• Gregory Mccullough posted an update 3 days, 8 hours ago

    The COVID-19 pandemic has urged for the repurposing of existing drugs for rapid management and treatment. Renin inhibitors down regulation of ACE2, which is an essential receptor for SARS-CoV-2 infection that is responsible for COVID-19, in addition to their ability to act as protease inhibitors were encouraging aspects for their investigation as possible inhibitors of main protease of SARS-CoV-2 via computational studies. A Pharmacophore model was generated using the newly released SARS-COV-2 main protease inhibitors. Virtual screening was performed on renin inhibitors, and Drug likeness filter identified remikiren and 0IU as hits. Molecular docking for both compounds showed that the orally active renin inhibitor remikiren (Ro 42-5892) of Hoffmann-La Roche exhibited good molecular interaction with Cys145 and His41 in the catalytic site of SARS-CoV-2 main protease. Molecular dynamics simulation suggested that the drug is stable in the active site of the enzyme.Once infected, hosts can rely on two strategies to cope with parasites fight them (resist the infection) or minimize the damage they induce (tolerate the infection). While there is evidence that aging reduces resistance, how tolerance varies as hosts become old has been barely studied. Here, we used a rodent malaria parasite (Plasmodium yoelii) to investigate whether 2- and 12-month old house mice differ in their capacity to resist and tolerate the infection. We found that 12-month old mice harbored higher parasitemia, showing that age reduces resistance to malaria. Infection-induced deterioration of host health was assessed using red blood cell and body mass loss. Using both traits, the rate of decline in host health, as parasitemia increased, was more pronounced in 12- than in 2-month old mice, showing that age is also associated with impaired tolerance to malaria. Overall, resistance and tolerance positively covaried; however, this was only due to the age effect, since, within age classes, the two traits were not correlated. These results show that senescing individuals might be both more susceptible to infectious diseases and less able to cope with the damage that infection induces.Terrestrial and aquatic birds have been proposed as sentinels for the spread of antimicrobial resistant bacteria, but few species have been investigated specifically in the context of AMR in the marine ecosystem. This study contrasts the occurrence of class 1 integrons and associated antimicrobial resistance genes in wild and captive little penguins (Eudyptula minor), an Australian seabird with local population declines. PCR screening of faecal samples (n = 448) revealed a significant difference in the prevalence of class 1 integrons in wild and captive groups, 3.2% and 44.7% respectively, with genes that confer resistance to streptomycin, spectinomycin, trimethoprim and multidrug efflux pumps detected. Class 1 integrons were not detected in two clinically relevant bacterial species, Klebsiella pneumoniae or Escherichia coli, isolated from penguin faeces. The presence of class 1 integrons in the little penguin supports the use of marine birds as sentinels of AMR in marine environments.Recent meta-analysis reported higher dementia risks associated with lower body mass index (BMI) and decreasing BMI. We examined to what extent these associations were attenuated by changes in behaviours and local environment. Multilevel discrete time-to-event models examined associations between baseline and change in BMI with dementia detected through prescription medications (source Department of Human Services), hospitalisations and death certificates among 144,456 participants in the Sax Institute’s 45 and Up Study. Models were adjusted for socioeconomic factors and measures of change in adherence to published guidelines for moderate to vigorous physical activity, sleep duration, alcohol, and fruit and vegetable consumption, as well as incidence of cardiometabolic diseases, and indicators of area-level disadvantage and rurality. Puromycin Data was analysed in 2020. Higher dementia risks (albeit with imprecision) were found among participants who were underweight (Incidence Hazard Ratio (IHR) 1.30, 95%CI=0.86-1.86) and lower risks among those who were overweight (IHR=0.78, 95%CI=0.70-0.86) or obese (IHR=0.72, 95%CI=0.62-0.83) compared with ‘normal’ BMI. A ≥0.8 kg/m2 reduction in BMI associated with IHR=1.81 (95%CI=1.64-2.01) higher dementia risk relative to those with stable BMI. Higher dementia risk with decreasing BMI was fairly consistent relative to baseline BMI category. Adherence to physical activity and sleep duration guidelines were associated with reduced dementia risk, but neither these, nor adjustment for other behaviours and local factors, explained the BMI-dementia association. In conclusion, we replicated the BMI-dementia findings from a recent meta-analysis and provide further support to preventive strategies focussed on increasing physical activity and improving sleep duration. Other potential environmental risk factors outside of socioeconomic and urban/rural circumstances warrant investigation.Metal-organic frameworks (MOFs) have shown promising properties for removal of chemical warfare agents, in particular for material decontamination and functionalized fabrics. The MOF-properties could also be beneficial for skin decontamination, especially when exposed to highly toxic and low volatile nerve agents. In such exposures, efficient decontamination is crucial for adequate medical management. In the present study, seven zirconium-based MOFs were evaluated for their ability to degrade VX and subsequently tested in vitro for decontamination of VX on human dermatomed skin. Of the MOFs evaluated, MOF-808 showed the greatest ability to degrade VX in an alkaline buffer with complete degradation of VX within 5 min. PCN-777, Zr-NDC and NU-1000 displayed degradation half-lives of approximately 10 min. When including MOF-808 in a skin friendly carrier with slightly acidic pH, a decreased agent degradation rate was observed, requiring over 24 h to reach complete degradation. In skin decontamination experiments, MOF-808 enhanced the efficacy compared to the carrier alone, essentially by improved agent absorption. Adding MOF-808 to Reactive Skin Decontamination Lotion (RSDL) did not improve the high effectiveness of RSDL alone. The present study showed that including MOF in skin decontamination lotions could be beneficial. Further studies should include optimizing the particulates and formulations.