Pharmacologic Targeting of the C-Terminus of Heat Shock Protein 90 Improves Neuromuscular Function in Animal Models of Charcot Marie Tooth X1 Disease.

Charcot-Marie-Tooth X1 (CMTX1) disease is an inherited peripheral neuropathy that arises from loss-of-function mutations in the protein connexin 32 (Cx32). CMTX1 currently lacks a pharmacologic approach toward disease management, and we have previously shown that modulating the expression of molecular chaperones using novologue therapy may provide a viable disease-modifying approach to treat metabolic and demyelinating neuropathies. Cemdomespib is an orally bioavailable novologue that manifests neuroprotective activity by modulating the expression of heat shock protein 70 (Hsp70). We examined if 1 to 5 months of daily cemdomespib therapy may improve neuropathic symptoms in three mouse models of CMTX1 (Cx32 deficient (Cx32def), T55I-Cx32def, and R75W-Cx32 mice). Daily drug therapy significantly improved motor nerve conduction velocity (MNCV) and grip strength in all three models, but the compound muscle action potential was only improved in Cx32def mice. Drug efficacy required Hsp70 as improvements in MNCV, and the grip strength was abrogated in Cx32def × Hsp70 knockout mice. Five months of novologue therapy was associated with improved neuromuscular junction morphology, femoral motor nerve myelination, reduction in foamy macrophages, and a decrease in Schwann cell c-jun levels. To determine if c-jun may be downstream of Hsp70 and necessary for drug efficacy, c-jun expression was specifically deleted in Schwann cells of Cx32def mice. While the deletion of c-jun worsened the neuropathy, cemdomespib therapy remained effective in improving MNCV and grip strength. Our data show that cemdomespib therapy improves CMTX1-linked neuropathy in an Hsp70-dependent but a c-jun-independent manner and without regard to the nature of the underlying Cx32 mutation.

Synthesis and evaluation of 3'- and 4'-substituted cyclohexyl noviomimetics that modulate mitochondrial respiration.

KU-32 (2) and KU-596 (3), are first and second generation cytoprotective novologues that are derivatives of novobiocin (1), a heat shock protein 90 (Hsp90) C-terminal inhibitor. Although 2 and 3 improve mitochondrial bioenergetics and have demonstrated considerable cytoprotective activity, they contain a synthetically demanding noviose sugar. This issue was initially addressed by creating noviomimetics, such as KU-1202 (4), which replaced the noviose sugar with ether-linked cyclohexyl derivatives that retained some cytoprotective potential due to their ability to increase mitochondrial bioenergetics. Based on structure-activity relationship (SAR) studies of KU-1202 (4), the current study investigated 3'- and 4'-substituted cyclohexyl scaffolds as noviomimetics and determined their efficacy at increasing mitochondrial bioenergetic as a marker for cytoprotective potential.

Effect of glandularity on the detection of simulated cancers in planar, tomosynthesis, and synthetic 2D imaging of the breast using a hybrid virtual clinical trial.

PURPOSE: The purpose of this study was to measure the threshold diameter of calcifications and masses for 2D imaging, digital breast tomosynthesis (DBT), and synthetic 2D images, for a range of breast glandularities. This study shows the limits of detection for each of the technologies and the strengths and weaknesses of each in terms of visualizing the radiological features of small cancers. METHODS: Mathematical voxel breast phantoms with glandularities by volume of 9%, 18%, and 30% with a thickness of 53 mm were created. Simulated ill-defined masses and calcification clusters with a range of diameters were inserted into some of these breast models. The imaging characteristics of a Siemens Inspiration X-ray system were measured for a 29 kV, tungsten/rhodium anode/filter combination. Ray tracing through the breast models was undertaken to create simulated 2D and DBT projection images. These were then modified to adjust the image sharpness, and to add scatter and noise. The mean glandular doses for the images were 1.43, 1.47, and 1.47 mGy for 2D and 1.92, 1.97, and 1.98 mGy for DBT for the three glandularities. The resultant images were processed to create 2D, DBT planes and synthetic 2D images. Patches of the images with or without a simulated lesion were extracted, and used in a four-alternative forced choice study to measure the threshold diameters for each imaging mode, lesion type, and glandularity. The study was undertaken by six physicists. RESULTS: The threshold diameters of the lesions were 6.2, 4.9, and 6.7 mm (masses) and 225, 370, and 399 µm, (calcifications) for 2D, DBT, and synthetic 2D, respectively, for a breast glandularity of 18%. The threshold diameter of ill-defined masses is significantly smaller for DBT than for both 2D (p≤0.006) and synthetic 2D (p≤0.012) for all glandularities. Glandularity has a significant effect on the threshold diameter of masses, even for DBT where there is reduced background structure in the images. The calcification threshold diameters for 2D images were significantly smaller than for DBT and synthetic 2D for all glandularities. There were few significant differences for the threshold diameter of calcifications between glandularities, indicating that the background structure has little effect on the detection of calcifications. We measured larger but nonsignificant differences in the threshold diameters for synthetic 2D imaging than for 2D imaging for masses in the 9% (p = 0.059) and 18% (p = 0.19) glandularities. The threshold diameters for synthetic 2D imaging were larger than for 2D imaging for calcifications (p < 0.001) for all glandularities. CONCLUSIONS: We have shown that glandularity has only a small effect on the detection of calcifications, but the threshold diameter of masses was significantly larger for higher glandularity for all of the modalities tested. We measured nonsignificantly larger threshold diameters for synthetic 2D imaging than for 2D imaging for masses at the 9% (p = 0.059) and 18% (p = 0.19) glandularities and significantly larger diameters for calcifications (p < 0.001) for all glandularities. The lesions simulated were very subtle and further work is required to examine the clinical effect of not seeing the smallest calcifications in clusters.

Sleep and Coping in Early Childhood During the COVID-19 Pandemic.

Sleep disturbances in early childhood are associated with mood and anxiety disorders. Children also exhibit sleep disruptions, such as nighttime awakenings, nightmares, and difficulties falling asleep, in conjunction with adverse events and stress. Prior studies have examined independently the role of sleep on adaptive processing, as well as the effects of stress on sleep. However, how childhood sleep and children's adaptive behavior (i.e., coping strategies) bidirectionally interact is currently less known. Using a within-subjects design and actigraphy-measured sleep from 16 preschool-aged children (Mage = 56.4 months, SD = 10.8, range: 36-70 months), this study investigated how prior sleep patterns relate to children's coping during a potentially stressful event, the COVID-19 pandemic, and how prior coping skills may influence children's sleep during the pandemic. Children who woke earlier had greater negative expression both before and during the pandemic. During the pandemic, children slept longer and woke later on average compared to before the pandemic. Additionally, for children engaged in at-home learning, sleeping longer was associated with less negative expression. These findings highlight how sleep behaviors and coping strategies are related, and the stability of this relationship under stress.

Mindfulness-Based Stress Reduction Benefits Psychological Well-Being, Sleep Quality, and Athletic Performance in Female Collegiate Rowers.

Factors such as psychological well-being, sleep quality, and athletic coping skills can influence athletic performance. Mindfulness-based interventions, including mindfulness-based stress reduction (MBSR), have been shown to benefit these factors, suggesting they may, at least indirectly, benefit athletic performance. Moreover, while mindfulness training has been linked to better accuracy in some high-precision sports, whether it can improve non-precision elements of athletic performance is unclear. The objective of this study was to investigate the influence of MBSR on psychological well-being, sleep, athletic coping skills, and rowing performance in collegiate rowers in a controlled experimental design. Members of a Division I NCAA Women's Rowing team completed either an 8-week MBSR course along with their regular athletic training program (Intervention group) or the athletic training program alone (Control group). Measurements of interest were taken at baseline and again either during or shortly following the intervention. In contrast to the Control group, the Intervention group showed improvements in psychological well-being, subjective and objective sleep quality, athletic coping skills, and rowing performance as measured by a 6,000-m ergometer test. Improvements in athletic coping skills, psychological well-being, and subjective sleep quality were all correlated with increases in mindfulness in the Intervention group. These results suggest that mindfulness training may benefit non-precision aspects of athletic performance. Incorporating mindfulness training into athletic training programs may benefit quality of life and performance in student athletes.