Identification of Novel Functional Inhibitors of Acid Sphingomyelinase

We describe a hitherto unknown feature for 27 small drug-like molecules, namely functional inhibition of acid sphingomyelinase (ASM). These entities named FIASMAs (Functional Inhibitors of Acid SphingoMyelinAse), therefore, can be potentially used to treat diseases associated with enhanced activity of ASM, such as Alzheimer's disease, major depression, radiation- and chemotherapy-induced apoptosis and endotoxic shock syndrome. Residual activity of ASM measured in the presence of 10 µM drug concentration shows a bimodal distribution; thus the tested drugs can be classified into two groups with lower and higher inhibitory activity. All FIASMAs share distinct physicochemical properties in showing lipophilic and weakly basic properties. Hierarchical clustering of Tanimoto coefficients revealed that FIASMAs occur among drugs of various chemical scaffolds. Moreover, FIASMAs more frequently violate Lipinski's Rule-of-Five than compounds without effect on ASM. Inhibition of ASM appears to be associated with good permeability across the blood-brain barrier. In the present investigation, we developed a novel structure-property-activity relationship by using a random forest-based binary classification learner. Virtual screening revealed that only six out of 768 (0.78%) compounds of natural products functionally inhibit ASM, whereas this inhibitory activity occurs in 135 out of 2028 (6.66%) drugs licensed for medical use in humans

Circadian rhythms in water and solute handling in adults with a spinal cord injury

Purpose: We evaluated nocturnal urine production and circadian rhythms of renal function (glomerular filtration, and water and solute diuresis) in adults with spinal cord injury compared to controls. Materials and Methods: This prospective observational study was done at Ghent University Hospital, Belgium. Participants were asked to perform a 24-hour urine collection. A blood sample was taken to calculate the diuresis rate and the renal clearance of creatinine, free water, solutes, sodium and urea. Results: A total of 119 patients were divided into 32 with spinal cord injury, and 68 controls with and 19 without nocturnal polyuria. Spinal cord injured patients showed no circadian rhythms in the diuresis rate or in the renal clearance of creatinine, free water, solutes, sodium or urea. Controls without nocturnal polyuria reported a lower nighttime diuresis rate and lower nighttime clearance of creatinine, solutes, sodium and urea compared to daytime levels. Controls with nocturnal polyuria had no circadian rhythms in the diuresis rate or creatinine clearance and a significant increase in nocturnal free water clearance compared to daytime levels. Conclusions: Comparing the mechanisms underlying nocturnal urine production between patients with spinal cord injury and controls revealed important differences. Spinal cord injured patients showed absent circadian rhythms in the renal clearance of creatinine (glomerular filtration), free water (water diuresis) and solutes such as sodium and urea (solute diuresis). Future research must be done to evaluate the role of patient stratification to find the most effective and safe treatment or combination of treatments for spinal cord injured patients with complaints or complications related to nocturnal polyuria

Recovery of Salts from Synthetic Erythritol Culture Broth via Electrodialysis: An Alternative Strategy from the Bin to the Loop

Sustainability and circularity are currently two relevant drivers in the development and optimisation of industrial processes. This study assessed the use of electrodialysis (ED) to purify synthetic erythritol culture broth and for the recovery of the salts in solution, for minimising the generation of waste by representing an efficient alternative to remove ions, ensuring their recovery process contributing to reaching cleaner standards in erythritol production. Removal and recovery of ions was evaluated for synthetic erythritol culture broth at three different levels of complexity using a stepwise voltage in the experimental settings. ED was demonstrated to be a potential technology removing between 91.7–99.0% of ions from the synthetic culture broth, with 49–54% current efficiency. Besides this, further recovery of ions into the concentrated fraction was accomplished. The anions and cations were recovered in a second fraction reaching concentration factors between 1.5 to 2.5 times while observing low level of erythritol losses (<2%), with an energy consumption of 4.10 kWh/m3.1181

Catch Uncertainty and Reward Schemes in a Commons Dilemma: An Experimental Study

We design and conduct a laboratory experiment with students and a field experiment with fishermen to test how catch uncertainty and reward schemes affect extraction in an open access fishery. We find that uncertainty in the relationship between effort and catch increases extraction effort and accelerates resource depletion. Importantly, participants increase their extraction after a disadvantageous shock, but do not react to advantageous shocks. One possible explanation of this phenomenon is a self-serving bias. Price-responsive demand, relative to a fixed price setting, decreases extraction effort and increases efficiency. Price-responsive demand has a greater effect on students than on fishermen living inside a marine protected area, but fishermen outside this restricted area are very responsive to conditional pricing