Small molecule induced reactivation of mutant p53 in cancer cells

The p53 cancer mutant Y220C is an excellent paradigm for rescuing the function of conformationally unstable p53 mutants because it has a unique surface crevice that can be targeted by small-molecule stabilizers. Here, we have identified a compound, PK7088, which is active in vitro: PK7088 bound to the mutant with a dissociation constant of 140 μM and raised its melting temperature, and we have determined the binding mode of a close structural analogue by X-ray crystallography. We showed that PK7088 is biologically active in cancer cells carrying the Y220C mutant by a battery of tests. PK7088 increased the amount of folded mutant protein with wild-type conformation, as monitored by immunofluorescence, and restored its transcriptional functions. It induced p53-Y220C-dependent growth inhibition, cell-cycle arrest and apoptosis. Most notably, PK7088 increased the expression levels of p21 and the proapoptotic NOXA protein. PK7088 worked synergistically with Nutlin-3 on up-regulating p21 expression, whereas Nutlin-3 on its own had no effect, consistent with its mechanism of action. PK7088 also restored non-transcriptional apoptotic functions of p53 by triggering nuclear export of BAX to the mitochondria. We suggest a set of criteria for assigning activation of p53

White-nose syndrome survivors do not exhibit frequent arousals associated with Pseudogymnoascus destructans infection

Background: White-nose syndrome (WNS) has devastated bat populations in North America, with millions of bats dead. WNS is associated with physiological changes in hibernating bats, leading to increased arousals from hibernation and premature consumption of fat reserves. However, there is evidence of surviving populations of little brown myotis (Myotis lucifugus) close to where the fungus was first detected nearly ten years ago. Results: We examined the hibernation patterns of a surviving population of little brown myotis and compared them to patterns in populations before the arrival of WNS and populations at the peak of WNS mortality. Despite infection with Pseudogymnoascus destructans, the causative fungal agent, the remnant population displayed less frequent arousals from torpor and lower torpid body temperatures than bats that died from WNS during the peak of mortality. The hibernation patterns of the remnant population resembled pre-WNS patterns with some modifications. Conclusions: These data show that remnant populations of little brown myotis do not experience the increase in periodic arousals from hibernation typified by bats dying from WNS, despite the presence of the fungal pathogen on their skin. These patterns may reflect the use of colder hibernacula microclimates by WNS survivors, and/or may reflect differences in how these bats respond to the disease.Peer reviewe

Two Generations of CubeSat Missions (CSSWE and CIRBE) to Take on the Challenges of Measuring Relativistic Electrons in the Earth’s Magnetosphere

The Colorado Student Space Weather Experiment (CSSWE) CubeSat, carrying the Relativistic Electron and Proton Telescope integrated little experiment (REPTile) to measure 0.5 to \u3e3.8 MeV electrons and 8-40 MeV protons, operated for over two years, 2012-2014, in low Earth orbit (LEO). There have been 25 peer-reviewed publications, including two in Nature, and five Ph.D. dissertations associated with CSSWE. Another 3U CubeSat mission: Colorado Inner Radiation Belt Electron Experiment (CIRBE), has been under development to address an unresolved science question: Where is the break point in terms of electron energy below which electrons can be transported into the inner belt from the outer belt but above which they cannot? This requires clean measurements of energetic electrons with fine energy resolution in an environment where all instruments are subject to the unforgiving penetration from highly energetic protons (tens of MeV to GeV). An advanced version of REPTile has been designed and built, REPTile-2. It has been integrated into the CIRBE bus, which has active attitude control, deployable solar panels, and a S-band radio, provided by Blue Canyon Technologies. CIRBE advances our science capabilities and has significantly improved performance vs. CSSWE and is ready to be launched into a LEO in early 2023

Implementation of U.K. Earth system models for CMIP6

We describe the scientific and technical implementation of two models for a core set of experiments contributing to the sixth phase of the Coupled Model Intercomparison Project (CMIP6). The models used are the physical atmosphere-land-ocean-sea ice model HadGEM3-GC3.1 and the Earth system model UKESM1 which adds a carbon-nitrogen cycle and atmospheric chemistry to HadGEM3-GC3.1. The model results are constrained by the external boundary conditions (forcing data) and initial conditions.We outline the scientific rationale and assumptions made in specifying these. Notable details of the implementation include an ozone redistribution scheme for prescribed ozone simulations (HadGEM3-GC3.1) to avoid inconsistencies with the model's thermal tropopause, and land use change in dynamic vegetation simulations (UKESM1) whose influence will be subject to potential biases in the simulation of background natural vegetation.We discuss the implications of these decisions for interpretation of the simulation results. These simulations are expensive in terms of human and CPU resources and will underpin many further experiments; we describe some of the technical steps taken to ensure their scientific robustness and reproducibility

Bicycle Friendly Community Assessment Spring 2015

Completed by Cal Poly, San Luis Obispo City & Regional Planning students enrolled in a bicycle and pedestrian planning course (CRP 425), under the direction of Dr. William Riggs this report was designed to gather data in advance of the City of San Luis Obispo\u27s application to be a Bicycle Friendly Community. The report focuses on the key certification areas of Engineering, Education, Encouragement, Evaluation/Planning and Enforcement providing documentation for the City\u27s eventual application

Development of the Sandia Cooler.

This report describes an FY13 effort to develop the latest version of the Sandia Cooler, a breakthrough technology for air-cooled heat exchangers that was developed at Sandia National Laboratories. The project was focused on fabrication, assembly and demonstration of ten prototype systems for the cooling of high power density electronics, specifically high performance desktop computers (CPUs). In addition, computational simulation and experimentation was carried out to fully understand the performance characteristics of each of the key design aspects. This work culminated in a parameter and scaling study that now provides a design framework, including a number of design and analysis tools, for Sandia Cooler development for applications beyond CPU cooling

Dark sectors 2016 Workshop: community report

This report, based on the Dark Sectors workshop at SLAC in April 2016, summarizes the scientific importance of searches for dark sector dark matter and forces at masses beneath the weak-scale, the status of this broad international field, the important milestones motivating future exploration, and promising experimental opportunities to reach these milestones over the next 5-10 years