Systemic multicompartmental effects of the gut microbiome on mouse metabolic phenotypes

To characterize the impact of gut microbiota on host metabolism, we investigated the multicompartmental metabolic profiles of a conventional mouse strain (C3H/HeJ) (n=5) and its germ-free (GF) equivalent (n=5). We confirm that the microbiome strongly impacts on the metabolism of bile acids through the enterohepatic cycle and gut metabolism (higher levels of phosphocholine and glycine in GF liver and marked higher levels of bile acids in three gut compartments). Furthermore we demonstrate that (1) well-defined metabolic differences exist in all examined compartments between the metabotypes of GF and conventional mice: bacterial co-metabolic products such as hippurate (urine) and 5-aminovalerate (colon epithelium) were found at reduced concentrations, whereas raffinose was only detected in GF colonic profiles. (2) The microbiome also influences kidney homeostasis with elevated levels of key cell volume regulators (betaine, choline, myo-inositol and so on) observed in GF kidneys. (3) Gut microbiota modulate metabotype expression at both local (gut) and global (biofluids, kidney, liver) system levels and hence influence the responses to a variety of dietary modulation and drug exposures relevant to personalized health-care investigations

Role of Biotransformation Studies in Minimizing Metabolism-Related Liabilities in Drug Discovery

Metabolism-related liabilities continue to be a major cause of attrition for drug candidates in clinical development. Such problems may arise from the bioactivation of the parent compound to a reactive metabolite capable of modifying biological materials covalently or engaging in redox-cycling reactions leading to the formation of other toxicants. Alternatively, they may result from the formation of a major metabolite with systemic exposure and adverse pharmacological activity. To avert such problems, biotransformation studies are becoming increasingly important in guiding the refinement of a lead series during drug discovery and in characterizing lead candidates prior to clinical evaluation. This article provides an overview of the methods that are used to uncover metabolism-related liabilities in a pre-clinical setting and offers suggestions for reducing such liabilities via the modification of structural features that are used commonly in drug-like molecules

Analysis of time-related metabolic fluctuations induced by ethionine in the rat

The time-course of metabolic events following response to a model hepatotoxin ethionine (800 mg/kg) was investigated over a 7 day period in rats using high-resolution (1)H NMR spectroscopic analysis of urine and multivariate statistics. Complementary information was obtained by multivariate analysis of (1)H MAS NMR spectra of intact liver and by conventional histopathology and clinical chemistry of blood plasma. (1)H MAS NMR spectra of liver showed toxin-induced lipidosis 24 h postdose consistent with the steatosis observed by histopathology, while hypertaurinuria was suggestive of liver injury. Early biochemical changes in urine included elevation of guanidinoacetate, suggesting impaired methylation reactions. Urinary increases in 5-oxoproline and glycine suggested disruption of the gamma-glutamyl cycle. Signs of ATP depletion together with impairment of the energy metabolism were given from the decreased levels in tricarboxylic acid cycle intermediates, the appearance of ketone bodies in urine, the depletion of hepatic glucose and glycogen, and also hypoglycemia. The observed increase in nicotinuric acid in urine could be an indication of an increase in NAD catabolism, a possible consequence of ATP depletion. Effects on the gut microbiota were suggested by the observed urinary reductions in the microbial metabolites 3-/4-hydroxyphenyl propionic acid, dimethylamine, and tryptamine. At later stages of toxicity, there was evidence of kidney damage, as indicated by the tubular damage observed by histopathology, supported by increased urinary excretion of lactic acid, amino acids, and glucose. These studies have given new insights into mechanisms of ethionine-induced toxicity and show the value of multisystem level data integration in the understanding of experimental models of toxicity or disease

Heterometallic Mn^III₄Ln₂ (Ln = Dy, Gd, Tb) Cross-Shaped Clusters and Their Homometallic Mn^III₄Mn^II₂ Analogues

The employment of di-2-pyridyl ketone, (py)₂CO, in heterometallic Mn/4f and homometallic Mn cluster chemistry has yielded six Mn^III₄Ln₂ and two Mn^III₄Mn^II₂ structurally related clusters, namely, [Mn₄Ln₂O₂{(py)₂CO₂}₄(NO₃)₂­(RCO₂)₂(H₂O)₆]­(NO₃)₂ (Ln = Gd, <b>1</b>, <b>5</b>; Dy, <b>2</b>; Tb, <b>3</b>; R = Et, <b>1</b>–<b>3</b>; Me, <b>5</b>), [Mn₄Dy₂O₂{(py)₂CO₂}₄(NO₃)₄­(EtCO₂)₂(H₂O)₃(MeOH)]·0.7MeOH·0.8H₂O (<b>4</b>·0.7MeOH·0.8H₂O), [Mn₄Gd₂O₂{(py)₂CO₂}₄(NO₃)₄­(C₆H₄ClCO₂)₂(MeOH)₂(py)₂]·2MeOH (<b>6</b>·2MeOH), [Mn₆O₂{(py)₂CO₂}₄­(py)₄(H₂O)₄]­(ClO₄)₄·4H₂O (<b>7</b>·4H₂O), and [Mn₆O₂{(py)₂CO₂}₄­(NO₃)₄(py)₄] (<b>8</b>), where (py)₂CO₂^2– is the dianion of the <i>gem</i>-diol derivative of (py)₂CO. The compounds possess a new type of cross-shaped structural core, which in the case of <b>1</b>–<b>6</b> is essentially planar, whereas in <b>7</b> and <b>8</b> it deviates from planarity. Clusters <b>1</b>–<b>6</b> are rare examples of Mn/4f species bearing (py)₂CO or its derivatives, despite the fact that this ligand has been well-studied and proven a rich source of more than 200 metal compounds so far. Variable-temperature, solid-state direct-current and alternating-current magnetization studies were performed on complexes <b>1</b>–<b>5</b>, <b>7</b>, and <b>8</b> revealing that the dominant exchange interactions between the metal ions are antiferromagnetic and indicating ground-state spin values of <i>S</i> = 5 (for <b>1</b>), 6 (for <b>5</b>), and 2 (for <b>7</b> and <b>8</b>)

Nature of learning environment in concurrent enrollment mathematics classrooms: a cluster analysis

Concurrent enrollment programs, which allow college credit-bearing classes to be offered in the high school taught by qualified high-school teachers, are a potential solution to the student debt issues impacting the United States and other countries. However, the learning environments of these rapidly-growing programs have never been studied. Because concurrent enrollment classes are taught in high schools with college-level rigour, they present a learning environment that is distinct from both high-school and college classrooms. This study had two broad goals of (1) determining if the What Is Happening In this Class? (WIHIC) questionnaire is a valid and reliable instrument for the concurrent enrollment environment and, if so, (2) investigating the learning environments of 68 concurrent enrollment teachers’ classrooms using the WIHIC. The WIHIC was found to be valid and reliable, and cluster analysis of the concurrent enrollment classes revealed three distinct types of learning environments which we labeled ‘most conducive’ for learning, ‘conducive’ and ‘least conducive’. A follow-up discriminant function analysis revealed that the WIHIC scales of teacher support, involvement and student cohesion were most influential in determining cluster membership