Autonomic Nervous System in Obesity and Insulin-Resistance—The Complex Interplay between Leptin and Central Nervous System

The role of the autonomic nervous system in obesity and insulin-resistant conditions has been largely explored. However, the exact mechanisms involved in this relation have not been completely elucidated yet, since most of these mechanisms display a bi-directional effect. Insulin-resistance, for instance, can be caused by sympathetic activation, but, in turn, the associated hyperinsulinemia can activate the sympathetic branch of the autonomic nervous system. The picture is made even more complex by the implicated neural, hormonal and nutritional mechanisms. Among them, leptin plays a pivotal role, being involved not only in appetite regulation and glucose homeostasis but also in energy expenditure. The purpose of this review is to offer a comprehensive view of the complex interplay between leptin and the central nervous system, providing further insights on the impact of autonomic nervous system balance on adipose tissue and insulin-resistance. Furthermore, the link between the circadian clock and leptin and its effect on metabolism and energy balance will be evaluated.     

POD-assisted strategies for structural topology optimization

We propose a new numerical tool for structural optimization design. To cut down the computational burden typical of the Solid Isotropic Material with Penalization (SIMP) method, we apply Proper Orthogonal Decomposition on SIMP snapshots computed on a fixed grid to construct a rough structure (predictor) which becomes the input of a SIMP procedure performed on an anisotropic adapted mesh (corrector). The benefit of the proposed design tool is to deliver smooth and sharp layouts which require a contained computational effort before moving to the 3D printing production phase.     

Two-Dimensional Silicene–Stanene Heterostructures by Epitaxy

The synthesis of new Xenes and their potential applications prototypes have achieved significant milestones so far. However, to date the realization of Xene heterostructures in analogy with the well known van der Waals heterostructures remains an unresolved issue. Here, a Xene heterostructure concept based on the epitaxial combination of silicene and stanene on Ag(111) is introduced, and how one Xene layer enables another Xene layer of a different nature to grow on top is demonstrated. Single-phase (4 × 4) silicene is synthesized using stanene as a template, and stanene is grown on top of silicene on the other way around. In both heterostructures, in situ and ex situ probes confirm layer-by-layer growth without intercalations and intermixing. Modeling via density functional theory shows that the atomic layers in the heterostructures are strongly interacting, and hexagonal symmetry conservation in each individual layer is sequence selective. The results provide a substantial step toward currently missing Xene heterostructures and may inspire new paths for atomic-scale materials engineering.     

1,2,4-Oxadiazole Topsentin Analogs with Antiproliferative Activity against Pancreatic Cancer Cells,Targeting GSK3β Kinase

A new series of topsentin analogs, in which the central imidazole ring of the natural lead was replaced by a 1,2,4-oxadiazole moiety, was efficiently synthesized. All derivatives were pre-screened for antiproliferative activity against the National Cancer Institute (NCI-60) cell lines panel. The five most potent compounds were further investigated in various pancreatic ductal adenocarcinoma (PDAC) cell lines, including SUIT-2, Capan-1, and Panc-1 cells, eliciting EC₅₀ values in the micromolar and sub-micromolar range, associated with significant reduction of cell migration. These remarkable results might be explained by the effects of these new topsentin analogues on epithelial-to-mesenchymal transition markers, including SNAIL-1/2 and metalloproteinase-9. Moreover, flow cytometric analysis after Annexin V-FITC and propidium iodide staining demonstrated that these derivatives enhanced apoptosis of PDAC cells. Keeping with these data, the PathScan intracellular signaling and ELISA array revealed cleavage of caspase-3 and PARP and a significant inhibition of GSK3β phosphorylation, suggesting this kinase as a potential downstream target of our novel compounds. This was further supported by a specific assay for the evaluation of GSK3β activity, showing IC₅₀ values for the most active compounds against this enzyme in the micromolar range.     

Multifunctional Bioinstructive 3D Architectures to Modulate Cellular Behavior

Biological structures control cell behavior via physical, chemical, electrical, and mechanical cues. Approaches that allow us to build devices that mimic these cues in a combinatorial way are lacking due to there being no suitable instructive materials and limited manufacturing procedures. This challenge is addressed by developing a new conductive composite material, allowing for the fabrication of 3D biomimetic structures in a single manufacturing method based on two‐photon polymerization. The approach induces a combinatorial biostimulative input that can be tailored to a specific application. Development of the 3D architecture is performed with a chemically actuating photocurable acrylate previously identified for cardiomyocyte attachment. The material is made conductive by impregnation with multiwalled carbon nanotubes. The bioinstructive effect of 3D nano‐ and microtopography is combined with electrical stimulation, incorporating biochemical, and electromechanical cues to stimulate cells in serum‐free media. The manufactured architecture is combined with cardiomyocytes derived from human pluripotent stem cells. It is demonstrated that by mimicking biological occurring cues, cardiomyocyte behavior can be modulated. This represents a step change in the ability to manufacture 3D multifunctional biomimetic modulatory architectures. This platform technology has implications in areas spanning regenerative medicine, tissue engineering to biosensing, and may lead to more accurate models for predicting toxicity.     

SN-38 loading capacity of hydrophobic polymer blend nanoparticles: formulation,optimization and efficacy evaluation

One of the most important problems in nanoencapsulation of extremely hydrophobic drugs is poor drug loading due to rapid drug crystallization outside the polymer core. The effort to use nanoprecipitation, as a simple one-step procedure with good reproducibility and FDA approved polymers like Poly(lactic-co-glycolic acid) (PLGA) and Polycaprolactone (PCL), will only potentiate this issue. Considering that drug loading is one of the key defining characteristics, in this study we attempted to examine whether the nanoparticle (NP) core composed of two hydrophobic polymers will provide increased drug loading for 7-Ethyl-10-hydroxy-camptothecin (SN-38), relative to NPs prepared using individual polymers. D-optimal design was applied to optimize PLGA/PCL ratio in the polymer blend and the mode of addition of the amphiphilic copolymer Lutrol^®F127 in order to maximize SN-38 loading and obtain NPs with acceptable size for passive tumor targeting. Drug/polymer and polymer/polymer interaction analysis pointed to high degree of compatibility and miscibility among both hydrophobic polymers, providing core configuration with higher drug loading capacity. Toxicity studies outlined the biocompatibility of the blank NPs. Increased in vitro efficacy of drug-loaded NPs compared to the free drug was confirmed by growth inhibition studies using SW-480 cell line. Additionally, the optimized NP formulation showed very promising blood circulation profile with elimination half-time of 7.4?h.     

Controlled Micro/Nanodome Formation in Proton‐Irradiated Bulk Transition‐Metal Dichalcogenides

At the few‐atom‐thick limit, transition‐metal dichalcogenides (TMDs) exhibit strongly interconnected structural and optoelectronic properties. The possibility to tailor the latter by controlling the former is expected to have a great impact on applied and fundamental research. As shown here, proton irradiation deeply affects the surface morphology of bulk TMD crystals. Protons penetrate the top layer, resulting in the production and progressive accumulation of molecular hydrogen in the first interlayer region. This leads to the blistering of one‐monolayer thick domes, which stud the crystal surface and locally turn the dark bulk material into an efficient light emitter. The domes are stable (>2‐year lifetime) and robust, and host strong, complex strain fields. Lithographic techniques provide a means to engineer the formation process so that the domes can be produced with well‐ordered positions and sizes tunable from the nanometer to the micrometer scale, with important prospects for so far unattainable applications.     

Minimizing conservativity violations in ontology alignments: algorithms and evaluation

In order to enable interoperability between ontology-based systems, ontology matching techniques have been proposed. However, when the generated mappings lead to undesired logical consequences, their usefulness may be diminished. In this paper, we present an approach to detect and minimize the violations of the so-called conservativity principle where novel subsumption entailments between named concepts in one of the input ontologies are considered as unwanted. The practical applicability of the proposed approach is experimentally demonstrated on the datasets from the Ontology Alignment Evaluation Initiative.