Microbiota-Immune System Interactions in Diet-Induced Metabolic Syndrome

Metabolic syndrome (MetS) is the collective term for the interrelated abnormalities associated with obesity. Features of MetS promote a variety of chronic diseases that are amongst humanity’s most pressing public-health problems. MetS is increasingly appreciated to be associated with chronic inflammation driven by an imbalance of host immune cells and expression of pro-inflammatory cytokines. While numerous genetic factors influence the development of MetS, the increased incidence of this disorder occurring amidst changes in food production and dietary habits has led to the presumption that diet and the intestinal microbiota is a major determinant of MetS. The overall goal of my studies was to investigate this hypothesis. First, I sought to identify microbiota-based markers that might predict diet-induced obesity. Targeted and untargeted approaches were utilized including 16S rRNA gene amplicon sequencing for microbiome profiling and a TMT-based multiplexed mass spectrometry approach for analysis of the fecal metaproteome. Notably, we show that the fecal metaproteome appears to be a promising candidate for distinguishing differential responses to high-fat diets (HFD) and provides insight into potential mechanisms regarding the host-microbiota interactions mediating response to HFD exposure and highlights putative biomarkers for predicting obesity. Next, I explored gut-bacterial derived activators of innate-immune signaling as key drivers of adipose inflammation and insulin resistance that results from HFD. Hence, another goal of this study was to examine how ablation of gut microbiota influenced HFD-induced inflammation utilizing three approaches to alter microbiota; antibiotics, germ-free mice, and Altered Schaedler Flora mice. We described HFD–induced, microbiota-dependent changes in immune cell populations in adipose tissue that associated with pro-inflammatory gene expression and features of MetS. Lastly, I sought to ameliorate the inflammation that promotes MetS. One common feature of inflammation-associated microbiotas is increased levels of flagellin believed to cause intestinal inflammation due to flagellin’s ability to activate pro-inflammatory gene expression. Hence, I hypothesize that boosting levels of flagellin-specific IgA may help regulate flagellated bacteria and, protect against development of intestinal inflammation. Herein, we describe that administration of purified flagellin elicits a robust anti-flagellin fecal IgA response that reshapes microbiota composition, reduces flagellin expression, and protects against experimental colitis and MetS

Adverse drug reactions in the view of clinical pharmacology: a focus on the female population

The thalidomide tragedy drew significant attention to the gap between drug development and patients’ safety, notably in women. First, our pharmaco-epidemiological research showed that among pregnant women, drug utilization increased with age. Those over 35 years and a history of chronic drug use were at a clear increased risk of polypharmacy and exposure to potentially harmful medications. This highlights the need to individualize preconception drug counseling for prospective mothers. Second, we examined outcomes following drug use during pregnancy, including birth defects and preeclampsia. In these studies, vascular disrupting drugs were associated with an increased risk of malformations in the exposed offspring. Prevalence rates of exposure and malformations were low and research with big data is therefore warranted. Regarding reactive-intermediate inducing drugs, increased risks to the nervous system were observed. Risks were both structural and functional, especially when the exposure occurred in critical pregnancy periods of brain development and prolonged. In addition, differential risks of antidepressants according to targeted transporters/receptors for preeclampsia were found for tricyclic antidepressants and antidepressants with 5-HT2A antagonism. This was most noticeable when these drugs were continued beyond week 20 of gestation. Finally, we studied differential risks according to sex where type 2 diabetes was more frequently seen in patients treated with antidepressants. For drugs that antagonize M3 receptors, the risk of type 2 diabetes increased significantly for female users, but not in males. The findings suggest that drugs can pose differential risks in females regarding their therapeutic and adverse effects and, this needs to be addressed more in larger pharmacovigilance studies

Adverse drug reactions in the view of clinical pharmacology: a focus on the female population

The thalidomide tragedy drew significant attention to the gap between drug development and patients’ safety, notably in women. First, our pharmaco-epidemiological research showed that among pregnant women, drug utilization increased with age. Those over 35 years and a history of chronic drug use were at a clear increased risk of polypharmacy and exposure to potentially harmful medications. This highlights the need to individualize preconception drug counseling for prospective mothers. Second, we examined outcomes following drug use during pregnancy, including birth defects and preeclampsia. In these studies, vascular disrupting drugs were associated with an increased risk of malformations in the exposed offspring. Prevalence rates of exposure and malformations were low and research with big data is therefore warranted. Regarding reactive-intermediate inducing drugs, increased risks to the nervous system were observed. Risks were both structural and functional, especially when the exposure occurred in critical pregnancy periods of brain development and prolonged. In addition, differential risks of antidepressants according to targeted transporters/receptors for preeclampsia were found for tricyclic antidepressants and antidepressants with 5-HT2A antagonism. This was most noticeable when these drugs were continued beyond week 20 of gestation. Finally, we studied differential risks according to sex where type 2 diabetes was more frequently seen in patients treated with antidepressants. For drugs that antagonize M3 receptors, the risk of type 2 diabetes increased significantly for female users, but not in males. The findings suggest that drugs can pose differential risks in females regarding their therapeutic and adverse effects and, this needs to be addressed more in larger pharmacovigilance studies

Trade Liberalization and Development in ICT Sector and its impact on household welfare in Viet Nam

The ICT sector in Viet Nam had not been developed until the 1980s. However, over the last decade of rapid growth, it has had a powerful impact on many aspects of life in this country. Although the ICT sector is still at an early stage of development and lags behind many other countries in the region, the government of Viet Nam made strong commitments to upgrade the nation’s ICT capability and implemented significant reforms in terms of trade and investment liberalization in ICT sector over the last decade.Trade Liberalization, ICT, Household welfare, Viet Nam

A unique X-ray unabsorbed Seyfert 2 galaxy IRAS F01475-0740

X-ray unabsorbed Seyfert 2 galaxies appear to have X-ray absorption column densities that are too low (NH < 10^22 cm-2) to explain the absence of broad emission lines in their optical spectra, challenging the standard AGN unification model. In this paper we report Suzaku exposure on the X-ray unabsorbed Seyfert 2 galaxy IRAS F01475-0740, in which a hidden broad line region was detected through spectropolarimetric observation. The X-ray data show rapid and significant variations on time scales down to 5 ks, indicating that we are viewing its central engine directly. A newly obtained optical spectrum and previous optical/X-ray data suggest that state transition is unlikely in this source. These make IRAS F01475-0740 a very peculiar X-ray unabsorbed Seyfert 2 galaxy which can only be explained by absorption from materials with abnormally high dust-to-gas ratio (by a factor of > 4 larger than Galactic). This is in contrast to most AGNs, which typically show dust-to-gas ratios 3 - 100 times lower than the Galactic.Comment: 13 pages, 3 figures, 1 table, accepted to the Astrophysical Journal Letter

Exposure to particles from laser printers operating within office workplaces

While recent research has provided valuable information as to the composition of laser printer particles, their formation mechanisms, and explained why some printers are emitters whilst others are low emitters, fundamental questions relating to the potential exposure of office workers remained unanswered. In particular, (i) what impact does the operation of laser printers have on the background particle number concentration (PNC) of an office environment over the duration of a typical working day?; (ii) what is the airborne particle exposure to office workers in the vicinity of laser printers; (iii) what influence does the office ventilation have upon the transport and concentration of particles?; (iv) is there a need to control the generation of, and/or transport of particles arising from the operation of laser printers within an office environment?; (v) what instrumentation and methodology is relevant for characterising such particles within an office location? We present experimental evidence on printer temporal and spatial PNC during the operation of 107 laser printers within open plan offices of five buildings. We show for the first time that the eight-hour time-weighted average printer particle exposure is significantly less than the eight-hour time-weighted local background particle exposure, but that peak printer particle exposure can be greater than two orders of magnitude higher than local background particle exposure. The particle size range is predominantly ultrafine (< 100nm diameter). In addition we have established that office workers are constantly exposed to non-printer derived particle concentrations, with up to an order of magnitude difference in such exposure amongst offices, and propose that such exposure be controlled along with exposure to printer derived particles. We also propose, for the first time, that peak particle reference values be calculated for each office area analogous to the criteria used in Australia and elsewhere for evaluating exposure excursion above occupational hazardous chemical exposure standards. A universal peak particle reference value of 2.0 x 104 particles cm-3 has been proposed

Rectangular Stress-block Parameters for Fly-ash and Slag Based Geopolymer Concrete

Although there has been a numerous quantity of studies investigating the mechanical properties of geopolymer concrete (GPC), parameters for designing GPC structures are still not systematically investigated and carefully justified. ACI rectangular stress-block parameters are able to predict well the strength of conventional concrete structures but their applicability for GPC is questionable. This study aims to establish new sets of rectangular stress-block parameters for GPC with a broad range of the compressive strength up to 66 MPa. The proposed rectangular stress-block parameters in this study are based on two analytical concrete stress-strain models and measured curves from previous studies of GPC materials. The results from this study show that the use of ACI recommendations for concrete structure in designing GPC beams is still acceptable with high accuracy. However, the axial load-carrying capacity of GPC columns computed by ACI parameters deviate significantly from the experimental results while the proposed parameters provide a good correlation with these experimental data. The significant difference is mainly due to the modification of k3, which is the ratio of concrete strength in real structures to standard cylinder samples. This study suggests that the assumption of k3 = 0.9 in previous studies for conventional Portland concrete is not suitable for use in deriving the stress-block parameters of GPC. In some cases, this ratio should be reduced to 0.7 depending on the curing condition