Sphingolipid subtypes differentially control proinsulin processing and systemic glucose homeostasis

Impaired proinsulin-to-insulin processing in pancreatic β-cells is a key defective step in both type 1 diabetes and type 2 diabetes (T2D) (refs. $^{1}$$^{,}$$^{2}$), but the mechanisms involved remain to be defined. Altered metabolism of sphingolipids (SLs) has been linked to development of obesity, type 1 diabetes and T2D (refs. $^{3-8}$); nonetheless, the role of specific SL species in β-cell function and demise is unclear. Here we define the lipid signature of T2D-associated β-cell failure, including an imbalance of specific very-long-chain SLs and long-chain SLs. β-cell-specific ablation of CerS2, the enzyme necessary for generation of very-long-chain SLs, selectively reduces insulin content, impairs insulin secretion and disturbs systemic glucose tolerance in multiple complementary models. In contrast, ablation of long-chain-SL-synthesizing enzymes has no effect on insulin content. By quantitatively defining the SL-protein interactome, we reveal that CerS2 ablation affects SL binding to several endoplasmic reticulum-Golgi transport proteins, including Tmed2, which we define as an endogenous regulator of the essential proinsulin processing enzyme Pcsk1. Our study uncovers roles for specific SL subtypes and SL-binding proteins in β-cell function and T2D-associated β-cell failure

Structure of high-lying levels populated in the Y-96 -> Zr-96 beta decay

The nature of $J^{\pi}=1^-$ levels of $^{96}$Zr below the $\beta$-decay $Q_{\beta}$ value of $^{96}$Y has been investigated in high-resolution $\gamma$-ray spectroscopy following the $\beta$ decay as well as in a campaign of inelastic photon scattering experiments. Branching ratios extracted from $\beta$ decay allow the absolute $E1$ excitation strength to be determined for levels populated in both reactions. The combined data represents a comprehensive approach to the wavefunction of $1^-$ levels below the $Q_{\beta}$ value, which are investigated in the theoretical approach of the Quasiparticle Phonon Model. This study clarifies the nuclear structure properties associated with the enhanced population of high-lying levels in the $^{96}$Y$_{gs}$ $\beta$ decay, one of the three most important contributors to the high-energy reactor antineutrino spectrum

DIRECT ENERGY CONVERSION (DEC) FISSION REACTORS - A U.S. NERI PROJECT

The direct conversion of the electrical energy of charged fission fragments was examined early in the nuclear reactor era, and the first theoretical treatment appeared in the literature in 1957. Most of the experiments conducted during the next ten years to investigate fission fragment direct energy conversion (DEC) were for understanding the nature and control of the charged particles. These experiments verified fundamental physics and identified a number of specific problem areas, but also demonstrated a number of technical challenges that limited DEC performance. Because DEC was insufficient for practical applications, by the late 1960s most R&D ceased in the US. Sporadic interest in the concept appears in the literature until this day, but there have been no recent programs to develop the technology. This has changed with the Nuclear Energy Research Initiative that was funded by the U.S. Congress in 1999. Most of the previous concepts were based on a fission electric cell known as a triode, where a central cathode is coated with a thin layer of nuclear fuel. A fission fragment that leaves the cathode with high kinetic energy and a large positive charge is decelerated as it approaches the anode by a charge differential of several million volts, it then deposits its charge in the anode after its kinetic energy is exhausted. Large numbers of low energy electrons leave the cathode with each fission fragment; they are suppressed by negatively biased on grid wires or by magnetic fields. Other concepts include magnetic collimators and quasi-direct magnetohydrodynamic generation (steady flow or pulsed). We present the basic principles of DEC fission reactors, review the previous research, discuss problem areas in detail and identify technological developments of the last 30 years relevant to overcoming these obstacles. A prognosis for future development of direct energy conversion fission reactors will be presented

Microstructural study of AZ91C magnesium alloy castings produced by investment casting in as-cast state and after heat treatment

In this article, the microstructure of AZ91C magnesium alloy castings produced by investment casting was investigated. Castings were studied in as-cast state and after T4 and T6 heat treatment. The identification of all phases in microstructure was carried out using a scanning electron microscope (SEM) with energy dispersive X-ray spectroscopy (EDS) analysis. The influence of cooling rate after casting, temperature of solution annealing, temperature of artificial aging and cooling rate after heat treatment on the microstructural characteristics such as secondary dendrite arm spacing (SDAS) or grain size was studied. The SDAS analyses were carried out using a light microscopy with the subsequent image analysis. Except of Mg-Al solid solution and Mg17Al12 precipitates, the microstructure contains other phases based on Mg-Si and (Al,Si)-Mn in globular or needle morphology. The SDAS in as-cast state was measured and was of tens of micrometers, but after T4 heat treatment, the gran size exceeded 100 µm and the Mg17Al12 phase was still undissolved along the grain boundaries in samples with thicker wall dimension. After T6 heat treatment, continuous and discontinuous precipitates of Mg17Al12 phase were formed, most of them were nearby the grain boundaries proving the inhomogeneous distribution of Al atoms in solid solution after T4 heat treatment

Fish oil and aspirin effects on arteriovenous fistula function: secondary outcomes of the randomised omega-3 fatty acids (Fish oils) and Aspirin in Vascular access OUtcomes in REnal Disease (FAVOURED) trial

Background: Arteriovenous fistulas (AVF) for haemodialysis often experience early thrombosis and maturation failure requiring intervention and/or central venous catheter (CVC) placement. This secondary and exploratory analysis of the FAVOURED study determined whether omega-3 fatty acids (fish oils) or aspirin affected AVF usability, intervention rates and CVC requirements. Methods: In 567 adult participants planned for AVF creation, all were randomised to fish oil (4g/d) or placebo, and 406 to aspirin (100mg/d) or placebo, starting one day pre-surgery and continued for three months. Outcomes evaluated within 12 months included AVF intervention rates, CVC exposure, late dialysis suitability failure, and times to primary patency loss, abandonment and successful cannulation. Results: Final analyses included 536 participants randomised to fish oil or placebo (mean age 55 years, 64% male, 45% diabetic) and 388 randomised to aspirin or placebo. Compared with placebo, fish oil reduced intervention rates (0.82 vs 1.14/1000 patient-days, incidence rate ratio [IRR] 0.72, 95% confidence interval [CI] 0.54–0.97), particularly interventions for acute thrombosis (0.09 vs 0.17/1000 patient-days, IRR 0.53, 95% CI 0.34–0.84). Aspirin significantly reduced rescue intervention rates (IRR 0.45, 95% CI 0.27–0.78). Neither agent significantly affected CVC exposure, late dialysis suitability failure or time to primary patency loss, AVF abandonment or successful cannulation. Conclusion: Although fish oil and low-dose aspirin given for 3 months reduced intervention rates in newly created AVF, they had no significant effects on CVC exposure, AVF usability and time to primary patency loss or access abandonment. Reduction in access interventions benefits patients, reduces costs and warrants further study.Andrea K. Viecelli, Kevan R. Polkinghorne, Elaine M. Pascoe, Peta-Anne Paul-Brent, Carmel M. Hawley ... Stephen P. McDonald .. et al