Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system.

Nonalcoholic steatohepatitis (NASH) is an emerging health crisis with no approved therapies. Obeticholic acid (OCA), a farnesoid X receptor (FXR) agonist, shows promise in NASH trials. However, the precise mechanisms mediating OCA effects and impact on cholesterol metabolism are not fully understood. We explored the pharmaco-toxicological effects of OCA on patho-physiological pathways in hepatocytes using a previously described perfused organotypic liver system that allows culture in near-physiological insulin/glucose milieus, and exhibits drug responses at clinically-relevant concentrations. Primary hepatocytes experienced 48-hour exposure to OCA at concentrations approximating therapeutic (0.5µM) and supratherapeutic (10µM) levels. Global transcriptomics by RNAseq was complimented by cellular viability (MTT), CYP activity assays, and secreted FGF19 levels in the media. Dose-dependent, transcriptional effects suggested suppression of bile acid synthesis (↓CYP7A1, ↓CYP27A1) and increased bile efflux (↑ABCB4, ↑ABCB11, ↑OSTA, ↑OSTB). Pleiotropic effects included suppression of TGFß and IL-6 signaling pathways, and signatures suggestive of HDL suppression (↑SCARB1, ↓ApoAI, ↓LCAT) and LDL elevation (↑ApoB, ↓CYP7A1). OCA exhibited direct FXR-mediated effects with increased FGF19 secretion. Transcriptomics revealed regulation of metabolic, anti-inflammatory, and anti-fibrotic pathways beneficial in NASH, and predicted cholesterol profiles consistent with clinical findings. Follow-up studies under lipotoxic/inflammatory conditions would corroborate these effects in a disease-relevant environment.

Interaction between cytokines and inflammatory cells in islet dysfunction, insulin resistance and vascular disease.

Inflammation is an established pathogenic player in insulin resistance, islet demise and atherosclerosis. The complex interactions between cytokines, immune cells and affected tissues result in sustained inflammation in diabetes and atherosclerosis. 12- and 15-lipoxygenase (LO), such as 12/15-LO, produces a variety of metabolites through peroxidation of fatty acids and potentially contributes to the complex molecular crosstalk at the site of inflammation. 12- and 15-LO pathways are frequently activated in tissues affected by diabetes and atherosclerosis including adipose tissue (AT), islets and the vasculature. Moreover, mice with whole body and tissue-specific knockout of 12/15-LO are protected against insulin resistance, hyperglycaemia and atherosclerosis supporting functional contribution of 12- and 15-LO pathways in diabetes and atherosclerosis. Recently, it has emerged that there is a temporal regulation of the particular isoforms of 12- and 15-LO in human AT and islets during the development of type 1 and type 2 diabetes and obesity. Analyses of tissues affected by diabetes and atherosclerosis also implied the roles of interleukin (IL)-12 and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-1 (NOX-1) in islets and IL-17A in atherosclerosis. Future studies should aim to test the efficacy of inhibitions of these mediators for treatment of diabetes and atherosclerosis.

What is a "schedule of reinforcement"?

Several ambiguities in the present terminology of behavior theory obscure some important theoretical assumptions and experimental details in current research. Left unclarified, such ambiguities impede the accurate analysis of laboratory procedures, and prevent reliable communication among researchers. This paper focuses on the term "schedule of reinforcement". It points out that two distinguishable operational rules are implicated in the term: in the case where reinforcement is of the so-called response contingent type, the "schedule" is really a rule to identify the response to be reinforced; in the case of non-contingent reinforcement, the "schedule" is truly a rule for delivery of reinforcement. Other terminological ambiguities that are encountered in a discussion of this term include "reinforcement" and "intermittency." A resolution of these problems will necessarily involve the procedures of non-contingent reinforcement, and the parameter of reinforcement probability.

The role of proctoring in personalized instruction.

The effect of amount of student-proctor interaction was investigated within the framework of Keller's (1968) method of personalized instruction. College students enrolled in introductory psychology were randomly assigned to five groups: 0%, 25%, 50%, 75%, and 100%, reflecting the percentage of units on which each student was proctored. The results indicated that (a) the proctored students were superior to the non-proctored students as measured by final examination performance, (b) for the proctored groups, the amount of proctoring did not differentially affect final examination performance, and (c) the major effect of increased proctoring was an acceleration of the rate of progress through the course.

Response rate under varying frequency of non-contingent reinforcement.

Two White Carneaux hen pigeons were exposed to a 60-sec random-interval baseline procedure. Six different exteroceptive stimuli were successively correlated, within a single session, with blocks of 10 reinforcement presentations. Following this training, a non-contingent reinforcement procedure was instated with inter-reinforcement intervals of 5, 15, 30, 60, 120, and 240 sec. Within a single session, each non-contingent frequency was correlated with one of the previously presented discriminative stimuli. After an initial increase in the rate of responding as the result of a high density of non-contingent reinforcements, the rate declined as exposure to each non-contingent frequency was prolonged.