Genome wide transcriptome profiling of a murine acute melioidosis model reveals new insights into how Burkholderia pseudomallei overcomes host innate immunity

Abstract Background At present, very little is known about how Burkholderia pseudomallei (B. pseudomallei) interacts with its host to elicit melioidosis symptoms. We established a murine acute-phase melioidosis model and used DNA microarray technology to investigate the global host/pathogen interaction. We compared the transcriptome of infected liver and spleen with uninfected tissues over an infection period of 42 hr to identify genes whose expression is altered in response to an acute infection. Results Viable B. pseudomallei cells were consistently detected in the blood, liver and spleen during the 42 hr course of infection. Microarray analysis of the liver and spleen over this time course demonstrated that genes involved in immune response, stress response, cell cycle regulation, proteasomal degradation, cellular metabolism and signal transduction pathways were differentially regulated. Up regulation of toll-like receptor 2 (TLR2) gene expression suggested that a TLR2-mediated signalling pathway is responsible for recognition and initiation of an inflammatory response to the acute B. pseudomallei infection. Most of the highly elevated inflammatory genes are a cohort of "core host immune response" genes commonly seen in general inflammation infections. Concomitant to this initial inflammatory response, we observed an increase in transcripts associated with cell-death, caspase activation and peptidoglysis that ultimately promote tissue injury in the host. The complement system responsible for restoring host cellular homeostasis and eliminating intracellular bacteria was activated only after 24 hr post-infection. However, at this time point, diverse host nutrient metabolic and cellular pathways including glycolysis, fatty acid metabolism and tricarboxylic acid (TCA) cycle were repressed. Conclusions This detailed picture of the host transcriptional response during acute melioidosis highlights a broad range of innate immune mechanisms that are activated in the host within 24 hrs, including the core immune response commonly seen in general inflammatory infections. Nevertheless, this activation is suppressed at 42 hr post-infection and in addition, suboptimal activation and function of the downstream complement system promotes uncontrolled spread of the bacteria.</p

Differential effects of calcium- and vitamin D-fortified milk with FOS-inulin compared to regular milk, on bone biomarkers in Chinese pre- and postmenopausal women

PURPOSE: To compare the effects of a high-calcium vitamin D-fortified milk with added FOS-inulin versus regular milk on serum parathyroid hormone, and bone turnover markers in premenopausal (Pre-M) and postmenopausal (PM) women over 12 weeks. METHODS: Premenopausal women (n = 136, mean age 41 (±5) years) and postmenopausal women [n = 121, mean age 59 (±4) years] were recruited, and each age group randomised into two groups to take two glasses per day of control = regular milk (500 mg calcium per day) or intervention (Int) = fortified milk (1000 mg calcium for pre-M women and 1200 mg calcium for PM women, 96 mg magnesium, 2.4 mg zinc, 15 µg vitamin D, 4 g FOS-inulin per day). At baseline, week 4 and week 12 serum minerals and bone biochemical markers were measured and bone density was measured at baseline. RESULTS: Mean 25-hydroxyvitamin D [25(OH) vitamin D3] levels among groups were between 49 and 65 nmol/L at baseline, and over the 12 weeks of supplementation, the fortified milk improved vitamin D status in both Int groups. CTx-1 and PINP reduced significantly in both Pre-M and PM groups over the 12 weeks, with the changes in CTx-1 being significantly different (P < 0.035) between PM control and PM Int groups at week 12. Parathyroid hormone levels were significantly reduced in all groups over time, except for control PM group where levels increased at 12 weeks. CONCLUSION: The overall pattern of responses indicates that while both regular milk and fortified milk reduce bone resorption in young and older women, fortified milk is measurably more effective

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Fortified Milk Supplementation Improves Vitamin D Status, Grip Strength, and Maintains Bone Density in Chinese Premenopausal Women Living in Malaysia

This study compared the effects of a high-calcium vitamin D fortified milk with added FOS-Inulin versus regular milk on serum parathyroid hormone (PTH), vitamin D status, grip strength (GS), as well as bone density in Chinese premenopausal women over 52 weeks. Premenopausal women (n = 133), mean age 41 (&#177;5.1) years were randomized into control (n = 66; regular milk at 500 mg calcium per day) or intervention (Int; n = 67; fortified milk at 1200 mg calcium, 15 μg vitamin D, and 4 g FOS-Inulin per day) groups. Assessments were at baseline, weeks 12, 24, 36, and 52 for changes in vitamin D status, levels of PTH, and GS. Bone mineral densities (BMDs) of the lumbar spine (LS), femoral neck (FN), and whole body (WB) were assessed at baseline and week 52 using GE Lunar iDEXA (GE Healthcare, Madison, WI). At baseline, WB lean mass was positively associated with LS BMD (r = 0.30, p &lt; 0.001) and FN BMD (r = 0.33, p = 0.003). Baseline 25(OH) vitamin D3 levels were 48.6 and 53.2 nmol/L (p = 0.57), respectively, and after the 12 months at 60.8 nmol/L (Int) versus 55.0 nmol/L (controls; p &lt; 0.05 for change from baseline for both groups; no difference between groups at week 52). PTH levels decreased in both groups compared to baseline (p &lt; 0.001), with no significant difference between groups. WB bone mineral content (BMC) and FN Z-score increased significantly in the Int group (p = 0.024 and p = 0.008). GS was positively associated with body weight, increasing in both groups over 52 weeks. Fortified milk improved vitamin D status, WB BMC, and Z-score of the FN, while regular milk maintained BMD. In addition, vitamin D status and GS improved