Experimental variables that impact outcomes in Caenorhabditis elegans aging stress response.

Cellular stress is a fundamental component of age-associated disease. Cells encounter various forms of stress - oxidative stress, protein misfolding, DNA damage, etc. - and respond by activating specific, well-defined stress response pathways. As we age, the burden of stress and resulting damage increases while our cells' ability to deal with the consequences becomes diminished due to dysregulation of cellular stress response pathways. Many interventions that extend lifespan activate one or more stress response pathways or allow cells to maintain normal stress response later in life. The nematode Caenorhabditis elegans is a commonly used model for both aging and stress response research. As such, stress response experiments are regularly conducted as part of studies focused on mechanisms of aging in C. elegans. However, experimental design across experiments in the field are highly variable, including stressor dose, age at exposure, culture type (liquid vs. solid), bacterial strain used as a food source, and environmental temperature. These differences can result in different experimental outcomes, making comparison of results between studies challenging. Here we evaluate several experimental variables that are variable in the published literature and find that each can meaningfully alter experimental outcomes for multiple stressors. Our goal is to raise awareness of the issue of experimental variability within the field and suggest a standardized experimental design to serve as a set of guidelines for future experiments. By adopting these guidelines as a starting point, and explicitly noting differences in specific experiments, we aim to promote rigor and reproducibility, ultimately fostering more interpretable and translatable outcomes in geroscience research.

3-Hydroxyanthranilic Acid Delays Paralysis in Caenorhabditis elegans Models of Amyloid-Beta and Polyglutamine Proteotoxicity.

Age is the primary risk factor for neurodegenerative diseases such as Alzheimer's and Huntington's disease. Alzheimer's disease is the most common form of dementia and a leading cause of death in the elderly population of the United States. No effective treatments for these diseases currently exist. Identifying effective treatments for Alzheimer's, Huntington's, and other neurodegenerative diseases is a major current focus of national scientific resources, and there is a critical need for novel therapeutic strategies. Here, we investigate the potential for targeting the kynurenine pathway metabolite 3-hydroxyanthranilic acid (3HAA) using Caenorhabditis elegans expressing amyloid-beta or a polyglutamine peptide in body wall muscle, modeling the proteotoxicity in Alzheimer's and Huntington's disease, respectively. We show that knocking down the enzyme that degrades 3HAA, 3HAA dioxygenase (HAAO), delays the age-associated paralysis in both models. This effect on paralysis was independent of the protein aggregation in the polyglutamine model. We also show that the mechanism of protection against proteotoxicity from HAAO knockdown is mimicked by 3HAA supplementation, supporting elevated 3HAA as the mediating event linking HAAO knockdown to delayed paralysis. This work demonstrates the potential for 3HAA as a targeted therapeutic in neurodegenerative disease, though the mechanism is yet to be explored.

Copper(I) thiocyanate-amine networks: synthesis, structure, and luminescence behavior.

A series of metal-organic networks of CuSCN were prepared by direct reactions with substituted pyridine and aliphatic amine ligands, L. Thiocyanate bridging is seen in all but 1 of 11 new X-ray structures. Structures are reported for (CuSCN)L sheets (L = 3-chloro- and 3-bromopyridine, N-methylmorpholine), ladders (L = 2-ethylpyridine, N-methylpiperidine), and chains (L = 2,4,6-collidine). X-ray structures of (CuSCN)L(2) are chains (L = 4-ethyl- and 4-t-butylpyridine, piperidine, and morpholine). A unique N-thiocyanato monomer structure, (CuSCN)(3-ethylpyridine)(3), is also reported. In most cases, amine ligands are thermally released at temperatures <100 °C. Strong yellow-to-green luminescence at ambient temperature is observed for the substituted pyridine complexes. High solid state quantum efficiencies are seen for many of the CuSCN-L complexes. Microsecond phosphorescence lifetimes seen for CuSCN-L are in direct contrast to the nanosecond-lifetime emission of CuSCN. MLCT associated with pyridine π* orbitals is proposed as the excitation mechanism.

Betrixaban for Extended Venous Thromboembolism Prophylaxis in High-Risk Hospitalized Patients: Putting the APEX Results into Practice.

Acutely ill hospitalized medical patients remain at high thromboembolic risk for several weeks after discharge. Previous trials with extended-duration thromboprophylaxis using enoxaparin, apixaban, and rivaroxaban failed to achieve acceptable net clinical benefit, largely due to excess of major bleeding. Betrixaban is a novel factor Xa inhibitor with unique pharmacokinetic properties, including low renal clearance, long half-life, and low peak-to-trough ratio. The phase III APEX trial (N = 7513) compared a betrixaban 160 mg loading dose followed by 80 mg once daily for 35-42 days, with enoxaparin 40 mg once daily for 6-14 days; the betrixaban dose was reduced for renal impairment or a concomitant strong P-glycoprotein (P-gp) inhibitor. The primary efficacy endpoint of composite thrombotic events was not different between treatment arms in cohort 1 (D-dimer ≥ 2 × upper limit of normal). Subsequent exploratory analyses showed a statistically significant difference favoring betrixaban for symptomatic venous thromboembolism and net clinical benefit in the overall population. For the primary safety outcome, betrixaban did not significantly increase major bleeding compared with enoxaparin. Based on available data from the APEX trial and subanalyses, the use of betrixaban in patients similar to those enrolled in the APEX trial can reduce the risk of thromboembolic events without increasing the risk of major bleeding. Patients who may benefit more from betrixaban therapy include those with elevated D-dimer, history of venous thromboembolism, hospitalized for ischemic stroke, hospitalized for heart failure with N-terminal pro-B-type natriuretic peptide ≥ 1975 ng/L, or two or more VTE risk factors. Reduced-dose betrixaban does not appear to provide the same clinical utility as full-dose betrixaban.