A curated dataset for data-driven turbulence modelling.

The recent surge in machine learning augmented turbulence modelling is a promising approach for addressing the limitations of Reynolds-averaged Navier-Stokes (RANS) models. This work presents the development of the first open-source dataset, curated and structured for immediate use in machine learning augmented corrective turbulence closure modelling. The dataset features a variety of RANS simulations with matching direct numerical simulation (DNS) and large-eddy simulation (LES) data. Four turbulence models are selected to form the initial dataset: k-ε, k-ε-ϕt-f, k-ω, and k-ω SST. The dataset consists of 29 cases per turbulence model, for several parametrically sweeping reference DNS/LES cases: periodic hills, square duct, parametric bumps, converging-diverging channel, and a curved backward-facing step. At each of the 895,640 points, various RANS features with DNS/LES labels are available. The feature set includes quantities used in current state-of-the-art models, and additional fields which enable the generation of new feature sets. The dataset reduces effort required to train, test, and benchmark new corrective RANS models. The dataset is available at  https://doi.org/10.34740/kaggle/dsv/2637500 .

Synthesis of Dextran-Phenoxodiol and Evaluation of Its Physical Stability and Biological Activity.

Phenoxodiol, an isoflavene anti-tumor agent, was conjugated on the polysaccharide dextran using immobilized laccase as biocatalyst. The success of the enzymatic conjugation was determined by UV-vis spectrophotometry and its functionalization degree was assessed by 1H NMR and was found to be 3.25 mg phenoxodiol/g of conjugate. An accelerated stability test showed that the resultant conjugate was nine times more stable than the free phenoxodiol when tested for its residual anti-oxidant activity with the Folin-Ciocalteu assay. The in vitro anti-proliferative activity of the conjugate was evaluated against neuroblastoma SKN-BE(2)C, triple-negative breast cancer MDA-MB-231, and glioblastoma U87 cancer cells. The conjugate was shown to be generally more potent than phenoxodiol against all three cell types tested. Additionally, the cytotoxicity and anti-angiogenic activity of the conjugate were also evaluated against non-malignant human lung fibroblast MRC-5 and human microvascular endothelial cells HMEC-1, respectively. The conjugate was found to be 1.5 times less toxic than phenoxodiol while mostly retaining 62% of its anti-angiogenic activity in the conjugate form. This study provides further evidence that the conjugation of natural product-derived drugs onto polysaccharide molecules such as dextran can lead to better stability and enhanced biological activity of the conjugate compared to the free drug alone.

In vivo [64Cu]CuCl2 PET imaging reveals activity of Dextran-Catechin on tumor copper homeostasis.

Given the strong clinical evidence that copper levels are significantly elevated in a wide spectrum of tumors, copper homeostasis is considered as an emerging target for anticancer drug design. Monitoring copper levels in vivo is therefore of paramount importance when assessing the efficacy of copper-targeting drugs. Herein, we investigated the activity of the copper-targeting compound Dextran-Catechin by developing a [64Cu]CuCl2 PET imaging protocol to monitor its effect on copper homeostasis in tumors. Methods: Protein expression of copper transporter 1 (CTR1) in tissue microarrays representing 90 neuroblastoma patient tumors was assessed by immunohistochemistry. Western blotting analysis was used to study the effect of Dextran-Catechin on the expression of CTR1 in neuroblastoma cell lines and in tumors. A preclinical human neuroblastoma xenograft model was used to study anticancer activity of Dextran-Catechin in vivo and its effect on tumor copper homeostasis. PET imaging with [64Cu]CuCl2 was performed in such preclinical neuroblastoma model to monitor alteration of copper levels in tumors during treatment. Results: CTR1 protein was found to be highly expressed in patient neuroblastoma tumors by immunohistochemistry. Treatment of neuroblastoma cell lines with Dextran-Catechin resulted in decreased levels of glutathione and in downregulation of CTR1 expression, which caused a significant decrease of intracellular copper. No changes in CTR1 expression was observed in normal human astrocytes after Dextran-Catechin treatment. In vivo studies and PET imaging analysis using the neuroblastoma preclinical model revealed elevated [64Cu]CuCl2 retention in the tumor mass. Following treatment with Dextran-Catechin, there was a significant reduction in radioactive uptake, as well as reduced tumor growth. Ex vivo analysis of tumors collected from Dextran-Catechin treated mice confirmed the reduced levels of CTR1. Interestingly, copper levels in blood were not affected by treatment, demonstrating potential tumor specificity of Dextran-Catechin activity. Conclusion: Dextran-Catechin mediates its activity by lowering CTR1 and intracellular copper levels in tumors. This finding further reveals a potential therapeutic strategy for targeting copper-dependent cancers and presents a novel PET imaging method to assess patient response to copper-targeting anticancer treatments.

Guanidine functionalized anthranilamides as effective antibacterials with biofilm disruption activity.

We describe a library of amphiphilic anthranilamide compounds as antimicrobial peptide (AMP) mimics. These contain a hydrophobic naphthoyl side chain and different hydrophilic cationic groups such as amino, quaternary ammonium and guanidino groups. These are prepared via the ring-opening of different isatoic anhydrides. The antibacterial activity against S. aureus and E. coli of compounds containing guanidino cationic groups was greater than that for amino and quaternary ammonium cationic groups. The fluoro-substituted guanidinium compound 9b showed a minimum inhibitory concentration (MIC) of 2.0 µM against S. aureus, and reduced established biofilms of S. aureus by 92% at 64 µM concentration. The bromo-substituted guanidinium compound 9d exhibited good MIC against S. aureus (3.9 µM) and E. coli (15.6 µM) and disrupted established biofilms of S. aureus by 83% at 62.4 µM concentration. Cytoplasmic membrane permeability studies suggested that depolarization and disruption of the bacterial cell membrane could be a possible mechanism for antibacterial activity and the in vitro toxicity studies against MRC-5 human lung fibroblast cells showed that the potent compounds are non-toxic against mammalian cells.

Water Soluble Antioxidant Dextran-Quercetin Conjugate with Potential Anticancer Properties.

Quercetin, a naturally occurring potent antioxidant, is limited in therapeutic use, owing to its poor water solubility and stability. Herein, a method of conjugating quercetin to an aldehyde functionalized dextran via an HCl catalyzed condensation reaction to yield a water soluble quercetin functionalized polymer is reported. The prepared conjugate is characterized by 1 H and 1 H-13 C heteronuclear single quantum correlation (HSQC) NMR, which demonstrate that conjugation occurs via both the A- and B-rings of quercetin. The degree of quercetin functionalization can be tuned by varying the reaction temperature and/or the concentration of the HCl catalyst. However, as temperatures and HCl concentrations are increased above 40 °C and 2 m, respectively, the increase in functionalization is accompanied by an increase in the oxidation of the conjugated quercetin and a decrease in polymer yield. The prepared conjugate is shown to have improved stability compared with native quercetin while maintaining substantial free-radical scavenging activity. Anticancer activity is evaluated in vitro in a neuroblastoma cell line. The dextran-aldehyde-quercetin conjugate prepared at 40 °C and 2 m HCl is shown to be cytotoxic to neuroblastoma cells (SH-SY5Y-IC50 = 123 µg mL-1 and BE(2)-C-IC50 = 380 µg mL-1 ) but shows no activity against nonmalignant MRC-5 cells at concentrations up to 400 µg mL-1 .

Design and synthesis of short amphiphilic cationic peptidomimetics based on biphenyl backbone as antibacterial agents.

Antimicrobial peptides (AMPs) and their synthetic mimics have received recent interest as new alternatives to traditional antibiotics in attempts to overcome the rise of antibiotic resistance in many microbes. AMPs are part of the natural defenses of most living organisms and they also have a unique mechanism of action against bacteria. Herein, a new series of short amphiphilic cationic peptidomimetics were synthesized by incorporating the 3'-amino-[1,1'-biphenyl]-3-carboxylic acid backbone to mimic the essential properties of natural AMPs. By altering hydrophobicity and charge, we identified the most potent analogue 25g that was active against both Gram-positive Staphylococcus aureus (MIC = 15.6 µM) and Gram-negative Escherichia coli (MIC = 7.8 µM) bacteria. Cytoplasmic permeability assay results revealed that 25g acts primarily by depolarization of lipids in cytoplasmic membranes. The active compounds were also investigated for their cytotoxicity to human cells, lysis of lipid bilayers using tethered bilayer lipid membranes (tBLMs) and their activity against established biofilms of S. aureus and E. coli.

Dextran-Catechin inhibits angiogenesis by disrupting copper homeostasis in endothelial cells.

Formation of blood vessels, or angiogenesis, is crucial to cancer progression. Thus, inhibiting angiogenesis can limit the growth and spread of tumors. The natural polyphenol catechin has moderate anti-tumor activity and interacts with copper, which is essential for angiogenesis. Catechin is easily metabolized in the body and this limits its clinical application. We have recently shown that conjugation of catechin with dextran (Dextran-Catechin) improves its serum stability, and exhibits potent anti-tumor activity against neuroblastoma by targeting copper homeostasis. Herein, we investigated the antiangiogenic activity of Dextran-Catechin and its mechanism. We found that Dextran-Catechin displayed potent antiangiogenic activity in vitro and in vivo. We demonstrated Dextran-Catechin generates reactive oxygen species which in turns disrupts copper homeostasis by depleting the copper importer CTR-1 and copper trafficking ATOX-1 protein. Mechanistically, we showed that disrupting copper homeostasis by knockdown of either CTR-1 or ATOX-1 protein can inhibit angiogenesis in endothelial cells. This data strongly suggests the Dextran-Catechin potent antiangiogenic activity is mediated by disrupting copper homeostasis. Thus, compounds such as Dextran-Catechin that affects both tumor growth and angiogenesis could lead the way for development of new drugs against high copper levels tumors.

Synthesis and biological evaluation of novel acyclic and cyclic glyoxamide based derivatives as bacterial quorum sensing and biofilm inhibitors.

Bacteria regulate the expression of various virulence factors and processes such as biofilm formation through a chemically-mediated communication mechanism called quorum sensing. Bacterial biofilms contribute to antimicrobial resistance as they can protect bacteria embedded in their matrix from the effects of antibiotics. Thus, developing novel quorum sensing inhibitors, which can inhibit biofilm formation, is a viable strategy to combat antimicrobial resistance. We report herein the synthesis of novel acyclic and cyclic glyoxamide derivatives via ring-opening reactions of N-acylisatins. These compounds were evaluated for their quorum sensing inhibition activity against P. aeruginosa MH602 and E. coli MT102. Compounds 20, 21 and 30 displayed the greatest quorum sensing inhibition activity against P. aeruginosa MH602, with 71.5%, 71.5%, and 74% inhibition, respectively, at 250 µM. Compounds 18, 20 and 21 exhibited the greatest QSI activity against E. coli MT102, with 71.5%, 72.1% and 73.5% quorum sensing inhibition activity, respectively. In addition, the biofilm inhibition activity was also investigated against P. aeruginosa and E. coli at 250 µM. The glyoxamide compounds 16, 18 and 19 exhibited 71.2%, 66.9%, and 66.5% inhibition of P. aeruginosa biofilms, respectively; whereas compounds 12, 20, and 22 showed the greatest inhibitory activity against E. coli biofilms with 87.9%, 90.8% and 89.5%, respectively. Finally, the determination of the in vitro toxicity against human MRC-5 lung fibroblast cells revealed that these novel glyoxamide compounds are non-toxic to human cells.

Computational Acoustic Beamforming for Noise Source Identification for Small Wind Turbines.

This paper develops a computational acoustic beamforming (CAB) methodology for identification of sources of small wind turbine noise. This methodology is validated using the case of the NACA 0012 airfoil trailing edge noise. For this validation case, the predicted acoustic maps were in excellent conformance with the results of the measurements obtained from the acoustic beamforming experiment. Following this validation study, the CAB methodology was applied to the identification of noise sources generated by a commercial small wind turbine. The simulated acoustic maps revealed that the blade tower interaction and the wind turbine nacelle were the two primary mechanisms for sound generation for this small wind turbine at frequencies between 100 and 630 Hz.

Synthesis of isoflavene-thiosemicarbazone hybrids and evaluation of their anti-tumor activity.

Phenoxodiol is an isoflavene with potent anti-tumor activity. In this study, a series of novel mono- and di-substituted phenoxodiol-thiosemicarbazone hybrids were synthesized via the condensation reaction between phenoxodiol with thiosemicarbazides. The in vitro anti-proliferative activities of the hybrids were evaluated against the neuroblastoma SKN-BE(2)C, the triple negative breast cancer MDA-MB-231, and the glioblastoma U87 cancer cell lines. The mono-substituted hybrids exhibited potent anti-proliferative activity against all three cancer cell lines, while the di-substituted hybrids were less active. Selected mono-substituted hybrids were further investigated for their cytotoxicity against normal MRC-5 human lung fibroblast cells, which identified two hybrids with superior selectivity for cancer cells over normal cells as compared to phenoxodiol. This suggests that mono-substituted phenoxodiol-thiosemicarbazone hybrids have promising potential for further development as anti-cancer agents.

Preparation, characterization and in vitro biological evaluation of (1:2) phenoxodiol-ß-cyclodextrin complex.

Phenoxodiol is an isoflavone analogue that possesses potent anticancer properties. However, the poor water solubility of phenoxodiol limits its overall efficacy as an anticancer agent. To overcome this, ß-cyclodextrin was used to encapsulate phenoxodiol. The phenoxodiol-ß-cyclodextrin complex was prepared via a modified co-evaporation method and characterized by 1H NMR and X-ray crystallography, revealing a 1:2 stoichiometry. The 2D ROESY NMR spectroscopy suggested the limited motion of phenoxodiol within the cavity of ß-cyclodextrin while the X-ray crystal data displays by far the best 'ship-in-a-bottle' case of 1:2 inclusion complex. The aqueous solubility of the phenoxodiol in ß-cyclodextrin had improved and the in vitro biological evaluation revealed enhanced anti-proliferative activity against three cancer cell lines. Additionally, the toxicity of the complex against normal human cell line was 2.5 times lower. These data indicates that the encapsulation of phenoxodiol into ß-cyclodextrin leads to an improvement in its overall water solubility and biological activity.

Amphipathic guanidine-embedded glyoxamide-based peptidomimetics as novel antibacterial agents and biofilm disruptors.

Antimicrobial resistance in bacteria is becoming increasingly prevalent, posing a critical challenge to global health. Bacterial biofilm formation is a common resistance mechanism that reduces the effectiveness of antibiotics. Thus, the development of compounds that can disrupt bacterial biofilms is a potential strategy to combat antimicrobial resistance. We report herein the synthesis of amphipathic guanidine-embedded glyoxamide-based peptidomimetics via ring-opening reactions of N-naphthoylisatins with amines and amino acids. These compounds were investigated for their antibacterial activity by the determination of minimum inhibitory concentration (MIC) against S. aureus and E. coli. Compounds 35, 36, and 66 exhibited MIC values of 6, 8 and 10 µg mL-1 against S. aureus, respectively, while compounds 55 and 56 showed MIC values of 17 and 19 µg mL-1 against E. coli, respectively. Biofilm disruption and inhibition activities were also evaluated against various Gram-positive and Gram-negative bacteria. The most active compound 65 exhibited the greatest disruption of established biofilms by 65% in S. aureus, 61% in P. aeruginosa, and 60% in S. marcescens respectively, at 250 µM concentration, while compound 52 inhibited the formation of biofilms by 72% in S. marcescens at 250 µM. We also report here the in vitro toxicity against MRC-5 human lung fibroblast cells. Finally, the pore forming capability of the three most potent compounds were tested using tethered bilayer lipid membrane (tBLM) technology.

Dextran-Catechin: An anticancer chemically-modified natural compound targeting copper that attenuates neuroblastoma growth.

Neuroblastoma is frequently diagnosed at advanced stage disease and treatment includes high dose chemotherapy and surgery. Despite the use of aggressive therapy survival rates are poor and children that survive their disease experience long term side effects from their treatment, highlighting the need for effective and less toxic therapies. Catechin is a natural polyphenol with anti-cancer properties and limited side effects, however its mechanism of action is unknown. Here we report that Dextran-Catechin, a conjugated form of catechin that increases serum stability, is preferentially and markedly active against neuroblastoma cells having high levels of intracellular copper, without affecting non-malignant cells. Copper transporter 1 (CTR1) is the main transporter of copper in mammalian cells and it is upregulated in neuroblastoma. Functional studies showed that depletion of CTR1 expression reduced intracellular copper levels and led to a decrease in neuroblastoma cell sensitivity to Dextran-Catechin, implicating copper in the activity of this compound. Mechanistically, Dextran-Catechin was found to react with copper, inducing oxidative stress and decreasing glutathione levels, an intracellular antioxidant and regulator of copper homeostasis. In vivo, Dextran-Catechin significantly attenuated tumour growth in human xenograft and syngeneic models of neuroblastoma. Thus, Dextran-Catechin targets copper, inhibits tumour growth, and may be valuable in the treatment of aggressive neuroblastoma and other cancers dependent on copper for their growth.

Synthesis and biological evaluation of N-naphthoyl-phenylglyoxamide-based small molecular antimicrobial peptide mimics as novel antimicrobial agents and biofilm inhibitors.

Antimicrobial peptides (AMPs) are a key component of the human immune system. Synthetic AMP mimics represent a novel strategy to counteract the increasing incidence of antimicrobial resistance. Here, we describe the synthesis of novel glyoxamide derivatives via ring-opening reactions of N-hexanoyl, N-benzoyl and N-naphthoylisatins with N,N-dimethylethane-1,2-diamine and N,N-dimethylpropane-1,3-diamine. These were converted to both the hydrochloric acid (HCl) or quaternary ammonium iodide (MeI) salts and their antibacterial activity against Staphylococcus aureus was investigated by their zone-of-inhibition and minimum inhibitory concentration (MIC). The HCl salt 22b exhibited the lowest MIC of 16 µg mL(-1), whereas the corresponding MeI salt 22c had a MIC of 39 µg mL(-1). We also investigated the in vitro toxicity of active compounds against the MRC-5 normal human lung fibroblasts and their activity against established biofilm in S. aureus.

Synthesis, biological evaluation and structure-activity relationship studies of isoflavene based Mannich bases with potent anti-cancer activity.

Phenoxodiol, an analogue of the isoflavone natural product daidzein, is a potent anti-cancer agent that has been investigated for the treatment of hormone dependent cancers. This molecular scaffold was reacted with different primary amines and secondary amines under different Mannich conditions to yield either benzoxazine or aminomethyl substituted analogues. These processes enabled the generation of a diverse range of analogues that were required for structure-activity relationship (SAR) studies. The resulting Mannich bases exhibited prominent anti-proliferative effects against SHEP neuroblastoma and MDA-MB-231 breast adenocarcinoma cell lines. Further cytotoxicity studies against MRC-5 normal lung fibroblast cells showed that the isoflavene analogues were selective towards cancer cells.

Bayesian Inference for Source Reconstruction: A Real-World Application.

This paper applies a Bayesian probabilistic inferential methodology for the reconstruction of the location and emission rate from an actual contaminant source (emission from the Chalk River Laboratories medical isotope production facility) using a small number of activity concentration measurements of a noble gas (Xenon-133) obtained from three stations that form part of the International Monitoring System radionuclide network. The sampling of the resulting posterior distribution of the source parameters is undertaken using a very efficient Markov chain Monte Carlo technique that utilizes a multiple-try differential evolution adaptive Metropolis algorithm with an archive of past states. It is shown that the principal difficulty in the reconstruction lay in the correct specification of the model errors (both scale and structure) for use in the Bayesian inferential methodology. In this context, two different measurement models for incorporation of the model error of the predicted concentrations are considered. The performance of both of these measurement models with respect to their accuracy and precision in the recovery of the source parameters is compared and contrasted.

Ensemble Nonlinear Autoregressive Exogenous Artificial Neural Networks for Short-Term Wind Speed and Power Forecasting.

Short-term wind speed and wind power forecasts (for a 72 h period) are obtained using a nonlinear autoregressive exogenous artificial neural network (ANN) methodology which incorporates either numerical weather prediction or high-resolution computational fluid dynamics wind field information as an exogenous input. An ensemble approach is used to combine the predictions from many candidate ANNs in order to provide improved forecasts for wind speed and power, along with the associated uncertainties in these forecasts. More specifically, the ensemble ANN is used to quantify the uncertainties arising from the network weight initialization and from the unknown structure of the ANN. All members forming the ensemble of neural networks were trained using an efficient particle swarm optimization algorithm. The results of the proposed methodology are validated using wind speed and wind power data obtained from an operational wind farm located in Northern China. The assessment demonstrates that this methodology for wind speed and power forecasting generally provides an improvement in predictive skills when compared to the practice of using an "optimal" weight vector from a single ANN while providing additional information in the form of prediction uncertainty bounds.

Synthesis of novel isoflavene-propranolol hybrids as anti-tumor agents.

Isoflavene-propranolol hybrid molecules were developed as potentially novel anti-tumour agents. Isoflavene itself has potent anti-cancer activity while propranolol can enhance anti-proliferative and anti-angiogenic properties of 5-fluorouracil and paclitaxel. The hybrids were produced via nucleophilic addition of substituted amine groups to a dioxiran intermediate, which was in turn generated from the Williamson-type reaction of isoflavene with (±)-epichlorohydrin. These analogues were tested in anti-cancer cell viability assays against SHEP neuroblastoma and MDA-MB-231 breast adenocarcinoma cell lines, and were found to exhibit potent anti-proliferative activities. These compounds also displayed anti-angiogenic and anti-proliferative effects in HMEC-1 human microvascular endothelial cell lines. Notably, the most potent hybrid molecules synthesized in this work showed enhanced potency against cancer cell lines compared to either isoflavene or propranolol alone, while retaining significant selectivity for cancer cells over MRC-5 normal lung fibroblast cells.

Scalar fluctuations from a point source in a turbulent boundary layer.

The downstream development of the concentration probability distribution along the mean-plume centerline of a dispersing plume in the wake of a ground-level continuous point source in a neutrally stratified wall-shear layer is studied. It is shown that the concentration distribution is well described by a family of one-parameter gamma distributions, as first suggested by Villermaux and Duplat [Phys. Rev. Lett. 91, 184501 (2003)] in the context of confined mixing. A prediction of the downstream evolution of the parameter k (which specifies the gamma distribution) is obtained. This prediction includes explicitly the effects of mean shear on the mean-square concentration.

Scaling laws of peripheral mixing of passive scalar in a wall-shear layer.

The scaling laws governing the concentration moments of a passive scalar released from a ground-level localized source in a neutrally stratified wall-shear layer are investigated using a theoretical framework recently formulated by Lebedev and Turitsyn [Phys. Rev. E 69, 036301 (2004)]. For the current application, this theoretical framework is generalized from the smooth random velocity field applicable in the viscous sublayer to the nonsmooth random velocity field that applies to the bulk of the wall-shear layer. Theoretical relationships for the passive scalar concentration moments are compared to a water-channel simulation of turbulent diffusion from a ground-level source in a wall-shear layer. The diffusion measurements in the wall-shear layer are shown to be consistent with the theoretical description and also imply the robustness of the identified scaling laws for the scalar concentration moments.