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     

Detection of DNA in virgin olive oils extracted from destoned fruits

Characterization of genetic identity using DNA extracted from olive oil has the potential to facilitate assessment of origin and varietal conformity. Such a prospect is particularly interesting in light of the increased regional spread of olive cultivars and their various contributions to olive oil mixtures for certification of denomination of origin. Towards this goal, we have devised a reliable method for extracting DNA from virgin olive oil that was utilized on monovariety oils from the single, self-sterile cultivar ‘Ogliarola salentina’. We show that DNA purified from oil can be used for microsatellite analysis and that the profile of DNA purified from a monovariety oil corresponds to the profile of DNA purified from the leaves of the same cultivar. While DNA from the pollinators present in the genome of the seed embryo, could potentially contain alleles not present in the genome fruit pulp, invalidating the molecular traceability of olive oil, we show for the first time that there is no contamination of seed embryo DNA in a monovariety oil. Thus, this molecular assay is applicable for monovariety olive oils.     

Epstein-Barr virus nuclear antigen 2 transactivates the long terminal repeat of human immunodeficiency virus type 1

Human immunodeficiency virus type 1 (HIV-1)-infected subjects show a high incidence of Epstein-Barr virus (EBV) infection. This suggests that EBV may function as a cofactor that affects HIV-1 activation and may play a major role in the progression of AIDS. To test this hypothesis, we generated two EBV-negative human B-cell lines that stably express the EBNA2 gene of EBV. These EBNA2-positive cell lines were transiently transfected with plasmids that carry either the wild type or deletion mutants of the HIV-1 long terminal repeat (LTR) fused to the chloramphenicol acetyltransferase (CAT) gene. There was a consistently higher HIV-1 LTR activation in EBNA2-expressing cells than in control cells, which suggested that EBNA2 proteins could activate the HIV-1 promoter, possibly by inducing nuclear factors binding to HIV-1 cis-regulatory sequences. To test this possibility, we used CAT-based plasmids carrying deletions of the NF-kappa B (pNFA-CAT), Sp1 (pSpA-CAT), or TAR (pTAR-CAT) region of the HIV-1 LTR and retardation assays in which nuclear proteins from EBNA2-expressing cells were challenged with oligonucleotides encompassing the NF-kappa B or Sp1 region of the HIV-1 LTR. We found that both the NF-kappa B and the Sp1 sites of the HIV-1 LTR are necessary for EBNA2 transactivation and that increased expression resulted from the induction of NF-kappa B-like factors. Moreover, experiments with the TAR-deleted pTAR-CAT and with the tat-expressing pAR-TAT plasmids indicated that endogenous Tat-like proteins could participate in EBNA2-mediated activation of the HIV-1 LTR and that EBNA2 proteins can synergize with the viral tat transactivator. Transfection experiments with plasmids expressing the EBNA1, EBNA3, and EBNALP genes did not cause a significant HIV-1 LTR activation. Thus, it appears that among the latent EBV genes tested, EBNA2 was the only EBV gene active on the HIV-1 LTR. The transactivation function of EBNA2 was also observed in the HeLa epithelial cell line, which suggests that EBV and HIV-1 infection of non-B cells may result in HIV-1 promoter activation. Therefore, a specific gene product of EBV, EBNA2, can transactivate HIV-1 and possibly contribute to the clinical progression of AIDS.     

Green Tax Reforms and Computational Economics A Do-it-yourself Approach

The double or even triple dividend hypothesis of green tax reforms has beena major issue of dispute in both the scientific community and the politicalarena during the last decade. Theoretical analysis has provided a number ofimportant qualitative insights to the debate but lacks of actual policyrelevance due to very restrictive assumptions. Applied research that takes thestep from stylized analytical to complex numerical models usually comes as ablackbox to non-expert modelers. This paper aims at bridging the gap betweenstylized theoretical work and numerical analysis. We develop a flexible,interactive simulation model which is accessible underhttp://brw.zew.de. Users can specify their own green tax reforms andevaluate the induced economic and environmental effects. Based on illustrativesimulations, we demonstrate the usefulness of our do-it-yourself approach fora better understanding of the double (triple) dividend hypothesis.     

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.