Rfx6 Maintains the Functional Identity of Adult Pancreatic β Cells.

SummaryIncreasing evidence suggests that loss of β cell characteristics may cause insulin secretory deficiency in diabetes, but the underlying mechanisms remain unclear. Here, we show that Rfx6, whose mutation leads to neonatal diabetes in humans, is essential to maintain key features of functionally mature β cells in mice. Rfx6 loss in adult β cells leads to glucose intolerance, impaired β cell glucose sensing, and defective insulin secretion. This is associated with reduced expression of core components of the insulin secretion pathway, including glucokinase, the Abcc8/SUR1 subunit of KATP channels and voltage-gated Ca2+ channels, which are direct targets of Rfx6. Moreover, Rfx6 contributes to the silencing of the vast majority of “disallowed” genes, a group usually specifically repressed in adult β cells, and thus to the maintenance of β cell maturity. These findings raise the possibility that changes in Rfx6 expression or activity may contribute to β cell failure in humans

Proglucagon-derived peptides do not significantly affect acute exocrine pancreas in rat

Reports have suggested a link between treatment with glucagon-like peptide 1 (GLP-1) analogs and an increased risk of pancreatitis. Oxyntomodulin, a dual agonist of both GLP-1 and glucagon receptors, is currently being investigated as a potential antiobesity therapy, but little is known about its pancreatic safety. The aim of the study was to investigate the acute effect of oxyntomodulin and other proglucagon-derived peptides on the rat exocrine pancreas.Glucagon-like peptide 1, oxyntomodulin, glucagon, and exendin-4 were infused into anesthetized rats to measure plasma amylase concentration changes. In addition, the effect of each peptide on both amylase release and proliferation in rat pancreatic acinar (AR42J) and primary isolated ductal cells was determined.Plasma amylase did not increase postpeptide infusion, compared with vehicle and cholecystokinin; however, oxyntomodulin inhibited plasma amylase when coadministered with cholecystokinin. None of the peptides caused a significant increase in proliferation rate or amylase secretion from acinar and ductal cells.The investigated peptides do not have an acute effect on the exocrine pancreas with regard to proliferation and plasma amylase, when administered individually. Oxyntomodulin seems to be a potent inhibitor of amylase release, potentially making it a safer antiobesity agent regarding pancreatitis, compared with GLP-1 agonists

Effect of Time of Access to Pasture and the Provision of a Total Mixed Ration on the Performance and Methane Production of High Yielding Dairy Cows

Allowing cows to spend time on pasture may improve their welfare, although high yielding cows are unable to consume sufficient amounts of grass to maintain milk yield and require supplementation (Charlton et al. 2011). The inclusion of grass in the diet of high yielding cows may have benefits as grass contains polyunsaturated fatty acids which can reduce methane production (Martin et al. 2008). Additionally, the soluble carbohydrate content in grass is higher in the afternoon which may increase intake (Trevaskis et al. 2004). The aim of the experiment was to determine the effects of timing of pasture access and the provision of access to total mixed ration (TMR) when at grass on the performance and methane production of high yielding dairy cows

Changes in the expression of the type 2 diabetes-associated gene VPS13C in the β cell are associated with glucose intolerance in humans and mice

Single nucleotide polymorphisms (SNPs) close to the VPS13C, C2CD4A and C2CD4B genes on chromosome 15q are associated with impaired fasting glucose and increased risk of type 2 diabetes. eQTL analysis revealed an association between possession of risk (C) alleles at a previously implicated causal SNP, rs7163757, and lowered VPS13C and C2CD4A levels in islets from female (n = 40, P < 0.041) but not from male subjects. Explored using promoter-reporter assays in β-cells and other cell lines, the risk variant at rs7163757 lowered enhancer activity. Mice deleted for Vps13c selectively in the β-cell were generated by crossing animals bearing a floxed allele at exon 1 to mice expressing Cre recombinase under Ins1 promoter control (Ins1Cre). Whereas Vps13cfl/fl:Ins1Cre (βVps13cKO) mice displayed normal weight gain compared with control littermates, deletion of Vps13c had little effect on glucose tolerance. Pancreatic histology revealed no significant change in β-cell mass in KO mice vs. controls, and glucose-stimulated insulin secretion from isolated islets was not altered in vitro between control and βVps13cKO mice. However, a tendency was observed in female null mice for lower insulin levels and β-cell function (HOMA-B) in vivo. Furthermore, glucose-stimulated increases in intracellular free Ca2+ were significantly increased in islets from female KO mice, suggesting impaired Ca2+ sensitivity of the secretory machinery. The present data thus provide evidence for a limited role for changes in VPS13C expression in conferring altered disease risk at this locus, particularly in females, and suggest that C2CD4A may also be involved

Coloring Mixed and Directional Interval Graphs

A mixed graph has a set of vertices, a set of undirected egdes, and a set ofdirected arcs. A proper coloring of a mixed graph $G$ is a function $c$ thatassigns to each vertex in $G$ a positive integer such that, for each edge $uv$in $G$, $c(u) \ne c(v)$ and, for each arc $uv$ in $G$, $c(u) mixed graph$G$, the chromatic number$\chi(G)$is the smallest number ofcolors in any proper coloring of$G$. A directional interval graph is a mixedgraph whose vertices correspond to intervals on the real line. Such a graph hasan edge between every two intervals where one is contained in the other and anarc between every two overlapping intervals, directed towards the interval thatstarts and ends to the right. Coloring such graphs has applications in routing edges in layered orthogonalgraph drawing according to the Sugiyama framework; the colors correspond to thetracks for routing the edges. We show how to recognize directional intervalgraphs, and how to compute their chromatic number efficiently. On the otherhand, for mixed interval graphs, i.e., graphs where two intersecting intervalscan be connected by an edge or by an arc in either direction arbitrarily, weprove that computing the chromatic number is NP-hard.<br

Modifying the stereochemistry of an enzyme-catalyzed reaction by directed evolution

Aldolases have potential as tools for the synthesis of stereochemically complex carbohydrates. Here, we show that directed evolution can be used to alter the stereochemical course of the reaction catalyzed by tagatose-1,6-bisphosphate aldolase. After three rounds of DNA shuffling and screening, the evolved aldolase showed an 80-fold improvement in k-cat/K-m toward the non-natural substrate fructose 1,6-bisphosphate, resulting in a 100-fold change in stereospecificity. (31)P NMR spectroscopy was used to show that, in the synthetic direction, the evolved aldolase catalyzes the formation of carbon—carbon bonds with unnatural diastereoselectivity, where the >99:<1 preference for the formation of tagatose 1,6-bisphosphate was switched to a 4:1 preference for the diastereoisomer, fructose 1,6-bisphosphate. This demonstration is of considerable significance to synthetic chemists requiring efficient syntheses of complex stereoisomeric products, such as carbohydrate mimetics

Sheffield Submission to the CHiC Ineractive Task: Exploring Digital Cultural Heritage

The Cultural Heritage in CLEF 2013 (CHiC) interactive task focused on acquiring and analysing interactive information retrieval (IIR)behaviour in a Digital Cultural Heritage collection. The University of Sheffield contributed 120 on-line and 20 in-lab participants to this task. The results of both the on-line and in-lab experiments strongly indicate that when faced with a new, unfamiliar collection and an open-ended task, participants will spend more time using the category hierarchy for exploration, than the search box. However, analysis of the the number of items the on-line participants view in detail and then saved to their workspace indicates that the two access methods fulfil different functions. From this we conclude that the categories are seemingly there to support the development of an initial overview over the collection, while the search is used to locate things in a more focused manner

Psychological distress in mid-life: evidence from the 1958 and 1970 British birth cohorts

BACKGROUND: This paper addresses the levels of psychological distress experienced at age 42 years by men and women born in 1958 and 1970. Comparing these cohorts born 12 years apart, we ask whether psychological distress has increased, and, if so, whether this increase can be explained by differences in their childhood conditions. METHOD: Data were utilized from two well-known population-based birth cohorts, the National Child Development Study and the 1970 British Cohort Study. Latent variable models and causal mediation methods were employed. RESULTS: After establishing the measurement equivalence of psychological distress in the two cohorts we found that men and women born in 1970 reported higher levels of psychological distress compared with those born in 1958. These differences were more pronounced in men (b = 0.314, 95% confidence interval 0.252-0.375), with the magnitude of the effect being twice as strong compared with women (b = 0.147, 95% confidence interval 0.076-0.218). The effect of all hypothesized early-life mediators in explaining these differences was modest. CONCLUSIONS: Our findings have implications for public health policy, indicating a higher average level of psychological distress among a cohort born in 1970 compared with a generation born 12 years earlier. Due to increases in life expectancy, more recently born cohorts are expected to live longer, which implies - if such differences persist - that they are likely to spend more years with mental health-related morbidity compared with earlier-born cohorts