Assessment of restrained shrinkage cracking of concrete through elliptical rings

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.An elliptical ring test method is presented to replace the circular ring test method for assessing cracking potential of concrete and other cement-based materials under restrained condition. The latter is recommended by both ASTM (American Society of Testing Materials (C1581/C 1581M-09a) and AASHTO (American Association of State Highway and Transportation Officials (PP34–39, 2004) as a standard test method for such purpose. However, there is no research published so far on comparing circular and elliptical ring test for assessing the relative likelihood of cracking of concrete and other cement-based materials as proposed in this study. Besides, ASTM proposes to use thin concrete rings with the wall thickness of 1.5 inches while AASHTO to use thick concrete rings with the wall thickness of 3 inches. The implication of these two ring wall thicknesses has not been well studied. The elliptical ring geometry employed here was used to facilitate unique ways of analysing cracking sensitivity of concrete. In line with this, the test program and numerical model developed was focused on investigating the mechanism of the elliptical ring test, irrespective of the concrete materials used which is also novel in this research as efforts towards this assessment are still yet to be published. The new experimental method investigated the use of elliptical rings for assessing the potential of concrete cracking under restrained condition to enable a faster and more reliable assessment of cracking tendency of concrete and other cement-based materials. A series of thin and thick elliptical concrete rings were tested alongside circular ones until cracking. Cracking age, position and propagation in various rings were carefully examined. It was found that thin elliptical rings with appropriate geometry can initiate crack quicker than circular ones which is desirable for accelerating the ring test. There were multiple visible cracks that occurred in elliptical rings and some cracks initiated but did not propagate through the ring wall, an interesting finding reported as the first time by this study. The features of multiple cracks in restrained elliptical rings were examined and their impact on interpreting elliptical ring test results was discussed. In addition, in restrained thin concrete rings, cracks initiated at their inner circumference and propagated towards their outer one while cracks initiated at the outer circumference and propagated towards their inner one for thick rings. To explore the mechanism of this new test method, a numerical model was developed to simulate stress development and crack initiation in concrete ring specimens under restrained shrinkage in which the effect of concrete shrinkage was simulated by an artificial temperature field externally applied on concrete causing the same strain as shrinkage does. A uniform artificial temperature field across the concrete ring wall generated good results and works well for simulating shrinkage cracking of thin concrete rings while an artificial temperature field with linear gradient across the concrete ring wall should be employed in order to predict cracking behaviour of thick concrete rings under restrained shrinkage reasonably well. Stress developed in concrete rings in the restrained shrinkage test was thus obtained through a combined thermal and structural analysis. Based on the maximum tensile stress cracking criterion, cracking age and position of a series of circular and elliptical, thin and thick rings were obtained from numerical analyses. It was found that numerical results match the experimental results in terms of initial cracking ages and position for a number of circular and elliptical concrete rings subject to restrained shrinkage. The effects of ring geometry on cracking in concrete were equally investigated by comparing the behaviour of the elliptical and the circular rings under restrained shrinkage. Both experimental and numerical results indicated that the ratio between the major and the minor semi-axes of an elliptical ring emerges as the main factor which affects the maximum circumferential tensile stress in concrete when subjected to restrained shrinkage. Thin elliptical rings with appropriate geometry can enable crack initiating earlier than circular rings, which is able to accelerate the ring test for assessing the potential of cracking of concrete mixtures. On the other hand, thick elliptical concrete rings do not to possess a favourable geometry effect over circular ones in accelerating ring test due to a relatively weaker restraining effect provided by the central steel ring. The results on crack position and stress development in concrete rings based on numerical analysis were examined to further explore the mechanism of the proposed elliptical ring test for assessing cracking potential of concrete. It was also found that the drying direction of the concrete ring has a substantial influence on the cracking age when thin concrete rings are considered.EPSRC U

Recent advances in functionalized quinoline scaffolds and hybrids—Exceptional pharmacophore in therapeutic medicine

Quinoline is one of the most common nitrogen-containing heterocycles owing to its fascinating pharmacological properties and synthetic value in organic and pharmaceutical chemistry. Functionalization of this moiety at different positions has allowed for varying pharmacological activities of its derivative. Several publications over the last few decades have specified various methods of synthesis. This includes classical methods of synthesizing the primary quinoline derivatives and efficient methods that reduce reaction time with increased yield employing procedures that fulfill one of the twelve green chemistry principles, “safer solvent”. The metal nanoparticle-catalyzed reaction also serves as a potent and effective technique for the synthesis of quinoline with excellent atom efficiency. The primary focus of this review is to highlight the routes to synthesizing functionalized quinoline derivatives, including hybrids that have moieties with predetermined activities bound to the quinoline moiety which are of interest in synthesizing drug candidates with dual modes of action, overcoming toxicity, and resistance amongst others. This was achieved using updated literature, stating the biological activities and mechanisms through which these compounds administer relief. The ADMET studies and Structure-Activity Relationship (SAR) of novel derivatives were also highlighted to explore the drug-likeness of the quinoline-hybrids and the influence of substituent characteristics and position on the biological activity of the compounds

In silico studies of benzothiazole derivatives as potential inhibitors of Anopheles funestus and Anopheles gambiae trehalase

IntroductionIn malaria management, insecticides play a crucial role in targeting disease vectors. Benzothiazole derivatives have also been reported to possess insecticidal properties, among several other properties they exhibit. The female Anopheles mosquito is responsible for transmitting the malaria parasite when infected. Anopheles gambiae (Ag) and Anopheles funestus (Af) are two of the most notable Anopheles species known to spread malaria in Nigeria. Trehalase is an enzyme that breaks down trehalose. Recent research has proposed it as a viable target for inhibition since it aids in flight and stress adaptation.MethodsThis study aimed to investigate benzothiazole derivatives as potential inhibitors of trehalase of Anopheles funestus (AfTre) and Anopheles gambiae (AgTre) using toxicity profiling, molecular docking, and dynamic simulation for future insecticidal intervention. A total of 4,214 benzothiazole-based compounds were obtained from the PubChem database and subjected to screening against the 3D modelled structure of AfTre and AgTre. Compounds with some toxicity levels were optimised, and the obtained lead compounds were further investigated through molecular docking studies. Furthermore, the best hit was subjected to parameters such as RMSD, RMSF, SASA, Rg, and hydrogen bond to confirm its stability when in a complex with AfTre, and these parameters were compared to that of validamycin A (control ligand).Results and discussionThe post-screening analysis showed binding affinities of −8.7 and −8.2 kcal/mol (compound 1), −8.2 and −7.4 kcal/mol (compound 2), compared to −6.3 and −5.1 kcal/mol (Validamycin A, a known inhibitor) against AfTre and AgTre, respectively. The molecular dynamics simulation showed that compound 1 (the best hit) had good stability when in complex with AfTre. These findings suggest that these best hits can serve as potential inhibitors for the development of novel insecticides in the control of malaria vectors

Synthesis, in silico and in vitro antimicrobial efficacy of substituted arylidene-based quinazolin-4(3H)-one motifs

Introduction: Quinazolin-4(3H)-one derivatives have attracted considerable attention in the pharmacological profiling of therapeutic drug targets. The present article reveals the development of arylidene-based quinazolin-4(3H)-one motifs as potential antimicrobial drug candidates.Methods: The synthetic pathway was initiated through thermal cyclization of acetic anhydride on anthranilic acid to produce 2-methyl-4H-3,1-benzoxazan-4-one 1, which (upon condensation with hydrazine hydrate) gave 3-amino-2-methylquinazolin-4(3H)-one 2. The reaction of intermediate 2 at its amino side arm with various benzaldehyde derivatives furnished the final products, in the form of substituted benzylidene-based quinazolin-4(3H)-one motifs 3a–l, and with thiophene-2-carbaldehyde to afford 3 m. The purified targeted products 3a–m were effectively characterized for structural authentication using physicochemical parameters, microanalytical data, and spectroscopic methods, including IR, UV, and 1H- and 13C-NMR, as well as mass spectral data. The substituted arylidene-based quinazolin-4(3H)-one motifs 3a–m were screened for both in silico and in vitro antimicrobial properties against selected bacteria and fungi. The in silico studies carried out consisted of predicted ADMET screening, molecular docking, and molecular dynamics (MD) simulation studies. Furthermore, in vitro experimental validation was performed using the agar diffusion method, and the standard antibacterial and antifungal drugs used were gentamicin and ketoconazole, respectively.Results and discussion: Most of the compounds possessed good binding affinities according to the molecular docking studies, while MD simulation revealed their levels of structural stability in the protein–ligand complexes. 2-methyl-3-((thiophen-2-ylmethylene)amino) quinazolin-4(3H)-one 3 m emerged as both the most active antibacterial agent (with an minimum inhibitory concentration (MIC) value of 1.95 μg/mL) against Staphylococcus aureus and the most active antifungal agent (with an MIC value of 3.90 μg/mL) against Candida albicans, Aspergillus niger, and Rhizopus nigricans

In Silico Design of Potential Small-Molecule Antibiotic Adjuvants against <i>Salmonella typhimurium</i> Ortho Acetyl Sulphydrylase Synthase to Address Antimicrobial Resistance

The inhibition of O-acetyl sulphydrylase synthase isoforms has been reported to represent a promising approach for the development of antibiotic adjuvants. This occurs via the organism developing an unpaired oxidative stress response, causing a reduction in antibiotic resistance in vegetative and swarm cell populations. This consequently increases the effectiveness of conventional antibiotics at lower doses. This study aimed to predict potential inhibitors of Salmonella typhimurium ortho acetyl sulphydrylase synthase (StOASS), which has lower binding energy than the cocrystalized ligand pyridoxal 5 phosphate (PLP), using a computer-aided drug design approach including pharmacophore modeling, virtual screening, and in silico ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) evaluation. The screening and molecular docking of 4254 compounds obtained from the PubChem database were carried out using AutoDock vina, while a post-screening analysis was carried out using Discovery Studio. The best three hits were compounds with the PubChem IDs 118614633, 135715279, and 155773276, possessing binding affinities of −9.1, −8.9, and −8.8 kcal/mol, respectively. The in silico ADMET prediction showed that the pharmacokinetic properties of the best hits were relatively good. The optimization of the best three hits via scaffold hopping gave rise to 187 compounds, and they were docked against StOASS; this revealed that lead compound 1 had the lowest binding energy (−9.3 kcal/mol) and performed better than its parent compound 155773276. Lead compound 1, with the best binding affinity, has a hydroxyl group in its structure and a change in the core heterocycle of its parent compound to benzimidazole, and pyrimidine introduces a synergistic effect and consequently increases the binding energy. The stability of the best hit and optimized compound at the StOASS active site was determined using RMSD, RMSF, radius of gyration, and SASA plots generated from a molecular dynamics simulation. The MD simulation results were also used to monitor how the introduction of new functional groups of optimized compounds contributes to the stability of ligands at the target active site. The improved binding affinity of these compounds compared to PLP and their toxicity profile, which is predicted to be mild, highlights them as good inhibitors of StOASS, and hence, possible antimicrobial adjuvants

Effects of delayed radical prostatectomy and active surveillance on localised prostate cancer - A systematic review and meta-analysis

© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/)External factors, such as the coronavirus disease 2019 (COVID-19), can lead to cancellations and backlogs of cancer surgeries. The effects of these delays are unclear. This study summarised the evidence surrounding expectant management, delay radical prostatectomy (RP), and neoadjuvant hormone therapy (NHT) compared to immediate RP. MEDLINE and EMBASE was searched for randomised controlled trials (RCTs) and non-randomised controlled studies pertaining to the review question. Risks of biases (RoB) were evaluated using the RoB 2.0 tool and the Newcastle–Ottawa Scale. A total of 57 studies were included. Meta-analysis of four RCTs found overall survival and cancer-specific survival were significantly worsened amongst intermediate-risk patients undergoing active monitoring, observation, or watchful waiting but not in low- and high-risk patients. Evidence from 33 observational studies comparing delayed RP and immediate RP is contradictory. However, conservative estimates of delays over 5 months, 4 months, and 30 days for low-risk, intermediate-risk, and high-risk patients, respectively, have been associated with significantly worse pathological and oncological outcomes in individual studies. In 11 RCTs, a 3-month course of NHT has been shown to improve pathological outcomes in most patients, but its effect on oncological outcomes is apparently limitedPeer reviewe