Mechanism Development, Testing, and Lessons Learned for the Advanced Resistive Exercise Device

The Advanced Resistive Exercise Device (ARED) has been developed at NASA Johnson Space Center, for the International Space Station (ISS) program. ARED is a multi-exercise, high-load resistive exercise device, designed for long duration, human space missions. ARED will enable astronauts to effectively maintain their muscle strength and bone mass in the micro-gravity environment more effectively than any other existing devices. ARED's resistance is provided via two, 20.3 cm (8 in) diameter vacuum cylinders, which provide a nearly constant resistance source. ARED also has a means to simulate the inertia that is felt during a 1-G exercise routine via the flywheel subassembly, which is directly tied to the motion of the ARED cylinders. ARED is scheduled to fly on flight ULF 2 to the ISS and will be located in Node 1. Presently, ARED is in the middle of its qualification and acceptance test program. An extensive testing program and engineering evaluation has increased the reliability of ARED by bringing potential design issues to light before flight production. Some of those design issues, resolutions, and design details will be discussed in this paper

The footprint of cometary dust analogues: II. Morphology as a tracer of tensile strength and application to dust collection by the Rosetta spacecraft

The structure of cometary dust is a tracer of growth processes in the formation of planetesimals. Instrumentation on board the Rosetta mission to comet 67P/Churyumov- Gerasimenko captured dust particles and analysed them in situ. However, these deposits are a product of a collision within the instrument. We conducted laboratory experiments with cometary dust analogues, simulating the collection process by Rosetta instruments (specifically COSIMA, MIDAS). In Paper I we reported that velocity is a key driver in determining the appearance of deposits. Here in Paper II we use materials with different monomer sizes, and study the effect of tensile strength on the appearance of deposits. We find that mass transfer efficiency increases from $\sim$1 up to $\sim$10% with increasing monomer diameter from 0.3 $\mu$m to 1.5 $\mu$m (i.e. tensile strength decreasing from $\sim$12 to $\sim$3 kPa), and velocities increasing from 0.5 to 6 m/s. Also, the relative abundance of small fragments after impact is higher for material with higher tensile strength. The degeneracy between the effects of velocity and material strength may be lifted by performing a closer study of the deposits. This experimental method makes it possible to estimate the mass transfer efficiency in the COSIMA instrument. Extrapolating these results implies that more than half of the dust collected during the Rosetta mission has not been imaged. We analysed two COSIMA targets containing deposits from single collisions. The collision that occurred closest to perihelion passage led to more small fragments on the target.Comment: 13 pages, 11 figures, accepted for publication in MNRA

The footprint of cometary dust analogs: I. Laboratory experiments of low-velocity impacts and comparison with Rosetta data

Cometary dust provides a unique window on dust growth mechanisms during the onset of planet formation. Measurements by the Rosetta spacecraft show that the dust in the coma of comet 67P/Churyumov-Gerasimenko has a granular structure at size scales from sub-um up to several hundreds of um, indicating hierarchical growth took place across these size scales. However, these dust particles may have been modified during their collection by the spacecraft instruments. Here we present the results of laboratory experiments that simulate the impact of dust on the collection surfaces of COSIMA and MIDAS, instruments onboard the Rosetta spacecraft. We map the size and structure of the footprints left by the dust particles as a function of their initial size (up to several hundred um) and velocity (up to 6 m/s). We find that in most collisions, only part of the dust particle is left on the target; velocity is the main driver of the appearance of these deposits. A boundary between sticking/bouncing and fragmentation as an outcome of the particle-target collision is found at v ~ 2 m/s. For velocities below this value, particles either stick and leave a single deposit on the target plate, or bounce, leaving a shallow footprint of monomers. At velocities > 2 m/s and sizes > 80 um, particles fragment upon collision, transferring up to 50 per cent of their mass in a rubble-pile-like deposit on the target plate. The amount of mass transferred increases with the impact velocity. The morphologies of the deposits are qualitatively similar to those found by the COSIMA instrument.Comment: 14 pages, 12 figures, accepted for publication in MNRA

Two C-terminal Sequence Variations Determine Differential Neurotoxicity Between Human and Mouse α-synuclein

BACKGROUND: α-Synuclein (aSyn) aggregation is thought to play a central role in neurodegenerative disorders termed synucleinopathies, including Parkinson\u27s disease (PD). Mouse aSyn contains a threonine residue at position 53 that mimics the human familial PD substitution A53T, yet in contrast to A53T patients, mice show no evidence of aSyn neuropathology even after aging. Here, we studied the neurotoxicity of human A53T, mouse aSyn, and various human-mouse chimeras in cellular and in vivo models, as well as their biochemical properties relevant to aSyn pathobiology. METHODS: Primary midbrain cultures transduced with aSyn-encoding adenoviruses were analyzed immunocytochemically to determine relative dopaminergic neuron viability. Brain sections prepared from rats injected intranigrally with aSyn-encoding adeno-associated viruses were analyzed immunohistochemically to determine nigral dopaminergic neuron viability and striatal dopaminergic terminal density. Recombinant aSyn variants were characterized in terms of fibrillization rates by measuring thioflavin T fluorescence, fibril morphologies via electron microscopy and atomic force microscopy, and protein-lipid interactions by monitoring membrane-induced aSyn aggregation and aSyn-mediated vesicle disruption. Statistical tests consisted of ANOVA followed by Tukey\u27s multiple comparisons post hoc test and the Kruskal-Wallis test followed by a Dunn\u27s multiple comparisons test or a two-tailed Mann-Whitney test. RESULTS: Mouse aSyn was less neurotoxic than human aSyn A53T in cell culture and in rat midbrain, and data obtained for the chimeric variants indicated that the human-to-mouse substitutions D121G and N122S were at least partially responsible for this decrease in neurotoxicity. Human aSyn A53T and a chimeric variant with the human residues D and N at positions 121 and 122 (respectively) showed a greater propensity to undergo membrane-induced aggregation and to elicit vesicle disruption. Differences in neurotoxicity among the human, mouse, and chimeric aSyn variants correlated weakly with differences in fibrillization rate or fibril morphology. CONCLUSIONS: Mouse aSyn is less neurotoxic than the human A53T variant as a result of inhibitory effects of two C-terminal amino acid substitutions on membrane-induced aSyn aggregation and aSyn-mediated vesicle permeabilization. Our findings highlight the importance of membrane-induced self-assembly in aSyn neurotoxicity and suggest that inhibiting this process by targeting the C-terminal domain could slow neurodegeneration in PD and other synucleinopathy disorders

Contact dermatitis and other skin conditions in instrumental musicians

BACKGROUND: The skin is important in the positioning and playing of a musical instrument. During practicing and performing there is a permanent more or less intense contact between the instrument and the musician's skin. Apart from aggravation of predisposed skin diseases (e.g., atopic eczema or psoriasis) due to music-making, specific dermatologic conditions may develop that are directly caused by playing a musical instrument. METHODS: To perform a systematic review on instrument-related skin diseases in musicians we searched the PubMed database without time limits. Furthermore we studied the online bibliography "Occupational diseases of performing artist. A performing arts medicine bibliography. October, 2003" and checked references of all selected articles for relevant papers. RESULTS: The most prevalent skin disorders of instrumental musicians, in particular string instrumentalists (e.g., violinists, cellists, guitarists), woodwind players (e.g., flautists, clarinetists), and brass instrumentalists (e.g., trumpeters), include a variety of allergic contact sensitizations (e.g., colophony, nickel, and exotic woods) and irritant (physical-chemical noxae) skin conditions whose clinical presentation and localization are usually specific for the instrument used (e.g., "fiddler's neck", "cellist's chest", "guitar nipple", "flautist's chin"). Apart from common callosities and "occupational marks" (e.g., "Garrod's pads") more or less severe skin injuries may occur in musical instrumentalists, in particular acute and chronic wounds including their complications. Skin infections such as herpes labialis seem to be a more common skin problem in woodwind and brass instrumentalists. CONCLUSIONS: Skin conditions may be a significant problem not only in professional instrumentalists, but also in musicians of all ages and ability. Although not life threatening they may lead to impaired performance and occupational hazard. Unfortunately, epidemiological investigations have exclusively been performed on orchestra musicians, though the prevalence of instrument-related skin conditions in other musician groups (e.g., jazz and rock musicians) is also of interest. The practicing clinician should be aware of the special dermatologic problems unique to the musical instrumentalist. Moreover awareness among musicians needs to be raised, as proper technique and conditioning may help to prevent affection of performance and occupational impairment

Association of variants in the SPTLC1 gene with juvenile amyotrophic lateral sclerosis

Importance Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation. Objective To identify the genetic variants associated with juvenile ALS. Design, Setting, and Participants In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism. Main Outcomes and Measures De novo variants present only in the index case and not in unaffected family members. Results Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway. Conclusions and Relevance These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene