Possible role of death receptor-mediated apoptosis by the E3 ubiquitin ligases Siah2 and POSH

<p>Abstract</p> <p>Background</p> <p>A functioning ubiquitin proteasome system (UPS) is essential for a number of diverse cellular processes and maintenance of overall cellular homeostasis. The ability of proteasome inhibitors, such as Velcade, to promote extrinsic apoptotic effects illustrates the importance of the ubiquitin proteasome system in the regulation of death receptor signaling. Here, we set out to define the UPS machinery, particularly the E3 ubiquitin ligases, that repress apoptosis through the extrinsic pathway. A cell-based genome-wide E3 ligase siRNA screen was established to monitor caspase-8 activity following the addition of TRAIL.</p> <p>Results</p> <p>Data from the high-throughput screen revealed that targeting the RING-finger containing E3 ligase Siah2 as well as the signaling platform molecule POSH (SH3RF1) conferred robust caspase-8 activation in response to TRAIL stimulus. Silencing Siah2 or POSH in prostate cancer cells led to increased caspase activity and apoptosis in response to both TRAIL and Fas ligand. The E3 activity of Siah2 was responsible for mediating apoptosis resistance; while POSH protein levels were critical for maintaining viability. Further characterization of Siah2 revealed it to function downstream of early death receptor events in the apoptotic pathway. The observed apoptosis resistance provides one biological explanation for the induction of Siah2 and POSH reported in lung and prostate cancer, respectively. Expanding on an initial yeast-two-hybrid screen we have confirmed a physical interaction between E3 ligases Siah2 and POSH. Utilizing a yeast-two-hybrid mapping approach we have defined the spacer region of POSH, more specifically the RPxAxVxP motif encompassing amino acids 601-607, to be the site of Siah2 binding.</p> <p>Conclusions</p> <p>The data presented here define POSH and Siah2 as important mediators of death receptor mediated apoptosis and suggest targeting the interaction of these two E3 ligases is a promising novel cancer therapeutic strategy.</p

Seismic anisotropy reveals crustal flow driven by mantle vertical loading in the Pacific NW

Buoyancy anomalies within Earth’s mantle create large convective currents that are thought to control the evolution of the lithosphere. While tectonic plate motions provide evidence for this relation, the mechanism by which mantle processes influence near-surface tectonics remains elusive. Here, we present an azimuthal anisotropy model for the Pacific Northwest crust that strongly correlates with high-velocity structures in the underlying mantle but shows no association with the regional mantle flow field. We suggest that the crustal anisotropy is decoupled from horizontal basal tractions and, instead, created by upper mantle vertical loading, which generates pressure gradients that drive channelized flow in the mid-lower crust. We then demonstrate the interplay between mantle heterogeneities and lithosphere dynamics by predicting the viscous crustal flow that is driven by local buoyancy sources within the upper mantle. Our findings reveal how mantle vertical load distribution can actively control crustal deformation on a scale of several hundred kilometers

Stabilization of the arrival time of a relativistic electron beam to the 50 fs level

We report the results of a low-latency beam phase feed-forward system built to stabilize the arrival time of a relativistic electron beam. The system was operated at the Compact Linear Collider (CLIC) Test Facility (CTF3) at CERN where the beam arrival time was stabilized to approximately 50 fs. The system latency was 350 ns and the correction bandwidth >23 MHz. The system meets the requirements for CLIC.Comment: 5 pages, 9 figures, 1 tabl

Seismic anisotropy reveals crustal flow driven by mantle vertical loading in the Pacific NW

Buoyancy anomalies within Earth’s mantle create large convective currents that are thought to control the evolution of the lithosphere. While tectonic plate motions provide evidence for this relation, the mechanism by which mantle processes influence near-surface tectonics remains elusive. Here, we present an azimuthal anisotropy model for the Pacific Northwest crust that strongly correlates with high-velocity structures in the underlying mantle but shows no association with the regional mantle flow field. We suggest that the crustal anisotropy is decoupled from horizontal basal tractions and, instead, created by upper mantle vertical loading, which generates pressure gradients that drive channelized flow in the mid-lower crust. We then demonstrate the interplay between mantle heterogeneities and lithosphere dynamics by predicting the viscous crustal flow that is driven by local buoyancy sources within the upper mantle. Our findings reveal how mantle vertical load distribution can actively control crustal deformation on a scale of several hundred kilometers

Energy Efficient Microlith-Based Catalytic Reactor and Recuperator for Air Quality Control Applications

Precision Combustion, Inc. (PCI) and NASAs Marshall Space Flight Center (MSFC) have been developing, characterizing, and optimizing high temperature catalytic oxidizers (HTCO) based on PCIs patented Microlith technology to meet the requirements of future extended human spaceflight explorations. Previous efforts focused on integrating PCIs HTCO unit with a compact, simple recuperative heat exchanger to reduce the overall system size and weight. Significant improvement was demonstrated over traditional approaches of integrating the HTCO with an external recuperative heat exchanger. While the critical target performance metrics were achieved, the thermal effectiveness of PCIs recuperator remained a potential area of improvement to further reduce the energy requirements of the integrated system. Using the same material combinations and an improved recuperator design, the redesigned prototype has experimentally demonstrated 20 30% reduction (flow dependent) in steady state power consumption compared to the earlier prototype without compromising the destruction efficiency of methane and volatile organic compounds (VOCs). Moreover, design modifications and improvements allow our redesigned prototype to be more easily manufactured compared to traditional brazed plate-fin recuperator designs. The redesigned prototype was delivered to MSFC for validation testing. Here, we report and discuss the performance of the improved prototype HTCO unit with a high efficiency recuperative heat exchanger based on testing at PCI and MSFC. The device is expected to provide a reliable and robust means of disposing of trace levels of methane and VOCs by oxidizing them into carbon dioxide and water in order to maintain clean air in enclosed spaces, such as crewed spacecraft cabins

Discovery and Precise Characterization by the MEarth Project of LP 661-13, an Eclipsing Binary Consisting of Two Fully Convective Low-mass Stars

We report the detection of stellar eclipses in the LP 661-13 system. We present the discovery and characterization of this system, including high resolution spectroscopic radial velocities and a photometric solution spanning two observing seasons. LP 661-13 is a low mass binary system with an orbital period of $4.7043512^{+0.0000013}_{-0.0000010}$ days at a distance of $24.9 \pm 1.3$ parsecs. LP 661-13A is a $0.30795 \pm 0.00084$ $M_\odot$ star while LP 661-13B is a $0.19400 \pm 0.00034$ $M_\odot$ star. The radius of each component is $0.3226 \pm 0.0033$ $R_\odot$ and $0.2174 \pm 0.0023$ $R_\odot$, respectively. We detect out of eclipse modulations at a period slightly shorter than the orbital period, implying that at least one of the components is not rotating synchronously. We find that each component is slightly inflated compared to stellar models, and that this cannot be reconciled through age or metallicity effects. As a nearby eclipsing binary system where both components are near or below the full-convection limit, LP 661-13 will be a valuable test of models for the structure of cool dwarf stars.Comment: 24 pages, 8 tables, 6 figures. Submitted to ApJ, comments welcom

DEVELOPMENT OF A FAST MICRON-RESOLUTION BEAM POSITION MONITOR SIGNAL PROCESSOR FOR LINEAR COLLIDER BEAMBASED FEEDBACK SYSTEMS

We present the design of a prototype fast beam position monitor (BPM) signal processor for use in inter-bunch beam-based feedbacks for linear colliders and electron linacs. We describe the FONT4 intra-train beam-based digital position feedback system prototype deployed at the Accelerator test facility (ATF) extraction line at KEK, Japan. The system incorporates a fast analogue beam position monitor front-end signal processor, a digital feedback board, and a fast kicker-driver amplifier. The total feedback system latency is less than 150ns, of which less than 10ns is used for the BPM processor. We report preliminary results of beam tests using electron bunches separated by c. 150ns. Position resolution of order 1 micron was obtained

BEAM TEST RESULTS WITH THE FONT4 ILC PROTOTYPE INTRA-TRAIN BEAM FEEDBACK SYSTEM

We present the design and beam test results of a prototype beam-based digital feedback system for the Interaction Point of the International Linear Collider. A custom analogue front-end processor, FPGA-based digital signal processing board, and kicker drive amplifier have been designed, built, and tested on the extraction line of the KEK Accelerator Test Facility (ATF). The system was measured to have a latency of approximately 140 ns

Study protocol: can a school gardening intervention improve children's diets?

BACKGROUND: The current academic literature suggests there is a potential for using gardening as a tool to improve children's fruit and vegetable intake. This study is two parallel randomised controlled trials (RCT) devised to evaluate the school gardening programme of the Royal Horticultural Society (RHS) Campaign for School Gardening, to determine if it has an effect on children's fruit and vegetable intake. METHOD/DESIGN: Trial One will consist of 26 schools; these schools will be randomised into two groups, one to receive the intensive intervention as "Partner Schools" and the other to receive the less intensive intervention as "Associate Schools". Trial Two will consist of 32 schools; these schools will be randomised into either the less intensive intervention "Associate Schools" or a comparison group with delayed intervention. Baseline data collection will be collected using a 24-hour food diary (CADET) to collect data on dietary intake and a questionnaire exploring children's knowledge and attitudes towards fruit and vegetables. A process measures questionnaire will be used to assess each school's gardening activities. DISCUSSION: The results from these trials will provide information on the impact of the RHS Campaign for School Gardening on children's fruit and vegetable intake. The evaluation will provide valuable information for designing future research in primary school children's diets and school based interventions. TRIAL REGISTRATION: ISRCTN11396528