Early life vitamin C deficiency does not alter morphology of hippocampal CA1 pyramidal neurons or markers of synaptic plasticity in a Guinea pig model

Approximately 15% of the Western world population, including pregnant women and their children, is characterized as vitamin C (vitC) deficient. In guinea pigs, early life vitC deficiency causes spatial memory deficits, decreased hippocampal volume and neuron numbers, in otherwise clinically healthy animals. We hypothesized that vitC deficiency leads to decreased brain-derived neurotrophic factor and synaptic plasticity markers in selected brain areas (frontal cortex, hippocampus and striatum) and cause morphological changes in cornu ammonis 1 pyramidal neurons of the hippocampus either through a direct effect or indirectly by increased oxidative stress. Fifty-seven female guinea pigs were allocated to three groups receiving either 1390, 100 or 0–50 mg vitC/kg feed for 11 weeks. Dietary vitC levels were reflected in the plasma, cortical and adrenal gland levels, however, redox imbalance was only present in the adrenal glands allowing for the investigation of a direct influence of vitC deficiency on the chosen parameters in the brain. Synaptic plasticity markers were not affected in the investigated brain areas and no differences in isolated pyramidal neuron morphology was recorded. Based on our findings, it appears that vitC deficiency may primarily elicit impaired neuronal function through increased levels of oxidative stress

Measurements of body fat is associated with markers of inflammation, insulin resistance and lipid levels in both overweight and in lean, healthy subjects

Background & aims: Low-grade inflammation is associated with fat mass in overweight. Whether this association exists in lean persons is unknown. Aims were to investigate associations between anthropometric measures of fat distribution and fat mass (% and kg) assessed by bioelectrical impedance analysis (BIA). Furthermore we wanted to investigate the relationship between fat mass and markers of insulin resistance, inflammation, and lipids in healthy subjects in different BMI categories. Methods: We compared 47 healthy overweight adults (BMI 26e40 kg/m2) and 40 lean (BMI 17e25 kg/ m2) matched for age and sex. Waist and hip circumferences, waist-to-hip ratio, waist-to-height ratio and triceps skinfold were used to evaluate fat distribution. BIA was used to estimate fat mass (% and kg). Markers of insulin resistance, lipids, inflammation and adipokines were measured. Results: Hip circumference was associated (P < 0.01) with BIA-assessed fat mass (%) in both groups (lean: regression coefficient B ¼ 0.4; overweight: B ¼ 0.5). An increase in hip circumference in all tertiles was associated with higher plasma levels of leptin, CRP and C-peptide in both groups. Conclusions: Fat mass may play a role in low-grade inflammation also in subjects within the normal range of BMI. Hip circumference may be a surrogate measure for fat mass in subjects in different BMI categories, and may be useful for identification of people with risk of developing overweight-related chronic disease

Changes in Oxidative Status Biomarkers in Saliva and Serum in the Equine Gastric Ulcer Syndrome and Colic of Intestinal Aetiology : a Pilot Study

Altres ajuts: Gobierno Regional Murcia, programa Séneca 19894/GERM/15Changes in the oxidative status of the blood of horses suffering from gastric ulcers and colic of intestinal aetiology (CIE) have been reported. However, saliva can also be a source of biomarkers of oxidative status. Therefore, this study aims to validate automated assays for the measurement of oxidative status biomarkers (ferric reducing ability of saliva/serum-FRAS/FRAP, cupric reducing antioxidant capacity-CUPRAC, the Trolox equivalent antioxidant capacity-TEAC, uric acid, and advanced oxidation protein products-AOPP) in the saliva and serum of horses, to assess their changes in the different ulcer gastric diseases (squamous-ESGD and glandular-EGGD) and CIE, and to evaluate their relationship with serum amyloid A (SAA), adenosine deaminase (ADA), and the systemic inflammatory response syndrome (SIRS) status. The assays showed a low imprecision and good linearity with enough sensitivity in both fluids. In EGGD, higher levels of FRAS, uric acid, and AOPP in saliva were observed compared to the healthy group, correlating with the salivary ADA levels. Horses with CIE showed increases in uric acid concentrations in serum associated with their SIRS status and outcome of the disease. In conclusion, analytes related to the oxidative status can be measured in the saliva and serum from horses by automated assays, and some of them can potentially be assessed as biomarkers in horses with gastric ulcers and CIE

Colorectal cancer-associated SNP rs17042479 is involved in the regulation of NAF1 promoter activity

A novel risk locus at 4q32.2, located between the Nuclear Assembly Factor 1 (NAF1) and Follistatin Like 5 (FSTL5) genes, was associated with increased risk of developing colorectal cancer (CRC), with SNP rs17042479 being the most associated. However, the link between CRC development and the risk locus at 4q32.2 is unknown. We investigated the promoter activity of NAF1 and FSTL5 and analyzed the risk locus at 4q32.2 as gene regulatory region. Our results showed that the activity of the FSTL5 promoter was low compared to the NAF1 promoter. Analyses of the NAF1 promoter in conjunction with the region containing the risk locus at 4q32.2 showed that the region functions as gene regulatory region with repressor activity on NAF1 promoter activity. The SNP rs17042479(G) increased the repressor effect of the region. CRC patients’ biopsies were genotyped for SNP rs17042479(A/G), and NAF1 expression profiles were examined. We found an association between SNP rs17042479(G), cancer stage and tumor location. Additionally, patients with SNP rs17042479(G) showed lower NAF1 expression in comparison to patients with SNP rs17042479(A) in tumor tissue and the NAF1 expression in tumor tissue was lower compared to healthy tissue. The results in the study imply that reduced NAF1 expression in the tumor contribute to a more aggressive phenotype. Furthermore, this study suggests that the SNP rs17042479(G) change the expression of NAF1 and thereby increases the risk of developing CRC

Effect of the fat composition of a single high-fat meal on inflammatory markers in healthy young women

The aim of the present study was to examine the effect of a single high-fat meal with different fat quality on circulating inflammatory markers and gene expression in peripheral blood mononuclear cells (PBMC) to elucidate the role of fat quality on postprandial inflammation. A postprandial study with fourteen healthy females consuming three test meals with different fat quality was performed. Test days were separated by 2 weeks. Fasting and postprandial blood samples at 3 and 6 h after intake were analysed. The test meal consisted of three cakes enriched with coconut fat (43 % energy as saturated fat and 1 % energy as a-linolenic acid (ALA)), linseed oil (14 % energy as ALA and 30 % energy as saturated fat) and cod liver oil (5 % energy as EPA and DHA and 5 % energy as ALA in addition to 31 % energy as saturated fat). In addition, ex vivo PBMC experiments were performed in eight healthy subjects investigating the effects of EPA and ALA on release and gene expression of inflammatory markers. The IL-8 mRNA level was significantly increased after intake of the cod liver oil cake at 6 h compared with fasting level, which was significantly different from the effect observed after the intake of linseed cake. In contrast, no effect was seen on circulating level of IL-8. In addition, ALA and EPA were shown to elicit different effects on the release and mRNA expression levels of inflammatory markers in PBMC cultured ex vivo, with EPA having the most prominent proinflammatory potentia

Transcriptional and epigenomic profiling identifies YAP signaling as a key regulator of intestinal epithelium maturation

During intestinal organogenesis, equipotent epithelial progenitors mature into phenotypically distinct stem cells that are responsible for lifelong maintenance of the tissue. While the morphological changes associated with the transition are well characterized, the molecular mechanisms underpinning the maturation process are not fully understood. Here, we leverage intestinal organoid cultures to profile transcriptional, chromatin accessibility, DNA methylation, and three-dimensional (3D) chromatin conformation landscapes in fetal and adult epithelial cells. We observed prominent differences in gene expression and enhancer activity, which are accompanied by local changes in 3D organization, DNA accessibility, and methylation between the two cellular states. Using integrative analyses, we identified sustained Yes-Associated Protein (YAP) transcriptional activity as a major gatekeeper of the immature fetal state. We found the YAP-associated transcriptional network to be regulated at various levels of chromatin organization and likely to be coordinated by changes in extracellular matrix composition. Together, our work highlights the value of unbiased profiling of regulatory landscapes for the identification of key mechanisms underlying tissue maturation

“The people who are out of ‘right’ English”: Japanese university students' social evaluations of English language diversity and the internationalisation of Japanese higher education

Previous research indicates that evaluations of speech forms reflect stereotypes of, and attitudes towards, the perceived group(s) of speakers of the language/variety under consideration. This study, employing both implicit and explicit attitude measures, investigates 158 Japanese university students' perceptions of forms of UK, US, Japanese, Chinese, Thai and Indian English speech. The results show a general convergence between students' explicit and implicit attitudes, for instance, regarding US and UK English as the most correct, and solidarity with Japanese speakers of English. The findings are discussed in relation to intergroup relations between the traditional Japanese cohort and specific groups of overseas students, particularly in light of recent internationalisation policies adopted by many Japanese universities, and the resultant increase in international students from South and East Asia

Identification of known and novel recurrent viral sequences in data from multiple patients and multiple cancers

Virus discovery from high throughput sequencing data often follows a bottom-up approach where taxonomic annotation takes place prior to association to disease. Albeit effective in some cases, the approach fails to detect novel pathogens and remote variants not present in reference databases. We have developed a species independent pipeline that utilises sequence clustering for the identification of nucleotide sequences that co-occur across multiple sequencing data instances. We applied the workflow to 686 sequencing libraries from 252 cancer samples of different cancer and tissue types, 32 non-template controls, and 24 test samples. Recurrent sequences were statistically associated to biological, methodological or technical features with the aim to identify novel pathogens or plausible contaminants that may associate to a particular kit or method. We provide examples of identified inhabitants of the healthy tissue flora as well as experimental contaminants. Unmapped sequences that co-occur with high statistical significance potentially represent the unknown sequence space where novel pathogens can be identified

Molecular characterization of irinotecan (SN-38) resistant human breast cancer cell lines

Background: Studies in taxane and/or anthracycline refractory metastatic breast cancer (mBC) patients have shown approximately 30% response rates to irinotecan. Hence, a significant number of patients will experience irinotecan-induced side effects without obtaining any benefit. The aim of this study was to lay the groundwork for development of predictive biomarkers for irinotecan treatment in BC. Methods: We established BC cell lines with acquired or de novo resistance to SN-38, by exposing the human BC cell lines MCF-7 and MDA-MB-231 to either stepwise increasing concentrations over 6months or an initial high dose of SN-38 (the active metabolite of irinotecan), respectively. The resistant cell lines were analyzed for cross-resistance to other anti-cancer drugs, global gene expression, growth rates, TOP1 and TOP2A gene copy numbers and protein expression, and inhibition of the breast cancer resistance protein (ABCG2/BCRP) drug efflux pump. Results: We found that the resistant cell lines showed 7-100 fold increased resistance to SN-38 but remained sensitive to docetaxel and the non-camptothecin Top1 inhibitor LMP400. The resistant cell lines were characterized by Top1 down-regulation, changed isoelectric points of Top1 and reduced growth rates. The gene and protein expression of ABCG2/BCRP was up-regulated in the resistant sub-lines and functional assays revealed BCRP as a key mediator of SN-38 resistance. Conclusions: Based on our preclinical results, we suggest analyzing the predictive value of the BCRP in breast cancer patients scheduled for irinotecan treatment. Moreover, LMP400 should be tested in a clinical setting in breast cancer patients with resistance to irinotecan