RESUMEN
Sensory afferent inputs play an important role in neuromuscular functions. Subsensory level noise electrical stimulation enhances the sensitivity of peripheral sensory system and improves lower extremity motor function. The current study aimed to investigate the immediate effects of noise electrical stimulation on proprioceptive senses and grip force control, and whether there are associated neural activities in the central nervous system. Fourteen healthy adults participated in 2 experiments on 2 different days. In day 1, participants performed grip force and joint proprioceptive tasks with and without (sham) noise electrical stimulation. In day 2, participants performed grip force steady hold task before and after 30-min noise electrical stimulation. Noise stimulation was applied with surface electrodes secured along the course of the median nerve and proximal to the coronoid fossa EEG power spectrum density of bilateral sensorimotor cortex and coherence between EEG and finger flexor EMG were calculated and compared. Wilcoxon Signed-Rank Tests were used to compare the differences of proprioception, force control, EEG power spectrum density and EEG-EMG coherence between noise electrical stimulation and sham conditions. The significance level (alpha) was set at 0.05. Our study found that noise stimulation with optimal intensity could improve both force and joint proprioceptive senses. Furthermore, individuals with higher gamma coherence showed better force proprioceptive sense improvement with 30-min noise electrical stimulation. These observations indicate the potential clinical benefits of noise stimulation on individuals with impaired proprioceptive senses and the characteristics of individuals who might benefit from noise stimulation.
Asunto(s)
Músculo Esquelético , Propiocepción , Adulto , Humanos , Músculo Esquelético/fisiología , Propiocepción/fisiología , Estimulación Eléctrica , Nervio Mediano , Dedos/fisiologíaRESUMEN
As part of an ongoing effort to develop a drug targeting the type 1 cholecystokinin receptor (CCK1R) to help prevent and/or treat obesity, we recently performed a high throughput screening effort of small molecules seeking candidates that enhanced the action of the natural agonist, CCK, thus acting as positive allosteric modulators without exhibiting intrinsic agonist action. Such probes would be expected to act in a temporally finite way to enhance CCK action to induce satiety during and after a meal and potentially even modulate activity at the CCK1R in a high cholesterol environment present in some obese patients. The current work focuses on the best scaffold, representing tetracyclic molecules identified through high throughput screening we previously reported. Extensive characterization of the two top "hits" from the previous effort demonstrated them to fulfill the desired pharmacologic profile. We undertook analog-by-catalog expansion of this scaffold using 65 commercially available analogs. In this effort, we were able to eliminate an off-target effect observed for this scaffold while retaining its activity as a positive allosteric modulator of CCK1R in both normal and high cholesterol membrane environments. These insights should be useful in the rational medicinal chemical enhancement of this scaffold and in the future development of candidates to advance to pre-clinical proof-of-concept and to clinical trials.
RESUMEN
Human RPE cell lines, especially the ARPE-19â¯cell line, are widely-used in eye research, as well as general epithelial cell studies. In comparison with primary RPE cells, they offer relative convenience and consistency, but cultures derived from these lines are typically not well differentiated. We describe a simple, rapid method to establish cultures from ARPE-19â¯cells, with significantly improved epithelial cell morphology and cytoskeletal organization, and RPE-related functions. We identify the presence of nicotinamide, a member of the vitamin B family, as an essential factor in promoting the observed differentiation, indicating the importance of metabolism in RPE cell differentiation.