A myriad of cellular pathophysiological responses are mediated by polymodal ion channels that respond to chemical and physical stimuli such as thermoTRP channels. Intriguingly, these channels are pivotal therapeutic targets with limited clinical pharmacology.
methods offer an unprecedented opportunity for discovering new lead compounds targeting thermoTRP channels with improved pharmacological activity and therapeutic index.

This article reviews the progress on thermoTRP channel pharmacology because of (i) advances in solving their atomic structure using cryo-electron microscopy and, (ii) progress on computational techniques including homology modeling, molecular docking, virtual screening, molecular dynamics, ADME/Tox and artificial intelligence. Together, they have increased the number of lead compounds with clinical potential to treat a variety of pathologies. We used original and review articles from Pubmed (1997-2020), as well as the clinicaltrials.gov database, containing the terms thermoTRP, artificial intelligence, docking, and molecular dynamics.

The atomic structure of thermoTRP channels along with computational methods constitute a realistic first line strategy for designing drug candidates with improved pharmacology and clinical translation.
approaches can also help predict potential side-effects that can limit clinical development of drug candidates. Together, they should provide drug candidates with upgraded therapeutic properties.
The atomic structure of thermoTRP channels along with computational methods constitute a realistic first line strategy for designing drug candidates with improved pharmacology and clinical translation. In silico approaches can also help predict potential side-effects that can limit clinical development of drug candidates. Together, they should provide drug candidates with upgraded therapeutic properties.The objective of this study was to evaluate maternal outcomes with an extended second stage of labor and determine if an extended second stage is cost effective. This theoretical model evaluated expectant management to 4 h compared to delivery at 3 h in the setting of a prolonged second stage of labor in nulliparous women with epidural analgesia. In our theoretical cohort of 165,000 women, we found that an extended second stage resulted in 53,268 more spontaneous vaginal deliveries, 14,163 fewer operative vaginal deliveries, and 39,105 fewer cesarean deliveries. This approach also resulted in 1 fewer instance of maternal death. An extended second stage, however, led to 14,025 more cases of chorioamnionitis, 1699 more episodes of postpartum hemorrhage requiring transfusion, and 119 more severe perineal lacerations, suggesting that while an extended second stage of labor results in overall improved maternal outcomes, there are tradeoffs. Expectant management to 4 h was the dominant strategy in the model, as it saved over $114 million US dollars and resulted in 4000 additional QALYs over our theoretical cohort. Sensitivity analysis indicated that expectant management until 4 h was cost-effective as long as the probability of cesarean delivery at 4 h was below 41.8%, and was the dominant strategy below 38.2% (baseline input 19.5%). Multivariable sensitivity analysis demonstrated that the model was robust over a wide range of assumptions. Expectant management of the second stage of labor until 4 h is a cost-effective strategy to prevent primary cesarean deliveries, decrease costs, and improve some maternal outcomes, despite tradeoffs.Micropollutants are frequently detected in groundwater. Thus, the question arises whether they are eliminated by natural attenuation so that pesticide degradation would be observed with increasing residence time in groundwater. Conventional analytical approaches rely on parent compound/metabolite ratios. These are difficult to interpret if metabolites are sorbed or further transformed. Compound-specific stable isotope analysis (CSIA) presents an alternative for identifying degradation based on the analysis of natural isotope abundances in pesticides and their changes during degradation. However, CSIA by gas chromatography-isotope ratio mass spectrometry is challenged by the low concentrations (ng/L) of micropollutants in groundwater. Consequently, large amounts of water need to be sampled requiring enrichment and clean-up steps from interfering matrix effects that must not introduce artefacts in measured isotope values. The aim of this study was to evaluate the accuracy of isotope ratio measurements of the frequently detected micropollutants atrazine, desethylatrazine and 2,6-dichlorobenzamide after enrichment from large water volumes (up to 100 L) by solid-phase extraction with consecutive clean-up by HPLC. Associated artefacts of isotope discrimination were found to depend on numerous factors including organic matter content and extraction volume. This emphasizes the necessity to perform a careful method evaluation of sample preparation and sample pre-treatment prior reliable CSIA.
ELX-02, an investigational compound that is structurally an aminoglycoside analog, induces read-through of nonsense mutations through interaction with the ribosome, through which full-length functional proteins can be produced. It is being developed as a therapy for genetic diseases caused by nonsense mutations such as cystic fibrosis (CF) and nephropathic cystinosis. In Phase 1 clinical trials, 105 volunteers were exposed to ELX-02. To date, ELX-02 is well tolerated and there has been no reported treatment-related serious adverse events or deaths.

The development of this molecule, from its pharmacology to the ongoing Phase 2 clinical trials is discussed.

Globally, nonsense mutations account for ~11% of all described gene lesions causing inherited monogenetic diseases. In CF and nephropathic cystinosis, they comprise from 10% to 12% of the disease-causative alleles. ELX-02 is in development as a therapeutic for patients with these alleles as
and
data demonstrated dose-dependent read-through of nonsense mutations to produce full-length, functional proteins. E64d in vivo Since read-through efficiency varies between alleles and mRNA context, careful consideration of target patient populations is required. The results to date support the ongoing Phase 2 clinical evaluations of ELX-02 as a read-through agent.
Globally, nonsense mutations account for ~11% of all described gene lesions causing inherited monogenetic diseases. In CF and nephropathic cystinosis, they comprise from 10% to 12% of the disease-causative alleles. ELX-02 is in development as a therapeutic for patients with these alleles as in vitro and in vivo data demonstrated dose-dependent read-through of nonsense mutations to produce full-length, functional proteins. Since read-through efficiency varies between alleles and mRNA context, careful consideration of target patient populations is required. The results to date support the ongoing Phase 2 clinical evaluations of ELX-02 as a read-through agent.E64d in vivo