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Background: Evidence-based physical employment standards are vital for recruiting, training and maintaining the operational effectiveness of personnel in physically demanding occupations. Aims: (i) Develop criterion tests for in-service physical assessment, which simulate the role-related physical demands of UK fire and rescue service (UK FRS) personnel. (ii) Develop practical physical selection tests for FRS applicants. (iii) Evaluate the validity of the selection tests to predict criterion test performance. Methods: Stage 1: we conducted a physical demands analysis involving seven workshops and an expert panel to document the key physical tasks required of UK FRS personnel and to develop 'criterion' and 'selection' tests. Stage 2: we measured the performance of 137 trainee and 50 trained UK FRS personnel on selection, criterion and 'field' measures of aerobic power, strength and body size. Statistical models were developed to predict criterion test performance. Stage 3: matter experts derived minimum performance standards. Results: We developed single person simulations of the key physical tasks required of UK FRS personnel as criterion and selection tests (rural fire, domestic fire, ladder lift, ladder extension, ladder climb, pump assembly, enclosed space search). Selection tests were marginally stronger predictors of criterion test performance (r = 0.88-0.94, 95% Limits of Agreement [LoA] 7.6-14.0%) than field test scores (r = 0.84-0.94, 95% LoA 8.0-19.8%) and offered greater face and content validity and more practical implementation. Conclusions: This study outlines the development of role-related, gender-free physical employment tests for the UK FRS, which conform to equal opportunities law. [ABSTRACT FROM AUTHOR]

A series of 19 novel α-aminophosphonate-tetrahydroisoquinoline hybrids were synthesized through a cross dehydrogenative coupling reaction between N-aryl-tetrahydroisoquinolines and dialkylphosphites, using tert-butyl hydroperoxide as oxidazing agent. This simple procedure provided products with high atom economy and moderate to high yields. In vitro cholinesterase inhibitory activity of these compounds was evaluated. All the synthesized compounds showed good to excellent selective inhibition against butyrylcholinesterase. Compound 3bc was found to be the most active derivative with an IC 50  of 9 nM. Molecular modelling studies suggested that the inhibitor is located in the peripheral anionic site (PAS) of the enzyme and interacts with some residue of the catalytic anionic site. Kinetic studies revealed that 3bc acts as a non-competitive inhibitor. Predicted ADME showed good pharmacokinetics and drug-likeness properties for most hybrids. Each newly synthesized compound was characterized by IR, 1 H NMR, 13 C NMR, 31 P NMR spectral studies and also HRMS. The results of this study suggest that α-aminophosphonate-tetrahydroisoquinoline hybrids can be promising lead compounds in the discovery of new and improved drugs for the treatment of Alzheimer's disease and related neurodegenerative disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that has no cure because its etiology is still unknown, and its main treatment is the administration of acetylcholinesterase (AChE) inhibitors. The study of the mechanism of action of this family of compounds is critical for the design of new more potent and specific inhibitors. In this work, we study the molecular basis of an uncompetitive inhibitor (compound 1 , 2β, 3α-dihydroxy-5α-cholestan-6-one disulfate), which we have proved to be a peripheral anionic site (PAS)-binding AChE inhibitor. The pipeline designed in this work is key to the development of other PAS inhibitors that not only inhibit the esterase action of the enzyme but could also modulate the non-cholinergic functions of AChE linked to the process of amylogenesis. Our studies showed that 1 inhibits the enzyme not simply by blocking the main gate but by an allosteric mechanism. A detailed and careful analysis of the ligand binding position and the protein dynamics, particularly regarding their secondary gates and active site, was necessary to conclude this. The same analysis was executed with an inactive analogue (compound 2 , 2β, 3α-dihydroxy-5α-cholestan-6-one). Our first computational results showed no differences in affinity to AChE between both steroids, making further analysis necessary. This work highlights the variables to be considered and develops a refined methodology, for the successful design of new potent dual-action drugs for AD, particularly PAS inhibitors, an attractive strategy to combat AD., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Background: Currently approved Alzheimer's disease medications mainly comprise acetylcholinesterase inhibitors. Many of these inhibitors are either natural compounds or synthetic molecules inspired in natural compounds. Hybrid molecules that can interact with different target sites of the enzyme could lead to the discovery of effective multitarget drugs., Objective: To design, synthesize, and evaluate a series of new aza-resveratrol analogs as in vitro acetyl- and butyrylcholinesterase inhibitors., Methods: The synthesis is achieved by a simple and efficient microwave-assisted method, from commercially available starting materials. Compounds are designed as hybrids of an aza-stilbene nucleus (Schiff base) connected to a tertiary amine by a hydrocarbon chain of variable length, designed to interact both with the peripheric anionic site and the catalytic site of the enzyme., Results: All the derivatives inhibit both enzymes in a concentration-dependent manner, acting as moderate to potent cholinesterase inhibitors. The most potent inhibitors are compounds 12b (IC 50 = 0.43 μM) and 12a (IC 50 = 0.31 μM) for acetyl- and butyrylcholinesterase, respectively. Compounds 12a and 12b also exhibit significant acetylcholinesterase inhibition in SH-SY5Y human neuroblastoma cells without cytotoxic properties. Enzyme kinetic studies and molecular modeling reveal that inhibitor 12b targets both the catalytic active site and the peripheral anionic site of acetylcholinesterase what makes it able to modulate the self-induced β-amyloid aggregation. Furthermore, the molecular modeling analysis helps to assess the impact of the linker length in the inhibitory activity of this family of new cholinesterase inhibitors., Conclusion: These compounds have the potential to serve as a dual binding site inhibitor and might provide a useful template for the development of new anti-Alzheimer's disease agents., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Ionic-transport processes govern performance in many classic and emerging devices, ranging from battery storage to modern mixed-conduction organic electrochemical transistors (OECT). Here, we study local ion-transport dynamics in polymer films using time-resolved electrostatic force microscopy (trEFM). We establish a correspondence between local and macroscopic measurements using local trEFM and macroscopic electrical impedance spectroscopy (EIS). We use polymer films doped with lithium bis(trifluoromethane)sulfonimide (LiTFSI) as a model system where the polymer backbone has oxanorbornenedicarboximide repeat units with an oligomeric ethylene oxide side chain of length n. Our results show that the local polymer response measured in the time domain with trEFM follows stretched-exponential relaxation kinetics, consistent with the Havriliak-Negami relaxation we measure in the frequency-domain EIS data for macroscopic samples of the same polymers. Furthermore, we show that the trEFM results capture the same trends as the EIS results-changes in ion dynamics with increasing temperature, increasing salt concentration, and increasing volume fraction of ethylene oxide side chains in the polymer matrix evolve with the same trends in both measurement techniques. We conclude from this correlation that trEFM data reflect, at the nanoscale, the same ionic processes probed in conventional EIS at the device level. Finally, as an example application for emerging materials syntheses, we use trEFM and infrared photoinduced force microscopy (PiFM) to image a diblock copolymer electrolyte for next-generation solid-state energy storage applications.

A set of triterpenoids with different grades of oxidation in the lupane skeleton were prepared and evaluated as cholinesterase inhibitors. Allylic oxidation with selenium oxide and Jones's oxidation were employed to obtain mono-, di- and tri-oxolupanes, starting from calenduladiol (1) and lupeol (3). All the derivatives showed a selective inhibition of butyrylcholinesterase over acetylcholinesterase (BChE vs. AChE). A kinetic study proved that compounds 2 and 9, the more potent inhibitors of the series, act as competitive inhibitors. Molecular modeling was used to understand their interaction with BChE, the role of carbonyl at C-16 and the selectivity towards this enzyme over AChE. These results indicate that oxidation at C-16 of the lupane skeleton is a key transformation in order to improve the cholinesterase inhibition of these compounds., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Over the last decades, much effort has been devoted to the design of the "ideal" library for screening, the most promising strategies being those which draw inspiration from biogenic compounds, as the aim is to add biological relevance to such libraries. On the other hand, there is a growing understanding of the role that molecular complexity plays in the discovery of new bioactive small molecules. Nevertheless, the introduction of molecular complexity must be balanced with synthetic accessibility. In this work, we show that both concepts can be efficiently merged-in a minimalist way-by using very simple guidelines during the design process along with the application of multicomponent reactions as key steps in the synthetic process. Natural phenanthrenoids, a class of plant aromatic metabolites, served as inspiration for the synthesis of a library in which complexity-enhancing features were introduced in few steps using multicomponent reactions. These resulting chemical entities were not only more complex than the parent natural products, but also interrogated an alternative region of the chemical space, which led to an outstanding hit rate in an antiproliferative assay: four out of twenty-six compounds showed in vitro activity, one of them being more potent than the clinically useful drug 5-fluorouracil., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Telestroke uses videoconferencing technology to allow off-site experts to provide stroke thrombolysis decision support to less experienced front line clinicians., Aim: To assess the impact of a new telestroke service on thrombolysis rates and door-to-needle times in participating provincial hospitals and service resources to aid transition to a sustainable telestroke service., Methods: This is a sequential comparison of 'pre' (December 2015 to May 2016) and 'post' (June 2016 to December 2016) implementation outcomes. The main outcomes were thrombolysis rate and door-to-needle time. All patient data were captured prospectively in a central database. Data captured and analysed also included technical problems, consumer and clinician feedback, and additional service resources required., Results: Over the study period, 164 telestroke assessments were completed, including the 'hub' hospital. Among the participating provincial hospitals, 21 of 343 patients (6.1%) were thrombolysed in the 6-months prior to June 2016 and 50 of 318 patients (15.7%) during the 6-month following implementation of telestroke; odds ratio 2.86 (95% confidence interval 1.68-4.89); P = 0.0001. Overall, mean (standard deviation) regional hospital door-to-needle time reduced from 79.6 (31.4) to 62.7 (23.3) min (P = 0.015). Videoconferencing failure occurred in 4.8% of cases. Consumer and clinician feedback was positive. The main resource challenge was doubling of out-of-hours neurologist workload., Conclusion: Telestroke was associated with a significant increase in thrombolysis rate and reduction in door-to-needle time in provincial hospitals indicating improved patient care. Quantification of the extra neurologist workload allowed for a seamless transition to 'business as usual' using a novel annual subscription funding and service model., (© 2017 Royal Australasian College of Physicians.)

Twelve polyhydroxylated sulfated steroids synthesized from a 5α-cholestane skeleton with different substitutions in C-2, C-3 and C-6 were evaluated for cytotoxicity and antiviral activity against herpes simplex virus (HSV) by a virus plaque reduction assay. Four compounds elicited a selective inhibitory effect against HSV. The disodium salt of 2β,3α-dihydroxy-6E-hydroximine-5α-cholestane-2,3-disulfate, named compound 7, was the most effective inhibitor of HSV-1, HSV-2 and pseudorabies virus (PrV) strains, including acyclovir-resistant variants, in human and monkey cell lines. Preliminary mechanistic studies demonstrated that compound 7 did not affect the initial steps of virus entry but inhibited a subsequent event in the infection process of HSV.

Tumor necrosis factor (TNF, TNF-α, cachectin) is a pleiotropic, proinflammatory cytokine with multiple biological effects, many of which are not yet fully understood. Although TNF was initially described as an anti-tumor agent more than three decades ago, current knowledge places it central to immune system homeostasis. TNF plays a critical role in host defense against infection, as well as an inhibitory role in autoimmune disease. However, TNF overproduction generates deleterious effects by inducing the transcription of genes involved in acute and chronic inflammatory responses including asthma, rheumatoid arthritis, Crohn's disease, and psoriasis. Direct inhibition of TNF by biologics, such as monoclonal antibodies and circulating TNF receptor constructs, has produced effective treatments for these disorders and validated the inhibition of this proinflammatory cytokine as an effective therapy. Unfortunately, these biological therapies suffer from several drawbacks, including high cost and the induction of autoantibody production. Thus, the development of small molecules able to modulate TNF production or signaling pathways remains a central challenge in Medicinal Chemistry. Considerable efforts have been made over the past two decades to develop such inhibitors, which could potentially be administered orally and would presumably be cheaper. This review is focused on the recent development of compounds that modulate the activity of this cytokine by acting at different levels, such as TNF expression, processing, binding to its receptors and direct inhibition. These approaches will be compared and discussed.

Alzheimer's disease (AD) is a neurodegenerative disorder associated with memory impairment and cognitive deficit. Most of the drugs currently available for the treatment of AD are acetylcholinesterase (AChE) inhibitors. In a preliminary study, significant AChE inhibition was observed for the ethanolic extract of Grindelia ventanensis (IC₅₀=0.79 mg/mL). This result prompted us to isolate the active constituent, a normal labdane diterpenoid identified as 17-hydroxycativic acid (1), through a bioassay guided fractionation. Taking into account that 1 showed moderate inhibition of AChE (IC₅₀=21.1 μM), selectivity over butyrylcholinesterase (BChE) (IC₅₀=171.1 μM) and that it was easily obtained from the plant extract in a very good yield (0.15% w/w), we decided to prepare semisynthetic derivatives of this natural diterpenoid through simple structural modifications. A set of twenty new cativic acid derivatives (3-6) was prepared from 1 through transformations on the carboxylic group at C-15, introducing a C2-C6 linker and a tertiary amine group. They were tested for their inhibitory activity against AChE and BChE and some structure-activity relationships were outlined. The most active derivative was compound 3c, with an IC₅₀ value of 3.2 μM for AChE. Enzyme kinetic studies and docking modeling revealed that this inhibitor targeted both the catalytic active site and the peripheral anionic site of this enzyme. Furthermore, 3c showed significant inhibition of AChE activity in SH-SY5Y human neuroblastoma cells, and was non-cytotoxic., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

A set of twenty one lupane derivatives (2-22) was prepared from the natural triterpenoid calenduladiol (1) by transformations on the hydroxyl groups at C-3 and C-16, and also on the isopropenyl moiety. The derivatives were tested for their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) and some structure-activity relationships were outlined with the aid of enzyme kinetic studies and docking modelization. The most active compound resulted to be 3,16,30-trioxolup-20(29)-ene (22), with an IC50 value of 21.5μM for butyrylcholinesterase, which revealed a selective inhibitor profile towards this enzyme., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Four new 6E-hydroximinosteroids (1, 2a, 3 and 4) have been synthesized from the corresponding ketones, 2β,3β-dihydroxy-5α-cholestan-6-one (5), 2α,3α-dihydroxy-5α-cholestan-6-one (6), 2β,3α-dihydroxy-5α-cholestan-6-one (7) and 2β,3α-dihydroxy-5α-cholestan-6-one-disulfate (8). The cytotoxic activity of the steroidal oximes was evaluated against two prostate carcinoma cell lines (PC-3 and LNCaP) and compared with that of five polyhydroxylated sulfated analogs (8-12). Oxime 3 and trisulfated analog 11 were the most active compounds with IC50 values of 10.8μM (PC-3) and 7.9μM (LNCaP), respectively., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Disulfated and trisulfated steroids have been synthesized from cholesterol and their acetylcholinesterase inhibitory activity has been evaluated. In our studies we have found that the activity was not only dependent on the location of the sulfate groups but on their configurations. 2β,3α,6α-trihydroxy-5α-cholestan-6-one trisulfate (18) was the most active steroid with an IC50 value of 15.48 μM comparable to that of 2β,3α-dihydroxy-5α-cholestan-6-one disulfate (1). Both compounds were found to be less active than the reference compound eserine. The butyrylcholinesterase activity of 1 and 18 was one magnitude lower than that against acetylcholinesterase revealing a selective inhibitor profile., (Copyright © 2013 Elsevier Inc. All rights reserved.)

This study developed a multivariate model to predict free-living energy expenditure (EE) in independent military cohorts. Two hundred and eighty-eight individuals (20.6 ± 3.9 years, 67.9 ± 12.0 kg, 1.71 ± 0.10 m) from 10 cohorts wore accelerometers during observation periods of 7 or 10 days. Accelerometer counts (PAC) were recorded at 1-minute epochs. Total energy expenditure (TEE) and physical activity energy expenditure (PAEE) were derived using the doubly labelled water technique. Data were reduced to n = 155 based on wear-time. Associations between PAC and EE were assessed using allometric modelling. Models were derived using multiple log-linear regression analysis and gender differences assessed using analysis of covariance. In all models PAC, height and body mass were related to TEE (P < 0.01). For models predicting TEE (r (2) = 0.65, SE = 462 kcal · d(-1) (13.0%)), PAC explained 4% of the variance. For models predicting PAEE (r (2) = 0.41, SE = 490 kcal · d(-1) (32.0%)), PAC accounted for 6% of the variance. Accelerometry increases the accuracy of EE estimation in military populations. However, the unique nature of military life means accurate prediction of individual free-living EE is highly dependent on anthropometric measurements.

Disodium 2β,3α-dihydroxy-5α-cholestan-6-one disulfate (8) has been synthesized using cholesterol (1) as starting material. Sulfation was performed using trimethylamine-sulfur trioxide complex in dimethylformamide as the sulfating agent. The acetylcholinesterase inhibitory activity of compound 8 was evaluated and compared to that of disodium 2β,3α-dihydroxy-5α-cholestane disulfate (10) and diols 7 and 9. Compounds 8 and 10 were active with IC(50) values of 14.59 and 59.65 μM, respectively. Diols 7 and 9 showed no inhibitory activity (IC(50)>500 μM)., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Dietary copper deficiency is known to affect metabolism of neutral lipids, phospholipids, prostaglandins, Cu-Zn superoxide dismutase and crosslinks of connective tissues. To investigate the effects of copper deficiency on lung ultrastructure, dietary copper deficiency was induced by feeding female guinea-pigs a diet marginally deficient in copper (0.8 microgram Cu/g diet) and compared with those fed a diet sufficient in copper (5.8 micrograms Cu/g diet). After 10 months on the diets, at age 340 days, animals were killed and the lungs removed and processed for electron microscopy to study the changes in cellular morphology. Type II epithelial cells in lung alveoli of copper deficient guinea-pigs, revealed larger lamellar bodies, in comparison with lungs of copper supplemented guinea-pigs (2.1 +/- 0.67 vs 1.35 +/- 0.47 microns). Fusion of lamellar bodies had occurred. Lipid droplets were found in the cytoplasm, which, in 20% of these cells, was as a single large lipid droplet approximately 10 microns in diameter. Features of the bronchiolar Clara cells in response to copper deficiency included the formation of packed tubular structures, 50 nm diameter. These tubules resembled smooth endoplasmic reticulums, and occupied 35.6% of the cell profiles by stereologic analysis. Clara cells from copper deficient guinea-pigs also contained many uniform, hexagonal crystal structures, in greater concentration than reported previously. Residual macrophages and monocytes observed in the capillaries contained giant lipid inclusions, which were stained by Sudan Black, indicative of neutral lipids. In this study, we suggest that perturbations in protein, lipid and membrane metabolism resulting from dietary copper deficiency in the guinea-pig may have altered the synthesis or degradation of lipid and protein components of lung cells or prevented their normal secretion into the airways or extracellular spaces.

Dietary copper-deficient guinea pig dams (0.8 microgram Cu/g diet) were administered oxytocin to induce delivery of pups, whereas dietary copper-sufficient guinea pig dams (5.8 micrograms Cu/g diet) had uneventful deliveries with 79% surviving pups. The copper-deficient dams carried the fully-formed fetuses to term but did not go into labor unless 0.5 to 6.2 U oxytocin was administered (i.m.). Birth of live pups from copper-deficient dams increased from 28% overall, to 50% if oxytocin was administered in a timely manner. Many pups died of internal hemorrhages probably the result of defective connective tissue crosslinks requiring copper as a co-factor for lysyl oxidase activity. Dietary copper deficiency may be a factor in depressed parturition in the copper-deficient guinea pig dam that responds to administration of exogenous oxytocin for delivery of pups.