Diphenyl-Methane Based Thyromimetic Inhibitors for Transthyretin Amyloidosis

Thyromimetics, whose physicochemical characteristics are analog to thyroid hormones (THs) and their derivatives, are promising candidates as novel therapeutics for neurodegenerative and metabolic pathologies. In particular, sobetirome (GC-1), one of the initial halogen-free thyromimetics, and newly synthesized IS25 and TG68, with optimized ADME-Tox profile, have recently attracted attention owing to their superior therapeutic benefits, selectivity, and enhanced permeability. Here, we further explored the functional capabilities of these thyromimetics to inhibit transthyretin (TTR) amyloidosis. TTR is a homotetrameric transporter protein for THs, yet it is also responsible for severe amyloid fibril formation, which is facilitated by tetramer dissociation into non-native monomers. By combining nuclear magnetic resonance (NMR) spectroscopy, computational simulation, and biochemical assays, we found that GC-1 and newly designed diphenyl-methane-based thyromimetics, namely IS25 and TG68, are TTR stabilizers and efficient suppressors of TTR aggregation. Based on these observations, we propose the novel potential of thyromimetics as a multi-functional therapeutic molecule for TTR-related pathologies, including neurodegenerative diseases.     

Resveratrol as Chemosensitizer Agent: State of Art and Future Perspectives

Resistance to chemotherapy still remains a major challenge in the clinic, impairing the quality of life and survival rate of patients. The identification of unconventional chemosensitizing agents is therefore an interesting aspect of cancer research. Resveratrol has emerged in the last decades as a fascinating molecule, able to modulate several cancer-related molecular mechanisms, suggesting a possible application as an adjuvant in cancer management. This review goes deep into the existing literature concerning the possible chemosensitizing effect of resveratrol associated with the most conventional chemotherapeutic drugs. Despite the promising effects observed in different cancer types in in vitro studies, the clinical translation still presents strong limitations due to the low bioavailability of resveratrol. Recently, efforts have been moved in the field of drug delivery to identifying possible strategies/formulations useful for a more effective administration. Despite the necessity of a huge implementation in this research area, resveratrol appears as a promising molecule able to sensitize resistant tumors to drugs, suggesting its potential use in therapy-refractory cancer patients.     

Preliminary Evidence on the Diagnostic and Molecular Role of Circulating Soluble EGFR in Non-Small Cell Lung Cancer

Assessment of biological diagnostic factors providing clinically-relevant information to guide physician decision-making are still needed for diseases with poor outcomes, such as non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) is a promising molecule in the clinical management of NSCLC. While the EGFR transmembrane form has been extensively investigated in large clinical trials, the soluble, circulating EGFR isoform (sEGFR), which may have a potential clinical use, has rarely been considered. This study investigates the use of sEGFR as a potential diagnostic biomarker for NSCLC and also characterizes the biological function of sEGFR to clarify the molecular mechanisms involved in the course of action of this protein. Plasma sEGFR levels from a heterogeneous cohort of 37 non-advanced NSCLC patients and 54 healthy subjects were analyzed by using an enzyme-linked immunosorbent assay. The biological function of sEGFR was analyzed in vitro using NSCLC cell lines, investigating effects on cell proliferation and migration. We found that plasma sEGFR was significantly decreased in the NSCLC patient group as compared to the control group (median value: 48.6 vs. 55.6 ng/mL respectively; p = 0.0002). Moreover, we demonstrated that sEGFR inhibits growth and migration of NSCLC cells in vitro through molecular mechanisms that included perturbation of EGF/EGFR cell signaling and holoreceptor internalization. These data show that sEGFR is a potential circulating biomarker with a physiological protective role, providing a first approach to the functional role of the soluble isoform of EGFR. However, the impact of these data on daily clinical practice needs to be further investigated in larger prospective studies.     

Watermarked 3-D Mesh Quality Assessment

This paper addresses the problem of assessing distortions produced by watermarking 3D meshes. In particular, a new methodology for subjective evaluation of the quality of 3D objects is proposed and implemented. Two objective metrics derived from measures of surface roughness are then proposed and their efficiency to predict the perceptual impact of 3D watermarking is assessed and compared with the state of the art. Results obtained show good correlations between the proposed objective metrics and subjective assessments by human observers     

Superconductivity in a new quaternary phase with HgSm0.5In0.5Pb2 composition

This work reports a systematic study on the structural and superconducting properties in the Hg-Sm-In-Pb system. It is investigated how In and Sm dopings influence the superconducting properties of the HgPb₂ phase which was recently reported. Results for the HgSm_1 − xPb₂ system show that Sm atoms substitute Hg vacancies in the tetragonal phase which do not affect the onset critical temperature of the HgPb₂ compound. Simultaneous Sm and In doping effects on the properties of the HgPb₂ phase are also studied. Experimental and simulations of X-ray powder diffractograms suggest that the HgSm_1 − xIn_xPb₂ system (0.2 ≤ x ≤ 0.7) has a pseudo-cubic structure with lattice parameters near 4.88 Å. Superconducting properties measurements show that this system has an optimum doping at x ∼ 0.5 with the onset critical temperature close to 6.9 K. This is the highest superconducting critical temperature for the AuCu prototype so far reported.     

An implementation of storage management in capability environments

The exploitation of the salient features of capability-based addressing environments leads to a high number of small objects existing in memory at the same time. It is thus necessary to enhance the efficiency of the mechanisms for object relocation, and to avoid congestion of input/output devices due to swapping. In this paper, we present an approach to the management of a large virtual memory space aimed at solving these problems. We insert partial information concerning the physical allocation of each object into the virtual identifier of this object. Objects are grouped into large swapping units, called pages. The page size is independent of the average object size. This results in enhanced efficiency in managing the relocation information both with regard to memory requirements and access times. The allocation of objects into pages, and the movement of pages through the memory hierarchy, are controlled by user processes. This means that programs which have knowledge of their own use of virtual memory can increase their locality of reference, diminish the number of swap operations and reduce fragmentation.     

An exploratory study of the impact of antipatterns on class change- and fault-proneness

Antipatterns are poor design choices that are conjectured to make object-oriented systems harder to maintain. We investigate the impact of antipatterns on classes in object-oriented systems by studying the relation between the presence of antipatterns and the change- and fault-proneness of the classes. We detect 13 antipatterns in 54 releases of ArgoUML, Eclipse, Mylyn, and Rhino, and analyse (1) to what extent classes participating in antipatterns have higher odds to change or to be subject to fault-fixing than other classes, (2) to what extent these odds (if higher) are due to the sizes of the classes or to the presence of antipatterns, and (3) what kinds of changes affect classes participating in antipatterns. We show that, in almost all releases of the four systems, classes participating in antipatterns are more change-and fault-prone than others. We also show that size alone cannot explain the higher odds of classes with antipatterns to underwent a (fault-fixing) change than other classes. Finally, we show that structural changes affect more classes with antipatterns than others. We provide qualitative explanations of the increase of change- and fault-proneness in classes participating in antipatterns using release notes and bug reports. The obtained results justify a posteriori previous work on the specification and detection of antipatterns and could help to better focus quality assurance and testing activities.     

Preparation and flame resistance properties of revolutionary self-extinguishing epoxy nanocomposites based on layered double hydroxides

Layered double hydroxides/epoxy (LDHs/EP) nanocomposites were prepared from organo-modified LDHs, a diglycidyl ether of bisphenol A monomer (DGEBA) and amine curing agents. The organo-modified LDHs were obtained by ionic exchange of a magnesium-aluminum carbonate LDH in an acid medium. X-ray diffraction and transmission electron microscopy showed a dispersion of the layers at a nanometer scale, indicating the formation of LDH/EP nanocomposites. The thermal degradation and flame resistance properties of LDH/EP nanocomposites, montmorillonite-epoxy (MMT/EP) nanocomposites, LDH/EP microcomposites and aluminum hydroxide-epoxy microcomposites were compared by thermogravimetrical analyses, simultaneous thermal analyses, UL94 and cone calorimeter tests. Only LDH/EP nanocomposites showed self-extinguishing behavior in the horizontal UL94 test; LDH/EP microcomposites and MMT/EP nanocomposites samples burned completely showing that the unique flame resistance of LDH/EP nanocomposites is related to both the level of dispersion and the intrinsic properties of LDH clay. Furthermore, cone calorimeter revealed intumescent behavior for LDH/EP nanocomposites and a higher reduction in the peak heat release rate compared to MMT/EP nanocomposites.     

Fluoroelastomers-dependence of relaxation phenomena on composition

The dynamic-mechanical properties of some fluoroelastomers were determined as a function of composition at low frequency (≈ 1 Hz), by means of a free oscillation torsion pendulum, between −180°C and the softening point. Vinylidenefluoride (VDF)-hexafluoropropene (HFP) copolymers of molar composition 0–39% HFP and terpolymers of VDF and HFP with up to 30mol% tetrafluoroethylene (TFE) and a constant VDF to HFP molar ratio of 3.4 were considered. Two relaxation processes typical of the amorphous phase were found. The first, located at about −87°C, is related to local motions and the transition temperature was found to be independent of composition for copolymers, while it depends on TFE molar content for terpolymers. The second is related to the glass transition and the transition temperature depends on the composition. However, for semicrystalline copolymers the double glass transition phenomenon was observed. When crystallinity goes to zero at about 20 mol% HFP, only one transition is observed. It was also found that ordered structures can take place for terpolymers when TFE molar concentration exceeds 20%. The crystal disorder transition of pure PVDF (75°C) is observed also for low HFP concentrations but the transition temperature is strongly reduced. Analogies between the VDF-HFP and E-P systems are also discussed.