Contributors to the June Issue/Notes

Notes by Henry S. Romano, William C. Malone, Joseph F. Rudd, Leonard D. Bodkin, James D. Sullivan, Robert J. Callahan, Jr., William Meehan, Alphonse Spahn, Robert E. Sullivan, John F. Power, Francis J. Paulson, John Merryman, J. Barrett Guthrie, Robert T. Fanning, Robert T. Stewart, and R. L. Miller

Contributors to the June Issue/Notes

Notes by Henry S. Romano, William C. Malone, Joseph F. Rudd, Leonard D. Bodkin, James D. Sullivan, Robert J. Callahan, Jr., William Meehan, Alphonse Spahn, Robert E. Sullivan, John F. Power, Francis J. Paulson, John Merryman, J. Barrett Guthrie, Robert T. Fanning, Robert T. Stewart, and R. L. Miller

A Thiazolidinedione Improves In Vivo Insulin Action on Skeletal Muscle Glycogen Synthase in Insulin-Resistant Monkeys

Thiazolidinediones (TZD) have been shown to have anti-diabetic effects including the ability to decrease fasting hyperglycemia and hyperinsulinemia, increase insulin-mediated glucose disposal rate (M) and decrease hepatic glucose production, but the mechanisms of action are not well established. To determine whether a TZD (R-102380, Sankyo Company Ltd., Tokyo, Japan) could improve insulin action on skeletal muscle glycogen synthase (GS), the rate-limiting enzyme in glycogen synthesis, 4 insulin-resistant obese monkeys were given I mg/kg/ day R-102380 p.o. for a 6-week period. Skeletal muscle GS activity and glucose 6-phosphate (G6P) content were compared between pre-dosing and dosing periods before and during the maximal insulin-stimulation of a euglycemic hyperinsulinemic clamp

Loftid Aeroshell Engineering Development Unit Structural Testing

NASAs Hypersonic Inflatable Aerodynamic Decelerator (HIAD) technology was selected for a Technology Demonstration Mission under the Space Technology Mission Directorate in 2017. HIAD is an enabling technology that can facilitate atmospheric entry of heavy payloads to planets such as Earth and Mars using a deployable aeroshell. The deployable nature of the HIAD technology allows it to avoid the size constraints imposed on current rigid aeroshell entry systems. This enables use of larger aeroshells resulting in increased entry system performance (e.g. higher pay-load mass and/or volume, higher landing altitude at Mars). The Low Earth Orbit Flight Test of an Inflatable Decelerator (LOFTID) is currently scheduled for late-2021. LOFTID will be launched out of Vandenberg Air Force Base as a secondary payload on an Atlas V rocket. The flight test features a 6m diameter, 70-deg sphere-cone aeroshell and will provide invaluable high-energy orbital re-entry flight data. This data will be essential in supporting the HIAD team to mature the technology to diameters of 10m and greater. Aeroshells of this scale are applicable to potential near-term commercial applications and future NASA missions. Currently the LOFTID project has completed fabrication of the engineering design unit (EDU) inflatable structure (IS) and the flexible thermal protection system (F-TPS). These two components along with the rigid nose and center body comprise the HIAD aeroshell system. This EDU aeroshell is the precursor to the LOFTID aeroshell that will be used for flight. The EDU was built to verify the design given the subtle differences between the LOFTID aeroshell and past aeroshell designs that have been fabricated under the NASA HIAD project. To characterize the structural performance of the LOFTID aeroshell design, three structural tests will be performed. The first test to be conducted is static load testing, which will induce a uniform load across the forward surface of the aeroshell to simulate the expected pressure forces during atmospheric entry. The IS integrated with the rigid center body will first be tested alone to provide data for analytical model correlation, and then the F-TPS will be integrated for a second series of static load testing of the full aeroshell system. Instrumentation will be employed during the test series to measure component loads during testing, and a laser scanner will be used to generate a 3D map of the aeroshell surface to verify that the shape of the structure is acceptable at the simulated flight loads. After static load testing, pack and deployment testing will be conducted multiple times on the integrated system to demonstrate the aeroshells ability to fit within the required packed volume for the LOFTID mission without experiencing significant damage. Finally, the aeroshell will undergo modal testing to characterize its structural response. This presentation will discuss the setup and execution of each of the three tests that the EDU aeroshell will undergo. In addition, initial results of the testing will be presented outlining key findings as LOFTID moves for-ward with fabrication of the flight aeroshell

Utilization of Mid-Thigh Magnetic Resonance Imaging to Predict Lean Body Mass and Knee Extensor Strength in Obese Adults

PurposeTo train and test a machine learning model to automatically measure mid-thigh muscle cross-sectional area (CSA) to provide rapid estimation of appendicular lean mass (ALM) and predict knee extensor torque of obese adults.MethodsObese adults [body mass index (BMI) = 30–40 kg/m2, age = 30–50 years] were enrolled for this study. Participants received full-body dual-energy X-ray absorptiometry (DXA), mid-thigh MRI, and completed knee extensor and flexor torque assessments via isokinetic dynamometer. Manual segmentation of mid-thigh CSA was completed for all MRI scans. A convolutional neural network (CNN) was created based on the manual segmentation to develop automated quantification of mid-thigh CSA. Relationships were established between the automated CNN values to the manual CSA segmentation, ALM via DXA, knee extensor, and flexor torque.ResultsA total of 47 obese patients were enrolled in this study. Agreement between the CNN-automated measures and manual segmentation of mid-thigh CSA was high (>0.90). Automated measures of mid-thigh CSA were strongly related to the leg lean mass (r = 0.86, p < 0.001) and ALM (r = 0.87, p < 0.001). Additionally, mid-thigh CSA was strongly related to knee extensor strength (r = 0.76, p < 0.001) and moderately related to knee flexor strength (r = 0.48, p = 0.002).ConclusionCNN-measured mid-thigh CSA was accurate compared to the manual segmented values from the mid-thigh. These values were strongly predictive of clinical measures of ALM and knee extensor torque. Mid-thigh MRI may be utilized to accurately estimate clinical measures of lean mass and function in obese adults

Environmental cold exposure increases blood flow and affects pain sensitivity in the knee joints of CFA-induced arthritic mice in a TRPA1-dependent manner

BACKGROUND: The effect of cold temperature on arthritis symptoms is unclear. The aim of this study was to investigate how environmental cold affects pain and blood flow in mono-arthritic mice, and examine a role for transient receptor potential ankyrin 1 (TRPA1), a ligand-gated cation channel that can act as a cold sensor. METHODS: Mono-arthritis was induced by unilateral intra-articular injection of complete Freund’s adjuvant (CFA) in CD1 mice, and in mice either lacking TRPA1 (TRPA1 KO) or respective wildtypes (WT). Two weeks later, nociception and joint blood flow were measured following exposure to 10 °C (1 h) or room temperature (RT). Primary mechanical hyperalgesia in the knee was measured by pressure application apparatus; secondary mechanical hyperalgesia by automated von Frey system; thermal hyperalgesia by Hargreaves technique, and weight bearing by the incapacitance test. Joint blood flow was recorded by full-field laser perfusion imager (FLPI) and using clearance of (99m)Technetium. Blood flow was assessed after pretreatment with antagonists of either TRPA1 (HC-030031), substance P neurokinin 1 (NK(1)) receptors (SR140333) or calcitonin gene-related peptide (CGRP) (CGRP(8–37)). TRPA1, TAC-1 and CGRP mRNA levels were examined in dorsal root ganglia, synovial membrane and patellar cartilage samples. RESULTS: Cold exposure caused bilateral primary mechanical hyperalgesia 2 weeks after CFA injection, in a TRPA1-dependent manner. In animals maintained at RT, clearance techniques and FLPI showed that CFA-treated joints exhibited lower blood flow than saline-treated joints. In cold-exposed animals, this reduction in blood flow disappears, and increased blood flow in the CFA-treated joint is observed using FLPI. Cold-induced increased blood flow in CFA-treated joints was blocked by HC-030031 and not observed in TRPA1 KOs. Cold exposure increased TRPA1 mRNA levels in patellar cartilage, whilst reducing it in synovial membranes from CFA-treated joints. CONCLUSIONS: We provide evidence that environmental cold exposure enhances pain and increases blood flow in a mono-arthritis model. These changes are dependent on TRPA1. Thus, TRPA1 may act locally within the joint to influence blood flow via sensory nerves, in addition to its established nociceptive actions

Extending in silico mechanism-of-action analysis by annotating targets with pathways: application to cellular cytotoxicity readouts.

BACKGROUND: An in silico mechanism-of-action analysis protocol was developed, comprising molecule bioactivity profiling, annotation of predicted targets with pathways and calculation of enrichment factors to highlight targets and pathways more likely to be implicated in the studied phenotype. RESULTS: The method was applied to a cytotoxicity phenotypic endpoint, with enriched targets/pathways found to be statistically significant when compared with 100 random datasets. Application on a smaller apoptotic set (10 molecules) did not allowed to obtain statistically relevant results, suggesting that the protocol requires modification such as analysis of the most frequently predicted targets/annotated pathways. CONCLUSION: Pathway annotations improved the mechanism-of-action information gained by target prediction alone, allowing a better interpretation of the predictions and providing better mapping of targets onto pathways.This is the author's accepted manuscript. The final version is available from Future Science in Future Medicinal Chemistry (http://dx.doi.org/10.4155/fmc.14.137)

Regulation of NGF Signaling by an Axonal Untranslated mRNA

Neurons are extraordinarily large and highly polarized cells that require rapid and efficient communication between cell bodies and axons over long distances. In peripheral neurons, transcripts are transported along axons to growth cones, where they are rapidly translated in response to extrinsic signals. While studying Tp53inp2, a transcript highly expressed and enriched in sympathetic neuron axons, we unexpectedly discovered that Tp53inp2 is not translated. Instead, the transcript supports axon growth in a coding-independent manner. Increasing evidence indicates that mRNAs may function independently of their coding capacity; for example, acting as a scaffold for functionally related proteins. The Tp53inp2 transcript interacts with the nerve growth factor (NGF) receptor TrkA, regulating TrkA endocytosis and signaling. Deletion of Tp53inp2 inhibits axon growth in vivo, and the defects are rescued by a non-translatable form of the transcript. Tp53inp2 is an atypical mRNA that regulates axon growth by enhancing NGF-TrkA signaling in a translation-independent manner