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

Resolving parameter degeneracies in long-baseline experiments by atmospheric neutrino data

In this work we show that the physics reach of a long-baseline (LBL) neutrino oscillation experiment based on a superbeam and a megaton water Cherenkov detector can be significantly increased if the LBL data are combined with data from atmospheric neutrinos (ATM) provided by the same detector. ATM data are sensitive to the octant of $\theta_{23}$ and to the type of the neutrino mass hierarchy, mainly through three-flavor effects in e-like events. This allows to resolve the so-called $\theta_{23}$- and sign($\Delta m^2_{31}$)-parameter degeneracies in LBL data. As a consequence it becomes possible to distinguish the normal from the inverted neutrino mass ordering at $2\sigma$ CL from a combined LBL+ATM analysis if $\sin^2 2\theta_{13} \gtrsim 0.02$. The potential to identify the true values of $\sin^2 2\theta_{13}$ and the CP-phase $\delta_{cp}$ is significantly increased through the lifting of the degeneracies. These claims are supported by a detailed simulation of the T2K (phase II) LBL experiment combined with a full three-flavor analysis of ATM data in the HyperKamiokande detector.Comment: 25 pages, 10 figure

Self-healing of dense asphalt concrete by two different approaches: electromagnetic induction and infrared radiation

Self-healing of cracks in asphalt mixtures is a phenomenon that can be accelerated by reducing the viscosity of bitumen as it increases the capillarity flow through the cracks. One method to achieve this is by increasing temperature, which also produces a thermal expansion that contributes to the circulation of the bitumen through cracks. In the present paper, the healing performance of asphalt mixture heated using infrared heating to simulate the natural solar radiation, and induction heating, a new method to increase the temperature of asphalt pavements, were compared in terms of time and healing temperature. Healing was defined as the relationship between the 3-point bending strength of an asphalt beam before and after healing. The results show that both methods reach similar and satisfactory healing ratios at around 90 %. However, induction heating is more energy efficient because the effect is concentrated on the binder, instead of heating the whole mix. This can be translated into much shorter heating times to reach the same healing level. Finally, an optimum radiation energy was found, after which higher amounts of infrared radiation damage the properties of the healed material

Observation of a New Excited Ds+ Meson in B0 →d-D+K+π-Decays

Using pp collision data corresponding to an integrated luminosity of 5.4 fb−1 collected with the LHCb detector at a center-of-mass energy of 13 TeV, the B0 → D−DþKþπ− decay is studied. A new excited Dþ s meson is observed decaying into the DþKþπ− final state with large statistical significance. The pole mass and width, and the spin parity of the new state are measured with an amplitude analysis to be mR ¼ 2591 6 7 MeV, ΓR ¼ 89 16 12 MeV, and JP ¼ 0−, where the first uncertainty is statistical and the second systematic. Fit fractions for all components in the amplitude analysis are also reported. The new resonance, denoted as Ds0ð2590Þþ, is a strong candidate to be the Dsð21 S0Þþ state, the radial excitation of the pseudoscalar ground-state Dþ s meson

Earnings responses to disability insurance stringency

Accurate assessment of earnings capacity is critical to the efficient operation of disability insurance (DI) programs. We use administrative data on the universe of Dutch DI recipients to estimate employment and earnings responses to reassessment of their earnings capacity under more stringent rules. We estimate that reassessment of recipients aged 30–44 removed 17 percent from the program and reduced benefit income by 20 percent, on average. In response, employment increased by 6.7 percentage points and earnings rose by 18 percent. Recipients were able to increase earnings by € 636 for every € 1000 reduction in DI benefit. This earnings response was strongest from those with more subjectively defined disabilities and a shorter claim duration, as well as younger and female recipients

Proper motions of the HH1 jet

We describe a new method for determining proper motions of extended objects, and a pipeline developed for the application of this method. We then apply this method to an analysis of four epochs of [S~II] HST images of the HH~1 jet (covering a period of $\sim 20$~yr). We determine the proper motions of the knots along the jet, and make a reconstruction of the past ejection velocity time-variability (assuming ballistic knot motions). This reconstruction shows an "acceleration" of the ejection velocities of the jet knots, with higher velocities at more recent times. This acceleration will result in an eventual merging of the knots in $\sim 450$~yr and at a distance of $\sim 80"$ from the outflow source, close to the present-day position of HH~1.Comment: 12 pages, 8 figure