Intronic Cis-Regulatory Modules Mediate Tissue-Specific and Microbial Control of angptl4/fiaf Transcription

The intestinal microbiota enhances dietary energy harvest leading to increased fat storage in adipose tissues. This effect is caused in part by the microbial suppression of intestinal epithelial expression of a circulating inhibitor of lipoprotein lipase called Angiopoietin-like 4 (Angptl4/Fiaf). To define the cis-regulatory mechanisms underlying intestine-specific and microbial control of Angptl4 transcription, we utilized the zebrafish system in which host regulatory DNA can be rapidly analyzed in a live, transparent, and gnotobiotic vertebrate. We found that zebrafish angptl4 is transcribed in multiple tissues including the liver, pancreatic islet, and intestinal epithelium, which is similar to its mammalian homologs. Zebrafish angptl4 is also specifically suppressed in the intestinal epithelium upon colonization with a microbiota. In vivo transgenic reporter assays identified discrete tissue-specific regulatory modules within angptl4 intron 3 sufficient to drive expression in the liver, pancreatic islet β-cells, or intestinal enterocytes. Comparative sequence analyses and heterologous functional assays of angptl4 intron 3 sequences from 12 teleost fish species revealed differential evolution of the islet and intestinal regulatory modules. High-resolution functional mapping and site-directed mutagenesis defined the minimal set of regulatory sequences required for intestinal activity. Strikingly, the microbiota suppressed the transcriptional activity of the intestine-specific regulatory module similar to the endogenous angptl4 gene. These results suggest that the microbiota might regulate host intestinal Angptl4 protein expression and peripheral fat storage by suppressing the activity of an intestine-specific transcriptional enhancer. This study provides a useful paradigm for understanding how microbial signals interact with tissue-specific regulatory networks to control the activity and evolution of host gene transcription

Constitutive modelling of skin ageing

The objective of this chapter is to review the main biomechanical and structural aspects associated with both intrinsic and extrinsic skin ageing, and to present potential research avenues to account for these effects in mathematical and computational models of the skin. This will be illustrated through recent work of the authors which provides a basis to those interested in developing mechanistic constitutive models capturing the mechanobiology of skin across the life course

Purinergic signalling and immune cells

This review article provides a historical perspective on the role of purinergic signalling in the regulation of various subsets of immune cells from early discoveries to current understanding. It is now recognised that adenosine 5'-triphosphate (ATP) and other nucleotides are released from cells following stress or injury. They can act on virtually all subsets of immune cells through a spectrum of P2X ligand-gated ion channels and G protein-coupled P2Y receptors. Furthermore, ATP is rapidly degraded into adenosine by ectonucleotidases such as CD39 and CD73, and adenosine exerts additional regulatory effects through its own receptors. The resulting effect ranges from stimulation to tolerance depending on the amount and time courses of nucleotides released, and the balance between ATP and adenosine. This review identifies the various receptors involved in the different subsets of immune cells and their effects on the function of these cells

Total family unit Helicobacter pylori eradication and pediatric re-infection rates

Background. Re-infection with Helicobacter pylori is more common in children than adults, and it is generally accepted that the family unit plays a significant role in primary childhood infection. We investigated whether the family unit plays a significant role in pediatric re-infection and if eradication of H. pylori from the entire family reduces the risk of childhood re-infection.Methods. Fifty families, each with an H. pylori-infected pediatric index case (mean age 9.48 years), were recruited. A 13carbon urea breath test was performed on all family members in the same house as the index case. Each family unit was randomized into a 'family unit treatment' group (all infected family members treated) or an 'index case treatment' group (index case only treated).Results. At long-term follow-up (mean 62.2 months), there were three re-infected children in the 'index case treatment' group compared with one in the 'family unit treatment' group. The re-infection rate was 2.4% per patient per year in the 'index case treatment' group and 0.7% per patient per year in the 'family unit treatment' group (p = .31).Conclusions. This study is the first to evaluate the effect of total family unit H. pylori eradication on pediatric re-infection rates and reports the longest period of re-infection follow-up in children. In childhood, re-infection with H. pylori is not significantly reduced by family unit H. pylori eradication