HLA-B*58:01 and rs9263726 have a linkage, but not absolute linkage disequilibrium in Han Chinese population

HLA-B*58:01 has been demonstrated to be associated with allopurinol-induced severe cutaneous adverse reactions. Since HLA-B*58:01 is too complicated to be identified, it is necessary to select an appropriate surrogate biomarker. In Japan, the rs9263726 allele was considered as a surrogate biomarker for HLA-B*58:01, but this was not the case with the Australian cohort. Due to the conflict results, in this study, we aim to demonstrate whether the rs9263726 allele is a surrogate biomarker for HLA-B*58:01 in Han Chinese population. A total of 353 samples (200 cases from the south and 153 cases from the north) were selected to detect HLA-B*58:01 and rs9263726 allele. The HLA-B*58:01 was identified by sequencing-based method, and the rs9263726 allele was identified by Taqman SNP Genotyping Assays. The results showed that the two alleles had a linkage, but not absolute linkage disequilibrium in Han Chinese population.

Human rhomboid family-1 modulates clathrin coated vesicle-dependent pro-transforming growth factor α membrane trafficking to promote breast cancer progression

Epidermal growth factor receptor (EGFR) signalling is critical in epithelial cancer development. Human rhomboid family-1 (RHBDF1) facilitates the secretion of TGFα, an EGFR ligand, in breast cancer; however, the underlying mechanism remains unclear. We evaluated the role for RHBDF1 in clathrin-coated vesicle (CCV)-dependent pro-TGFα membrane trafficking in breast cancer cells upon stimulation by G-protein coupled receptor (GPCR) agonists.

Modelling the spreading process of extreme risks via a simple agent-based model: Evidence from the China stock market

This paper focuses on investigating financial returns' extreme risks, which are defined as the negative log-returns over a certain threshold. A simple agent-based model is constructed to explain the behavior of the market traders when extreme risks occur. We consider both the volatility clustering and the heavy tail characteristics when constructing the model. Empirical study uses the China securities index 300 daily level data and applies the method of simulated moments to estimate the model parameters. The stationarity and ergodicity tests provide evidence that the proposed model is good for estimation and prediction. The goodness-of-fit measures show that our proposed model fits the empirical data well. Our estimated model performs well in out-of-sample Value-at-Risk prediction, which contributes to the risk management.

MaaS in Bike-Sharing: Smart Phone GPS Data Based Layout Optimization and Emission Reduction Potential Analysis

Vitamin D status after colorectal cancer diagnosis and patient survival according to immune response to tumour

High-level plasma 25-hydroxyvitamin D [25(OH)D] has been associated with lower colorectal cancer incidence and mortality. Considering evidence indicating immunomodulatory effects of vitamin D, we hypothesised that survival benefits from high systemic vitamin D level might be stronger for colorectal carcinoma with lower immune response to tumour.

Sex differences in the gastrointestinal tract of rats and the implications for oral drug delivery

Pre-clinical research often uses rodents as animal models to guide the selection of appropriate oral drug and dose selection in humans. However, traditionally, such research fails to consider the gastrointestinal differences between the sexes of rats and the impact on oral drug delivery. This study aimed to identify and characterise the potential sex-related differences in the gastrointestinal environment of sacrificed male and female Wistar rats. Their gastrointestinal tracts were excised and segmented into the stomach, duodenum, jejunum, ileum, caecum and colon. The respective contents and tissue sections were collected and analysed for pH, buffer capacity, surface tension, osmolality and relative P-glycoprotein (P-gp) expression. The pH in the stomach of females was found to be lower than in males. Female rats also exhibited a higher buffer capacity in the caecum and colon when compared with their male counterparts. Males were found to have a higher osmolality than females in the duodenum, ileum and colon. Significant sex differences (p < 0.05) in surface tension were observed in the ileum, where females exhibited a higher surface tension. Interestingly, female rats displayed significantly higher relative P-gp expression levels (p < 0.05) when compared with male rats in the duodenum (1.24 ± 0.85 vs. 0.36 ± 0.26), jejunum (1.45 ± 0.88 vs. 0.38 ± 0.26) and ileum (0.92 ± 0.43 vs. 0.40 ± 0.18) but not in the colon (0.5 ± 0.32 vs. 0.33 ± 0.16) segments. The work reported has demonstrated the stark physiological differences between male and female rats at a physiological level, indicating how the 'sex of the gut' could influence oral drug delivery. These findings, therefore, are of critical importance in pre-clinical research and drug development.

An animal's sex influences the effects of the excipient PEG 400 on the intestinal P-gp protein and mRNA levels, which has implications for oral drug absorption

There is a growing body of evidence which suggests that formerly regarded "inert" pharmaceutical excipients have the potential to influence oral drug bioavailability. The solubilizing agent polyethylene glycol 400 (PEG 400), for instance, has a sex-specific effect on P-glycoprotein (P-gp)-mediated drug bioavailability. We hypothesized that such an effect could be via PEG-induced alteration of P-gp activity and/or expression to different extents in males and females. To test this hypothesis in vivo, we investigated the influence of orally administered PEG 400 on the protein content and mRNA expression of P-gp in different regions of the gastrointestinal tract in male and female rats. Fasted rats received an oral dose of PEG 400 and at different time intervals, rats were sacrificed and their intestines were collected. The P-gp protein and mRNA expression in different intestinal segments (duodenum, jejunum, ileum and colon) were measured by Western blotting and PCR, respectively. It was found that P-gp protein and mRNA levels increased along the gastrointestinal tract in control animals (i.e. without PEG administration), and was higher in males compared to the female rats. The oral administration of PEG 400 decreased the P-gp expression in the jejunum, ileum and colon of males but not in the corresponding segments in females. This sex-dependent influence of PEG 400 on P-gp levels reflects and explains the sex-related effect of PEG 400 on oral absorption of certain drugs. The data further adds to the growing literature on the importance of taking into consideration an individual's sex for optimal drug administration.

P-glycoprotein expression in the gastrointestinal tract of male and female rats is influenced differently by food

The aim of this study was to explore the influence of food on P-glycoprotein (P-gp) relative expression in both male and female rats, and its effect on intestinal permeation of P-gp substrates (ranitidine and ganciclovir) and a P-gp non-substrate (metformin). The intestine of 12 male and 12 female Wistar rats were excised and segmented into the duodenum, jejunum, ileum and colon. P-gp extracted from each segment was then determined via Western-blotting. In male rats, the relative P-gp expression decreased significantly after food intake in all segments of the intestine except in the duodenum. The most notable change was demonstrated in the colon where relative expression decreased from 1.75 ± 0.36 in the fasted-state to 0.31 ± 0.15 in the fed-state. In female rats, a fundamentally different result was observed. Food ingestion resulted in a significant increase in relative P-gp expression in all regions of the intestine except in the colon. The largest difference was observed in the jejunum of the fed-state female rat intestine where P-gp expression was 1.76 ± 0.95 which was a six-fold increase from the fasted state at 0.34 ± 0.13. Intestinal permeation studies in an Ussing chamber showed that both ganciclovir and ranitidine exhibited a sex difference in intestinal permeability in the fasted-state. No sex differences and food effects were observed on metformin small intestine permeability. The permeability results of the three drugs highly supported that there was a sex-related food effect on P-gp function in the small intestine. In summary, the current study reports stark differences between male and female rats at a physiological level relating to P-gp expression and the influence of food.

Stress induced by incorporation of sulfate ions into aluminum oxide films

Policy implications from revealing consumption-based carbon footprint of major economic sectors in Japan