Development of a multistage laser frequency stabilization for an interferometric gravitational-wave detector

Laser frequency stabilization is essential for interferometric gravitational-wave detectors to attain their target sensitivity. We have designed a multistage laser frequency stabilization system which has been applied in the development of the TAMA 300 gravitational-wave detector in Japan. The control topology consisting of two cascaded loops were employed to secure high feedback gain and reliable detector operation and thus allow the best frequency stability and uninterrupted long-term observation. We achieved simultaneously a frequency stability of 5 × 10^(−5) Hz/√HZ , and a common-mode rejection ratio (which reduces the coupling of frequency noise to spurious signals in the detector) of 37 dB. The developed system enabled us to operate TAMA 300 with sufficient sensitivity and stability that it had the potential to register gravitational-wave events. The system was confirmed to be suitable for a gravitational-wave detector from the observation run of TAMA 300

Amniotic Fluid Ingestion Enhances\ud Opioid-Mediated But Not\ud Nonopioid-Mediated Analgesia

Ingestion of amniotic fluid or placenta by rats has been shown to enhance several types of opioid-mediated analgesia: that induced by morphine, footshock, vaginal/cervical stimulation, and late pregnancy. This enhancement has also been blocked by administration of opioid antagonists. The present study was designed to examine further the specificity of the enhancement effect for opioid-mediated analgesia by testing for enhancement following administration of aspirin, a nonopioid analgesic. The formalin test was used as the pain threshold assay. Amniotic fluid or beef bouillon was administered by orogastric tube to rats that were treated either with morphine sulfate or saline. or pretreated with naltrexone, then treated with aspirin or vehicle. Both morphine and aspirin treatments produced analgesia. Amniotic fluid significantly enhanced the analgesia produced by morphine, but did not enhance the analgesia produced by aspirin, further suggesting that the enhancing effect of amniotic fluid ingestion is specific for opioid-mediated analgesia, such as that existing at the start of parturition

Gut microbial trimethylamine is elevated in alcohol-associated hepatitis and contributes to ethanol-induced liver injury in mice

There is mounting evidence that microbes residing in the human intestine contribute to diverse alcohol-associated liver diseases (ALD) including the most deadly form known as alcohol-associated hepatitis (AH). However, mechanisms by which gut microbes synergize with excessive alcohol intake to promote liver injury are poorly understood. Furthermore, whether drugs that selectively target gut microbial metabolism can improve ALD has never been tested. We used liquid chromatography tandem mass spectrometry to quantify the levels of microbe and host choline co-metabolites in healthy controls and AH patients, finding elevated levels of the microbial metabolite trimethylamine (TMA) in AH. In subsequent studies, we treated mice with non-lethal bacterial choline TMA lyase (CutC/D) inhibitors to blunt gut microbe-dependent production of TMA in the context of chronic ethanol administration. Indices of liver injury were quantified by complementary RNA sequencing, biochemical, and histological approaches. In addition, we examined the impact of ethanol consumption and TMA lyase inhibition on gut microbiome structure via 16S rRNA sequencing. We show the gut microbial choline metabolite TMA is elevated in AH patients and correlates with reduced hepatic expression of the TMA oxygenase flavin-containing monooxygenase 3 (FMO3). Provocatively, we find that small molecule inhibition of gut microbial CutC/D activity protects mice from ethanol-induced liver injury. CutC/D inhibitor-driven improvement in ethanol-induced liver injury is associated with distinct reorganization of the gut microbiome and host liver transcriptome. The microbial metabolite TMA is elevated in patients with AH, and inhibition of TMA production from gut microbes can protect mice from ethanol-induced liver injury

Potency of a human monoclonal antibody to diphtheria toxin relative to equine diphtheria anti-toxin in a guinea pig intoxication model

Prompt administration of anti-toxin reduces mortality following Corynebacterium diphtheriae infection. Current treatment relies upon equine diphtheria anti-toxin (DAT), with a 10% risk of serum sickness and rarely anaphylaxis. The global DAT supply is extremely limited; most manufacturers have ceased production. S315 is a neutralizing human IgG1 monoclonal antibody to diphtheria toxin that may provide a safe and effective alternative to equine DAT and address critical supply issues. To guide dose selection for IND-enabling pharmacology and toxicology studies, we dose-ranged S315 and DAT in a guinea pig model of diphtheria intoxication based on the NIH Minimum Requirements potency assay. Animals received a single injection of antibody premixed with toxin, were monitored for 30 days, and assigned a numeric score for clinical signs of disease. Animals receiving \u3e /= 27.5 microg of S315 or \u3e /= 1.75 IU of DAT survived whereas animals receiving \u3c /= 22.5 microg of S315 or \u3c /= 1.25 IU of DAT died, yielding a potency estimate of 17 microg S315/IU DAT (95% CI 16-21) for an endpoint of survival. Because some surviving animals exhibited transient limb weakness, likely a systemic sign of toxicity, DAT and S315 doses required to prevent hind limb paralysis were also determined, yielding a relative potency of 48 microg/IU (95% CI 38-59) for this alternate endpoint. To support advancement of S315 into clinical trials, potency estimates will be used to evaluate the efficacy of S315 versus DAT in an animal model with antibody administration after toxin exposure, more closely modeling anti-toxin therapy in humans

Bystander experiences of domestic violence and abuse during the COVID-19 pandemic

This article seeks to understand the experiences of bystanders to domestic violence and abuse (DVA) during the COVID-19 pandemic in Wales. Globally, professionals voiced concern over the COVID-19 restrictions exacerbating conditions for DVA to occur. Yet evidence suggests this also increased opportunities for bystanders to become aware of DVA and take action against it. This mixed methods study consists of a quantitative online survey and follow-up interviews with survey respondents. Conducted in Wales, UK, during a national lockdown in 2021, this article reports on the experiences of 186 bystanders to DVA during the pandemic.Results suggest that bystanders had increased opportunity to become aware of DVA due to the pandemic restrictions. Results support the bystander situational model whereby respondents have to become aware of the behaviour, recognise it as a problem, feel that they possess the correct skills, and have confidence in their skills, before they will take action. Having received bystander training was a significant predictor variable in bystanders taking action against DVA; this is an important finding that should be utilised to upskill general members of the community