan di-2-ethylhexyl phthalate (DEHP) episode. Methods: We recruited 204 children, aged 3–12 y, from 3 hospitals in Taiwan between 2012 and 2013. First-morning urine samples were collected for analyzing 5 phthalate metabolites. We applied a Bayesian model to estimate the past DEHP exposure (estDEHPADD) of each participant before the 2011 DEHP episode. Demographic information, consumption of phthalate-tainted products, and maternal education, of each participant were obtained using a questionnaire. We used the Wechsler intelligence evaluation tools for assessing the children’s and maternal intelligence quotient. Results and discussion: The median levels of mono-2-ethylhexyl phthalate, mono(2-ethyl-5-hydroxyhexyl) phthalate, mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono-n-butyl phthalate, and mono-iso-butyl phthalate in the children were 9.97, 45.8, 32.2, 46.2, and 24.3 μg/g creatinine, respectively. Using the aforementioned urinary phthalate metabolites, we found that the children’s verbal comprehension index (N =98) was significantly negatively associated with urinary log10 MEOHP (β, −11.92; SE, 5.33; 95%CI, −22.52~ −1.33; P=0.028) and log10 ΣDBP metabolites (β, −10.95; SE, 4.93; 95%CI, −20.74~ −1.16; P=0.029) after adjustment for age, gender, maternal IQ and education, passive smoking, estDEHPADD, active and passive smoking during pregnancy. Through a tolerable daily intake-based approach, we only found a significant negative association between past estimate DEHPADD and VIQ≥3–<6 in preschool children whereas no correlation was observed between current DEHP exposure and IQ≥3–<6 score with/ without estimate DEHPADD adjustment. It revealed that the effect of past high-DEHP exposure on verbal-related neurodevelopment of younger child are more sensitive. Conclusion: Our results are consistent with the hypothesis that exposure to DEHP and DnBP affects intellectual development in preschool and school-aged children, particularly their language learning or expression ability.
A 10 kilo-tonne dual-phase liquid argon TPC is one of the detector options considered for the Deep Underground Neutrino Experiment (DUNE). The detector technology relies on amplification of the ionisation charge in ultra-pure argon vapour and offers several advantages compared to the traditional single-phase liquid argon TPCs. A 4.2 tonne dual-phase liquid argon TPC prototype, the largest of its kind, with an active volume of 3 × 1 × 1 m3 has been constructed and operated at CERN. In this paper we describe in detail the experimental setup and detector components as well as report on the operation experience. We also present the first results on the achieved charge amplification, prompt scintillation and electroluminescence detection, and purity of the liquid argon from analyses of a collected sample of cosmic ray muons.
The 3×1×1 m3 demonstrator is a dual phase liquid argon time projection chamber that has recorded cosmic rays events in 2017 at CERN. The light signal in these detectors is crucial to provide precise timing capabilities. The performance of the photon detection system, composed of five PMTs, are discussed. The collected scintillation and electroluminescence light created by passing particles has been studied in various detector conditions. In particular, the scintillation light production and propagation processes have been analyzed and compared to simulations, improving the understanding of some liquid argon properties.
Abstract A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74–0.81, p = 3.1 × 10−31).
Abstract In this study we aim to examine gene–environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 × 10−3). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 × 10−4). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.