A Digital Edition of a Spanish 18th Century Account Book: Formalisation and Encoding

In this, part two of a two part paper, we will discuss our approach to the formalisation of our document encoding approach, derived from software engineering, which treats of the three classes of a digital edition; the Logical, the Physical and the Interaction Classes. We specifically address our decision to use XML (Extensible Mark-up Language), not TEI (Text Encoding Initiative), as our encoding language. An argument is provided as to why TEI is unsuitable for function-based documents, this addresses both source integrity and the restrictive nature of TEI. TEI does not support our forward engineering approach, which allows us to simultaneously produce the model, the encoding and the software environment

The β-cell/EC axis: how do islet cells talk to each other?

Author version made available in accordance with the publisher's policy.Within the pancreatic islet, the beta cell represents the ultimate biosensor. Its central function is to accurately sense glucose levels in the blood, and consequently release appropriate amounts of insulin. As the only cell type capable of insulin production, the beta cell must balance this crucial workload with self-preservation and, when required, regeneration. Evidence suggests that the beta cell has an important ally in intra-islet endothelial cells. As well as providing a conduit for delivery of the primary input stimulus (glucose) and dissemination of its most important effector (insulin), intra-islet blood vessels deliver oxygen to these dense clusters of metabolically active cells. Furthermore, it appears that endothelial cells directly impact insulin gene expression, secretion and beta cell survival. This review discusses the molecules and pathways involved in the crosstalk between beta cells and intra-islet endothelial cells. The evidence supporting the intra-islet endothelial cell as an important partner for beta cell function is examined to highlight the relevance of this axis in the context of type 1 and type 2 diabetes. Recent work which has established the potential of endothelial cells or their progenitors to enhance the reestablishment of glycaemic control following pancreatic islet transplantation in animal models is discussed

Huntingtin-associated protein 1: Eutherian adaptation from a TRAK-like protein, conserved gene promoter elements, and localization in the human intestine

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background: Huntingtin-associated Protein 1 (HAP1) is expressed in neurons and endocrine cells, and is critical for postnatal survival in mice. HAP1 shares a conserved “HAP1_N” domain with TRAfficking Kinesin proteins TRAK1 and TRAK2 (vertebrate), Milton (Drosophila) and T27A3.1 (C. elegans). HAP1, TRAK1 and TRAK2 have a degree of common function, particularly regarding intracellular receptor trafficking. However, TRAK1, TRAK2 and Milton (which have a “Milt/TRAK” domain that is absent in human and rodent HAP1) differ in function to HAP1 in that they are mitochondrial transport proteins, while HAP1 has emerging roles in starvation response. We have investigated HAP1 function by examining its evolution, and upstream gene promoter sequences. We performed phylogenetic analyses of the HAP1_N domain family of proteins, incorporating HAP1 orthologues (identified by genomic synteny) from 5 vertebrate classes, and also searched the Dictyostelium proteome for a common ancestor. Computational analyses of mammalian HAP1 gene promoters were performed to identify phylogenetically conserved regulatory motifs. Results: We found that as recently as marsupials, HAP1 contained a Milt/TRAK domain and was more similar to TRAK1 and TRAK2 than to eutherian HAP1. The Milt/TRAK domain likely arose post multicellularity, as it was absent in the Dictyostelium proteome. It was lost from HAP1 in the eutherian lineage, and also from T27A3.1 in C. elegans. The HAP1 promoter from human, mouse, rat, rabbit, horse, dog, Tasmanian devil and opossum contained common sites for transcription factors involved in cell cycle, growth, differentiation, and stress response. A conserved arrangement of regulatory elements was identified, including sites for caudal-related homeobox transcription factors (CDX1 and CDX2), and myc-associated factor X (MAX) in the region of the TATA box. CDX1 and CDX2 are intestine-enriched factors, prompting investigation of HAP1 protein expression in the human duodenum. HAP1 was localized to singly dispersed mucosal cells, including a subset of serotonin-positive enterochromaffin cells. Conclusion: We have identified eutherian HAP1 as an evolutionarily recent adaptation of a vertebrate TRAK protein-like ancestor, and found conserved CDX1/CDX2 and MAX transcription factor binding sites near the TATA box in mammalian HAP1 gene promoters. We also demonstrated that HAP1 is expressed in endocrine cells of the human gut

The presence of 5-HT in myenteric varicosities is not due to uptake of 5-HT released from the mucosa during dissection: use of a novel method for quantifying 5-HT immunoreactivity in myenteric ganglia

Author version made available according to Publisher copyright policy. This is the accepted version of the following article: 
Keating, D. J., Peiris, H., Kyloh, M., Brookes, S. J. H. and Spencer, N. J. (2013), The presence of 5-HT in myenteric varicosities is not due to uptake of 5-HT released from the mucosa during dissection: use of a novel method for quantifying 5-HT immunoreactivity in myenteric ganglia. Neurogastroenterology & Motility, 25: 849–853, 

which has been published in final form at 
http://dx.doi.org/10.1111/nmo.12189. 

In addition, authors may also transmit, print and share copies with colleagues, provided that there is no systematic distribution of the submitted version, e.g. posting on a listserve, network or automated delivery

What is the role of endogenous gut serotonin in the control of gastrointestinal motility?

© 2018 Elsevier Ltd. . This manuscript version is made available under the CC-BY-NC-ND 4.0 license:http://creativecommons.org/licenses/by-nc-nd/4.0/ This author accepted manuscript is made available following 12 month embargo from date of publication (June 2018) in accordance with the publisher’s archiving policyIn recent years, there have been dramatic changes in our understanding of the role of endogenous 5-Hydroxytryptamine (5-HT or serotonin) in the control of gastrointestinal (GI) motility. Whilst it is well accepted that there are numerous types of 5-HT receptors expressed on enteric neurons and that exogenous 5-HT potently stimulates GI-motility, understanding the role of endogenous 5-HT in GI-motility has been substantially more difficult to resolve. Recent studies found 5-HT3 and 5-HT4 antagonists have the same effects on peristalsis in colon preparations depleted of endogenous 5-HT. Then, recent work revealed that in mice with genetic mutations to prevent the synthesis of endogenous 5-HT from enterochromaffin EC) cells did not block major neurogenic motor patterns in the gut wall and did not reduce GI-transit in conscious animals, raising doubts about early hypotheses that endogenous 5-HT was critical for neurogenic GI-motility patterns. Indeed, functional evidence now suggests that 5-HT3 and 5-HT4 receptors on enteric nerves display constitutive activity. In summary, recent findings demonstrate that endogenous 5-HT released from the mucosa or enteric neurons is not required for the generation of major neurogenic motor patterns, at least in the large intestine, but that it likely acts as a modulator of contractile frequency. This review will discuss how and why our understanding of endogenous 5-HT has dramatically changed in the past few years

RCAN1 regulates vesicle recycling and quantal release kinetics via effects on calcineurin activity

Author version made available in accordance with the publisher's policy.We have previously shown that Regulator of Calcineurin 1 (RCAN1) regulates multiple stages of vesicle exocytosis. However, the mechanisms by which RCAN1 affects secretory vesicle exocytosis and quantal release kinetics remain unknown. Here we use carbon fiber amperometry to detect exocytosis from chromaffin cells and identify these underlying mechanisms. We observe reduced exocytosis with repeated stimulations in chromaffin cells overexpressing RCAN1 (RCAN1ox), but not in wild type (WT) cells, indicating a negative effect of RCAN1 on vesicle recycling and endocytosis. Acute exposure to calcineurin inhibitors, cyclosporine A and FK-506, replicates this effect in WT cells but has no additional effect in RCAN1ox cells. When we chronically expose WT cells to cyclosporine A and FK-506 we find that catecholamine release per vesicle and pre-spike foot (PSF) signal parameters are decreased, similar to that in RCAN1ox cells. Inhibiting calcineurin activity in RCAN1ox cells has no additional effect on the amount of catecholamine release per vesicle but further reduces PSF signal parameters. Electron microscopy studies indicate these changes are not due to altered vesicle number or distribution in RCAN1ox cells but reduced vesicle release may be cause by decreased vesicle and dense core size in RCAN1ox cells. Thus, our results indicate that RCAN1 may negatively affects vesicle recycling and quantal release kinetics via the inhibition of calcineurin activity

The Influence of the Gut Microbiome on Host Metabolism Through the Regulation of Gut Hormone Release

The microbial community of the gut conveys significant benefits to host physiology. A clear relationship has now been established between gut bacteria and host metabolism in which microbial-mediated gut hormone release plays an important role. Within the gut lumen, bacteria produce a number of metabolites and contain structural components that act as signaling molecules to a number of cell types within the mucosa. Enteroendocrine cells within the mucosal lining of the gut synthesize and secrete a number of hormones including CCK, PYY, GLP-1, GIP, and 5-HT, which have regulatory roles in key metabolic processes such as insulin sensitivity, glucose tolerance, fat storage, and appetite. Release of these hormones can be influenced by the presence of bacteria and their metabolites within the gut and as such, microbial-mediated gut hormone release is an important component of microbial regulation of host metabolism. Dietary or pharmacological interventions which alter the gut microbiome therefore pose as potential therapeutics for the treatment of human metabolic disorders. This review aims to describe the complex interaction between intestinal microbiota and their metabolites and gut enteroendocrine cells, and highlight how the gut microbiome can influence host metabolism through the regulation of gut hormone release

The Regulation of Peripheral Metabolism by Gut-Derived Hormones

Enteroendocrine cells lining the gut epithelium constitute the largest endocrine organ in the body and secrete over 20 different hormones in response to cues from ingested foods and changes in nutritional status. Not only do these hormones convey signals from the gut to the brain via the gut-brain axis, they also act directly on metabolically important peripheral targets in a highly concerted fashion to maintain energy balance and glucose homeostasis. Gut-derived hormones released during fasting tend to be orexigenic and have hyperglycaemic potential. Conversely, gut hormones secreted postprandially generally promote satiety and facilitate glucose clearance. Although some of the metabolic benefits conferred by bariatric surgeries have been ascribed to changes in the secretory profiles of various gut hormones, the therapeutic potential of the enteroendocrine system as a viable target against metabolic diseases remain largely underexploited, except for incretin-mimetics. This review provides a brief overview of the physiological importance and highlights the therapeutic potential of the following gut hormones: serotonin, glucose-dependent insulinotropic peptide, glucagon-like peptide 1, oxyntomodulin, peptide YY, insulin-like peptide 5, and ghrelin

Identification of a rhythmic firing pattern in the enteric nervous system that generates rhythmic electrical activity in smooth muscle

The enteric nervous system (ENS) contains millions of neurons essential for organization of motor behavior of the intestine. It is well established that the large intestine requires ENS activity to drive propulsive motor behaviors. However, the firing pattern of the ENS underlying propagating neurogenic contractions of the large intestine remains unknown. To identify this, we used high-resolution neuronal imaging with electrophysiology from neighboring smooth muscle. Myoelectric activity underlying propagating neurogenic contractions along murine large intestine [also referred to as colonic migrating motor complexes, (CMMCs)] consisted of prolonged bursts of rhythmic depolarizations at a frequency of ∼2 Hz. Temporal coordination of this activity in the smooth muscle over large spatial fields (∼7 mm, longitudinally) was dependent on the ENS. During quiescent periods between neurogenic contractions, recordings from large populations of enteric neurons, in mice of either sex, revealed ongoing activity. The onset of neurogenic contractions was characterized by the emergence of temporally synchronized activity across large populations of excitatory and inhibitory neurons. This neuronal firing pattern was rhythmic and temporally synchronized across large numbers of ganglia at ∼2 Hz. ENS activation preceded smooth muscle depolarization, indicating rhythmic depolarizations in smooth muscle were controlled by firing of enteric neurons. The cyclical emergence of temporally coordinated firing of large populations of enteric neurons represents a unique neural motor pattern outside the CNS. This is the first direct observation of rhythmic firing in the ENS underlying rhythmic electrical depolarizations in smooth muscle. The pattern of neuronal activity we identified underlies the generation of CMMCs

Gut Mechanisms Linking Intestinal Sweet Sensing to Glycemic Control

Sensing nutrients within the gastrointestinal tract engages the enteroendocrine cell system to signal within the mucosa, to intrinsic and extrinsic nerve pathways, and the circulation. This signaling provides powerful feedback from the intestine to slow the rate of gastric emptying, limit postprandial glycemic excursions, and induce satiation. This review focuses on the intestinal sensing of sweet stimuli (including low-calorie sweeteners), which engage similar G-protein-coupled receptors (GPCRs) to the sweet taste receptors (STRs) of the tongue. It explores the enteroendocrine cell signals deployed upon STR activation that act within and outside the gastrointestinal tract, with a focus on the role of this distinctive pathway in regulating glucose transport function via absorptive enterocytes, and the associated impact on postprandial glycemic responses in animals and humans. The emerging role of diet, including low-calorie sweeteners, in modulating the composition of the gut microbiome and how this may impact glycemic responses of the host, is also discussed, as is recent evidence of a causal role of diet-induced dysbiosis in influencing the gut-brain axis to alter gastric emptying and insulin release. Full knowledge of intestinal STR signaling in humans, and its capacity to engage host and/or microbiome mechanisms that modify glycemic control, holds the potential for improved prevention and management of type 2 diabetes