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Hyperthermia induced by phenethylamines, such as 3,4–methylenedioxymethamphetamine (MDMA), can lead to life-threatening complications and death. Activation of the sympathetic nervous system and subsequent release of norepinephrine and activation of uncoupling proteins have been demonstrated to be the key mediators of phenethylamine-induced hyperthermia (PIH). Recently, the gut microbiome was shown to also play a contributing role in PIH. Here, the hypothesis that bile acids (BAs) produced by the gut microbiome are essential to PIH was tested. Changes in the serum concentrations of unconjugated primary BAs cholic acid (CA) and chenodeoxycholic acid (CDCA) and secondary BA deoxycholic acid (DCA) were measured following MDMA (20 mg/kg, sc) treatment in antibiotic treated and control rats. MDMA-induced a significant hyperthermic response and reduced the serum concentrations of three BAs 60 min post-treatment. Pretreatment with antibiotics (vancomycin, bacitracin and neomycin) in the drinking water for five days resulted in the depletion of BAs and a hypothermic response to MDMA. Gut bacterial communities in the antibiotic-treated group were distinct from the MDMA or saline treatment groups, with decreased microbiome diversity and alteration in taxa. Metagenomic functions inferred using the bioinformatic tool PICRUSt2 on 16S rRNA gene sequences indicated that bacterial genes associated to BA metabolism are less abundant in the antibiotic-MDMA treated group. Overall, these findings suggest that gut bacterial produced BAs might play an important role in MDMA-induced hyperthermia. [ABSTRACT FROM AUTHOR]

The main contribution of this paper is the development and demonstration of a novel methodology that can be followed to develop a simulation twin of a railway track switch system to test the functionality in a digital environment. This is important because, globally, railway track switches are used to allow trains to change routes; they are a key part of all railway networks. However, because track switches are single points of failure and safety-critical, their inability to operate correctly can cause significant delays and concomitant costs. In order to better understand the dynamic behaviour of switches during operation, this paper has developed a full simulation twin of a complete track switch system. The approach fuses finite element for the rail bending and motion, with physics-based models of the electromechanical actuator system and the control system. Hence, it provides researchers and engineers the opportunity to explore and understand the design space around the dynamic operation of new switches and switch machines before they are built. This is useful for looking at the modification or monitoring of existing switches, and it becomes even more important when new switch concepts are being considered and evaluated. The simulation is capable of running in real time or faster meaning designs can be iterated and checked interactively. The paper describes the modelling approach, demonstrates the methodology by developing the system model for a novel "REPOINT" switch system, and evaluates the system level performance against the dynamic performance requirements for the switch. In the context of that case study, it is found that the proposed new actuation system as designed can meet (and exceed) the system performance requirements, and that the fault tolerance built into the actuation ensures continued operation after a single actuator failure. [ABSTRACT FROM AUTHOR]