Een vergoeding voor Chroom VI-slachtoffers bij Defensie

Hervorming Sociale Regelgevin

Reduced somatostatin signalling leads to hypersecretion of glucagon in mice fed a high-fat diet

Objectives:&nbsp;Elevated plasma glucagon is an early symptom of diabetes, occurring in subjects with impaired glucose regulation. Here, we explored alpha-cell function in female mice fed a high-fat diet (HFD)&mdash;a widely used mouse model of prediabetes. Methods:&nbsp;We fed female mice expressing the Ca2+&nbsp;indicator GCaMP3 specifically in alpha-cells an HFD or control (CTL) diet. We then conducted&nbsp;in&nbsp;vivo&nbsp;phenotyping of these mice, as well as experiments on isolated (ex&nbsp;vivo) islets and in the&nbsp;in situ&nbsp;perfused pancreas. Results:&nbsp;In&nbsp;vivo,&nbsp;HFD-fed mice exhibited increased fed plasma glucagon levels and a reduced response to elevations in plasma glucose. Glucagon secretion from isolated islets and in the perfused mouse pancreas was elevated under both hypo- and hyperglycaemic conditions. In mice fed a CTL diet, increasing glucose reduced intracellular Ca2+&nbsp;([Ca2+]i) (oscillation frequency and amplitude). This effect was also observed in HFD mice; however, both the frequency and amplitude of the [Ca2+]i&nbsp;oscillations were higher than those in CTL alpha-cells. Given that alpha-cells are under strong paracrine control from neighbouring somatostatin-secreting delta-cells, we hypothesised that this elevation of alpha-cell output was due to a lack of somatostatin (SST) secretion. Indeed, SST secretion in isolated islets from HFD mice was reduced but exogenous SST also failed to suppress glucagon secretion and [Ca2+]i&nbsp;activity from HFD alpha-cells, in contrast to observations in CTL mice. Conclusions:&nbsp;These findings suggest that reduced delta-cell function, combined with intrinsic changes in alpha-cell sensitivity to somatostatin, accounts for the hyperglucagonaemia in mice fed an HFD.</p

Evaluation of two interaction techniques for visualization of dynamic graphs

Several techniques for visualization of dynamic graphs are based on different spatial arrangements of a temporal sequence of node-link diagrams. Many studies in the literature have investigated the importance of maintaining the user's mental map across this temporal sequence, but usually each layout is considered as a static graph drawing and the effect of user interaction is disregarded. We conducted a task-based controlled experiment to assess the effectiveness of two basic interaction techniques: the adjustment of the layout stability and the highlighting of adjacent nodes and edges. We found that generally both interaction techniques increase accuracy, sometimes at the cost of longer completion times, and that the highlighting outclasses the stability adjustment for many tasks except the most complex ones.Comment: Appears in the Proceedings of the 24th International Symposium on Graph Drawing and Network Visualization (GD 2016

Identification of a Novel β-Cell Glucokinase (GCK) Promoter Mutation (−71G>C) That Modulates GCK Gene Expression Through Loss of Allele-Specific Sp1 Binding Causing Mild Fasting Hyperglycemia in Humans

OBJECTIVE: Inactivating mutations in glucokinase (GCK) cause mild fasting hyperglycemia. Identification of a GCK mutation has implications for treatment and prognosis; therefore, it is important to identify these individuals. A significant number of patients have a phenotype suggesting a defect in glucokinase but no abnormality of GCK. We hypothesized that the GCK beta-cell promoter region, which currently is not routinely screened, could contain pathogenic mutations; therefore, we sequenced this region in 60 such probands. RESEARCH DESIGN AND METHODS: The beta-cell GCK promoter was sequenced in patient DNA. The effect of the identified novel mutation on GCK promoter activity was assessed using a luciferase reporter gene expression system. Electrophoretic mobility shift assays (EMSAs) were used to determine the impact of the mutation on Sp1 binding. RESULTS: A novel -71G>C mutation was identified in a nonconserved region of the human promoter sequence in six apparently unrelated probands. Family testing established cosegregation with fasting hyperglycemia (> or = 5.5 mmol/l) in 39 affected individuals. Haplotype analysis in the U.K. family and four of the Slovakian families demonstrated that the mutation had arisen independently. The mutation maps to a potential transcriptional activator binding site for Sp1. Reporter assays demonstrated that the mutation reduces promoter activity by up to fourfold. EMSAs demonstrated a dramatic reduction in Sp1 binding to the promoter sequence corresponding to the mutant allele. CONCLUSIONS: A novel beta-cell GCK promoter mutation was identified that significantly reduces gene expression in vitro through loss of regulation by Sp1. To ensure correct diagnosis of potential GCK-MODY (maturity-onset diabetes of the young) cases, analysis of the beta-cell GCK promoter should be included

Trust and distrust in contradictory information transmission

We analyse the problem of contradictory information distribution in networks of agents with positive and negative trust. The networks of interest are built by ranked agents with different epistemic attitudes. In this context, positive trust is a property of the communication between agents required when message passing is executed bottom-up in the hierarchy, or as a result of a sceptic agent checking information. These two situations are associated with a confirmation procedure that has an epistemic cost. Negative trust results from refusing verification, either of contradictory information or because of a lazy attitude. We offer first a natural deduction system called SecureNDsim to model these interactions and consider some meta-theoretical properties of its derivations. We then implement it in a NetLogo simulation to test experimentally its formal properties. Our analysis concerns in particular: conditions for consensus-reaching transmissions; epistemic costs induced by confirmation and rejection operations; the influence of ranking of the initially labelled nodes on consensus and costs; complexity results

Local history – local history collection basis

Cilj je rada skrenuti pozornost na nekoliko elemenata bitnih za zavičajne zbirke i ukazati na njihov značaj. Prvenstveno i osnovno – lokalna je povijest temelj zavičajne zbirke. Njezino istraživanje, zasnovano na brojnim znanstveno-istraživačkim metodama, polazišna je točka za izgradnju zbirke, prezentaciju i komunikaciju sadržaja, a temeljeno na multidisciplinarnosti. Uz tradicionalne oblike prezentacije i komunikacije, knjižničarima na raspolaganju stoje i elektronički, posebice mrežna stranica. Takav pristup podrazumijeva dodatne kompetencije i afinitete zavičajnoga knjižničara. Istaknuta su dva, često zanemarena izvora za istraživanje povijesti – usmena povijest kao temelj socijalne povijesti te efemerna građa, kao „blago, a ne smeće“.The aim is to direct attention to several elements essential for the local history collections and indicate their importance. Firstly and foremost – a local history is the basis of local history collection. Research, based on a number of scientific research methods, is the starting point for building a collection, content presentation and communication, and justified on the multidisciplinary. In addition to traditional forms of presentation and communication, library materials are also available electronically, in particular web page. Such an approach entails additional competence and affinity local history librarians. Two often overlooked source for research history are featured – oral history as the foundation of social history and the ephemera, as “a treasure, not trash.

Loss of ZnT8 function protects against diabetes by enhanced insulin secretion.

A rare loss-of-function allele p.Arg138* in SLC30A8 encoding the zinc transporter 8 (ZnT8), which is enriched in Western Finland, protects against type 2 diabetes (T2D). We recruited relatives of the identified carriers and showed that protection was associated with better insulin secretion due to enhanced glucose responsiveness and proinsulin conversion, particularly when compared with individuals matched for the genotype of a common T2D-risk allele in SLC30A8, p.Arg325. In genome-edited human induced pluripotent stem cell (iPSC)-derived β-like cells, we establish that the p.Arg138* allele results in reduced SLC30A8 expression due to haploinsufficiency. In human β cells, loss of SLC30A8 leads to increased glucose responsiveness and reduced KATP channel function similar to isolated islets from carriers of the T2D-protective allele p.Trp325. These data position ZnT8 as an appealing target for treatment aimed at maintaining insulin secretion capacity in T2D

Neutrophils in cancer: neutral no more

Neutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view. The traditionally held belief that neutrophils are inert bystanders is being challenged by the recent literature. Emerging evidence indicates that tumours manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumour behaviour. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets

Influence of genetic variants on gene expression in human pancreatic islets – implications for type 2 diabetes

Most signals detected by genome-wide association studies map to non-coding sequence and their tissue-specific effects influence transcriptional regulation. However, many key tissues and cell-types required for appropriate functional inference are absent from large-scale resources such as ENCODE and GTEx. We explored the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using RNA-Seq and genotyping data from 420 islet donors. We find: (a) eQTLs have a variable replication rate across the 44 GTEx tissues (&lt;73%), indicating that our study captured islet-specific cis-eQTL signals; (b) islet eQTL signals show marked overlap with islet epigenome annotation, though eQTL effect size is reduced in the stretch enhancers most strongly implicated in GWAS signal location; (c) selective enrichment of islet eQTL overlap with the subset of T2D variants implicated in islet dysfunction; and (d) colocalization between islet eQTLs and variants influencing T2D or related glycemic traits, delivering candidate effector transcripts at 23 loci, including DGKB and TCF7L2. Our findings illustrate the advantages of performing functional and regulatory studies in tissues of greatest disease-relevance while expanding our mechanistic insights into complex traits association loci activity with an expanded list of putative transcripts implicated in T2D development