Prediction of pharmacological activities from chemical structures with graph convolutional neural networks.

Many therapeutic drugs are compounds that can be represented by simple chemical structures, which contain important determinants of affinity at the site of action. Recently, graph convolutional neural network (GCN) models have exhibited excellent results in classifying the activity of such compounds. For models that make quantitative predictions of activity, more complex information has been utilized, such as the three-dimensional structures of compounds and the amino acid sequences of their respective target proteins. As another approach, we hypothesized that if sufficient experimental data were available and there were enough nodes in hidden layers, a simple compound representation would quantitatively predict activity with satisfactory accuracy. In this study, we report that GCN models constructed solely from the two-dimensional structural information of compounds demonstrated a high degree of activity predictability against 127 diverse targets from the ChEMBL database. Using the information entropy as a metric, we also show that the structural diversity had less effect on the prediction performance. Finally, we report that virtual screening using the constructed model identified a new serotonin transporter inhibitor with activity comparable to that of a marketed drug in vitro and exhibited antidepressant effects in behavioural studies.

Gain of long tonic immobility behavioral trait causes the red flour beetle to reduce anti-stress capacity.

Tonic immobility (death-feigning) behavior of the red flour beetle, Tribolium castaneum, is a predator defense mechanism; it is a reflex elicited when a beetle is jarred with the substrate, often a result of the activities of a predator. We previously demonstrated that the frequency of predation by a jumping spider, Hasarius adansoni, was significantly lower among beetles with higher frequencies and longer durations of tonic immobility (L-type) than those with lower frequencies and shorter durations of tonic immobility (S-type). However, we found that the population of L-type beetles is much smaller than that of S-type beetles in their natural habitat. Here we demonstrated that L-type beetles are significantly more sensitive to environmental stressors such as mechanical vibration and high or low temperatures. We measured expression levels of stress-responsive genes such as heat shock proteins (Hsps) and antioxidant enzymes in both types of beetles. Among the genes we investigated, only catalase gene expression levels were significantly higher in S-type than in L-type beetles. Furthermore, a similar difference in the gene expression was observed in the T. castaneum ortholog of the insect cytokine growth-blocking peptide (GBP) gene. These results indicate the possibility that high expression of catalase and GBP in S-type beetles contributes to augmentation of their anti-stress capacity and expansion of their population in their natural habitat.

A small-animal pharmacokinetic/pharmacodynamic PET study of central serotonin 1A receptor occupancy by a potential therapeutic agent for overactive bladder.

Serotonin 1A (5-HT1A) receptors have been mechanistically implicated in micturition control, and there has been a need for an appropriate biomarker surrogating the potency of a provisional drug acting on this receptor system for developing a new therapeutic approach to overactive bladder (OAB). Here, we analyzed the occupancy of 5-HT1A receptors in living Sprague-Dawley rat brains by a novel candidate drug for OAB, E2110, using positron emission tomography (PET) imaging, and assessed the utility of a receptor occupancy (RO) assay to establish a pharmacodynamic index translatable between animals and humans. The plasma concentrations inducing 50% RO (EC50) estimated by both direct and effect compartment models were in good agreement. Dose-dependent therapeutic effects of E2110 on dysregulated micturition in different rat models of pollakiuria were also consistently explained by achievement of 5-HT1A RO by E2110 in a certain range (≥ 60%). Plasma drug concentrations inducing this RO range and EC50 would accordingly be objective indices in comparing pharmacokinetics-RO relationships between rats and humans. These findings support the utility of PET RO and plasma pharmacokinetic assays with the aid of adequate mathematical models in determining the in vivo characteristics of a drug acting on 5-HT1A receptors and thereby counteracting OAB.

Comparison of four silane primers and an isocyanate primer for bonding of tri-n-butylborane resin to a leucite-reinforced glass ceramic.

PURPOSE: The purpose of the present study was to compare the effectiveness of an isocyanate monomer and four different silane monomers as primer components for bonding a leucite-reinforced glass ceramic (GN-Ceram Block). METHODS: Four different methyl-methacrylate based primers, each with three different concentrations (1, 4, or 16wt%) of 2-methacryloxyethylisocyanate (MOI), 3-methacryloxypropylmethyldimethoxysilane (MDS), 3-methacryloxypropyltrimethoxysilane (MTS), and 3-acryloxypropyltrimethoxysilane (ATS) were prepared. A commercially available silane primer (ESPE™Sil) was also used as a control. The GN-Ceram Block specimen was ground with silicon carbide paper, rinsed, primed, and then bonded to a resin composite disk using a tri-n-butylborane-initiated self-curing luting agent. After 24-h immersion in water, the shear bond strengths were determined. RESULTS: The highest level of bond strength was obtained with 4wt% MTS (45.2 MPa) and 4wt% ATS (38.7 MPa), followed by 4wt% MOI (29.8 MPa), ESPE™Sil (28.1 MPa), and 4wt% MDS (27.9 MPa). For each MTS, ATS, MOI, and MDS, the bond strengths for concentrations of 4wt% and 16wt% were not significantly different. No significant differences were found between 4wt% ATS, 4wt% MOI, ESPE™Sil, and 4wt% MDS. The use of any of these primers led to a significant increase in bond strength compared to an unprimed control (13.8 MPa). CONCLUSIONS: The type and concentration of monomers dissolved in the primer influence the bond strength between a tri-n-butylborane resin and a leucite-reinforced glass ceramic GN-Ceram Block. The effectiveness of MOI was found to be comparable to that of MDS, ATS, and ESPE™Sil, but inferior to that of MTS.

Effects of primer containing silane and thiophosphate monomers on bonding resin to a leucite-reinforced ceramic.

OBJECTIVES: Silane primers are commonly used for bonding between resin-based luting agents and ceramic restorations. The purpose of the present study was to evaluate the effects of nine silane primers on the bond strength of resin to a leucite-reinforced ceramic. METHODS: The commercially available dental primers used were five silane primers (GC Ceramic Primer, GP; Clearfil Ceramic Primer, CP; Tokuso Ceramic Primer, TP; Porcelain Liner M, PM; and Monobond Plus, MB). Four experimental primers (MDS, MTS, MDS/MPII, and MTS/MPII) and two control primers (MMA and MMA/MPII) were also prepared. The ceramic specimen was ground with silicon carbide paper, primed, and then bonded to a resin composite disc using a dual-curing luting agent. After a 24-h immersion in water, the shear bond strengths were determined. RESULTS: Shear bond testing revealed that the bond strength was significantly improved with the use of a MTS/MPII primer when compared to MDS, MTS, MMA, MDS/MPII and MMA/MPII. Although no significant differences were detected between GP, CP, PM, and MB, the primers CP, TP, PM, and MTS/MPII exhibited the highest bond strengths, followed by GP and MB, whilst the no-primer control resulted in the lowest values. CONCLUSION: The maximum bond strengths were obtained with CP, TP, PM, and MTS/MPII. It was suggested that the thiophosphate monomer accelerated the role of the silane monomer. When selecting a primer to bond ceramic restorations, clinicians should be aware that not only the silane monomer but also additional components of the primer considerably affect the bond strength.

Silane primers rather than heat treatment contribute to adhesive bonding between tri-n-butylborane resin and a machinable leucite-reinforced ceramic.

The purpose of the present study was to evaluate the effects of silane primers with and without heat treatment on bonding between a resin and a leucite-reinforced ceramic (GN-Ceram). Six dental primers (GC Ceramic Primer, GP; Clearfil Ceramic Primer, CP; RelyX Ceramic Primer, RP; Tokuso Ceramic Primer, TP; Shofu Porcelain Primer, SP; and Porcelain Liner M, PM) and five experimental primers (MDS, MTS, MDES, MTES, and ATS) were evaluated. GN-Ceram specimen was primed, heated at 100°C for 60 min (Heat), and then bonded to a resin composite using a self-curing resin. Shear bond testing revealed that GP, GP/Heat, CP, CP/Heat, RP, RP/Heat, TP, TP/Heat, SP, SP/Heat, PM, PM/Heat, MDS/Heat, MTS, MTS/Heat, and ATS/Heat exhibited superior bond strengths. No-primer, No-primer/Heat, MDS, MDES, MTES, and ATS exhibited low bond strengths, while there were no significant differences in bond strength among SP, MDS, MDES/Heat, and MTES/Heat. It seemed that heat treatment improved the bonding performance for MDS, MTES, and ATS only.

Bond strength between luting materials and a fiber-reinforced resin composite for indirect restorations.

The purpose of the present study was to evaluate the bond strength between a fiber-reinforced composite (FRC) and six luting agents (Panavia F 2.0, Linkmax MC, Chemiace II, Multibond, Super-Bond C&B, and Fuji I). A prosthodontic resin composite material (RC-control) and a luting agent containing no functional monomer (MT) were used as controls. Shear bond strengths between alumina-blasted FRC and the luting agents were determined after 20,000 thermocycles. The FRC showed superior bond strength when compared with the RC-control. Highest bond strengths were achieved when FRC was bonded with Panavia F 2.0, Linkmax MC, Multibond, Super-Bond C&B, and MT, whereas Chemiace II trailed in the list of resin-based luting agents evaluated. Insufficient bonding was obtained with Fuji I. Results of the present study revealed that when fabricating restorations, the clinician should select an appropriate combination of resin composite material and luting agent so as to ensure the longevity of restorations.