In Silico Selection and In Vitro Evaluation of New Molecules That Inhibit the Adhesion of Streptococcus mutans through Antigen I/II

Streptococcus mutans is the main early colonizing cariogenic bacteria because it recognizes salivary pellicle receptors. The Antigen I/II (Ag I/II) of S. mutans is among the most important adhesins in this process, and is involved in the adhesion to the tooth surface and the bacterial co-aggregation in the early stage of biofilm formation. However, this protein has not been used as a target in a virtual strategy search for inhibitors. Based on the predicted binding affinities, drug-like properties and toxicity, molecules were selected and evaluated for their ability to reduce S. mutans adhesion. A virtual screening of 883,551 molecules was conducted; cytotoxicity analysis on fibroblast cells, S. mutans adhesion studies, scanning electron microscopy analysis for bacterial integrity and molecular dynamics simulation were also performed. We found three molecules ZINC19835187 (ZI-187), ZINC19924939 (ZI-939) and ZINC19924906 (ZI-906) without cytotoxic activity, which inhibited about 90% the adhesion of S. mutans to polystyrene microplates. Molecular dynamic simulation by 300 nanoseconds showed stability of the interaction between ZI-187 and Ag I/II (PDB: 3IPK). This work provides new molecules that targets Ag I/II and have the capacity to inhibit in vitro the S. mutans adhesion on polystyrene microplates.     

Further SAR on the (Phenylsulfonyl)piperazine Scaffold as Inhibitors of the Aedes aegypti Kir1 (AeKir) Channel and Larvicides

Zika virus (ZIKV), dengue fever (DENV) and chikungunya (CHIKV) are arboviruses that are spread to humans from the bite of an infected adult female Aedes aegypti mosquito. As there are no effective vaccines or therapeutics for these diseases, the primary strategy for controlling the spread of these viruses is to prevent the mosquito from biting humans through the use of insecticides. Unfortunately, the commonly used classes of insecticides have seen a significant increase in resistance, thus complicating control efforts. Inhibiting the renal inward rectifier potassium (Kir) channel of the mosquito vector Aedes aegypti has been shown to be a promising target for the development of novel mosquitocides. We have shown that Kir1 channels play key roles in mosquito diuresis, hemolymph potassium homeostasis, flight, and reproduction. Previous work from our laboratories identified a novel (phenylsulfonyl)piperazine scaffold as potent AeKir channel inhibitors with activity against both adult and larval mosquitoes. Herein, we report further SAR work around this scaffold and have identified additional compounds with improved in vitro potency and mosquito larvae toxicity.     

The Role of Glycosyltransferases in Colorectal Cancer

Colorectal cancer (CRC) is one of the main causes of cancer death in the world. Post-translational modifications (PTMs) have been extensively studied in malignancies due to its relevance in tumor pathogenesis and therapy. This review is focused on the dysregulation of glycosyltransferase expression in CRC and its impact in cell function and in several biological pathways associated with CRC pathogenesis, prognosis and therapeutic approaches. Glycan structures act as interface molecules between cells and their environment and in several cases facilitate molecule function. CRC tissue shows alterations in glycan structures decorating molecules, such as annexin-1, mucins, heat shock protein 90 (Hsp90), β1 integrin, carcinoembryonic antigen (CEA), epidermal growth factor receptor (EGFR), insulin-like growth factor-binding protein 3 (IGFBP3), transforming growth factor beta (TGF-β) receptors, Fas (CD95), PD-L1, decorin, sorbin and SH3 domain-containing protein 1 (SORBS1), CD147 and glycosphingolipids. All of these are described as key molecules in oncogenesis and metastasis. Therefore, glycosylation in CRC can affect cell migration, cell–cell adhesion, actin polymerization, mitosis, cell membrane repair, apoptosis, cell differentiation, stemness regulation, intestinal mucosal barrier integrity, immune system regulation, T cell polarization and gut microbiota composition; all such functions are associated with the prognosis and evolution of the disease. According to these findings, multiple strategies have been evaluated to alter oligosaccharide processing and to modify glycoconjugate structures in order to control CRC progression and prevent metastasis. Additionally, immunotherapy approaches have contemplated the use of neo-antigens, generated by altered glycosylation, as targets for tumor-specific T cells or engineered CAR (Chimeric antigen receptors) T cells.     

PECVD OF HARD AND ELASTIC BCN COATINGS

Compounds of the B-C-N system are very promising to produce superhard coatings with good tribological, chemical and thermal properties. Consequently, BCN films were prepared by plasma enhanced chemical vapor deposition (PECVD). The films were deposited from gaseous mixtures of BCl3-C2H4-N2-H2-Ar in different unipolar and bipolar pulsed glow discharges at 550℃ and analyzed with respect to composition, electronic structure and mechanical properties. The micro structure and composition of the BCN films were determined by scanning electron microscopy (SEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS) and reflection electron energy loss spectroscopy (REELS). Mechanical properties were characterized using both the traditional Vickers method and nanoindentation. The films, that were deposited using a bipolar pulsed generator, were weak and had a sponge-like structure, whereas the films prepared using an unipolar generator were well adherent, had a hardness of more than 11GPa and very high e     

Evaluation of the uniform current density assumption in cathodic protection systems with close anode‐to‐cathode arrangement

Cathodic protection modelling often involves making assumptions about geometric features and material characteristics that directly impact accuracy of solutions. In the present paper, predictive power of the model using approximate uniform current boundary condition on the cathode is validated against the model using nonlinear cathode polarization curves representative of low‐carbon steel structure of common geometry, buried in soil or immersed in seawater. In order to explore the worst case scenario, the present example deals with a large diameter pipeline (Ø 1.2 m) and a wire anode (Ø 0.05 m), separated by a distance d, both embedded in an infinite space of conductivity κ. The calculation is performed for the two sets of parameters – κ and limiting current density of oxygen reduction, i_l. For simulation of CP systems in seawater κ = 4.79 S/m and i_l = ?86 µA/cm² and for CP system in soil, κ = 10^?3 S/m and i_l = ?1.1 µA/cm². The other physical parameters were identical for both systems (Tafel slopes b_a = 60 mV/dec, b_c = 120 mV/dec and equilibrium potentials , ). The results were visualized to best exemplify the general trends in potential and current distributions that appear upon switch between uniform and nonlinear cathodic boundary conditions.     

Corrosion inhibition of 70Cu–30Ni alloy in LiBr + ethylene glycol + H2O mixtures by inorganic compounds

The corrosion inhibition of a 70 wt% Cu–30Ni alloy in a 55 wt% lithium bromide (LiBr) + ethylene glycol + H₂O by inorganic inhibitors has been evaluated at different temperatures by using electrochemical techniques. Inhibitors used included lithium chromate (Li₂CrO₄), lithium molybdate (LiMoO₄), and lithium nitrate (LiNO₃), in a concentration of 5 ppm at 25, 50, and 80 °C. Employed techniques included potenthiodynamic polarization curves, linear polarization resistance, and potentiostatic measurements. Results have shown that the alloy had an active–passive behavior at 25 and 50 °C, and the passive film properties were improved with the addition of inhibitors, whereas at 80 °C the inhibitors did not have any effect. Similarly, in general terms, the best corrosion performance at 25, 50, and 80 °C was obtained by adding Li₂CrO₄, LiNO₃, and LiMoO₄, respectively. However, the alloy was not susceptible to pitting corrosion in presence of inhibitors but it was highly susceptible towards pitting type of corrosion in absence of inhibitors.     

A model for the injection boundary conditions in the context of 3D simulation of Diesel Spray: Methodology and validation

Downstream Inflow Turbulent Boundary Conditions (DITurBC) are presented for the Eulerian-Eulerian Large Eddy Simulation (LES) or Reynolds Average Navier-Stokes (RANS) simulation of Diesel Sprays. These boundary conditions initiate the spray physics close to the nozzle exit, which avoids the difficulties linked to the 3D simulation of cavitation, primary break-up and turbulence in the near-nozzle region. An injector model is combined with mass and axial momentum conservation equations to obtain mean profiles of velocity, volume fraction and droplet diameter at a given distance downstream from the nozzle exit. In order to take into account the unsteadiness of the flow, velocity fluctuations are added to the mean profile. These boundary conditions are assessed by comparison with existing data on injection velocity, spray angle and velocity profiles from numerous experiments.     

Interleukin-17A Gene Expression in Morbidly Obese Women

Data from recent studies conducted in rodent models and humans suggest that interleukin-17A (IL-17A) plays a role in the induction of inflammation in adipose tissue during obesity. The aim of this study was to assess the gene expression of IL-17A in adipose tissue of morbidly obese patients. We used RT-PCR to evaluate the expression of IL-17A and several adipo/cytokines in the visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) of 10 normal-weight control women (BMI < 25 kg/m²) and 30 morbidly obese women (MO, BMI > 40 kg/m²). We measured serum levels of IL-17A and adipo/cytokines in MO and normal weight women. IL-17A expression was significantly higher in VAT than in SAT in MO patients (p = 0.0127). It was very low in normal-weight controls in both VAT and SAT tissues. We found positive correlations between IL-17A and IL-6, lipocalin-2 and resistin in VAT of MO patients. The circulating level of IL-17A was higher in the normal-weight group than the MO patients (p = 0.032), and it was significantly related to adiponectin and TNFRII levels. In conclusion, IL-17A expression in VAT is increased in morbidly obese women, which suggests a link between obesity and innate immunity in low-grade chronic inflammation in morbidly obese women.     

Probing inhibitory effects of nanocrystalline cellulose: inhibition versus surface charge

NCC derived from different biomass sources was probed for its plausible cytotoxicity by electric cell-substrate impedance sensing (ECIS). Two different cell lines, Spodoptera frugiperda Sf9 insect cells and Chinese hamster lung fibroblast V79, were exposed to NCC and their spreading and viability were monitored and quantified by ECIS. Based on the 50%-inhibition concentration (ECIS(50)), none of the NCC produced was judged to have any significant cytotoxicity on these two cell lines. However, NCC derived from flax exhibited the most pronounced inhibition on Sf9 compared to hemp and cellulose powder. NCCs from flax and hemp pre-treated with pectate lyase were also less inhibitory than NCCs prepared from untreated flax and hemp. Results also suggested a correlation between the inhibitory effect and the carboxylic acid contents on the NCC.     

A Dynamic Light Scattering Study on the Complex Assembly of Glycinin Soy Globulin in Aqueous Solutions

In this work, the complex assembly of one of the major storage proteins in soybean, glycinin, was analyzed using dynamic light scattering, from the hydrodynamic diameter of assembled forms in solution. The protein concentration and temperature were maintained constant at 10⁻¹% w/w and 20 °C, respectively, and the pH was 7.6, 7.0 and 3.0. By analyzing the intensity and volume size distributions, a complex equilibrium between self-assembled forms could be determined. At pH 7.6 and an ionic strength of 0.5 M, where the self-assembly of glycinin has been widely reported in the literature, the DLS technique revealed an equilibrium between different assembled forms, that shifted towards the 11S form. At a lower ionic strength for pH 3.0 or 7.0, the 7S form predominated. The hydrodynamic diameter evolved differently upon heating, depending on pH and ionic strength. For pH 7 (I = 0.05) and 7.6 (I = 0.5) a significant increase in d_H was observed at a temperatures of 55 and 70 °C, respectively, which were significantly lower than the denaturation onset temperatures as determined by DSC. No changes in d_H nor a transition endotherm were observed at pH 3.