Constrained and unconstrained deep image prior optimization models with automatic regularization.

Deep Image Prior (DIP) is currently among the most efficient unsupervised deep learning based methods for ill-posed inverse problems in imaging. This novel framework relies on the implicit regularization provided by representing images as the output of generative Convolutional Neural Network (CNN) architectures. So far, DIP has been shown to be an effective approach when combined with classical and novel regularizers. Unfortunately, to obtain appropriate solutions, all the models proposed up to now require an accurate estimate of the regularization parameter. To overcome this difficulty, we consider a locally adapted regularized unconstrained model whose local regularization parameters are automatically estimated for additively separable regularizers. Moreover, we propose a novel constrained formulation in analogy to Morozov's discrepancy principle which enables the application of a broader range of regularizers. Both the unconstrained and the constrained models are solved via the proximal gradient descent-ascent method. Numerical results demonstrate the robustness with respect to image content, noise levels and hyperparameters of the proposed models on both denoising and deblurring of simulated as well as real natural and medical images.

Upper Extremity Functional Rehabilitation for Stroke Survivors Using Error-Augmented Visual Feedback: Interim Results.

Stroke rehabilitation is often terminated once a plateau in motor recovery is observed, but new training modalities have demonstrated that further functional improvement is possible after the onset of the chronic phase. In particular, feedback technologies augmenting error proved to foster the relearning process. Here we explore the possibility of a robot-free implementation of Error-Augmentation (EA), where only visual feedback is distorted. We present the interim results from our ongoing blinded, randomized, controlled clinical trial testing the efficacy of parallel bimanual reaching with visual EA. Subjects trained in the virtual environment in 45-minute sessions, three times a week, for three weeks, half with and half without EA. A blinded therapist performed clinical evaluations before, 1 week after, and two months after training. Available results showed that both groups significantly improved. An advantage in the treatment group could be tracked at all time points, but no statistical significance was detectable between groups. Gains in the two groups were found to be compatible with the results of previous studies using robots and may prove to have similar effectiveness without the need for a costly and complicated robotic device. One new finding was that EA caused significantly higher inter-trial variability.

Exploring the Biological Activity of a Library of 1,2,5-Oxadiazole Derivatives Endowed With Antiproliferative Activity.

BACKGROUND/AIM: The identification of a series of oxadiazole-based compounds, as promising antiproliferative agents, has been previously reported. The aim of this study was to explore the SAR of newly-synthesized oxadiazole derivatives and identify their molecular targets. MATERIALS AND METHODS: A small library of 1,2,5-oxadiazole derivatives was synthetized and their antiproliferative activity was tested by the MTT assay. Their interaction with topoisomerase I was evaluated and a molecular docking study was performed. RESULTS: Several candidates showed cytotoxicity towards two human tumor cell lines, HCT-116 (colorectal carcinoma) and HeLa (cervix adenocarcinoma). Some derivatives exhibited inhibitory effects on the catalytic activity of topoisomerase I and this effect was supported by docking studies. CONCLUSION: The enzyme inhibition results, although not directly related to cytotoxicity, suggest that a properly modified 1,2,5 oxadiazole scaffold could be considered for the development of new anti-topoisomerase agents.

A field-based disparity analysis of new 1,2,5-oxadiazole derivatives endowed with antiproliferative activity.

A series of 1,2,5-oxadiazoles were synthesized as new potential antiproliferative agents. The in vitro cytotoxic activity evaluation of title compounds through MTT assay revealed that some of them showed significant activity against the HCT-116 cancer cell line. The field-based disparity analysis provided indications about the electrostatic, hydrophobic, and shape features underlying the cytotoxicity, suggesting that increasing the negative electrostatic field on the heterocyclic core of the structure has positive effects on the activity. The structure-activity relationships (SAR) around a particular compound can be explained allowing for a structural rationale for the differences in activity. The SAR provided by this series of compounds can be exploited to carry out further lead optimization.

An in vivo active 1,2,5-oxadiazole Pt(II) complex: A promising anticancer agent endowed with STAT3 inhibitory properties.

New Pt(II) complexes (Pt-1-3) bearing 1,2,5-oxadiazole ligands (1-3) were synthesized, characterized and evaluated for their ability to disrupt STAT3 dimerization. Ligand 3·HCl showed cytotoxic effects on HCT-116 cells (IC50 = 95.2 µM) and a selective ability to interact with STAT3 (IC50 = 8.2 µM) versus STAT1 (IC50 > 30 µM). Its corresponding platinum complex Pt-3 exhibited an increased cytotoxicity (IC50 = 18.4 µM) and a stronger interaction with STAT3 (IC50 = 1.4 µM), leading to inhibition of its signaling pathway. Pt-3 was also evaluated in cell-based assays for its action on p53 expression and on STAT3 phosphorylation. In syngeneic murine Lewis lung carcinoma (LLC) implanted in C57BL/6 mice, Pt-3 showed a higher antitumor activity with fewer side effects than cisplatin.

Antimicrobial activity of four essential oils against pigmenting Pseudomonas fluorescens and biofilmproducing Staphylococcus aureus of dairy origin.

Essential oils (EOs) are mixtures of secondary metabolites of plant origin with many useful properties, among which the antimicrobial activity is also of interest for the food industry. EOs can exert their antimicrobial potential both directly, in food products and active packaging, and indirectly, as sanitizing and anti-biofilm agents of food facility surfaces. Aim of this research was to evaluate the antimicrobial activity of four EOs (bergamot, cinnamon, manuka and thyme) against Pseudomonas fluorescens and Staphylococcus aureus isolated from milk and dairy products. The chemical composition of EOs was evaluated by Gas Chromatography-Mass Spectrometry analysis. Minimum Inhibitory Concentration values were determined by a microplate method against 9 Ps. fluorescens from marketed mozzarella with blue discoloration defect, and 3 biofilm-producing S. aureus from milk. Reference ATCC strains were included. Pigment production activity by Ps. fluorescens was assessed both in culture and in cheese. EOs of manuka (leptospermone 23%) and thyme (carvacrol 30%, pcymene 20%, thymol 15%) showed the highest antimicrobial activity against S. aureus, MIC values were 0.012%-0.024% and 0.024% v/v, respectively; meanwhile EOs from thyme and cinnamon (cinnamaldehyde 55%) exhibited the best activity against Ps. fluorescens with MIC values of 0.098%-0.195% and 0.195%-0.391% v/v, respectively. The antimicrobial activity of these EOs is promising and they could be exploited in the dairy production chain.

Identification of a new STAT3 dimerization inhibitor through a pharmacophore-based virtual screening approach.

Signal transducer and activator of transcription 3 (STAT3) plays an essential role in cell growth regulation and survival. An aberrant STAT3 activation and/or expression is implied in various solid and blood tumors as well as in other pathologies like rheumatoid arthritis and pulmonary fibrosis, thus making the search for STAT3 inhibitors a growing field of study. With the aim of identifying new inhibitors of STAT3 dimerization, we screened a database including more than 1 320 000 commercially available compounds using a receptor-based pharmacophore model comprising the key protein-protein interactions identified in the STAT3 dimer and refining the search through docking and molecular dynamic simulations studies. STAT3 binding assays revealed a significant STAT3 inhibitory activity and selectivity versus Grb2 for one of the four top-scored compounds, thus verifying the reliability of the virtual screening workflow. Moreover, such compound could already be considered as a lead for the development of new and more potent STAT3 dimerization inhibitors.

Mycobacterium tuberculosis Low Molecular Weight Phosphatases (MPtpA and MPtpB): From Biological Insight to Inhibitors.

Mycobacterium tuberculosis (Mtb), the main aetiological agent of tuberculosis (TB) in humans, is estimated to cause nearly two million deaths every year. Despite their huge therapeutic value, existing antitubercular drugs have several shortcomings, such as for instance the insurgence of drug resistance, which is mostly triggered by lack of compliance during the lengthy treatment. Novel and more effective drugs against Mtb acting on new molecular targets are therefore in demand in order to reduce treatment time and address the severe issue related to the progressive loss of antibiotic efficacy. Mtb encodes for two low molecular weight tyrosine specific phosphatases (MPtpA and MPtpB) that are crucially involved in Mtb pathogenesis. While MPtpA interferes with phagosome acidification blocking its maturation, MPtpB disrupts host signal transduction cascades, causing immune response subversion in the host. The important role played by both MPtpA and MPtpB in host-pathogen interaction makes them appealing targets for TB drug discovery. Here, we provide an exhaustive review of the current knowledge on MPtpA and MPtpB characterization and role in TB pathogenesis. In particular, special emphasis is placed on all class of inhibitors that have been developed and studied to date; their binding mode, design strategies, biological activities, main pharmacophore features as well as the efforts to overcome the poor druggability of their target are summarized in detail.