Improving bone properties and fracture susceptibility: experimental models of genetic manipulation, pharmacologic intervention, and cellular perturbation reveal new approaches for improving bone health

poster abstractBone, a crucial support structure in the human body, is often taken for granted for its lightweight properties and unparalleled strength. Skeletal fracture is a major clinical condition affecting millions of Americans, which results from abnormal aging, hormonal imbalance, genetic conditions, and lifestyle choices (e.g., exercise). Because fractures are caused by a number of different factors, reducing fracture incidence requires a multifactorial approach to unraveling the underlying biology of bone metabolism, in order to discover new ways to improve bone properties and prevent fractures. We have taken such an approach by conducting (1) genetic manipulation experiments in mice, where genes predicted to be involved in bone mass regulation were mutated; (2) pharmacologic experiments to quantify the dose-response effect of an agent that inhibits bone loss, and (3) cell culture experiments, aimed at revealing molecular pathways activated by mechanical stimulation. METHODS: Mice with mutations in two genes, likely to regulate bone mass (SOST, DKK1) were generated and subjected to in vivo dual energy x-ray absorptiometry (DEXA) scans at 6-wk old. Whole body scans were analyzed for bone mineral density (BMD) using Lunar Piximus II v2.10 software. Mice (6-wk) were also dosed (0, 1, 10, 100, or 1000 mg/kg) with daily alendronate HCl, a bisphosphonate that inhibits osteoclast activity. Six wks later, the mice were sacrificed, and the femurs were dissected and sectioned for histological analysis of bone formation parameters, including mineralizing surface (MS/BS), mineral apposition rate (MAR), and bone formation rate (BFR/BS). To understand the cellular signaling events in response to mechanical loading, bone marrow mesenchymal stem cells (MSCs) were treated with 10, 20, 30, or 40μM PF7408671, an S6 kinase inhibitor. Cells then were subject to 100 cycles of biaxial mechanical strain (2%, 10 cycles/min). Protein lysates were separated by electrophoresis and probed for phosphorylation of Rictor and Akt by Western blot. RESULTS: Mice harboring mutations in either the SOST gene or the DKK1gene exhibited significantly increased BMD compared to wild-type control mice, though the SOST mutation had a stronger effect on BMD than DKK1. Mice with compound mutations (SOST and DKK1 mutations) had significantly greater BMD than mice with either single mutation, suggesting that inhibition of SOST and DKK1 might be an effective means to increase bone mass in patients susceptible to fracture. Mice treated with high-dose alendronate (100 or 1,000 mg/kg) exhibited significant decreases in bone formation parameters (MS/BS, MAR, and BFR/BS) compared to untreated (0 mg) mice, suggesting that while this compound might be beneficial for inhibiting bone loss, it also inhibits bone formation. The signaling hub, mTORC2, is a critical regulator of mechanical force in MSC progenitors. Our data demonstrate that S6 kinase is an upstream activator of mTORC2 in response to mechanical strain. CONCLUSION: Our experiments suggest that genetic manipulation of mice reveal viable protein targets (e.g., SOST, DKK1) that could ultimately be manipulated pharmacologically to improve bone mass. We also found that an FDA-approved class of drugs inhibits bone formation even at very low doses, suggesting that additional pro-anabolic compounds might benefit patients taking bisphosphonates. On a cell signaling level, we found that the mTORC2 pathway shows considerable promise for pharmacologic manipulation to simulate the effects of exercise. Taken together, these experiments highlight the utility of a broad approach to solving bone metabolism challenges that can affect fracture susceptibility

Design Considerations and Requirements for In-Flight Refueling of Unmanned Vehicles

The need to refuel in-flight has become a significant part of military strategy for air forces to work at further distances from safe shores. The use of Unmanned Vehicles is increasing and expected to be the principal part of military deployment. This paper will address the concepts and requirements for applying refueling unmanned vehicles in a military context for supporting fixed and rotor aircraft. Design aspects of human factors in the process are considered, reviewed and solutions proposed to allow for the first generation of designs to be developed. Furthermore, the practical and operational limitations will be addressed as part of the human factors implications. Finally, the design parameters are proposed for the first stage developments to achieve Unmanned Vehicle refueling

Propeller Design Requirements for Quadcopters Utilizing Variable Pitch Propellers

Unmanned aerial vehicles, UAV, has increases in the drastically in these past several years since their costs reduced. This research is based and built upon previous research presented in a conference. With the advent of commercial Quadcopters, four propeller systems, are used, being designed and used to operate the advantages of both flight and hovering. The basic design of their propeller blades has not evolved from the early days of manned flight when wooden fixed blades were used. In this paper that expands upon previous findings and discussions it explores the historical developments. Furthermore, how the expansion and reduction in costs of modern materials and manufacturing techniques that offer more accurate matching of blades’ needs and applications

Disentangling astroglial physiology with a realistic cell model in silico

Electrically non-excitable astroglia take up neurotransmitters, buffer extracellular K+ and generate Ca2+ signals that release molecular regulators of neural circuitry. The underlying machinery remains enigmatic, mainly because the sponge-like astrocyte morphology has been difficult to access experimentally or explore theoretically. Here, we systematically incorporate multi-scale, tri-dimensional astroglial architecture into a realistic multi-compartmental cell model, which we constrain by empirical tests and integrate into the NEURON computational biophysical environment. This approach is implemented as a flexible astrocyte-model builder ASTRO. As a proof-of-concept, we explore an in silico astrocyte to evaluate basic cell physiology features inaccessible experimentally. Our simulations suggest that currents generated by glutamate transporters or K+ channels have negligible distant effects on membrane voltage and that individual astrocytes can successfully handle extracellular K+ hotspots. We show how intracellular Ca2+ buffers affect Ca2+ waves and why the classical Ca2+ sparks-and-puffs mechanism is theoretically compatible with common readouts of astroglial Ca2+ imaging

Take-off Characteristics for NACA 4612 Aerofoil in a Twin-Wing Configuration With Optimum Angles of Attack

Unmanned Aerial Vehicles are used generally at low levels and speeds. The research reported in this article investigates the possible use of twin-wing designs for higher altitudes with a focus on the possible lift capable for either short runways or high payloads. The wing aerofoil and unique Angles of Attack, AoA, are set 5o on the upper wing and 10o on the lower. There is a positive upper wing stagger of 50% of the chord length at height separation of 1 chord. These parameters have been established from previous research and this research investigates how they generate lift at take-off and what lift and drag properties exist. It also determines if these parameters are in-line with those for high altitude flight

Communication Research

Contains reports on seven research projects.Rockefeller FoundationCarnegie Foundatio

Multi-Choice Questions and Their Problems When Used for Assessment of Aircraft Engineers Education

Licensed aircraft engineers under the European Aviation Safety Agency, EASA, undertake academic training to complement their practical and type specific studies. These exams are mainly Multi-Choice Questions, MCQ, and four 20-minute essays. The MCQ exams are as few as 16 questions to a maximum of 140 questions. A score of 75% is needed to pass each exam, and each question has three possible answers. This authors of this paper reviews the theory and design of the MCQ and asks if the assumptions are valid and that it achieves the academic level assumed for engineers who will be maintaining some of the most complex system in the world, and the safety of passengers. It will argue that there are failings and how this can be address, in particular, that repeated tests should have a higher pass level

Communication Research

Contains reports on nine research projects.Bell Telephone Laboratories, Incorporate