An adaptive IgA-BEM with hierarchical B-splines based on quasi-interpolation quadrature schemes

The isogeometric formulation of the boundary element method (IgA-BEM) is investigated within the adaptivity framework. Suitable weighted quadrature rules to evaluate integrals appearing in the Galerkin BEM formulation of 2D Laplace model problems are introduced. The proposed quadrature schemes are based on a spline quasi-interpolation (QI) operator and properly framed in the hierarchical setting. The local nature of the QI perfectly fits with hierarchical spline constructions and leads to an efficient and accurate numerical scheme. An automatic adaptive refinement strategy is driven by a residual-based error estimator. Numerical examples show that the optimal convergence rate of the Galerkin solution is recovered by the proposed adaptive method.     

On the interpolation of concentric curvature elements

A convex G² Hermite interpolation problem of concentric curvature elements is considered in this paper. It is first proved that there is no spiral arc solution with turning angle less than or equal to π and then, that any convex solution admits at least two vertices. The curvature and the evolute profiles of such an interpolant are analyzed. In particular, conditions for the existence of a G² convex interpolant with prescribed extremal curvatures are given.     

An Efficient Density-based Approach for Data Mining Tasks

We propose a locally adaptive technique to address the problem of setting the bandwidth parameters for kernel density estimation. Our technique is efficient and can be performed in only two dataset passes. We also show how to apply our technique to efficiently solve range query approximation, classification and clustering problems for very large datasets. We validate the efficiency and accuracy of our technique by presenting experimental results on a variety of both synthetic and real datasets.     

Discovery of Novel Trace Amine-Associated Receptor 5 (TAAR5) Antagonists Using a Deep Convolutional Neural Network

Trace amine-associated receptor 5 (TAAR5) is a G protein-coupled receptor that belongs to the TAARs family (TAAR1-TAAR9). TAAR5 is expressed in the olfactory epithelium and is responsible for sensing 3-methylamine (TMA). However, recent studies showed that TAAR5 is also expressed in the limbic brain regions and is involved in the regulation of emotional behaviour and adult neurogenesis, suggesting that TAAR5 antagonism may represent a novel therapeutic strategy for anxiety and depression. We used the AtomNet^® model, the first deep learning neural network for structure-based drug discovery, to identify putative TAAR5 ligands and tested them in an in vitro BRET assay. We found two mTAAR5 antagonists with low to submicromolar activity that are able to inhibit the cAMP production induced by TMA. Moreover, these two compounds also inhibited the mTAAR5 downstream signalling, such as the phosphorylation of CREB and ERK. These two hits exhibit drug-like properties and could be used to further develop more potent TAAR5 ligands with putative anxiolytic and antidepressant activity.     

A Review on the Molecular Mechanisms of Action of Natural Products in Preventing Bone Diseases

The drugs used for treating bone diseases (BDs), at present, elicit hazardous side effects that include certain types of cancers and strokes, hence the ongoing quest for the discovery of alternatives with little or no side effects. Natural products (NPs), mainly of plant origin, have shown compelling promise in the treatments of BDs, with little or no side effects. However, the paucity in knowledge of the mechanisms behind their activities on bone remodeling has remained a hindrance to NPs’ adoption. This review discusses the pathological development of some BDs, the NP-targeted components, and the actions exerted on bone remodeling signaling pathways (e.g., Receptor Activator of Nuclear Factor κ B-ligand (RANKL)/monocyte/macrophage colony-stimulating factor (M-CSF)/osteoprotegerin (OPG), mitogen-activated protein kinase (MAPK)s/c-Jun N-terminal kinase (JNK)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), Kelch-like ECH-associated protein 1 (Keap-1)/nuclear factor erythroid 2–related factor 2 (Nrf2)/Heme Oxygenase-1 (HO-1), Bone Morphogenetic Protein 2 (BMP2)-Wnt/β-catenin, PhosphatidylInositol 3-Kinase (PI3K)/protein kinase B (Akt)/Glycogen Synthase Kinase 3 Beta (GSK3β), and other signaling pathways). Although majority of the studies on the osteoprotective properties of NPs against BDs were conducted ex vivo and mostly on animals, the use of NPs for treating human BDs and the prospects for future development remain promising.     

PAPPA Expression in Indeterminate Thyroid Nodules as Screening Test to Select Patients for Molecular Testing

Pregnancy-associated plasma protein A (PAPPA) acts as an oncogene, and its expression is increased in multiple malignancies, including thyroid cancer. Molecular tests represent a useful tool in the management of indeterminate thyroid nodules; however, they are not conducted in all centers, and they contribute to increase the per-patient cost of nodule evaluation. In this study, we examined whether PAPPA expression could represent a promising new screening test in the management of indeterminate thyroid nodules. Toward this aim, PAPPA expression was evaluated in 107 fine needle aspiration cytologies (FNAC) belonging to Bethesda III–IV categories that had been sent to molecular biology to discriminate the nature of the nodules. We found that the PAPPA expression increased and showed an elevated sensitivity (97.14%) and negative predictive value (98%) in indeterminate cytological samples positive for mutations. The enhanced expression was not linked to a specific oncogene. Our findings demonstrated that assessing the PAPPA expression in indeterminate thyroid cytologies could represent a useful screening tool to select all patients that effectively need to be sent to molecular testing, thereby, leading to a potential cost reduction in the management of patients.