Regulation of Sulfotransferase and UDP-Glucuronosyltransferase Gene Expression by the PPARs

During phase II metabolism, a substrate is rendered more hydrophilic through the covalent attachment of an endogenous molecule. The cytosolic sulfotransferase (SULT) and UDP-glucuronosyltransferase (UGT) families of enzymes account for the majority of phase II metabolism in humans and animals. In general, phase II metabolism is considered to be a detoxication process, as sulfate and glucuronide conjugates are more amenable to excretion and elimination than are the parent substrates. However, certain products of phase II metabolism (e.g., unstable sulfate conjugates) are genotoxic. Members of the nuclear receptor superfamily are particularly important regulators of SULT and UGT gene transcription. In metabolically active tissues, increasing evidence supports a major role for lipid-sensing transcription factors, such as peroxisome proliferator-activated receptors (PPARs), in the regulation of rodent and human SULT and UGT gene expression. This review summarizes current information regarding the regulation of these two major classes of phase II metabolizing enzyme by PPARs

Technology readiness of a vertical-axis hydro-kinetic turbine

In this paper, the development of a vertical axis hydrokinetic twin turbine for harvesting energy from flowing water in man-made channels is described. The Technology Readiness Level (TRL) assessment procedure, developed by NASA and modified by the US Department of Energy, is followed and it is shown that the hydrokinetic turbine successfully reaches TRL 7, which is a full-scale, similar (prototypical) system demonstrated in a relevant environment. The concept of the twin turbine (TRL 1 - 3) is first validated and tested using a 1:10 scale laboratory model at Cardiff University and efficiencies of up to 75% are achieved (TRL 4 - 5). In order to justify system functionality and performance in a relevant environment as well as up-scalability, a 1:3 scale model of the twin turbine is implemented and tested in a discharge channel of a water treatment plant in Atlanta, thereby achieving TRL6. This paved the way for an application in the form of an array of ten full-scale twin turbine prototypes, including all relevant components such as housing, drive-train, gear-box and generator. Successful deployment and testing in the South Boulder Canal near Denver means that the hydrokinetic twin turbine system reached TRL7

AC-coupled GaAs microstrip detectors with a new type of integrated bias resistors

Full size single-sided GaAs microstrip detectors with integrated coupling capacitors and bias resistors have been fabricated on 3'' substrate wafers. PECVD deposited SiO_2 and SiO_2/Si_3N_4 layers were used to provide coupling capacitaces of 32.5 pF/cm and 61.6 pF/cm, respectively. The resistors are made of sputtered CERMET using simple lift of technique. The sheet resistivity of 78 kOhm/sq. and the thermal coefficient of resistance of less than 4x10^-3 / degree C satisfy the demands of small area biasing resistors, working on a wide temperature range.Comment: 20 pages, 9 figures, to be published in NIM

DIFFERENTIAL REGULATION OF INDIVIDUAL SULFOTRANSFERASE ISOFORMS BY PHENOBARBITAL IN MALE RAT LIVER

This paper is available online at http://www.dmd.org ABSTRACT: Xenobiotics that induce the cytochromes P450 also produce changes in rat hepatic sulfotransferase (SULT) gene expression. In the present study, male Sprague-Dawley rats were treated for 3 consecutive days with doses of phenobarbital (PB) that induce cytochrome P450 2B1/2 expression. The effects of PB treatment on hepatic aryl SULT (SULT1) and hydroxysteroid SULT (SULT2) mRNA and immunoreactive protein levels and on mRNA expression of individual SULT1 and SULT2 enzyme isoforms were characterized. PB suppressed SULT1A1 mRNA levels, increased the expression of the SULT-Dopa/tyrosine isoform, and did not produce significant changes in SULT1C1 and SULT1E2 mRNA expression. In rats injected with the highest test dose of PB (100 mg/kg), hepatic SULT1A1 mRNA levels were decreased to ϳ42% of control levels and SULT-Dopa/tyrosine mRNA levels were increased to ϳ417% of vehicle-treated control levels. Like the SULT1 subfamily, individual members of the SULT2 gene subfamily were differentially affected by PB treatment. PB (35, 80, and 100 mg/kg) suppressed SULT20/21 mRNA expression to ϳ61, ϳ30, and ϳ41% of vehicle-treated control levels, respectively. In contrast, SULT60 mRNA levels were increased to ϳ162% of control levels and SULT40/41 mRNA levels were increased to ϳ416% of vehicletreated control levels in rats treated with 100 mg/kg PB. These studies support a complex role for PB-mediated effects on the SULT multigene family in rat liver. Because individual SULT1 and SULT2 enzyme isoforms are known to metabolize a variety of potentially toxic substrates, varied responses to PB among members of the SULT multigene family might have important implications for xenobiotic hepatotoxicity

Chronic exposure to short chain fatty acids modulates transport and metabolism of microbiome-derived phenolics in human intestinal cells

Dietary fibre-derived short chain fatty acids (SCFA) and phenolics produced by the gut microbiome have multiple effects on health. We have tested the hypothesis that long term exposure to physiological concentrations of SCFA can affect the transport and metabolism of (poly)phenols by the intestinal epithelium using the Caco-2 cell model. Metabolites and conjugates of hesperetin (HT) and ferulic acid (FA), gut-derived from dietary hesperidin and chlorogenic acid respectively, were quantified by LC–MS with authentic standards following transport across differentiated cell monolayers. Changes in metabolite levels were correlated with effects on mRNA and protein expression of key enzymes and transporters. Propionate and butyrate increased both FA transport and rate of appearance of FA-glucuronide apically and basolaterally, linked to an induction of MCT1. Propionate was the only SCFA that augmented the rate of formation of basolateral FA-sulfate conjugates, possibly via basolateral transporter upregulation. In addition, propionate enhanced the formation of HT-glucuronide conjugates and increased HT-sulfate efflux towards the basolateral compartment. Acetate treatment amplified transepithelial transport of FA in the apical to basolateral direction, associated with lower levels of MCT1 protein expression. Metabolism and transport of both HT and FA were curtailed by the organic acid lactate owing to a reduction of UGT1A1 protein levels. Our data indicate a direct interaction between microbiota-derived metabolites of (poly)phenols and SCFA through modulation of transporters and conjugating enzymes, and increase our understanding of how dietary fibre, via the microbiome, may affect and enhance uptake of bioactive molecules

Invasion speeds for structured populations in fluctuating environments

We live in a time where climate models predict future increases in environmental variability and biological invasions are becoming increasingly frequent. A key to developing effective responses to biological invasions in increasingly variable environments will be estimates of their rates of spatial spread and the associated uncertainty of these estimates. Using stochastic, stage-structured, integro-difference equation models, we show analytically that invasion speeds are asymptotically normally distributed with a variance that decreases in time. We apply our methods to a simple juvenile-adult model with stochastic variation in reproduction and an illustrative example with published data for the perennial herb, \emph{Calathea ovandensis}. These examples buttressed by additional analysis reveal that increased variability in vital rates simultaneously slow down invasions yet generate greater uncertainty about rates of spatial spread. Moreover, while temporal autocorrelations in vital rates inflate variability in invasion speeds, the effect of these autocorrelations on the average invasion speed can be positive or negative depending on life history traits and how well vital rates ``remember'' the past

A Review of Volatile Organic Compound Contamination in Post-Industrial Urban Centers: Reproductive Health Implications Using a Detroit Lens

Volatile organic compounds (VOCs) are a group of aromatic or chlorinated organic chemicals commonly found in manufactured products that have high vapor pressure, and thus vaporize readily at room temperature. While airshed VOCs are well studied and have provided insights into public health issues, we suggest that belowground VOCs and the related vapor intrusion process could be equally or even more relevant to public health. The persistence, movement, remediation, and human health implications of subsurface VOCs in urban landscapes remain relatively understudied despite evidence of widespread contamination. This review explores the state of the science of subsurface movement and remediation of VOCs through groundwater and soils, the linkages between these poorly understood contaminant exposure pathways and health outcomes based on research in various animal models, and describes the role of these contaminants in human health, focusing on birth outcomes, notably low birth weight and preterm birth. Finally, this review provides recommendations for future research to address knowledge gaps that are essential for not only tackling health disparities and environmental injustice in post-industrial cities, but also protecting and preserving critical freshwater resources

The incidence of liver injury in Uyghur patients treated for TB in Xinjiang Uyghur autonomous region, China, and its association with hepatic enzyme polymorphisms nat2, cyp2e1, gstm1 and gstt1.

BACKGROUND AND OBJECTIVE: Of three first-line anti-tuberculosis (anti-TB) drugs, isoniazid is most commonly associated with hepatotoxicity. Differences in INH-induced toxicity have been attributed to genetic variability at several loci, NAT2, CYP2E1, GSTM1and GSTT1, that code for drug-metabolizing enzymes. This study evaluated whether the polymorphisms in these enzymes were associated with an increased risk of anti-TB drug-induced hepatitis in patients and could potentially be used to identify patients at risk of liver injury. METHODS AND DESIGN: In a cross-sectional study, 2244 tuberculosis patients were assessed two months after the start of treatment. Anti-TB drug-induced liver injury (ATLI) was defined as an ALT, AST or bilirubin value more than twice the upper limit of normal. NAT2, CYP2E1, GSTM1 and GSTT1 genotypes were determined using the PCR/ligase detection reaction assays. RESULTS: 2244 patients were evaluated, there were 89 cases of ATLI, a prevalence of 4% 9 patients (0.4%) had ALT levels more than 5 times the upper limit of normal. The prevalence of ATLI was greater among men than women, and there was a weak association with NAT2*5 genotypes, with ATLI more common among patients with the NAT2*5*CT genotype. The sensitivity of the CT genotype for identifying patients with ATLI was 42% and the positive predictive value 5.9%. CT ATLI was more common among slow acetylators (prevalence ratio 2.0 (95% CI 0.95,4.20) )compared to rapid acetylators. There was no evidence that ATLI was associated with CYP2E1 RsaIc1/c1genotype, CYP2E1 RsaIc1/c2 or c2/c2 genotypes, or GSTM1/GSTT1 null genotypes. CONCLUSIONS: In Xinjiang Uyghur TB patients, liver injury was associated with the genetic variant NAT2*5, however the genetic markers studied are unlikely to be useful for screening patients due to the low sensitivity and low positive predictive values for identifying persons at risk of liver injury

Crystal Structure of the PAC1R Extracellular Domain Unifies a Consensus Fold for Hormone Recognition by Class B G-Protein Coupled Receptors

Pituitary adenylate cyclase activating polypeptide (PACAP) is a member of the PACAP/glucagon family of peptide hormones, which controls many physiological functions in the immune, nervous, endocrine, and muscular systems. It activates adenylate cyclase by binding to its receptor, PAC1R, a member of class B G-protein coupled receptors (GPCR). Crystal structures of a number of Class B GPCR extracellular domains (ECD) bound to their respective peptide hormones have revealed a consensus mechanism of hormone binding. However, the mechanism of how PACAP binds to its receptor remains controversial as an NMR structure of the PAC1R ECD/PACAP complex reveals a different topology of the ECD and a distinct mode of ligand recognition. Here we report a 1.9 Å crystal structure of the PAC1R ECD, which adopts the same fold as commonly observed for other members of Class B GPCR. Binding studies and cell-based assays with alanine-scanned peptides and mutated receptor support a model that PAC1R uses the same conserved fold of Class B GPCR ECD for PACAP binding, thus unifying the consensus mechanism of hormone binding for this family of receptors

Risk Factors for Canine Osteoarthritis and Its Predisposing Arthropathies: A Systematic Review

Osteoarthritis is a common clinical and pathological end-point from a range of joint disorders, that ultimately lead to structural and functional decline of the joint with associated lameness and pain. Increasing understanding of the risk factors associated with osteoarthritis will assist in addressing the significant threat it poses to the welfare of the dog population and implementing preventive measures. Presented here, is the first comprehensive systematic review and evaluation of the literature reporting risk factors for canine osteoarthritis. This paper aimed to systematically collate, review and critically evaluate the published literature on risk factors for canine osteoarthritis and its predisposing conditions such as developmental joint dysplasias, cruciate ligament degeneration, and patellar luxation. Peer-reviewed publications were systematically searched for both osteoarthritis and predisposing arthropathies on Web of Science and PubMed following PRISMA (2009) guidelines, using pre-specified combinations of keywords. Sixty-two papers met the inclusion criteria and were evaluated and graded on reporting quality. Identified risk factors included both modifiable factors (neuter status and body weight) for which intervention can potentially affect the risk of occurrence of osteoarthritis, and unmodifiable factors (sex, breed, and age) which can be used to identify individuals most “at risk.” Osteoarthritis in dogs frequently develops from predisposing arthropathies, and therefore risk factors for these are also important to consider. Papers evaluated in this study were rated as medium to high-quality; gap analysis of the literature suggests there would be significant benefit from additional research into the interactions between and relative weighting of risk factors. There are a number of examples where research outcomes are conflicting such as age and sex; and further investigation into these factors would be beneficial to attain greater understanding of the nature of these risks. Comprehensively collating the published risk factors for osteoarthritis and its predisposing conditions offers opportunities to identify possible means for control and reduction within the population through preventative methods and control strategies. These factors are highlighted here, as well as current literature gaps where further research is warranted, to aid future research direction