Short term e-bicycle riding results in favorable cardiometabolic shifts in moderately active adults.

PURPOSE: Electric bikes (EB) are a form of active transportation with demonstrated health benefits. The purpose of this study was to determine the influence of riding an EB for one week on indices of cardiometabolic health in middle-aged adults. METHODS: Adults (n = 22; age = 57.1 ± 11.3 year; BMI = 27.7 ± 4.9) participated in a 2 week study. During Week 1, participants were instructed to continue regular activities. Starting Week 2 participants were provided an EB to ride at least 3 days for a minimum of 30 min·day-1. Physical activity (PA) and glucose were measured continuously. Body composition, blood lipids, glucose, insulin, hemoglobin A1c (HbA1c), plasma endothelin-1 (ET-1), and carotid-femoral pulse wave velocity (cf-PWV) were measured on days 1 and 14.Data and Statistical analyses or Statistics. Each participant served as their own control. Paired t-tests compared dependent variables between week 1 (without EB) and week 2 (with EB). RESULTS: When provided an EB for one week, moderate to vigorous PA increased by 6-9 min·day-1 (P < 0.05) and sedentary time decreased by ~ 77 min·day-1 (P < 0.05). Data from 24 h continuous glucose monitoring showed the percentage of time in healthy range (70-120 mg·dl-1 glucose) increased (P < 0.05) from week 1 to week 2. Compared to day 1, cf-PWV was lower at day 14 (P < 0.05) following one week of riding an EB. CONCLUSION: Moderately-active, middleaged adults showed improved continuous glucose regulation and lower central arterial stiffness following one week of riding an EB.

Transitioning From High-dose Methadone to Buprenorphine Using a Microdosing Approach: Unique Considerations at ASAM Level 3 Facilities.

Transitions from high-dose methadone to buprenorphine for treatment of opioid use disorder (OUD) present risk of precipitated withdrawal related to the introduction of a high-affinity partial agonist at the mu-opioid receptor after occupancy by a lower-affinity full agonist. Various strategies have been explored to maintain patient stability during this process, including microdosing buprenorphine. Current literature lacks consensus on an optimal setting and strategy for initiating a buprenorphine microdosing protocol and gives little detail on patients' conditions after the acute transition period. We report a 6-day microdosing transition from methadone 100 mg directly to sublingual buprenorphine, followed by a 20-day period of monitoring and additional treatment. This patient tolerated a sublingual buprenorphine microdosing protocol while using supportive medications with a peak Clinical Opiate Withdrawal Scale score of 6. The patient's most significant withdrawal symptoms occurred several days after completion of the microdosing process. This case demonstrates the feasibility of using a transmucosal buprenorphine formulation in microdosing transitions from high-dose methadone directly to buprenorphine, and highlights the utility of a medically monitored intensive inpatient setting (American Society of Addiction Medicine level 3.7) in providing appropriate monitoring and treatment during and after a microdosing transition.

Characterisation of a cyclic peptide that binds to the RAS binding domain of phosphoinositide 3-kinase p110α.

P110α is a member of the phosphoinositide 3-kinase (PI3K) enzyme family that functions downstream of RAS. RAS proteins contribute to the activation of p110α by interacting directly with its RAS binding domain (RBD), resulting in the promotion of many cellular functions such as cell growth, proliferation and survival. Previous work from our lab has highlighted the importance of the p110α/RAS interaction in tumour initiation and growth. Here we report the discovery and characterisation of a cyclic peptide inhibitor (cyclo-CRVLIR) that interacts with the p110α-RBD and blocks its interaction with KRAS. cyclo-CRVLIR was discovered by screening a "split-intein cyclisation of peptides and proteins" (SICLOPPS) cyclic peptide library. The primary cyclic peptide hit from the screen initially showed a weak affinity for the p110α-RBD (Kd about 360 µM). However, two rounds of amino acid substitution led to cyclo-CRVLIR, with an improved affinity for p110α-RBD in the low µM (Kd 3 µM). We show that cyclo-CRVLIR binds selectively to the p110α-RBD but not to KRAS or the structurally-related RAF-RBD. Further, using biophysical, biochemical and cellular assays, we show that cyclo-CRVLIR effectively blocks the p110α/KRAS interaction in a dose dependent manner and reduces phospho-AKT levels in several oncogenic KRAS cell lines.

Development of a cell-free split-luciferase biochemical assay as a tool for screening for inhibitors of challenging protein-protein interaction targets.

Targeting the interaction of proteins with weak binding affinities or low solubility represents a particular challenge for drug screening. The NanoLuc â ® Binary Technology (NanoBiT â ®) was originally developed to detect protein-protein interactions in live mammalian cells. Here we report the successful translation of the NanoBit cellular assay into a biochemical, cell-free format using mammalian cell lysates. We show that the assay is suitable for the detection of both strong and weak protein interactions such as those involving the binding of RAS oncoproteins to either RAF or phosphoinositide 3-kinase (PI3K) effectors respectively, and that it is also effective for the study of poorly soluble protein domains such as the RAS binding domain of PI3K. Furthermore, the RAS interaction assay is sensitive and responds to both strong and weak RAS inhibitors. Our data show that the assay is robust, reproducible, cost-effective, and can be adapted for small and large-scale screening approaches. The NanoBit Biochemical Assay offers an attractive tool for drug screening against challenging protein-protein interaction targets, including the interaction of RAS with PI3K.

Vitamin A and Wound Healing.

Vitamin A is a general term for retinoids. Vitamin A deficiency leads to a variety of cutaneous manifestations. It also functions as a hormone through retinoic acid receptors altering the activity of multiple cell lines. Pancreatic vitamin A levels are critical for retinoid signaling and normal pancreatic control of glucose. Vitamin A deficiency is more common during infection, and supplementation reduces severe morbidity and mortality from infectious diseases. Vitamin A modulates activities at the cellular level and, via its interrelationship with hormones such as thyroid, insulin, and corticosteroids, has diffuse metabolic effects on the body. It plays an important role in all stages of wound healing. Vitamin A is known for its ability to stimulate epithelial growth, fibroblasts, granulation tissue, angiogenesis, collagen synthesis, epithelialization, and fibroplasia. Local (topical) and systemic supplementation with vitamin A has been proven to increase dermal collagen deposition. There are numerous animal studies and limited human studies regarding physiologic effect of vitamin A on acute or chronic wounds via systemic or topical administration. The most common use of vitamin A supplementation is to offset steroids' effect. When considering supplementation, the potential benefits must be weighed against the risk of harm. Vitamin A toxicity can be critical and even result in death. The evidence for supplementation with vitamin A is currently limited to expert opinion and is not backed up by rigorous trials. There is an acute need for therapeutic trials with vitamin A supplementations.