The two major brain nicotinic acetylcholine receptors (nAChRs) involved in cognitive function are the α4β2 and α7 nAChRs. A “methyl scan” of the pyrrolidinyl ring was used to detect differences in the interactions of nicotine with these two receptors. Each methylnicotine was investigated using voltage-clamp and radioligand binding techniques. Methylation at each ring carbon elicited unique changes in nicotine’s receptor interactions. Replacing the 1′-N methyl with an ethyl group or adding a second 1′-N methyl group significantly reduced interaction with α4β2 but not α7 receptors. 2′-methylation uniquely enhanced binding and agonist potency at α7 receptors. Although 3’and 5’trans-methylations were much better tolerated by α7 receptors than α4β2 receptors, both 4′ methylations decreased potency and efficacy at α7 receptors much more than at α4β2 receptors. Cis-5′-methylnicotine lacked agonist activity and displayed a low affinity at both receptors, but trans-5’methylnicotine retained considerable α7 receptor acial sites for nicotine structure modification have been identified that may be useful in the design of new drugs targeting these receptors. .Drug discovery programs routinely perform pharmacokinetic (PK) studies in mouse to prioritize lead compounds based on anticipated exposure-efficacy and exposure-toxicity relationships. Due to logistical and/or technical issues, the strain of mouse in early discovery PK studies may not always match the strain in toxicity or efficacy studies. This elicits the question do appreciable strain-dependent differences in PK parameters exist to an extent that would warrant conducting PK studies in a strain that matches efficacy and toxicity models? To understand the impact that strain may have on PK parameters, we selected 8 marketed drugs with well characterized absorption, distribution, metabolism, and excretion properties and diverse structures to perform PK studies in three common mouse strains (BALB/c, C57BL/6, and CD-1). Some statistical strain-dependent differences were observed, however, we found good general agreeance of PK between strains 88%, 100%, 75%, and 88% of compounds were within two-fold across strains for Cl, Vss, t1/2, and F, respectively. Overall, we recommend that an approach using a single strain of mouse is appropriate for discovery screening PK studies, provided that proper caution is exercised. SIGNIFICANCE STATEMENT Pharmaceutical research programs routinely execute mouse PK studies to characterize PK properties of compounds as a filtering criterion to advance candidates through the pipeline as well as to support efficacy and toxicology studies. The mouse strain in discovery PK studies may not match the strain in efficacy and tox studies. Currently, there is gap in the literature addressing if differences in PK parameters across mouse strains exist such that multiple PK studies are warranted. The results from this study indicated that the PK properties of clinically used drugs between mouse strains are within an acceptable range such that single strain PK is appropriate.Human liver microsomes (HLM) are a commonly used tool to study drug metabolism in vitro. Typical experiments conducted using suspensions of HLM can be challenging to separate from the incubation solution without lengthy ultracentrifugation steps. Magnetizable beads coated with silica (MGBS) were found to bind strongly to HLM, which could then be isolated and purified using a magnet. Binding of HLM to the MGBS (HLM-MGBS) was demonstrated to be mediated by strong interactions between microsomal phospholipids and MGBS, as artificially prepared phosphatidylcholine (PC) liposomes, could be more efficiently captured by the MGBS. HLM-MGBS complexes retained functional cytochrome P450 (CYP) and uridine-diphosphate-glucuronosyltransferase (UGT) activity as indicated by CYP2C8-mediated amodiaquine deethylation, CYP3A4-mediated midazolam 1’hydroxylation, UGT1A1-mediated glucuronidation of estradiol, UGT1A9-mediated glucuronidation of propofol, and UGT2B7-mediated glucuronidation of zidovudine. (AZT) When comparing suspension HLM alone with HLM-MGBS complexes containing equivalent amounts of HLM, the intrinsic clearance (CLint) of CYP450 substrates was comparable; however, CLint of UGT1A1, UGT1A9 and UGT2B7 was increased in the HLM-MGBS system between 1.5- to 6-fold. HLM-MGBS used in an incubation could also be readily replaced with fresh HLM-MGBS to maintain the presence of active enzymes. Thus, HLM-MGBS demonstrate increased in vitro metabolic efficiency and manipulability, providing a new platform for determination of accurate metabolic parameters. SIGNIFICANCE STATEMENT The following work describes the strong binding of HLM to magnetizable beads. this website In addition, the preservation of enzyme activity on the bound HLM provide a novel means to conduct preclinical metabolism studies.Introduction Epidemiological data captured from military exercises and operations can highlight treatment requirements specific to operating in certain environmental conditions. Such data is invaluable to enable accurate planning for future exercises. Epidemiological data were collected during Exercise SAIF SAREEA 3 (SS3) to provide an insight into medical provision requirements for low-tempo military operations in hot, desert climates. Method Epidemiological data was collected from all consultations conducted during the exercise within the LAND Medical Reception Station, 24 August-14 November 2018, using Epi-NATO surveillance systems. Results Of the 1414 total consultations recorded, 759 were first presentations and 665 were follow-up consultations, with 35 referrals made to hospitals. 1348 days of limited duties were given and 258 working days were lost. The most common coding reported for consultations were ‘non-battle non-sport related injuries’, ‘sport related injuries’ and ‘dermatological’. DISCUSSION The data highlight the most common cause of injuries and the role of assets such as dental, sexual and mental health services for future deployments. A number of explanations are considered in relation to the patterns identified and the effect on future planning for working in hot climates. Furthermore, Exercise SS3 had reduced numbers of personnel requiring deployed Role 2 or host nation hospital services, which again raises further considerations for future deployments.