Development of Naphthalene PLIF for Visualizing Ablation Products From a Space Capsule Heat Shield

The Orion Multi-Purpose Crew Vehicle (MPCV) will use an ablative heat shield. To better design this heat shield and others that will undergo planetary entry, an improved understanding of the ablation process would be beneficial. Here, a technique developed at The University of Texas at Austin that uses planar laser-induced fluorescence (PLIF) of a low-temperature sublimating ablator (naphthalene) to enable visualization of the ablation products in a hypersonic flow is applied. Although high-temperature ablation is difficult and expensive to recreate in a laboratory environment, low-temperature sublimation creates a limited physics problem that can be used to explore ablation-product transport in a hypersonic flow-field. In the current work, a subscale capsule reentry vehicle model with a solid naphthalene heat shield has been tested in a Mach 5 wind tunnel. The PLIF technique provides images of the spatial distribution of sublimated naphthalene in the heat-shield boundary layer, separated shear layer, and backshell recirculation region. Visualizations of the capsule shear layer using both naphthalene PLIF and Schlieren imaging compared favorably. PLIF images have shown high concentrations of naphthalene in the capsule separated flow region, intermittent turbulent structures on the heat shield surface, and interesting details of the capsule shear layer structure. It was shown that, in general, the capsule shear layer appears to be more unsteady at lower angels of attack. The PLIF images demonstrated that during a wind tunnel run, as the model heated up, the rate of naphthalene ablation increased, since the PLIF signal increased steadily over the course of a run. Additionally, the shear layer became increasingly unsteady over the course of a wind tunnel run, likely because of increased surface roughness but also possibly because of the increased blowing. Regions with a relatively low concentration of naphthalene were also identified in the capsule backshell recirculation region and are most likely the result of cross-flow-induced vortices on the capsule afterbody

Visualization of Capsule Reentry Vehicle Heat Shield Ablation Using Naphthalene PLIF

The Orion Multi-Purpose Crew Vehicle (MPCV) will use an ablative heat shield and improved understanding of the ablation process would be beneficial for design purposes. Given that ablation is a multi-physics process involving heat and mass transfer, codes aiming to predict heat shield ablation are in need of experimental data pertaining to the turbulent transport of ablation products for validation. At The University of Texas at Austin, a technique is being developed that uses planar laser-induced fluorescence (PLIF) of a low-temperature sublimating ablator (naphthalene) to visualize the transport of ablation products in a supersonic flow. Since ablation at reentry temperatures can be difficult to recreate in a laboratory setting it is desirable to create a limited physics problem and simulate the ablation process at relatively low temperature conditions using naphthalene. A scaled Orion MPCV model with a solid naphthalene heat shield has been tested in a Mach 5 wind tunnel at various angles of attack in the current work. PLIF imaging reveals the distribution of the ablation products as they are transported into the heat-shield boundary layer and over the capsule shoulders into the separated shear layer and backshell recirculation region. Visualizations of the capsule shear layer using both naphthalene PLIF and Schlieren imaging compared favorably. High concentrations of naphthalene in the capsule separated flow region, intermittent turbulent structures on the heat shield surface, and interesting details of the capsule shear layer structure were observed using the naphthalene PLIF technique. The capsule shear layer was also shown to generally appear to be more turbulent at lower angles of attack. Furthermore, the PLIF signal increased steadily over the course of a run indicating that during a wind tunnel run the model heated up and the rate of naphthalene ablation increased. The shear layer showed increasing signs of turbulence over the course of a wind tunnel run as well, likely because of the combination of increased surface roughness and surface blowing rate. PLIF imaging also detected regions with a relatively low concentration of naphthalene in the capsule backshell recirculation region that are most likely the result of cross-flow-induced vortices on the capsule afterbody

Analysis of isoform-specific tau aggregates suggests a common toxic mechanism involving similar pathological conformations and axonal transport inhibition

© The Author(s), 2016. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Neurobiology of Aging 47 (2016): 113–126, doi:10.1016/j.neurobiolaging.2016.07.015.Misfolded tau proteins are characteristic of tauopathies, but the isoform composition of tau inclusions varies by tauopathy. Using aggregates of the longest tau isoform (containing 4 microtubule-binding repeats and 4-repeat tau), we recently described a direct mechanism of toxicity that involves exposure of the N-terminal phosphatase-activating domain (PAD) in tau, which triggers a signaling pathway that disrupts axonal transport. However, the impact of aggregation on PAD exposure for other tau isoforms was unexplored. Here, results from immunochemical assays indicate that aggregation-induced increases in PAD exposure and oligomerization are common features among all tau isoforms. The extent of PAD exposure and oligomerization was larger for tau aggregates composed of 4-repeat isoforms compared with those made of 3-repeat isoforms. Most important, aggregates of all isoforms exhibited enough PAD exposure to significantly impair axonal transport in the squid axoplasm. We also show that PAD exposure and oligomerization represent common pathological characteristics in multiple tauopathies. Collectively, these results suggest a mechanism of toxicity common to each tau isoform that likely contributes to degeneration in different tauopathies.This work was supported by NIH grants R01 AG044372 (Nicholas M. Kanaan), R01 NS082730 (Nicholas M. Kanaan and Scott T. Brady), BrightFocus Foundation (A2013364S, Nicholas M. Kanaan), the Jean P. Schultz Biomedical Research Endowment (Nicholas M. Kanaan), the Secchia Family Foundation (Nicholas M. Kanaan) and NS066942A (Gerardo Morfini)

Tau: a signaling hub protein

© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Mueller, R. L., Combs, B., Alhadidy, M. M., Brady, S. T., Morfini, G. A., & Kanaan, N. M. Tau: a signaling hub protein. Frontiers in Molecular Neuroscience, 14, (2021): 647054, https://doi.org/10.3389/fnmol.2021.647054.Over four decades ago, in vitro experiments showed that tau protein interacts with and stabilizes microtubules in a phosphorylation-dependent manner. This observation fueled the widespread hypotheses that these properties extend to living neurons and that reduced stability of microtubules represents a major disease-driving event induced by pathological forms of tau in Alzheimer’s disease and other tauopathies. Accordingly, most research efforts to date have addressed this protein as a substrate, focusing on evaluating how specific mutations, phosphorylation, and other post-translational modifications impact its microtubule-binding and stabilizing properties. In contrast, fewer efforts were made to illuminate potential mechanisms linking physiological and disease-related forms of tau to the normal and pathological regulation of kinases and phosphatases. Here, we discuss published work indicating that, through interactions with various kinases and phosphatases, tau may normally act as a scaffolding protein to regulate phosphorylation-based signaling pathways. Expanding on this concept, we also review experimental evidence linking disease-related tau species to the misregulation of these pathways. Collectively, the available evidence supports the participation of tau in multiple cellular processes sustaining neuronal and glial function through various mechanisms involving the scaffolding and regulation of selected kinases and phosphatases at discrete subcellular compartments. The notion that the repertoire of tau functions includes a role as a signaling hub should widen our interpretation of experimental results and increase our understanding of tau biology in normal and disease conditions.This work was supported by NIH grants (R01AG067762 and R01AG044372 to NK, R01NS082730 to NK and SB, R01NS118177 and R21NS120126 to GM, R01NS023868 and R01NS041170 to SB), a gift from Neurodegenerative Research Inc. (GM), a Zenith Award from the Alzheimer’s Association (SB), a grant from the Secchia Family Foundation (NK), NIH/National Institute on Aging (NIA) funded Michigan Alzheimer’s Disease Research Center 5P30AG053760 (BC), the Office of the Assistant Secretary of Defense for Health Affairs through the Peer-Reviewed Alzheimer’s Research Program (Award No. W81XWH-20-1-0174 to BC), and an Alzheimer’s Association Research Grant 20-682085 (BC)

Pseudophosphorylation of tau at S422 enhances SDS-stable dimer formation and impairs both anterograde and retrograde fast axonal transport

AbstractIn Alzheimer's disease (AD), tau undergoes numerous modifications, including increased phosphorylation at serine-422 (pS422). In the human brain, pS422 tau protein is found in prodromal AD, correlates well with cognitive decline and neuropil thread pathology, and appears associated with increased oligomer formation and exposure of the N-terminal phosphatase-activating domain (PAD). However, whether S422 phosphorylation contributes to toxic mechanisms associated with disease-related forms of tau remains unknown. Here, we report that S422-pseudophosphorylated tau (S422E) lengthens the nucleation phase of aggregation without altering the extent of aggregation or the types of aggregates formed. When compared to unmodified tau aggregates, the S422E modification significantly increased the amount of SDS-stable tau dimers, despite similar levels of immunoreactivity with an oligomer-selective antibody (TOC1) and another antibody that reports PAD exposure (TNT1). Vesicle motility assays in isolated squid axoplasm further revealed that S422E tau monomers inhibited anterograde, kinesin-1 dependent fast axonal transport (FAT). Unexpectedly, and unlike unmodified tau aggregates, which selectively inhibit anterograde FAT, aggregates composed of S422E tau were found to inhibit both anterograde and retrograde FAT. Highlighting the relevance of these findings to human disease, pS422 tau was found to colocalize with tau oligomers and with a fraction of tau showing increased PAD exposure in the human AD brain. This study identifies novel effects of pS422 on tau biochemical properties, including prolonged nucleation and enhanced dimer formation, which correlate with a distinct inhibitory effect on FAT. Taken together, these findings identify a novel mechanistic basis by which pS422 confers upon tau a toxic effect that may directly contribute to axonal dysfunction in AD and other tauopathies

Configuration development study of the X-24C hypersonic research airplane

Bottom line results were made of a three-phase study to determine the feasibility of designing, building, and operating, and maintaining an air-launched high performance aircraft capable of cruising at speeds up to Mach 8 for short durations. The results show that Lockalloy heat-sink structure affords the capability for a 'work-horse' vehicle which can serve as an excellent platform for this research. It was further concluded that the performance of a blended wing body configuration surpassed that of a lifting body design for typical X-24C missions. The cost of a two vehicle program, less engines, B-52 modification and contractor support after delivery, can be kept within $70M (in Jan. 1976 dollars)

Are the average gait speeds during the 10 meter and 6 minute walk tests redundant in Parkinson disease?

Published in final edited form as: Gait Posture. 2017 February ; 52: 178–182. doi:10.1016/j.gaitpost.2016.11.033.We investigated the relationships between average gait speed collected with the 10Meter Walk Test (Comfortable and Fast) and 6Minute Walk Test (6MWT) in 346 people with Parkinson disease (PD) and how the relationships change with increasing disease severity. Pearson correlation and linear regression analyses determined relationships between 10Meter Walk Test and 6MWT gait speed values for the entire sample and for sub-samples stratified by Hoehn & Yahr (H&Y) stage I (n=53), II (n=141), III (n=135) and IV (n=17). We hypothesized that redundant tests would be highly and significantly correlated (i.e. r>0.70, p<0.05) and would have a linear regression model slope of 1 and intercept of 0. For the entire sample, 6MWT gait speed was significantly (p<0.001) related to the Comfortable 10 Meter Walk Test (r=0.75) and Fast 10Meter Walk Test (r=0.79) gait speed, with 56% and 62% of the variance in 6MWT gait speed explained, respectively. The regression model of 6MWT gait speed predicted by Comfortable 10 Meter Walk gait speed produced slope and intercept values near 1 and 0, respectively, especially for participants in H&Y stages II-IV. In contrast, slope and intercept values were further from 1 and 0, respectively, for the Fast 10Meter Walk Test. Comfortable 10 Meter Walk Test and 6MWT gait speeds appeared to be redundant in people with moderate to severe PD, suggesting the Comfortable 10 Meter Walk Test can be used to estimate 6MWT distance in this population.This study was funded by the Davis Phinney Foundation, the Parkinson's Disease Foundation, and the National Institutes of Health (R01 NS077959, K12 HD055931, UL1 TR000448). The funding sources had no input related to study design, data collection, or decision to submit for publication. (Davis Phinney Foundation; Parkinson's Disease Foundation; R01 NS077959 - National Institutes of Health; K12 HD055931 - National Institutes of Health; UL1 TR000448 - National Institutes of Health

NO PLIF Visualizations of the Orion Capsule in LENS-I

Planar laser-induced fluorescence (PLIF) of nitric oxide (NO) was used to visualize the interaction of reaction-control-system (RCS) jet flows in the wake of a hypersonic capsule reentry vehicle. The tests were performed at the Calspan University at Buffalo Research Center's (CUBRC) LENS-I reflected shock tunnel facility. This was the first application of PLIF to study RCS jets in a large-scale pulsed hypersonic facility. The LENS-I facility allowed RCS jet flows to be studied while varying the flow enthalpy, Reynolds number, angle of attack and jet configuration. The interaction of pitch and roll jets with the flowfield was investigated. Additionally, thin film sensors were used to monitor heat transfer on the surface of the model to detect any localized heating resulting from the firing of the RCS jets. Tests were conducted with the model held at angles of attack of 18deg and 22deg. The nominal Mach number in all tests was 8, while Reynolds number based on model diameter ranged from 2.2x10(exp 6) - 1.5x10(exp 7). Images were processed using the Virtual Diagnostics Interface (ViDI) system developed at NASA Langley Research Center to provide a three-dimensional display of the experimental data

Trolling in asynchronous computer-mediated communication: From user discussions to academic definitions

Whilst computer-mediated communication (CMC) can benefit users by providing quick and easy communication between those separated by time and space, it can also provide varying degrees of anonymity that may encourage a sense of impunity and freedom from being held accountable for inappropriate online behaviour. As such, CMC is a fertile ground for studying impoliteness, whether it occurs in response to perceived threat (flaming), or as an end in its own right (trolling). Currently, first and secondorder definitions of terms such as im/politeness (Brown and Levinson 1987; Bousfield 2008; Culpeper 2008; Terkourafi 2008), in-civility (Lakoff 2005), rudeness (Beebe 1995, Kienpointner 1997, 2008), and etiquette (Coulmas 1992), are subject to much discussion and debate, yet the CMC phenomenon of trolling is not adequately captured by any of these terms. Following Bousfield (in press), Culpeper (2010) and others, this paper suggests that a definition of trolling should be informed first and foremost by user discussions. Taking examples from a 172-million-word, asynchronous CMC corpus, four interrelated conditions of aggression, deception, disruption, and success are discussed. Finally, a working definition of trolling is presented