Description of a digital computer simulation of an Annular Momentum Control Device (AMCD) laboratory test model

A description of a digital computer simulation of an Annular Momentum Control Device (AMCD) laboratory model is presented. The AMCD is a momentum exchange device which is under development as an advanced control effector for spacecraft attitude control systems. The digital computer simulation of this device incorporates the following models: six degree of freedom rigid body dynamics; rim warp; controller dynamics; nonlinear distributed element axial bearings; as well as power driver and power supply current limits. An annotated FORTRAN IV source code listing of the computer program is included

A pankreász vezetéksejtek szerepe az akut pankreatitisz patogenezisében. = THE ROLE OF EPITHELIAL CELLS IN THE PATHOGENESIS OF ACUTE PANCREATITIS

Az epesavak és tripszin hatását vizsgáltuk tengerimalac pankreászból izolált, intakt intra/interlobuláris duktuszokon illetve karakterizáltuk a PAR-2 kifejeződését humán pankreászban. Kísérleteink célja a duktális HCO3- szekréció vizsgálata volt patofiziológiás körülmények között. Megállapítottuk, hogy a pankreász duktuszok luminális membránján kifejeződő nagy vezetőképességű Ca2+-aktiválta K+ csatornák (BK) kulcsfontosságú szerepet játszanak a kis koncentrációban adott epesavak HCO3- szekréciót stimuláló hatásában. Kimutattuk, hogy a duktuszok luminális membránja felől adott specifikus BK csatornaaktiváló, NS11021 képes volt stimulálni a HCO3- szekréciót. Ezen eredmények azt sugallják, hogy BK csatornák egy terápiás célpontot jelenthetnek az akut pankreatitisz kezelsében. Továbbá megfigyeltük, hogy a PAR-2 receptorok a mind a humán mind pedig a tengerimalac pankreász duktuszok luminális membránjára lokalizálódik. Megállapítottuk, hogy a luminális membrán felől adott tripszin gátolja a HCO3- szekréciót az anion kicserélő (Slc26a6) és a cisztás fibrózis konduktancia regulátor, Cl- csatorna (CFTR) gátlásán keresztül. Kimutattuk, hogy a humán kationos tripszinogén autoaktivációja felgyorsul a pH csökkenésével illetve, hogy a PAR-2 kifejeződése erőteljesen lecsökken mind transzkripcionális mind pedig transzlációs szinten, krónikus pankreatitiszben. | Our general aims in this project were to investigate the effect of bile acids and trypsin on intact, guinea pig pancreatic intra/interlobular ducts and to characterize the expression pattern of PAR-2 in human pancreas. Our main aim was to study ductal HCO3- secretion under pathophysiological conditions. We have shown, that the luminal large conductance Ca2+-activated K+ channel (BK) plays an essential role in the stimulatory effect of low concentration of bile acids. We also found that luminal administration of NS11021, a specific BK channel activator, is able to stimulate ductal HCO3- secretion, which suggest, that BK channels may represent a novel therapeutic target in the development of new treatments for acute pancreatitis. Furthermore, we observed that PAR-2 localized to the apical membrane of human and guinea pig pancreatic ductal cells. Trypsin increased inhibited HCO3- secretion via the inhibition of the luminal anion exchanger and the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel. Autoactivation of human cationic trypsinogen accelerated when the pH was reduced. In addition we showed that PAR-2 expression was strongly down-regulated, at transcriptional and protein levels, in the ducts of patients with chronic pancreatitis

Bile Acids Trigger GLP-1 Release Predominantly by Accessing Basolaterally Located G Protein-Coupled Bile Acid Receptors.

Bile acids are well-recognized stimuli of glucagon-like peptide-1 (GLP-1) secretion. This action has been attributed to activation of the G protein-coupled bile acid receptor GPBAR1 (TGR5), although other potential bile acid sensors include the nuclear farnesoid receptor and the apical sodium-coupled bile acid transporter ASBT. The aim of this study was to identify pathways important for GLP-1 release and to determine whether bile acids target their receptors on GLP-1-secreting L-cells from the apical or basolateral compartment. Using transgenic mice expressing fluorescent sensors specifically in L-cells, we observed that taurodeoxycholate (TDCA) and taurolithocholate (TLCA) increased intracellular cAMP and Ca(2+). In primary intestinal cultures, TDCA was a more potent GLP-1 secretagogue than taurocholate (TCA) and TLCA, correlating with a stronger Ca(2+) response to TDCA. Using small-volume Ussing chambers optimized for measuring GLP-1 secretion, we found that both a GPBAR1 agonist and TDCA stimulated GLP-1 release better when applied from the basolateral than from the luminal direction and that luminal TDCA was ineffective when intestinal tissue was pretreated with an ASBT inhibitor. ASBT inhibition had no significant effect in nonpolarized primary cultures. Studies in the perfused rat gut confirmed that vascularly administered TDCA was more effective than luminal TDCA. Intestinal primary cultures and Ussing chamber-mounted tissues from GPBAR1-knockout mice did not secrete GLP-1 in response to either TLCA or TDCA. We conclude that the action of bile acids on GLP-1 secretion is predominantly mediated by GPBAR1 located on the basolateral L-cell membrane, suggesting that stimulation of gut hormone secretion may include postabsorptive mechanisms.Mesoscale GLP-1 immuno assays were performed by Keith Burling and colleagues at the Medical Research Council Metabolic Diseases Unit, Cambridge. Thisworkwas supported by the Wellcome Trust (grants 084 210/Z/07/Z, 088 357/Z/09/Z and 099 825/Z/12/Z) and the MRC (grant MRC_MC_UU_12012/ 3), the Novo Nordisk Center for Basic Metabolic Research (Novo Nordisk Foundation, Denmark) and the European Union’s Seventh Framework Programme for Research, Technological Development, and Demonstration Activities (Grant No. 266 408) Juraj Rievaj was supported by an EFSD Albert Renold Travel Fellowship. Ussing chamber equipment was initially kindly lent by Dr. Todd Alexander, Departments of Pediatrics& Physiology, University of Alberta, Canada.This is the final version of the article. It first appeared from Endocrine Society via http://dx.doi.org/10.1210/en.2015-132

The Brain-Gut-Microbiome Axis.

Preclinical and clinical studies have shown bidirectional interactions within the brain-gut-microbiome axis. Gut microbes communicate to the central nervous system through at least 3 parallel and interacting channels involving nervous, endocrine, and immune signaling mechanisms. The brain can affect the community structure and function of the gut microbiota through the autonomic nervous system, by modulating regional gut motility, intestinal transit and secretion, and gut permeability, and potentially through the luminal secretion of hormones that directly modulate microbial gene expression. A systems biological model is proposed that posits circular communication loops amid the brain, gut, and gut microbiome, and in which perturbation at any level can propagate dysregulation throughout the circuit. A series of largely preclinical observations implicates alterations in brain-gut-microbiome communication in the pathogenesis and pathophysiology of irritable bowel syndrome, obesity, and several psychiatric and neurologic disorders. Continued research holds the promise of identifying novel therapeutic targets and developing treatment strategies to address some of the most debilitating, costly, and poorly understood diseases

Bile acids and gpbar-1: Dynamic interaction involving genes, environment and gut microbiome

Bile acids (BA) are amphiphilic molecules synthesized in the liver from cholesterol. BA undergo continuous enterohepatic recycling through intestinal biotransformation by gut microbiome and reabsorption into the portal tract for uptake by hepatocytes. BA are detergent molecules aiding the digestion and absorption of dietary fat and fat-soluble vitamins, but also act as important signaling molecules via the nuclear receptor, farnesoid X receptor (FXR), and the membrane-associated G protein-coupled bile acid receptor 1 (GPBAR-1) in the distal intestine, liver and extra hepatic tissues. The hydrophilic-hydrophobic balance of the BA pool is finely regulated to prevent BA overload and liver injury. By contrast, hydrophilic BA can be hepatoprotective. The ultimate effects of BA-mediated activation of GPBAR-1 is poorly understood, but this receptor may play a role in protecting the remnant liver and in maintaining biliary homeostasis. In addition, GPBAR-1 acts on pathways involved in inflammation, biliary epithelial barrier permeability, BA pool hydrophobicity, and sinusoidal blood flow. Recent evidence suggests that environmental factors influence GPBAR-1 gene expression. Thus, targeting GPBAR-1 might improve liver protection, facilitating beneficial metabolic effects through primary prevention measures. Here, we discuss the complex pathways linked to BA effects, signaling properties of the GPBAR-1, mechanisms of liver damage, gene-environment interactions, and therapeutic aspects

Characterisation of L-cell secretory mechanisms and colonic enteroendocrine cell subpopulations

Enteroendocrine cells (EECs) are chemosensitive cells of the gastrointestinal epithelium that exert a wide range of physiological effects via production and secretion of hormones in response to ingested nutrients, bacterial metabolites and systemic signals. Glucagon-like peptide-1 (GLP-1) is one such hormone secreted from so-called L-cells found in both the small and large intestines. GLP-1 exerts an anorexigenic effect and together with glucose- dependent insulinotropic polypeptide (GIP), restores postprandial normoglycaemia through the incretin effect. These effects are exploited by GLP-1 analogues in the treatment of type 2 diabetes. GLP-1 may also contribute to weight-loss and remission of type 2 diabetes following bariatric surgery which increases postprandial GLP-1 excursions. Here we investigated stimulus secretion coupling in L-cells. A novel 2D culture system from murine small intestinal organoids was established as an in vitro model. This was used to characterise synergistic stimulation of GLP-1 secretion in response to concomitant stimulation by bile acids through the Gs-protein coupled receptor GPBAR1 and free fatty acids through the Gq-coupled receptor FFAR1. Roughly half of colonic, but not small intestinal, L-cells co-produce the orexigenic peptide insulin-like peptide 5 (INSL5). This hitherto poorly examined subpopulation of L-cells was characterised through transcriptomic analysis, intracellular calcium imaging (using a novel GCaMP6F-based transgenic mouse model), LC/MS peptide quantification and 3D super resolution microscopy (3D-SIM). Based on the observed prevalent co-storage of GLP-1 and INSL5 in secretory vesicles and similar secretory responses of both hormones to a range of different stimuli strengths (including short chain fatty acids, angiotensin II and arginine vasopressin (AVP)) it was concluded that GLP-1 and INSL5 are co-secreted, rather than being selectively recruited by different stimuli. To further characterise the diversity of colonic EECs, single cell RNA-sequencing (scRNA-seq) was performed on cells isolated from mice with a pan-EEC fluorescent marker (NeuroD1- Cre:Rosa26-EYFP). This illustrated that INSL5-producing L-cells form one of two transcriptomically distinct subpopulations of L-cells in the murine colon, with the other distinguished by expression of neurotensin (Nts). Another major EEC subpopulation, enterochromaffin (EC) cells could be split into three groups, mechanosensitive and pro- inflammatory EC cells distinguished by Piezo2 and Tac1 expression, respectively and a third Sct-expressing group. Immunofluorescent labelling and RT-qPCR analysis revealed that the Nts-expressing and Insl5-expressing L-cell subpopulations are proximally and distally enriched in the murine colon, respectively. In primary cultures, angiotensin II and AVP stimulated INSL5, GLP-1 and PYY but not NTS secretion, correlating with selective expression profiles of the cognate receptors in the L-cell subpopulations. In summary, the work presented suggests that different L-cell subpopulations exist that respond to different stimuli, but that hormones co-expressed in individual L-cells are co- released upon stimulation. Differences in receptor expression between these subpopulations and other EEC-populations might be exploitable for selective hormone recruitment for the therapy of diabetes, obesity and other diseases.Funded through the Wellcome Trust doctoral training program in metabolic and cardiovascular disease

TGR 5 signalling inhibits the production of pro‐inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in Crohn's disease

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97471/1/imm12045.pd