https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Index en-au 5 https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Repository/uon:3114 Wed 11 Apr 2018 14:34:07 AEST ]]> https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Repository/uon:18946 + currents could be a key model component requiring improvement to produce the longer-lasting bursting APs. Of the delayed rectifying K⁺ currents family it is of interest that KCNQ and hERG channels have been reported to be gestationally regulated in the uterus. These currents exhibit features similar to the broadly defined uterine I_K1 of the original mathematical model. We thus formulated new quantitative descriptions for several I_KCNQ and I_hERG. Incorporation of these currents into the uterine cell model enabled simulations of the long-lasting bursting APs. Moreover, we used this modified model to simulate the effects of different contributions of I_KCNQ and I_hERG on AP form. Our findings suggest that the alterations in expression of hERG and KCNQ channels can potentially provide a mechanism for fine tuning of AP forms that lends a malleability for changing between plateau-like and long-lasting bursting-type APs as uterine cells prepare for parturition.]]> Wed 11 Apr 2018 09:53:37 AEST ]]> https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Repository/uon:40008 Enterococcus faecalis/faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, and Enterobacte spp.), have become a public health threat worldwide. Development of new antimicrobial classes and the use of drugs in combination are potential strategies to treat MDR ESKAPE pathogen infections and promote optimal antimicrobial stewardship. Here, the in vitro antimicrobial activity of robenidine analog NCL195 alone or in combination with different concentrations of three outer membrane permeabilizers [ethylenediaminetetraacetic acid (EDTA), polymyxin B nonapeptide (PMBN), and polymyxin B (PMB)] was further evaluated against clinical isolates and reference strains of key Gram-negative bacteria. NCL195 alone was bactericidal against Neisseria meningitidis and Neisseria gonorrhoeae (MIC/MBC = 32 μg/mL) and demonstrated synergistic activity against P. aeruginosa, E. coli, K. pneumoniae, and Enterobacter spp. strains in the presence of subinhibitory concentrations of EDTA, PMBN, or PMB. The additive and/or synergistic effects of NCL195 in combination with EDTA, PMBN, or PMB are promising developments for a new chemical class scaffold to treat Gram-negative infections. Tokuyasu cryo ultramicrotomy was used to visualize the effect of NCL195 on bioluminescent S. aureus membrane morphology. Additionally, NCL195’s favorable pharmacokinetic and pharmacodynamic profile was further explored in in vivo safety studies in mice and preliminary efficacy studies against Gram-positive bacteria. Mice administered two doses of NCL195 (50 mg/kg) by the intraperitoneal (IP) route 4 h apart showed no adverse clinical effects and no observable histological effects in major organs. In bioluminescent Streptococcus pneumoniae and S. aureus murine sepsis challenge models, mice that received two 50 mg/kg doses of NCL195 4 or 6 h apart exhibited significantly reduced bacterial loads and longer survival times than untreated mice. However, further medicinal chemistry and pharmaceutical development to improve potency, solubility, and selectivity is required before efficacy testing in Gram-negative infection models.]]> Wed 06 Jul 2022 11:20:52 AEST ]]> https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Repository/uon:20078 Sat 24 Mar 2018 08:00:08 AEDT ]]> https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Repository/uon:4460 Sat 24 Mar 2018 07:18:30 AEDT ]]>