The role of dystroglycan in hearing and hearing loss

The transduction of sound waves into electrical signals in the hair cells is entirely dependent on the stereociliary hair bundles that reside on their apical surface. These hair-like projections are organised into three or more rows in a staircase structure, with the height of each stereocilium being similar within each row. The current theory is that this height disparity between the rows is entirely established and maintained via the differential localisation of several actin effector proteins. Epidermal growth factor receptor pathway substrate 8 (EPS8) selectively localises to the tips of the tallest row of stereocilia, on the pillar side of the hair cell, with only small amounts of the protein detectable at the second tallest row. Conversely, EPS8 like protein 2 (EPS8L2) selectively localises to the shorter two rows of stereocilia. Each of these two interacts with a distinct complex of actin effector proteins and isoforms of the myosin-15 (MYO15) specialised motor protein, but the exact mechanism by which this differential localisation is established and maintained remains unknown. Here, we investigate two proteins which were hypothesised to modulate the EPS8/EPS8L2 differential localisation axis. Dystroglycan, a specialised cell adhesion receptor best known for the role it plays in the pathogenesis of Duchenne’s muscular dystrophy, was identified as a potential interactor of EPS8L2. The inverse bin-amphiphysin-rvs (I-BAR) family member BAR/IMD domain containing adaptor protein 2 like 2 (BAIAP2L2) was identified as a potential interactor of EPS8, and reported as important in hearing loss by the IMPC mutagenesis screen. Dystroglycan expression could not be visualised within the organ of Corti with any of the antibodies at our disposal, and a hair cells specific knock-out of the protein did not result in elevated hearing thresholds. Single-cell whole-cell patch clamping experiments indicated that the basolateral profile of inner hair cells matured as normal. Conversely, the global knock-out of BAIAP2L2 resulted in deficits in hair cell mechanotransduction which became apparent at postnatal day 11 (P11). Hearing thresholds were significantly elevated at all ages tested and appeared to show a progressive phenotype reminiscent of a more severe version of the EPS8L2 knock-out. Scanning electron microscopy revealed that the shortest row of stereocilia had almost entirely degenerated by P54. Furthermore, immunostaining data indicated that EPS8 is not localised to the tips of the tallest stereocilia by BAIAP2L2 as originally hypothesised, and in fact BAIAP2L2 is dependent on the presence of EPS8 for proper localisation to the tips of the shorter two rows of stereocilia

Challenging Industry to Innovate! How the Government Can Apply Transparency, Collaboration, Unencumbered Communication, and Dynamic Engagement Through Challenge-Based Acquisition

Symposium PresentationApproved for public release; distribution is unlimited

Challenging Industry to Innovate! How the Government Can Apply Transparency, Collaboration, Unencumbered Communication, and Dynamic Engagement Through Challenge-Based Acquisition

Excerpt from the Proceedings of the Nineteenth Annual Acquisition Research SymposiumThe Defense Information Systems Agency (DISA) Telecommunications Advanced Research and Dynamic Spectrum Sharing Systems (TARDyS3) program demanded new ideas and novel approaches for sharing electromagnetic spectrum between the Department of Defense and commercial industry. To solve this problem, DISA created an acquisition structure that focused on building transparency, collaborating, and actively communicating with industry across the entire acquisition. This focus on dynamically engaging vendors and encouraging innovation allowed DISA to rapidly deploy high-quality and user-approved capabilities. Dynamic engagement involves a two-way exchange of ideas, listening to industry by seeking input, and conveying the government’s ideas and motivations to potential vendors, while innovation centricity consists of encouraging vendors to solve problems with unique solutions, providing a framework for future acquisitions. Dynamic engagement, coupled with innovation centricity, powerfully engages the vendor community to solve hard problems. Combining innovation with communication creates a vendor community that is motivated to meet the government’s needs, and it accelerates risk mitigation. Furthermore, it can improve product quality and shortens delivery time lines at a reasonable price. For these reasons, future programs should consider incorporating dynamic engagement and innovation-centric approaches at the core of their acquisition strategies.Approved for public release; distribution is unlimited

INTEGRATION OF THE SIMULATION ENVIRONMENT FOR AUTONOMOUS ROBOTS WITH ROBOTICS MIDDLEWARE

Robotic simulators have long been used to test code and designs before any actual hardware is tested to ensure safety and efficiency. Many current robotics simulators are either closed source (calling into question the fidelity of their simulations) or are very complicated to install and use. There is a need for software that provides good quality simulation as well as being easy to use. Another issue arises when moving code from the simulator to actual hardware. In many cases, the code must be changed drastically to accommodate the final hardware on the robot, which can possibly invalidate aspects of the simulation. This defense describes methods and techniques for developing high fidelity graphical and physical simulation of autonomous robotic vehicles that is simple to use as well as having minimal distinction between simulated hardware, and actual hardware. These techniques and methods were proven by the development of the Simulation Environment for Autonomous Robots (SEAR) described here. SEAR is a 3-dimensional open source robotics simulator written by Adam Harris in Java that provides high fidelity graphical and physical simulations of user-designed vehicles running user-defined code in user-designed virtual terrain. Multiple simulated sensors are available and include a GPS, triple axis accelerometer, triple axis gyroscope, a compass with declination calculation, LIDAR, and a class of distance sensors that includes RADAR, SONAR, Ultrasonic and infrared. Several of these sensors have been validated against real-world sensors and other simulation software

United States Department of Defense (DoD) Real Property Repair, Alterations, Maintenance, and Construction Project Contract Data: 2009–2020

Nearly one-half of all construction projects exceed planned costs and schedule, globally [1]. Owners and construction managers can analyze historical project performance data to inform cost and schedule overrun risk-reduction strategies. Though, the majority of open-source project datasets are limited by the number of projects, data dimensionality, and location. A significant global customer of the construction industry, the Department of Defense (DoD) maintains a vast database of historical project data that can be used to determine the sources and magnitude of construction schedule and cost overruns for many continental and international locations. The selection of data provided by the authors is a subset of the U.S. Federal Procurement Data System-Next Generation (FPDS-NG), which stores contractual obligations made by the U.S. Federal Government [2]. The data comprises more than ten fiscal years (1 Oct 2009 – 04 June 2020) of construction contract attributes that will enable researchers to investigate spatiotemporal schedule and cost performance by, but not limited to: contract type, construction type, delivery method, award date, and award value. To the knowledge of the authors, this is the most extensive open-source dataset of its kind, as it provides access to the contract data of 132,662 uniquely identified construction projects totaling $865 billion. Because the DoD\u27s facilities and infrastructure construction requirements and use of private construction firms are congruent with the remainder of the public sector and the private sector, results obtained from analyses of this dataset may be appropriate for broader application

A cross sectional study investigating the association between exposure to food outlets and childhood obesity in Leeds, UK

BACKGROUND: Current UK policy in relation to the influence of the ‘food environment’ on childhood obesity appears to be driven largely on assumptions or speculations because empirical evidence is lacking and findings from studies are inconsistent. The aim of this study was to investigate the number of food outlets and the proximity of food outlets in the same sample of children, without solely focusing on fast food. METHODS: Cross sectional study over 3 years (n = 13,291 data aggregated). Body mass index (BMI) was calculated for each participant, overweight and obesity were defined as having a BMI >85(th) (sBMI 1.04) and 95(th) (sBMI 1.64) percentiles respectively (UK90 growth charts). Home and school neighbourhoods were defined as circular buffers with a 2 km Euclidean radius, centred on these locations. Commuting routes were calculated using the shortest straight line distance, with a 2 km buffer to capture varying routes. Data on food outlet locations was sourced from Leeds City Council covering the study area and mapped against postcode. Food outlets were categorised into three groups, supermarkets, takeaway and retail. Proximity to the nearest food outlet in the home and school environmental domain was also investigated. Age, gender, ethnicity and deprivation (IDACI) were included as covariates in all models. RESULTS: There is no evidence of an association between the number of food outlets and childhood obesity in any of these environments; Home Q4 vs. Q1 OR = 1.11 (95% CI = 0.95-1.30); School Q4 vs. Q1 OR = 1.00 (95% CI 0.87 – 1.16); commute Q4 vs. Q1 OR = 0.1.00 (95% CI 0.83 – 1.20). Similarly there is no evidence of an association between the proximity to the nearest food outlet and childhood obesity in the home (OR = 0.77 [95% CI = 0.61 – 0.98]) or the school (OR = 1.01 [95% CI 0.84 – 1.23]) environment. CONCLUSIONS: This study provides little support for the notion that exposure to food outlets in the home, school and commuting neighbourhoods increase the risk of obesity in children. It seems that the evidence is not well placed to support Governmental interventions/recommendations currently being proposed and that policy makers should approach policies designed to limit food outlets with caution

Randomised controlled trial of the Limit of Detection of Troponin and ECG Discharge (LoDED) strategy versus usual care in adult patients with chest pain attending the emergency department: Study protocol

© 2018 Author(s). Published by BMJ. Introduction Observational data suggest a single high-sensitivity troponin blood test taken at emergency department (ED) presentation could be used to rule out major adverse cardiac events (MACE) in 10%-60% of ED patients with chest pain. This is done using an 'undetectable' cut-off (the Limit of Detection: LoD). We combined the LoD cut-off with ECG findings to create the LoDED strategy. We aim to establish whether the LoDED strategy works under real-life conditions, when compared with existing strategies, in a way that is cost-effective and acceptable to patients. Methods and analysis This is a parallel-group pragmatic randomised controlled trial across UK EDs. Adults presenting to ED with suspected cardiac chest pain will be randomised 1:1. Existing rule-out strategies in current use across study centres, using serial high-sensitivity troponin testing, will be compared with the LoDED strategy. The primary outcome is successful early discharge (discharge from hospital within 4 hours of arrival) without MACE occurring within 30 days. Secondary outcomes include initial length of hospital stay; comparative costs; patient satisfaction and acceptability to patients. To detect a 9% difference between the early discharge rates (assuming an 8% rate in the standard care group) with 90% power, 594 patients need to be recruited, assuming a 95% follow-up rate. Ethics and dissemination The study has been approved by the Frenchay Research Ethics Committee (reference 18/SW/0038). Results will be published in an international peer-reviewed journal. Lay summaries will be made available to patients

Formulation development and characterization of cellulose acetate nitrate based propellants for improved insensitive munitions properties

AbstractCellulose acetate nitrate (CAN) was used as an insensitive energetic binder to improve the insensitive munitions (IM) properties of gun propellants to replace the M1 propellant used in 105 mm artillery charges. CAN contains the energetic nitro groups found in nitrocellulose (NC), but also acetyl functionalities, which lowered the polymer's sensitivity to heat and shock, and therefore improved its IM properties relative to NC. The formulation, development and small-scale characterization testing of several CAN-based propellants were done. The formulations, using insensitive energetic solid fillers and high-nitrogen modifiers in place of nitramine were completed. The small scale characterization testing, such as closed bomb testing, small scale sensitivity, thermal stability, and chemical compatibility were done. The mechanical response of the propellants under high-rate uni-axial compression at, hot, cold, and ambient temperatures were also completed. Critical diameter testing, hot fragment conductive ignition (HFCI) tests were done to evaluate the propellants' responses to thermal and shock stimuli. Utilizing the propellant chemical composition, theoretical predictions of erosivity were completed. All the small scale test results were utilized to down-select the promising CAN based formulations for large scale demonstration testing such as the ballistic performance and fragment impact testing in the 105 mm M67 artillery charge configurations. The test results completed in the small and large scale testing are discussed

Structure of the first representative of Pfam family PF04016 (DUF364) reveals enolase and Rossmann-like folds that combine to form a unique active site with a possible role in heavy-metal chelation.

The crystal structure of Dhaf4260 from Desulfitobacterium hafniense DCB-2 was determined by single-wavelength anomalous diffraction (SAD) to a resolution of 2.01 Å using the semi-automated high-throughput pipeline of the Joint Center for Structural Genomics (JCSG) as part of the NIGMS Protein Structure Initiative (PSI). This protein structure is the first representative of the PF04016 (DUF364) Pfam family and reveals a novel combination of two well known domains (an enolase N-terminal-like fold followed by a Rossmann-like domain). Structural and bioinformatic analyses reveal partial similarities to Rossmann-like methyltransferases, with residues from the enolase-like fold combining to form a unique active site that is likely to be involved in the condensation or hydrolysis of molecules implicated in the synthesis of flavins, pterins or other siderophores. The genome context of Dhaf4260 and homologs additionally supports a role in heavy-metal chelation

Structure of a putative NTP pyrophosphohydrolase: YP_001813558.1 from Exiguobacterium sibiricum 255-15.

The crystal structure of a putative NTPase, YP_001813558.1 from Exiguobacterium sibiricum 255-15 (PF09934, DUF2166) was determined to 1.78 Å resolution. YP_001813558.1 and its homologs (dimeric dUTPases, MazG proteins and HisE-encoded phosphoribosyl ATP pyrophosphohydrolases) form a superfamily of all-α-helical NTP pyrophosphatases. In dimeric dUTPase-like proteins, a central four-helix bundle forms the active site. However, in YP_001813558.1, an unexpected intertwined swapping of two of the helices that compose the conserved helix bundle results in a `linked dimer' that has not previously been observed for this family. Interestingly, despite this novel mode of dimerization, the metal-binding site for divalent cations, such as magnesium, that are essential for NTPase activity is still conserved. Furthermore, the active-site residues that are involved in sugar binding of the NTPs are also conserved when compared with other α-helical NTPases, but those that recognize the nucleotide bases are not conserved, suggesting a different substrate specificity