D-β-Hydroxybutyrate Is Protective in Mouse Models of Huntington's Disease

Abnormalities in mitochondrial function and epigenetic regulation are thought to be instrumental in Huntington's disease (HD), a fatal genetic disorder caused by an expanded polyglutamine track in the protein huntingtin. Given the lack of effective therapies for HD, we sought to assess the neuroprotective properties of the mitochondrial energizing ketone body, D-β-hydroxybutyrate (DβHB), in the 3-nitropropionic acid (3-NP) toxic and the R6/2 genetic model of HD. In mice treated with 3-NP, a complex II inhibitor, infusion of DβHB attenuates motor deficits, striatal lesions, and microgliosis in this model of toxin induced-striatal neurodegeneration. In transgenic R6/2 mice, infusion of DβHB extends life span, attenuates motor deficits, and prevents striatal histone deacetylation. In PC12 cells with inducible expression of mutant huntingtin protein, we further demonstrate that DβHB prevents histone deacetylation via a mechanism independent of its mitochondrial effects and independent of histone deacetylase inhibition. These pre-clinical findings suggest that by simultaneously targeting the mitochondrial and the epigenetic abnormalities associated with mutant huntingtin, DβHB may be a valuable therapeutic agent for HD

Precast Concrete Models Fabricated with Big Area Additive Manufacturing

The traditional process of making precast concrete molds requires significant manual labor. The molds are made using hardwood, cost tens of thousands of dollars, and take weeks to build. Once built, a mold will last 5-10 pulls before becoming too heavily degraded to continue use. With additive manufacturing, the same mold can be built in eight hours, post-machined in eight hours, costs about $9000, and is projected to last nearly 200 pulls. Oak Ridge National Laboratory has been working with Big Area Additive Manufacturing (BAAM) to fabricate concrete molds for a new high-rise apartment complex in New York. The molded pieces will form structural window supports for the hundreds of windows in building façade. The magnitude of window molds is where additive manufacturing can shine when producing the geometry. This paper will discuss the methods and findings of using BAAM to replace conventional precast concrete pattern making.Mechanical Engineerin

Using Post-Tensioning in Large Scale Additive Parts for Load Bearing Structures

One of the perennial problems with additive manufacturing (AM) is the lack of inter-laminar bond strength between the layers, also known as z-strength. This can make the use of AM fabricated parts in load bearing applications problematic. This problem can be solved in some applications with post-tensioning. The use of post-tensioning in structures can be used to ensure that layer interfaces only see compressive stresses. This method is commonly used to strengthen concrete structures since concrete is weak in tension while strong in compression. This paper explores the successful application of post-tensioning to improve z-strength of large structures made with Big Area Additive Manufacturing (BAAM) where loads are significant. Theory and examples are presented herein.Mechanical Engineerin

Increasing Interlaminar Strength in Large Scale Additive Manufacturing

Interlaminar strength of extrusion-based additively manufactured parts is known to be weaker than the strength seen in the printed directions (X and Y). With Big Area Additive Manufacturing (BAAM), large parts lead to long layer times that are prone to splitting, sometimes referred to as delamination, between the layers. Fiber filled materials, such as carbon fiber reinforced ABS, are used to counteract the effects of thermal expansion by increasing the strength in the X and Y directions. These fibers stay in-plane meaning that no fibers span from layer to layer, which would help counteract the weak interlaminar strength that causes splitting. A solution to this is a patent pending approach called Z-Pinning. The process involves strategically positioning voids across multiple layers that are backfilled with hot extrudate. This paper will explore the benefits and results of using Z-Pinning in large scale additive manufacturing.Mechanical Engineerin

Fieldable Platform for Large-Scale Deposition of Concrete Structures

Oak Ridge National Laboratory’s Manufacturing Demonstration Facility is developing a novel, large-scale additive manufacturing, or 3D printing, system. The Sky Big Area Additive Manufacturing (SkyBAAM) system will ultimately be a fieldable concrete deposition machine with pick and place abilities that will allow for full-scale, automated construction of buildings. The system will be implemented with existing construction equipment meaning conventional cranes will be used to suspend the print head. SkyBAAM will be cable-driven by four base stations and suspended from a single crane. The elimination of a gantry system, found commonly in large-scale additive manufacturing systems, will enable SkyBAAM to be quickly set up with minimal site preparation. The medium-scale version of SkyBAAM is currently in development. The system design, cable stiffness analysis, and tactics for freezing rotational degrees-of-freedom (DOF), detailed in this paper, will provide a basis for the final, large-scale version of the SkyBAAM system.Mechanical Engineerin

Exploration of a Cable-Driven 3D Printer for Concrete Tower Structures

Researchers at Oak Ridge National Laboratory’s Manufacturing Research Demonstration Facility (MDF) are currently developing a cable-driven concrete additive manufacturing (AM) system called SKYBAAM. This system is a novel solution for 3D printing large structures using concrete. The current research focuses primarily on proof of concepts for the cable driven system, material selection, material pumping solutions, and the concrete extruder design. Looking forward from the success of the current research, this paper investigates the feasibility of using the SKYBAAM on a larger scale, specifically for extremely tall tower structures. The current system design presents challenges at a larger scale, and so the primary focus of this paper is to investigate new designs of a platform that would support large-scale SKYBAAM operations. Additionally, this paper will discuss the resulting deflections that can be expected due to machine operation and wind-loading. Excessive structural deflections could lead to loss of printing accuracy, or even a complete failure of the print, so it is important to establish that acceptable deflections can be reasonably achieved on these large-scale tower structures.Mechanical Engineerin

Using Big Area Additive Manufacturing to directly manufacture a boat hull mould

Big Area Additive Manufacturing (BAAM) is a large-scale, 3D printing technology developed by Oak Ridge National Laboratory's Manufacturing Demonstration Facility and Cincinnati, Inc. The ability to quickly and cost-effectively manufacture unique moulds and tools is currently one of the most significant applications of BAAM. This work details the application of a BAAM system to fabricate a 10.36 m (34 ft) catamaran boat hull mould. The goal of this project was to explore the feasibility of using BAAM to directly manufacture a mould without the need for thick coatings. The mould was printed in 12 individual sections over a five-day period. After printing, the critical surfaces of the mould were CNC-machined, the sections were assembled, and a final hull was manufactured using the mould. The success of this project illustrates the time and cost savings of BAAM in the fabrication of large moulds

Metabolic pathways of DβHB in mitochondria.

<p>The metabolism of DβHB in mitochondria is stereospecific to the D isoform. Under normal physiological conditions, the level of DβHB is low but becomes dramatically elevated during starvation, increased fatty acid metabolism or pathological conditions such as diabetes. From its site of production in the liver, DβHB is released into the blood and circulated for utilization by other tissues. In general, the rate of ketone body usage in the brain is proportional to the concentration in the circulation <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024620#pone.0024620-Sokoloff1" target="_blank">[59]</a>. Circulating DβHB readily crosses the blood-brain barrier and enters brain mitochondria where it is metabolized by mitochondrial β-hydroxybutyrate dehydrogenase to acetoacetate, which is subsequently converted to acetyl-coenzyme A to feed into the tricarboxylic acid cycle (TCA) cycle. The intermediate products generated from this cycle, NADH and succinate, in turn feed into the electron transport chain to subsequently generate ATP at complex V. Through this metabolic pathway, DβHB is an excellent alternative source of energy in the brain when glycolysis is not operative or when glucose supply is depleted such as during starvation <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024620#pone.0024620-Sokoloff1" target="_blank">[59]</a>.</p

DβHB extends life expectancy and stabilizes glucose levels of Tg-R6/2 mice.

<p>Animals from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024620#pone-0024620-g004" target="_blank">Figure 4</a> were monitored twice daily for their survival rate (<b>A</b>). These mice were considered to reach their end stage if they were unable to right themselves after being placed on their back or died overnight. DβHB significantly extended the survival time in Tg-R6/2 mice. <i>n</i> = 12 (Ntg-saline), <i>n</i> = 7 (Tg-saline), <i>n</i> = 7 (Tg-DβHB). <i>p</i><0.001 Kaplan-Meier analysis between Tg-sal and Tg- DβHB groups. These animals were also assessed weekly for glucose levels after six hours of fasting (<b>B</b>). One animal from the Tg-saline group survived up to 14 weeks and exhibited an elevated glucose level.</p