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Recent genetic and clinical evidence has implicated glucokinase regulatory protein (GKRP) in the pathogenesis of type 2 diabetes and related traits. The primary role of GKRP is to bind and inhibit hepatic glucokinase (GCK), a critically important protein in human health and disease that exerts a significant degree of control over glucose metabolism. As activation of GCK has been associated with improved glucose tolerance, perturbation of the GCK-GKRP interaction represents a potential therapeutic target for pharmacological modulation. Recent structural and kinetic advances are beginning to provide insight into the interaction of these two proteins. However, tools to comprehensively assess the GCK-GKRP interaction, particularly in the context of small molecules, would be a valuable resource. We therefore developed three robust and miniaturized assays for assessing the interaction between recombinant human GCK and GKRP: an HTRF assay, a diaphorase-coupled assay, and a luciferase-coupled assay. The assays are complementary, featuring distinct mechanisms of detection (luminescence, fluorescence, FRET). Two assays rely on GCK enzyme activity modulation by GKRP while the FRET-based assay measures the GCK-GKRP protein-protein interaction independent of GCK enzymatic substrates and activity. All three assays are scalable to low volumes in 1536-well plate format, with robust Z’ factors (>0.7). Finally, as GKRP sequesters GCK in the hepatocyte nucleus at low glucose concentrations, we explored cellular models of GCK localization and translocation. Previous findings from freshly isolated rat hepatocytes were confirmed in cryopreserved rat hepatocytes, and we further extended this study to cryopreserved human hepatocytes. Consistent with previous reports, there were several key differences between the rat and human systems, with our results suggesting that human hepatocytes can be used to interrogate GCK translocation in response to small molecules. The assay panel developed here should help direct future investigation of the GCK-GKRP interaction in these or other physiologically relevant human systems.

We report the results of a neutrino search in Super-Kamiokande for coincident signals with the first detected gravitational wave produced by a binary neutron star merger, GW170817, which was followed by a short gamma-ray burst, GRB170817A, and a kilonova/macronova. We searched for coincident neutrino events in the range from 3.5 MeV to $\sim$100 PeV, in a time window $\pm$500 seconds around the gravitational wave detection time, as well as during a 14-day period after the detection. No significant neutrino signal was observed for either time window. We calculated 90% confidence level upper limits on the neutrino fluence for GW170817. From the upward-going-muon events in the energy region above 1.6 GeV, the neutrino fluence limit is $16.0^{+0.7}_{-0.6}$ ($21.3^{+1.1}_{-0.8}$) cm$^{-2}$ for muon neutrinos (muon antineutrinos), with an error range of $\pm5^{\circ}$ around the zenith angle of NGC4993, and the energy spectrum is under the assumption of an index of $-2$. The fluence limit for neutrino energies less than 100 MeV, for which the emission mechanism would be different than for higher-energy neutrinos, is also calculated. It is $6.6 \times 10^7$ cm$^{-2}$ for anti-electron neutrinos under the assumption of a Fermi-Dirac spectrum with average energy of 20 MeV. Comment: 8 pages, 4 figures

We have determined the D0 lifetime from reconstructed vertices of D0 mesons produced in e+e- annihilations at an average center of mass energy of 42.2 GeV. From fifteen events the D0 lifetime was determined to be (4.3-1.4+2.0±0.8)×10-13s. © 1986 Springer-Verlag.

In the period 2015 to 2017, the Western Cape region has suffered from three consecutive years of below average rainfall - leading to a prolonged drought and acute water shortages, most prominently in the city of Cape Town. After testing that the precipitation deficit is the primary driver behind the reduced surface water availability, we undertake a multi-method attribution analysis for the meteorological drought, defined in terms of a deficit in the 3-year running mean precipitation averaged over the Western Cape area. The exact estimate of the return time of the event is sensitive to the number of stations whose data is incorporated in the analysis but the rarity of the event is unquestionable, with a return time of more than a hundred years. Synthesising the results from five different large model ensembles as well as observed data gives a significant increase by a factor of three (95% confidence interval 1.5 to 6) of such a drought to occur because of anthropogenic climate change. All the model results further suggest that this trend will continue with future global warming. These results are in line with physical understanding of the effect of climate change at these latitudes and highlights that measures to improve Cape Town’s resilience to future droughts are an adaptation priority.

Inclusive charged particle and event shape distributions are measured using 321 hadronic events collected with the DELPHI experiment at LEP at effective centre of mass energies of 130 to 136 GeV. These distributions are presented and compared to data at lower energies, in particular to the precise Z data. Fragmentation models describe the observed changes of the distributions well. The energy dependence of the means of the event shape variables can also be described using second order QCD plus power terms. A method independent of fragmentation model corrections is used to determine $\alpha_s$ from the energy dependence of the mean thrust and heavy jet mass. It is measured to be: % %\alpha_s(M_{\rm Z}) = 0.116 \pm 0.002_{exp} \pm 0.007_{theo} % % %\noindent %from the data up to Z energies and \alpha_s(133\mbox{ GeV}) = 0.116 \pm 0.007_{exp} {^{+0.005}_{-0.004}}_{theo} %\noindent from the high energy data.

Abstract Rising seas, more frequent storms and other climate-driven coastal hazards necessitate adaptation planning measures to protect people and property. To date, coastal vulnerability assessments have prioritized the most exposed areas of coastline, but there is a gap between recognized climate science and the feasibility or suitability considerations relevant for implementing coastal adaptation strategies—including legal, policy, financial, or engineered approaches—to address coastal threats. This paper sets forth a methodology for bridging the gap between climate science, law and coastal adaptation policies. This methodology seeks to connect spatial analysis methods with attributes of coastal adaptation strategies that make them inherently place-based—ranging from engineered solutions, to legal strategies and financial tools—to determine where they are legally feasible and suitable. Both spatial and non-spatial limiting and enabling conditions of coastal adaptation policies drive these determinations. The methodology integrates a spatial framework using feasibility statements derived by 1) coupling these conditions and features with spatial information (e.g., zoning, land use/land cover, geomorphologic features), and 2) identifying suitability conditions through synthesizing policy considerations for each coastal adaptation strategy.