Scaling factors for the in vitro-in vivo extrapolation (IV-IVE) of renal drug and xenobiotic glucuronidation clearance.

AIM: To determine the scaling factors required for inclusion of renal drug glucuronidation clearance in the prediction of total clearance via glucuronidation (CLUGT ). METHODS: Microsomal protein per gram of kidney (MPPGK) was determined for human 'mixed' kidney (n = 5) microsomes (MKM). The glucuronidation activities of deferiprone (DEF), propofol (PRO) and zidovudine (AZT) by MKM and paired cortical (KCM) and medullary (KMM) microsomes were measured, along with the UGT 1A6, 1A9 and 2B7 protein contents of each enzyme source. Unbound intrinsic clearances (CLint,u,UGT ) for PRO and morphine (MOR; 3- and 6-) glucuronidation by MKM, human liver microsomes (HLM) and recombinant UGT1A9 and 2B7 were additionally determined. Data were scaled using in vitro-in vivo extrapolation (IV-IVE) approaches to assess the influence of renal CLint,u,UGT on the prediction accuracy of the calculated CLUGT values of PRO and MOR. RESULTS: MPPGK was 9.3 ± 2.0 mg g(-1) (mean ± SD). The respective rates of DEF (UGT1A6), PRO (UGT1A9) and AZT (UGT2B7) glucuronidation by KCM were 1.4-, 5.2- and 10.5-fold higher than those for KMM. UGT 1A6, 1A9 and 2B7 were the only enzymes expressed in kidney. Consistent with the activity data, the abundance of each of these enzymes was greater in KCM than in KMM. The abundance of UGT1A9 in MKM (61.3 pmol mg(-1) ) was 2.7 fold higher than that reported for HLM. CONCLUSIONS: Scaled renal PRO glucuronidation CLint,u,UGT was double that of liver. Renal CLint,u,UGT should be accounted for in the IV-IVE of UGT1A9 and considered for UGT1A6 and 2B7 substrates

Carbon, Metals, and Grain Size Correlate with Bacterial Community Structure in Sediments of a High Arsenic Aquifer

Bacterial communities can exert significant influence on the biogeochemical cycling of arsenic (As). This has globally important implications since As in drinking water affects the health of over 100 million people worldwide, including in the Ganges–Brahmaputra Delta region of Bangladesh where geogenic arsenic in groundwater can reach concentrations of more than 10 times the World Health Organization’s limit. Thus, the goal of this research was to investigate patterns in bacterial community composition across gradients in sediment texture and chemistry in an aquifer with elevated groundwater As concentrations in Araihazar, Bangladesh. We characterized the bacterial community by pyrosequencing 16S rRNA genes from aquifer sediment samples collected at three locations along a groundwater flow path at a range of depths between 1.5 and 15 m. We identified significant differences in bacterial community composition between locations in the aquifer. In addition, we found that bacterial community structure was significantly related to sediment grain size, and sediment carbon (C), manganese (Mn), and iron (Fe) concentrations. Deltaproteobacteria and Chloroflexi were found in higher proportions in silty sediments with higher concentrations of C, Fe, and Mn. By contrast, Alphaproteobacteria and Betaproteobacteria were in higher proportions in sandy sediments with lower concentrations of C and metals. Based on the phylogenetic affiliations of these taxa, these results may indicate a shift to more Fe-, Mn-, and humic substance-reducers in the high C and metal sediments. It is well-documented that C, Mn, and Fe may influence the mobility of groundwater arsenic, and it is intriguing that these constituents may also structure the bacterial community

Niacin-mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system

Abstract: Remyelination following CNS demyelination restores rapid signal propagation and protects axons; however, its efficiency declines with increasing age. Both intrinsic changes in the oligodendrocyte progenitor cell population and extrinsic factors in the lesion microenvironment of older subjects contribute to this decline. Microglia and monocyte-derived macrophages are critical for successful remyelination, releasing growth factors and clearing inhibitory myelin debris. Several studies have implicated delayed recruitment of macrophages/microglia into lesions as a key contributor to the decline in remyelination observed in older subjects. Here we show that the decreased expression of the scavenger receptor CD36 of aging mouse microglia and human microglia in culture underlies their reduced phagocytic activity. Overexpression of CD36 in cultured microglia rescues the deficit in phagocytosis of myelin debris. By screening for clinically approved agents that stimulate macrophages/microglia, we have found that niacin (vitamin B3) upregulates CD36 expression and enhances myelin phagocytosis by microglia in culture. This increase in myelin phagocytosis is mediated through the niacin receptor (hydroxycarboxylic acid receptor 2). Genetic fate mapping and multiphoton live imaging show that systemic treatment of 9–12-month-old demyelinated mice with therapeutically relevant doses of niacin promotes myelin debris clearance in lesions by both peripherally derived macrophages and microglia. This is accompanied by enhancement of oligodendrocyte progenitor cell numbers and by improved remyelination in the treated mice. Niacin represents a safe and translationally amenable regenerative therapy for chronic demyelinating diseases such as multiple sclerosis

Close Encounters: Intimate service interactions in lap dancing work as a nexus of ‘self-others-things’

Drawing on ethnographic research on lap dancing work, this paper focuses on how the subjectivities, interactions and settings that constitute the lap dancing industry come into being through three interrelated processes of encoding, embodying and embedding. In considering how these processes combine to ‘enact’ the industry, the paper draws on Merleau Ponty’s understanding of the world as a dynamic nexus of ‘self-others-things’. Focusing on how this nexus shapes lived experiences of intimate service interactions, the analysis considers how dancers continually negotiate customers’ expectations of the service encounter given the ways in which these are: (i) encoded in depictions of lap dancing work in marketing and advertising materials on club websites; (ii) embodied by lap dancers through their interactions with customers; and (iii) embedded within the materiality of lap dancing clubs. The paper shows how intimate service encounters can be understood as the outcome of a nexus of ‘self-others-things’ through which particular organizational subjectivities and settings are brought into being through these three interrelated processes

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead