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Function allocation is a core activity of the human–machine systems discipline. Sixty years ago, Paul Fitts marked the outset of function allocation research with an 11-statements list. Since then numerous function allocation methods have been proposed, but strikingly the seminal Fitts list spans the entire history of this domain and continues to be cited today. In this paper, we intend to explain why the Fitts list is such a pervasive factor in function allocation research, despite having received extensive criticism. We invoke philosophy of science, and we show that the Fitts list fulfils six important criteria for appraising scientific theories: plausibility, explanatory adequacy, interpretability, simplicity, descriptive adequacy, and generalisability. Furthermore, we show that the Fitts report identified issues which decades later became known as the ironies of automation. We conclude that the Fitts list is an adequate approximation that captures the most important regularity of automation, and that the Fitts report represents an unprecedented intellectual achievement that has succeeded in its pioneering objective.

Background Navafenterol (AZD8871) is an inhaled long-acting dual-pharmacology muscarinic antagonist/β 2 -adrenoceptor agonist (MABA) in development for the treatment of obstructive airways diseases. The safety, tolerability, pharmacodynamics, and pharmacokinetics of navafenterol were investigated in patients with mild asthma. Methods This was a randomised, single-blind, placebo-controlled, single-ascending-dose study. Patients were randomly assigned to one of two cohorts which evaluated escalating doses of navafenterol (50–2100 μg) in an alternating manner over three treatment periods. The primary pharmacodynamic endpoint was the change from pre-dose baseline in trough forced expiratory volume in 1 s (FEV 1 ) for each treatment period. Results Sixteen patients were randomised; 15 completed treatment. Data from all 16 patients were analysed. The maximum tolerated dose was not identified, and all doses of navafenterol were well tolerated. The most frequently reported treatment-emergent adverse events (TEAEs) were headache ( n  = 10, 62.5%) and nasopharyngitis ( n  = 7, 43.8%). No TEAEs were serious, fatal, or led to discontinuation, and no dose dependency was identified. Navafenterol demonstrated a dose-ordered bronchodilatory response with a rapid onset of action (within 5 min post-dose). Doses ≥200 μg resulted in improvements in trough FEV 1 (mean change from baseline range 0.186–0.463 L) with sustained bronchodilation for 24–36 h. Plasma concentrations increased in a dose-proportional manner, peaking ~ 1 h post-dose, with a derived terminal elimination half-life of 15.96–23.10 h. Conclusions In this study navafenterol was generally well tolerated with a rapid onset of action which was sustained over 36 h. Trial registration ClinicalTrials.gov; No.: NCT02573155

To develop peptide drugs targeting integrin receptors, synthetic peptide ligands endowed with well-defined selective binding motifs are necessary. The snake venom KTS-containing disintegrins, which selectively block collagen α1β1 integrin, were used as lead compounds for the synthesis and structure–activity relationship of a series of linear peptides containing the KTS-pharmacophore and alternating natural amino acids and 3-aminobenzoic acid (MABA). To ensure a better stiffness and metabolic stability, one, two and three MABA residues, were introduced around the KTS pharmacophore motif. Molecular dynamics simulations determined that the solution conformation of MABA peptide 4 is more compact, underwent larger conformational changes until convergence, and spent most of the time in a single cluster. The peptides’ binding affinity has been characterized by an enzyme linked immunosorbent assay in which the most potent peptide 4 inhibited with IC50 of 324 ± 8 µM and 550 ± 45 µM the binding of GST-α1-A domain to collagen IV fragment CB3, and the cell adhesion to collagen IV using α1-overexpressor cells, respectively. Docking studies and MM-GBSA calculations confirmed that peptide 4 binds a smaller region of the integrin near the collagen-binding site and penetrated deeper into the binding site near Trp1. Peptide 4 inhibited tube formation by endothelial cell migration in the Matrigel angiogenesis in vitro assay. Peptide 4 was acutely tolerated by mice, showed stability in human serum, decreased tumor volume and angiogenesis, and significantly increased the survival of mice injected with B16 melanoma cells. These findings propose that MABA-peptide 4 can further serve as an α1β1-integrin antagonist lead compound for further drug optimization in angiogenesis and cancer therapy.

A series of N -arylidene-5-aryl-1,3,4-oxadiazol-2-amines ( 2a-d, 3a-d & 4a-d ) were synthesized with the help of aryl acids, semicarbazide, and aryl benzaldehyde. These synthesized compounds were characterized by elemental analysis, FT-IR, 1 H NMR, and mass spectral data analysis. The title compounds were evaluated as in-vitro antimycobacterial agents against Mycobacterium tuberculosis H37RV via the Microplate Alamar Blue Dye Assay (MABA) method. The in-vitro antimycobacterial result revealed that the most active compounds ( 2c, 2d, 3c, 3d, 4d & 4d ) showed a minimum inhibitory concentration (MIC) value of 6.25 μg/ml when compared with the standard drugs Ciprofloxacin, Pyrazinamide (3.125 μg/ml), and Streptomycin (6.25 μg/ml). Most of the title compounds exhibited MIC values ranging from 6.25 to 12.5 μg/ml. Compound 3a was found to be the least effective compound. Also, the electron-withdrawing group (Cl & NO 2 ) on the phenyl ring was found to be more effective than the electron-releasing groups (OH). All the synthesized compounds encouraged us to continue to progress and improve other novel compounds with effective antimycobacterial potential.

Tuberculosis is one of the leading causes of death across the world. The treatment regimens for tuberculosis are well established, but still the control of the disease faces many challenges such as lengthy treatment protocols, drug resistance and toxicity. In the present work, mycolic acid methyl transferase (MmaA1), a protein involved in the maturation of mycolic acids in the biochemical pathway of the Mycobacterium, was studied for novel drug discovery. The homology model of the MmaA1 protein was built and validated by using computational techniques. The MmaA1 protein has 286 amino acid residues consisting of 10 α-helices and 7 β-sheets. The active site of the MmaA1 protein was identified using CASTp, SiteMap and PatchDock. Virtual screening studies were performed with two small molecule ligand databases: Asinex synergy and Diverse_Elite_Gold_Platinum databases having a total of 43,446 molecules and generated 1,30,814 conformers against the predicted and validated active site of the MmaA1 protein. Binding analysis showed that the residues ASP 19, PHE 22, TRP 30, TYR 32, TRP 74 and ALA 77 of MmaA1 protein have consistent interactions with the ligands. The hit ligands were further filtered by in silico ADME properties to eliminate potentially toxic molecules. Of the top 10 molecules, 3-(2-morpholinoacetamido)-N-(1,4-dihydro-4-oxoquinazolin-6-yl) benzamide was synthesised and screened for in vitro anti-TB activity against Mtb H37Rv using MABA assay. The compound and its intermediates exhibited good in vitro anti-TB activity which can be taken up for future lead optimisation studies. Structure based virtual screening study was performed using a validated homology model against small molecules from two virtual compound libraries. Synthesised the lead compound 3-(2-morpholinoacetamido)-N-(1,4-dihydro-4-oxoquinazolin-6-yl)benzamide obtained from virtual screening. In vitro activity against Mtb H37Rv has given a promising result.

A series of 1-(2-amino-2,4,5,6,7,7a-hexahydrobenzo[ b ]-3-yl)-3-substitued-phenylpropane-1,3-dionederivatives were synthesized using the Gewald synthesis in first step which is followed by Baker−Venkataraman rearrangement to yield title compounds. The FTIR, MS and 1H NMR results of the produced derivatives were validated. The biological potential such as antimicrobial, antioxidant and antimycobacterial activity against a particularly virulent strain of MTB (MTB H37Ra) of the synthesized compounds were examined. Antimicrobial screening outcomes showed that compound S 17 turned to be the most effective antibacterial agent against Gram positive bacteria such as Staphylococcus aureus (MIC = 16.87 µM) and Bacillus subtilis (MIC = 9.45 µM) and Gram negative bacteria such as Escherichia coli (MIC = 16.87 µM) and compound S 7 against Salmonella typhi (MIC = 9.74 µM) and compound S 16 displayed remarkable antifungal activity toward each Candida albicans and Aspergillus niger (MIC = 15.23 µM). The standard drugs, cefadroxil (antibacterial), have MIC value against S. aureus, B. subtilis, E. coli and S. Typhi are 16.40 µM, 32.80 µM, 16.40 µM and 16.40 µM, respectively, and fluconazole (antifungal) has MIC value 20.40 µM against both the C. albicans and A.niger strain. In comparison with ascorbic acid, a standard drug (IC 50 44.91 µg/mL), compound S 10 demonstrated good antioxidant activity, with an IC 50 value of 45.29 µg/mL, according to the results of the antioxidant screening. The results of the in vitro antituberculosis screening showed that compound S 23 was found to be effective with an MIC value of 78.125 µg/mL. Molecular docking study of an enzymatic active site of “ DprE1-decaprenylphosphoryl-β-D-ribose-2′-epimerase ” shows a comparable binding mode to the native ligand with better docking score which contributes in understanding and development of models for ligand–protein interactions. Compound S 23 showed better docking score of − 8.516 as compared to the Isoniazid with the docking score of − 6.315 which in future will create the fundamental structural framework for MTB inhibition. Graphic abstract

Mycobacterium tuberculosis, the pathogen that causes tuberculosis, is responsible for the death of 1.5 million people each year and the number of bacteria resistant to the standard regimen is constantly increasing. This highlights the need to discover molecules that act on new M. tuberculosis targets. Mycolic acids, which are very long-chain fatty acids essential for M. tuberculosis viability, are synthesized by two types of fatty acid synthase (FAS) systems. MabA (FabG1) is an essential enzyme belonging to the FAS-II cycle. We have recently reported the discovery of anthranilic acids as MabA inhibitors. Here, the structure–activity relationships around the anthranilic acid core, the binding of a fluorinated analog to MabA by NMR experiments, the physico-chemical properties and the antimycobacterial activity of these inhibitors were explored. Further investigation of the mechanism of action in bacterio showed that these compounds affect other targets than MabA in mycobacterial cells and that their antituberculous activity is due to the carboxylic acid moiety which induces intrabacterial acidification.

Purpose First line antiTB drugs have several physical and toxic manifestations which limit their applications. RIF is a hydrophobic drug and has low water solubility and INH is hepatotoxic. The main objective of the study was to synthesize, characterize HPMA-PLA co-polymeric micelles for the effective dual delivery of INH and RIF. Methods HPMA-PLA co-polymer and HPMA-PLA-INH (HPI) conjugates were synthesized and characterized by FT-IR and 1 H–NMR spectroscopy. Later on RIF loaded HPMA-PLA-INH co-polymeric micelles (PMRI) were formulated and characterized for size, zeta potential and surface morphology (SEM, TEM) as well as critical micellar concentration. The safety was assessed through RBC’s interaction study. The prepared PMRI were evaluated through MABA assay against sensitive and resistant strains of M. Tuberculosis . Results Size, zeta and entrapment efficiency for RIF loaded HPMA-PLA-INH polymeric micelles (PMRI) was 87.64 ± 1.98 nm, −19 ± 1.93 mV and 97.2 ± 1.56%, respectively. In vitro release followed controlled and sustained delivery pattern. Sustained release was also supported by release kinetics. Haemolytic toxicity of HPI and PMRI was 8.57 and 7.05% ( p  < 0.01, INH Vs PMRI; p  < 0.0001, RIF Vs PMRI), respectively. MABA assay (cytotoxicity) based MIC values of PMRI formulation was observed as ≥0.0625 and ≥0.50 μg/mL (for sensitive and resistant strain). The microscopic analysis further confirmed that the delivery approach was effective than pure drugs. Conclusions RIF loaded and INH conjugated HPMA-PLA polymeric micelles (PMRI) were more effective against sensitive and resistant M tuberculosis . The developed approach can lead to improved patient compliance and reduced dosing in future, offering improved treatment of tuberculosis.

The persistent challenge posed by antibiotic-resistant bacteria and tuberculosis necessitates innovative approaches to antimicrobial treatment. This study explores the synthesis and characterization of NiZrO₃ nanoparticles integrated with graphene nanoplatelets (GNP) and multi-walled carbon nanotubes (MWCNT), using a microwave-assisted green synthesis route, employing fenugreek ( Trigonella foenum-graecum ) seed extract as a gelling agent. The synthesised nanocomposites were systematically analyzed using XRD, FT-IR, Raman spectroscopy, HR-SEM and HR TEM analysis to assess structural, optical, and morphological properties. The antimicrobial and antibiofilm efficacy was evaluated against drug-resistant strains, including Escherichia coli and Klebsiella pneumoniae , by well diffusion method and crystal violet—Microtitre plate (CV-MtP) method. Notably, the NiZrO₃@MWCNT composite exhibited a maximum antibacterial inhibition zone of 13 mm and showed superior biofilm inhibition of 92.8% against K. pneumoniae at 500 ppm. In contrast, NiZrO₃@GNP demonstrated a biofilm inhibition of 97% at 500 ppm. Furthermore, the microplate Alamar Blue assay (MABA) was employed to determine the minimum inhibitory concentration (MIC) against Mycobacterium smegmatis (MTS) with NiZrO₃@MWCNT achieving 96% inhibition and at 500 ppm. These results confirm the enhanced antimicrobial efficacy of the carbon-integrated nanocomposites over pure NiZrO₃, which showed limited activity. This research underscores the promise of NiZrO₃-based nanocomposites as advanced antimicrobial agents, offering a novel strategy to combat the global health threat of antibiotic resistance.

Background Navafenterol (AZD8871) is a dual-pharmacology muscarinic antagonist β 2− agonist (MABA) molecule in development for the treatment of chronic obstructive pulmonary disease (COPD). The pharmacodynamics, safety and tolerability of single doses of navafenterol were investigated in patients with moderate to severe COPD. Methods This was a randomized, five-way complete cross-over study. Patients received single doses of navafenterol 400 μg, navafenterol 1800 μg and placebo (all double-blind) and indacaterol 150 μg and tiotropium 18 μg (both open-label active comparators). The primary pharmacodynamic endpoint was change from baseline in trough forced expiratory volume in 1 s (FEV 1 ) on day 2. Safety and tolerability were monitored throughout. Results Thirty-eight patients were randomized and 28 (73.7%) completed the study. Navafenterol 400 μg and 1800 μg demonstrated statistically significant improvements vs placebo in change from baseline in trough FEV 1 (least squares mean [95% confidence interval]: 0.111 [0.059, 0.163] L and 0.210 [0.156, 0.264] L, respectively, both P  < .0001). The changes were significantly greater with navafenterol 1800 μg vs the active comparators (least squares mean treatment difference: 0.065–0.069 L, both P  < .05). The frequency of treatment-emergent adverse events was similar for placebo and the active comparators (range 34.4–37.5%), slightly higher for navafenterol 400 μg (52.9%), and lowest for navafenterol 1800 μg (22.6%). Conclusions Both doses of navafenterol demonstrated sustained bronchodilation over 24 h. Navafenterol was well tolerated and no safety concerns were raised. Trial registry ClinicalTrials.gov ; No.: NCT02573155 ; URL: www.clinicaltrials.gov . Registered 9th October, 2015.