C1QBP Inhibits DUX4-Dependent Gene Activation and Can Be Targeted with 4MU

FSHD is linked to the misexpression of the DUX4 gene contained within the D4Z4 repeat array on chromosome 4. The gene encodes the DUX4 protein, a cytotoxic transcription factor that presumably causes the symptoms of the disease. However, individuals have been identified who express DUX4 in their muscle biopsies, but who remain asymptomatic, suggesting that there are other factors that modify FSHD penetrance or severity. We hypothesized that an FSHD-modifying factor would physically interact with DUX4, and we took a proteomic approach to identify DUX4-interacting proteins. We identified the multifunctional C1QBP protein as one such factor. C1QBP is known to regulate several processes that DUX4 affects, including gene expression, oxidative stress, apoptosis, and pre-mRNA splicing. We used siC1QBP knockdown assays to determine if C1QBP affects DUX4 activity. While C1QBP had little effect on DUX4 activity in myotubes, we found that it inhibits the kinetics of DUX4-target gene activation during myogenic differentiation. This identifies C1QBP as a regulator of DUX4 activity and a potential target for FSHD therapeutics. Importantly, C1QBP is regulated by binding to the signaling molecule hyaluronic acid (HA). Decreasing HA by treating cells with 4-methylumbelliferone (4MU), an inhibitor of HA synthesis, resulted in a sharp decline in DUX4 activity and also greatly reduced its cytotoxicity. We have found that DUX4-induced cytotoxicity is associated with severe mislocalizaton of C1QBP, which is prevented by 4MU. This defect is not a downstream result of DUX4-induced oxidative stress, as it could not be prevented by treating cells with an antioxidant, nor could it be recapitulated by exposing cells to oxidants. This identifies C1QBP as a target for the treatment of FSHD, and in particular indicates that 4MU, already an approved drug in Europe and currently under investigation for other indications, may be an effective C1QBP-targeting FSHD therapeutic compound

Climate Change & US Inaction: A Comparative Analysis of Foreign Policy Determinants

Climate change is a hot potato policy: the responsibility for it is constantly passed between the domestic and international realms. By definition global climate change is a global problem yet, in the US, domestic concerns are preventing federal lawmakers from taking action and presidents from taking leadership at both the national and international levels. We propose that the on-going federal inaction on climate change is the product of it being caught between two phases in the public policy life cycle: policy adoption and implementation. During the heat wave of 1988, the green house effect emerged as an important problem and became a presidential campaign issue. Following a torrent of extreme weather events in 2012, climate change was widely acknowledged as a global crisis and foreign policy issue, but it was barely mentioned on the presidential campaign trail. In line with Putnam’s theory of two level games, we argue that the climate change stalemate at the domestic level accounts for the inaction of the US at the international level. We test our hypotheses with a comparative case study of climate change in the two campaign seasons

Nitrogen and boron ion implantation into electrodeposited hard chrome

Electrodeposited hard chrome was ion implanted with N alone, B alone, and a combination. Separate N and B implantation was done at 75 keV and incident doses of 2, 4, and 8x10{sup 17} at/cm{sup 2}. Samples with both N/B implants used 75 keV and incident dose levels of 4x10{sup 17} N- and B-at/cm{sup 2}. Beam-line system was used. Retained dose was measured using ion beam analysis, which indicated most of the incident dose was retained. Surface hardness, wear coefficient, and friction coefficient were determined by nanohardness indentation and pin-on-disk wear. At a depth of 50 nm, surface hardness increased from 18{+-}1 GPa (unimplanted) to a max of 23{+-}4 GPa for B implant and 26{+-}1 GPa for N implant. the wear coefficient was reduced by 1.3x to 7.4x, depending on implantation. N implant results in lower wear coefficients than B implant

Properties of ion implanted Ti-6Al-4V processed using beamline and PSII techniques

The surface of Ti-6Al-4V (Ti64) alloy has been modified using beamline implantation of boron. In separate experiments, Ti64 has been implanted with nitrogen using a plasma source ion implantation (PSII) technique utilizing either ammonia (NH{sub 3}), nitrogen (N{sub 2}), or their combinations as the source of nitrogen ions. Beamline experiments have shown the hardness of the N-implanted surface saturates at a dose level of {approximately} 4 {times} 10{sup 17} at/cm{sup 2} at {approximately} 10 GPa. The present work makes comparisons of hardness and tribological tests of (1) B implantation using beamline techniques, and (2) N implanted samples using ammonia and/or nitrogen gas in a PSII process. The results show that PSII using N{sub 2} or NH{sub 3} gives similar hardness as N implantation using a beamline process. The presence of H in the Ti alloy surface does not affect the hardness of the implanted surface. Boron implantation increased the surface hardness by as much as 2.5x at the highest dose level. Wear testing by a pin-on-disk method indicated that nitrogen implantation reduced the wear rate by as much as 120x, and boron implantation reduced the wear rate by 6.5x. Increased wear resistance was accompanied by a decreased coefficient of friction

Properties of Ion Implanted Ti-6Al-4V Processed using Beamline and PSII Techniques

The surface of Ti-6Al-4V (Ti64) alloy has been modified using beamline implantation of boron. In separate experiments, Ti64 has been implanted with nitrogen using a plasma source ion implantation (PSII) technique utilizing either ammonia (NH{sub 3}), nitrogen (N{sub 2}), or their combinations as the source of nitrogen ions. Beamline experiments have shown the hardness of the N-implanted surface saturates at a dose level of {approximately} 4 {times} 10{sup 17} at/cm{sup 2} at {approximately} 10 GPa. The present work makes comparisons of hardness and tribological tests of (1) B implantation using beamline techniques, and (2) N implanted samples using ammonia and/or nitrogen gas in a PSII process. The results show that PSII using N{sub 2} or NH{sub 3} gives similar hardness as N implantation using a beamline process. The presence of H in the Ti alloy surface does not affect the hardness of the implanted surface. Boron implantation increased the surface hardness by as much as 2.5x at the highest dose level. Wear testing by a pin-on-disk method indicated that nitrogen implantation reduced the wear rate by as much as 120x, and boron implantation reduced the wear rate by 6.5x. Increased wear resistance was accompanied by a decreased coefficient of friction