Myths and Methodologies: Understanding the health impact of head down bedrest for the benefit of older adults and astronauts. Study protocol of the Canadian Bedrest Study.

Weightlessness during spaceflight can harm various bodily systems, including bone density, muscle mass, strength and cognitive functions. Exercise appears to somewhat counteract these effects. A terrestrial model for this is head-down bedrest (HDBR), simulating gravity loss. This mirrors challenges faced by older adults in extended bedrest and space environments. The first Canadian study, backed by the Canadian Space Agency, Canadian Institutes of Health Research, and Canadian Frailty Network, aims to explore these issues. The study seeks to: (1) scrutinize the impact of 14-day HDBR on physiological, psychological and neurocognitive systems, and (2) assess the benefits of exercise during HDBR. Eight teams developed distinct protocols, harmonized in three videoconferences, at the McGill University Health Center. Over 26 days, 23 participants aged 55-65 underwent baseline measurements, 14 days of -6° HDBR, and 7 days of recovery. Half did prescribed exercise thrice daily combining resistance and endurance exercise for a total duration of 1 h. Assessments included demographics, cardiorespiratory fitness, bone health, body composition, quality of life, mental health, cognition, muscle health and biomarkers. This study has yielded some published outcomes, with more forthcoming. Findings will enrich our comprehension of HDBR effects, guiding future strategies for astronaut well-being and aiding bedrest-bound older adults. By outlining evidence-based interventions, this research supports both space travellers and those enduring prolonged bedrest.

Canadian aging and inactivity study: Spaceflight-inspired exercises during head-down tilt bedrest blunted reductions in muscle-pump but not cardiac baroreflex in older persons.

As part of the first Canadian aging and inactivity study (CAIS) we assessed the efficacy of space-based exercise countermeasures for maintenance of cardiac and muscle-pump baroreflex in older persons during bedrest. An initiative of the Canadian Space Agency, Canadian Institutes of Health Research and the Canadian Frailty Network, CAIS involved 14 days of 6-degree head-down tilt bedrest (HDBR) with (Exercise) or without (Control) combined upper and lower body strength, aerobic, and high-intensity interval training exercise countermeasures. Twenty healthy men and women aged 55 to 65, randomly divided into control and exercise groups (male control (MC, n = 5), male exercise (ME, n = 5), female control (FC, n = 6), female exercise (FE, n = 4)) (age: 58.7 ± 0.5 years, height: 1.67 ± 0.02 m, body mass: 70.2 ± 3.2 kg; mean ± SEM), completed the study. Cardiac and muscle-pump baroreflex activity were assessed with supine-to-stand tests. Wavelet transform coherence was used to characterise cardiac and muscle-pump baroreflex fraction time active (FTA) and gain values, and convergent cross-mapping was used to investigate causal directionality between blood pressure (BP) and heart rate, as well as BP and lower leg muscle electromyography (EMG). Seven of the twenty participants were unable to stand for 6 minutes after HDBR, with six of those being female. Our findings showed that 2 weeks of bedrest impaired skeletal muscle's ability to return blood to the venous circulation differently across various sexes and intervention groups. Comparing values after bed rest with before bed rest values, there was a significant increase in heart rates (∆ of +25%; +17% in MC to +33% in FC; p < 0.0001), beat-to-beat EMG decreased (∆ of -43%; -25% in ME to -58% in MC; p < 0.02), while BP change was dependent on sex and intervention groups. Unlike their male counterparts, in terms of muscle-pump baroreflex, female participants had considerably decreased FTA after HDBR (p < 0.01). All groups except female control demonstrated parallel decreases in cardiac active gain and causality, while the FC demonstrated an increase in cardiac causality despite a similar decline in cardiac active gain. Results showed that the proposed exercises may alleviate muscle-pump baroreflex declines but could not influence the cardiac baroreflex decline from 14 days of inactivity in older adults.

Ansellone J, a Potent in Vitro and ex Vivo HIV-1 Latency Reversal Agent Isolated from a Phorbas sp. Marine Sponge.

Five new minor sesterterpenoids, ansellones H (4), I (5), J (6), and K (7) and phorone C (8), have been isolated from a Phorbas sp. marine sponge collected in British Columbia. Their structures have been elucidated by detailed analysis of NMR and MS data. Ansellone J (6) and phorone C (8) are potent in vitro HIV-1 latency reversal agents that are more potent than the reference compound and control protein kinase C activator prostratin (3). The most potent Phorbas sesterterpenoid, ansellone J (6), was evaluated for HIV latency reversal in a primary cell context using CD4+ T cells obtained directly from four combination antiretroviral therapy-suppressed donors with HIV. To a first approximation, ansellone J (6) induced HIV latency reversal at levels similar to prostratin (3) ex vivo, but at a 10-fold lower concentration.

Novel Histone Deacetylase Inhibitors and HIV-1 Latency-Reversing Agents Identified by Large-Scale Virtual Screening.

Current antiretroviral therapies used for HIV management do not target latent viral reservoirs in humans. The experimental "shock-and-kill" therapeutic approach involves use of latency-reversal agents (LRAs) that reactivate HIV expression in reservoir-containing cells, followed by infected cell elimination through viral or host immune cytopathic effects. Several LRAs that function as histone deacetylase (HDAC) inhibitors are reported to reverse HIV latency in cells and in clinical trials; however, none to date have consistently reduced viral reservoirs in humans, prompting a need to identify new LRAs. Toward this goal, we describe here a virtual screening (VS) approach which uses 14 reported HDAC inhibitors to probe PubChem and identifies 60 LRA candidates. We then show that four screening "hits" including (S)-N-Hydroxy-4-(3-methyl-2-phenylbutanamido)benzamide (compound 15), N-(4-Aminophenyl)heptanamide (16), N-[4-(Heptanoylamino)phenyl]heptanamide (17), and 4-(1,3-Dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)-N-(2-hydroxyethyl)butanamide (18) inhibit HDAC activity and/or reverse HIV latency in vitro. This study demonstrates and supports that VS-based approaches can readily identify novel HDAC inhibitors and LRAs, which in turn may help toward inhibitor design and chemical optimization efforts for improved HIV shock-and-kill-based efforts.