Development of MTH1-Binding Nucleotide Analogs Based on 7,8-Dihalogenated 7-Deaza-dG Derivatives.

MTH1 is an enzyme that hydrolyzes 8-oxo-dGTP, which is an oxidatively damaged nucleobase, into 8-oxo-dGMP in nucleotide pools to prevent its mis-incorporation into genomic DNA. Selective and potent MTH1-binding molecules have potential as biological tools and drug candidates. We recently developed 8-halogenated 7-deaza-dGTP as an 8-oxo-dGTP mimic and found that it was not hydrolyzed, but inhibited enzyme activity. To further increase MTH1 binding, we herein designed and synthesized 7,8-dihalogenated 7-deaza-dG derivatives. We successfully synthesized multiple derivatives, including substituted nucleosides and nucleotides, using 7-deaza-dG as a starting material. Evaluations of the inhibition of MTH1 activity revealed the strong inhibitory effects on enzyme activity of the 7,8-dihalogenated 7-deaza-dG derivatives, particularly 7,8-dibromo 7-daza-dGTP. Based on the results obtained on kinetic parameters and from computational docking simulating studies, these nucleotide analogs interacted with the active site of MTH1 and competitively inhibited the substrate 8-oxodGTP. Therefore, novel properties of repair enzymes in cells may be elucidated using new compounds.

Virtual reality training for radiation safety in cardiac catheterization laboratories - an integrated study.

The advent of fluoroscopically guided cardiology procedures has greatly improved patient outcomes but has also increased occupational radiation exposure for healthcare professionals, leading to adverse health effects such as radiation-induced cataracts, alopecia, and cancer. This emphasizes the need for effective radiation safety training. Traditional training methods, often based on passive learning, fail to simulate the dynamic catheterization laboratory environment adequately. Virtual Reality (VR) offers a promising alternative by providing immersive, interactive experiences that mimic real-world scenarios without the risks of actual radiation exposure. Our study aims to assess the effectiveness of VR-based radiation safety training compared to traditional methods. We conducted a prospective cohort study involving 48 healthcare professionals in a catheterization lab setting. Participants underwent a 1-hour self-directed VR training session using Virtual Medical Coaching's RadSafe VR software, which simulates real-world clinical scenarios. Pre- and post-intervention radiation dose levels were measured using personal dosimeters at the eye, chest, and pelvis. Knowledge and skills were assessed through tests, and feedback was gathered through surveys and interviews. Statistical analysis revealed significant reductions in radiation exposure across all professional groups after VR training. For cardiologists, the eye dose dropped by 21.88% (from 2.88 mSv to 2.25 mSv), the chest dose decreased by 21.65% (from 4.11 mSv to 3.22 mSv), and the pelvis dose went down by 21.84% (from 2.06 mSv to 1.61 mSv). Perioperative nurses experienced similar reductions, with eye doses decreasing by 14.74% (from 1.56 mSv to 1.33 mSv), chest doses by 26.92% (from 2.6 mSv to 1.9 mSv), and pelvis doses by 26.92% (from 1.3 mSv to 0.95 mSv). Radiographers saw their eye doses reduced by 18.95% (from 0.95 mSv to 0.77 mSv), chest doses by 42.11% (from 1.9 mSv to 1.1 mSv), and pelvis doses by 27.63% (from 0.76 mSv to 0.55 mSv).Participants reported enhanced engagement, improved understanding of radiation safety, and a preference for VR over traditional methods. A cost analysis also demonstrated the economic advantages of VR training, with significant savings in staff time and rental costs compared to traditional methods. Our findings suggest that VR is a highly effective and cost-efficient training tool for radiation safety in healthcare, offering significant benefits over traditional training approaches.

Function of gastrin-releasing peptide receptors in ocular itch transmission in the mouse trigeminal sensory system.

The prevalence of allergic conjunctivitis in itchy eyes has increased constantly worldwide owing to environmental pollution. Currently, anti-allergic and antihistaminic eye drops are used; however, there are many unknown aspects about the neural circuits that transmit itchy eyes. We focused on the gastrin-releasing peptide (GRP) and GRP receptor (GRPR), which are reportedly involved in itch transmission in the spinal somatosensory system, to determine whether the GRP system is involved in itch neurotransmission of the eyes in the trigeminal sensory system. First, the instillation of itch mediators, such as histamine (His) and non-histaminergic itch mediator chloroquine (CQ), exhibited concentration-dependent high levels of eye scratching behavior, with a significant sex differences observed in the case of His. Histological analysis revealed that His and CQ significantly increased the neural activity of GRPR-expressing neurons in the caudal part of the spinal trigeminal nucleus of the medulla oblongata in GRPR transgenic mice. We administered a GRPR antagonist or bombesin-saporin to ablate GRPR-expressing neurons, followed by His or CQ instillation, and observed a decrease in CQ-induced eye-scratching behavior in the toxin experiments. Intracisternal administration of neuromedin C (NMC), a GRPR agonist, resulted in dose-dependent excessive facial scratching behavior, despite the absence of an itch stimulus on the face. To our knowledge, this is the first study to demonstrate that non-histaminergic itchy eyes were transmitted centrally via GRPR-expressing neurons in the trigeminal sensory system, and that NMC in the medulla oblongata evoked facial itching.