Inhibition of Nuclear Factor of Activated T-Cells (NFAT) Suppresses Accelerated Atherosclerosis in Diabetic Mice

OBJECTIVE OF THE STUDY: Diabetic patients have a much more widespread and aggressive form of atherosclerosis and therefore, higher risk for myocardial infarction, peripheral vascular disease and stroke, but the molecular mechanisms leading to accelerated damage are still unclear. Recently, we showed that hyperglycemia activates the transcription factor NFAT in the arterial wall, inducing the expression of the pro-atherosclerotic protein osteopontin. Here we investigate whether NFAT activation may be a link between diabetes and atherogenesis. METHODOLOGY AND PRINCIPAL FINDINGS: Streptozotocin (STZ)-induced diabetes in apolipoprotein E(-/-) mice resulted in 2.2 fold increased aortic atherosclerosis and enhanced pro-inflammatory burden, as evidenced by elevated blood monocytes, endothelial activation- and inflammatory markers in aorta, and pro-inflammatory cytokines in plasma. In vivo treatment with the NFAT blocker A-285222 for 4 weeks completely inhibited the diabetes-induced aggravation of atherosclerosis, having no effect in non-diabetic mice. STZ-treated mice exhibited hyperglycemia and higher plasma cholesterol and triglycerides, but these were unaffected by A-285222. NFAT-dependent transcriptional activity was examined in aorta, spleen, thymus, brain, heart, liver and kidney, but only augmented in the aorta of diabetic mice. A-285222 completely blocked this diabetes-driven NFAT activation, but had no impact on the other organs or on splenocyte proliferation or cytokine secretion, ruling out systemic immunosuppression as the mechanism behind reduced atherosclerosis. Instead, NFAT inhibition effectively reduced IL-6, osteopontin, monocyte chemotactic protein 1, intercellular adhesion molecule 1, CD68 and tissue factor expression in the arterial wall and lowered plasma IL-6 in diabetic mice. CONCLUSIONS: Targeting NFAT signaling may be a novel and attractive approach for the treatment of diabetic macrovascular complications

A four gap glass RPC time-of-flight array with 90 ps time resolution

In this work we describe the performance of a prototype developped in the context of the ALICE team-of-flight R&D system. The detector module consists of a 32-channel array of 3 x 3 cm2 glass-RPC cells, each of which has four accurately spaced gaps of 0.3. mm thickness arranged as a pair of double-gap resistive plate chambers. Operated with a non-flammable gas mixture at atmospheric pressure, the system achieved a time resolution of 90 ps at 90% efficiency with good uniformity and moderate crosstalk. This result shows the feasibility of large-area, high resolution time-of-flight systems based on RPCs at affordable cost

Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic β-cells

Diabetes is a global health problem caused primarily by the inability of pancreatic β-cells to secrete adequate levels of insulin. The molecular mechanisms underlying the progressive failure of β-cells to respond to glucose in type-2 diabetes remain unresolved. Using a combination of transcriptomics and proteomics, we find significant dysregulation of major metabolic pathways in islets of diabetic βV59M mice, a non-obese, eulipidaemic diabetes model. Multiple genes/proteins involved in glycolysis/gluconeogenesis are upregulated, whereas those involved in oxidative phosphorylation are downregulated. In isolated islets, glucose-induced increases in NADH and ATP are impaired and both oxidative and glycolytic glucose metabolism are reduced. INS-1 β-cells cultured chronically at high glucose show similar changes in protein expression and reduced glucose-stimulated oxygen consumption: targeted metabolomics reveals impaired metabolism. These data indicate hyperglycaemia induces metabolic changes in β-cells that markedly reduce mitochondrial metabolism and ATP synthesis. We propose this underlies the progressive failure of β-cells in diabetes.Peer reviewe

Paraphrases and summaries: A means of clarification or a vehicle for articulating a preferred version of student accounts?

The use of group discussions as a means to facilitate learning from experiences is well documented in adventure education literature. Priest and Naismith (1993) assert that the use of the circular discussion method, where the leader poses questions to the participants, is the most common form of facilitation in adventure education. This paper draws on transcripts of facilitation sessions to argue that the widely advocated practice of leader summaries or paraphrases of student responses in these sessions functions as a potential mechanism to control and sponsor particular knowledge(s). Using transcripts from recorded facilitation sessions the analysis focuses on how the leader paraphrases the students’ responses and how these paraphrases or ‘formulations’ function to modify or exclude particular aspects of the students’ responses. I assert that paraphrasing is not simply a neutral activity that merely functions to clarify a student response, it is a subtle means by which the leader of the session can, often inadvertently or unknowingly, alter the student’s reply with the consequence of favouring particular knowledge(s). Revealing the subtle work that leader paraphrases perform is of importance for educators who claim to provide genuine opportunities for students to learn from their experience

The concept of "compartment allergy": prilocaine injected into different skin layers

We herein present a patient with delayed-type allergic hypersensitivity against prilocaine leading to spreading eczematous dermatitis after subcutaneous injections for local anesthesia with prilocaine. Prilocaine allergy was proven by positive skin testing and subcutaneous provocation, whereas the evaluation of other local anesthetics - among them lidocaine, articaine and mepivacaine - did not exhibit any evidence for cross-reactivity

Front-end electronics for the ALICE TPC-detector

The Front-End electronics for the Time Projection Chamber (TPC) for the ALICE experiment consists of 5x105 channels. A single readout channel is comprised of three basic units: a charge sensitive amplifier/shaper with a fast tail cancellation; a 10 bit 10 Msamples/sec low power ADC; a digital ASIC which contains the zero suppression circuit and a multiple-event buffer. Data from a number of channels (4096) are multiplexed into an optical link (DDL) by means of a local custom bus which can support a data throughput of 2 Mbyte/event at a trigger rate of 50 Hz. The construction of a prototype of this electronics is presented in this paper

A Four-Gap Glass-RPC Time-of-Flight Array with 90 ps Time Resolution

In this paper, we describe the performance of a prototype developed in the context of the ALICE time-of-flight research and development system. The detector module consists of a 32-channel array of 3 x 3 cm2 glass resistive plate chamber (RPC) cells, each of which has four accurately space gaps of 0.3 mm thickness arranged as a pair of double-gap resisitive plate chambers. Operated with a nonflammable gas mixture at atmospheric pressure, the system achieved a time resolution of 90 ps at 98% efficiency with good uniformity and moderate crosstalk. This result shows the feasibility of large-area high-resolution time-of-flight systems based on RPCs at affordable cost

Detailed Mitochondrial Phenotyping by High Resolution Metabolomics

Mitochondrial phenotype is complex and difficult to define at the level of individual cell types. Newer metabolic profiling methods provide information on dozens of metabolic pathways from a relatively small sample. This pilot study used “top-down” metabolic profiling to determine the spectrum of metabolites present in liver mitochondria. High resolution mass spectral analyses and multivariate statistical tests provided global metabolic information about mitochondria and showed that liver mitochondria possess a significant phenotype based on gender and genotype. The data also show that mitochondria contain a large number of unidentified chemicals

Proton and antiproton distributions at mid-rapidity in proton-nucleus and sulphur-nucleus collisions

Experiment NA44 has measured proton and antiproton distributions at mid-rapidity in sulphur and proton collisions with nuclear targets at 200 and 450 GeV/c per nucleon respectively. The inverse slopes of transverse mass distributions increase with system size for both protons and antiprotons but are slightly lower for antiprotons. this could happen if antiprotons are annihilated in the nuclear medium. The antiproton yield increases with system size and centrality and is largest at mid-rapdity. The proton yield also increases with system size and centrality, but decreases from backward rapidity to midrapidity. The stopping of protons at these energies lies between the full stopping and nuclear transparency scenarios. The data are in reasonable agreement with RQMD predictions except for the antiproton yields from sulphur-nucleus collisions. PACS numbers 25.75.-q 13.85.-t 13.60.R