Different miRNA Profiles in Plasma Derived Small and Large Extracellular Vesicles from Patients with Neurodegenerative Diseases

Identifying biomarkers is essential for early diagnosis of neurodegenerative diseases (NDs). Large (LEVs) and small extracellular vesicles (SEVs) are extracellular vesicles (EVs) of different sizes and biological functions transported in blood and they may be valid biomarkers for NDs. The aim of our study was to investigate common and different miRNA signatures in plasma derived LEVs and SEVs of Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic Lateral Sclerosis (ALS) and Fronto-Temporal Dementia (FTD) patients. LEVs and SEVs were isolated from plasma of patients and healthy volunteers (CTR) by filtration and differential centrifugation and RNA was extracted. Small RNAs libraries were carried out by Next Generation Sequencing (NGS). MiRNAs discriminate all NDs diseases from CTRs and they can provide a signature for each NDs. Common enriched pathways for SEVs were instead linked to ubiquitin mediated proteolysis and Toll-like receptor signaling pathways and for LEVs to neurotrophin signaling and Glycosphingolipid biosynthesis pathway. LEVs and SEVs are involved in different pathways and this might give a specificity to their role in the spreading of the disease. The study of common and different miRNAs transported by LEVs and SEVs can be of great interest for biomarker discovery and for pathogenesis studies in neurodegeneration.     

Functional nanocomposites with graphene-DNA hybrid fillers: Synthesis and surface properties under UV irradiation

In this work, nanocomposites containing assemblies of graphene nanoplatelets (GNP) and double-stranded DNA are investigated as UV-sensitive materials, as they show good electrical properties combined with the chemical sensitivity of DNA to UV radiation, particularly to the more energetic UV-C band. Nanocomposite films were prepared by drop-casting technique after embedding the graphene-DNA fillers in a flexible polydimethylsiloxane (PDMS) matrix using a suitable solvent. The synthesis was optimized in order to improve the dispersion of the graphene-DNA elements in the polymer matrix, as the sensing properties of the nanocomposite materials are highly affected by the amount and homogeneity of the filler dispersion. The electrical and thermal properties of the GNP-DNA/PDMS films, as well as their surface morphology and wettability, were investigated before and after exposure to UV-C radiation using complementary techniques. Results give information on the potential applications of these novel functional nanocomposites for radiation monitoring in environments that are characterized by high levels of biologically-damaging UV radiation.     

Shape controlled spherical (0D) and rod-like (1D) silica nanoparticles in silica/styrene butadiene rubber nanocomposites: Role of the particle morphology on the filler reinforcing effect

Silica/styrene butadiene rubber (SBR) nanocomposites were prepared by blending method using shape-controlled spherical and rod-like nanoparticles with different aspect ratios as filler for the rubber reinforcement. The differently shaped silica particles were synthesized by sol–gel method using tetraethoxysilane (TEOS) and (3-mercaptopropyl) trimethoxysilane (MPTSM) as silica precursors, and cetyltrimethylammonium bromide (CTAB) as structure directing agent. This strategy allowed to study the influence of the particle morphology on the reinforcing effect independently of the silica surface chemistry and considering the aspect ratio as the only geometrical variance. Spherical and anisotropic rod-like particles, dispersed in the nanocomposites, formed a network of particles bridged by thin rubber layers throughout the SBR matrix. Moreover, differently oriented domains of aligned rods are observed when the aspect ratio of particles increases and is ≥2. Dynamic-mechanical properties demonstrated that the rod-like particles with the higher aspect ratio provided stronger reinforcement of the rubber. This was related to the self-alignment of the anisotropic particles and to the consequent larger filler/polymer interface, compared to that of spherical ones.     

Sugar‐Based Arylsulfonamide Carboxylates as Selective and Water‐Soluble Matrix Metalloproteinase‐12 Inhibitors

Matrix metalloproteinase‐12 (MMP‐12) can be considered an attractive target to study selective inhibitors useful in the development of new therapies for lung and cardiovascular diseases. In this study, a new series of arylsulfonamide carboxylates, with increased hydrophilicity resulting from conjugation with a β‐N‐acetyl‐d ‐glucosamine moiety, were designed and synthesized as MMP‐12 selective inhibitors. Their inhibitory activity was evaluated on human MMPs by using the fluorimetric assay, and a crystallographic analysis was performed to characterize their binding mode. Among these glycoconjugates, a nanomolar MMP‐12 inhibitor with improved water solubility, compound 3 [(R)‐2‐(N‐(2‐(3‐(2‐acetamido‐2‐deoxy‐β‐d ‐glucopyranosyl)thioureido)ethyl)biphenyl‐4‐ylsulfonamido)‐3‐methylbutanoic acid], was identified.     

Integrated analytical study for the authentication of five Russian icons (XVI–XVII centuries)

This article presents an integrated approach for the authentication of five Russian icons through the study of their paint materials (elemental composition and stratigraphic mapping), state of conservation and artistic technique. The results of the applied analytical protocol, involving optical and scanning electron microscopy coupled with energy‐dispersive X‐ray spectrometry and Fourier transformed infrared spectroscopy/microspectroscopy, led to the conclusion that the five icons belong to the same group and iconographic school (from Northern Russia) and date from the end of the 16th century to the beginning of 17th century. Because of massive overpainting, the icons “suffered” a change in iconographic style and significance, and restoration treatment brought to light the original painting and its attribution. Identification of the composition of the original chromatic palette used by the iconographer, the stratigraphic mapping and the conservation state of the painting materials, along with the features of the original artistic technique, furnished key elements for the icons' authentication. Here, we present the first experimental data concerning the identification of the authentication characteristics, being part of a large project that has as its final aim the evaluation of the effectiveness and effects of the cleaning agent on the paint layers. Microsc. Res. Tech. 2009. © 2009 Wiley‐Liss, Inc.     

Physical aging in graphite/epoxy composites

Matrix-dominated mechanical behavior of a graphite/epoxy composite has been found to be affected by sub-T_g annealing. Postcured (±45°)_4S specimens of Thornel 300 graphite/Narmco 5208 epoxy were quenched from above T_g and given a sub-T_g annealing at 140°C for times up to 10⁵ min. The ultimate tensile strength, strain-to-break, and toughness of the composite material were found to decrease as functions of sub-T_g annealing time. No weight loss was observed during the sub-T_g annealing. The time-dependent change in mechanical behavior is explained on the basis of free-volume changes that are related to the physical aging of the nonequilibrium glassy network-epoxy. The results imply possible changes in composite properties with service time.     

Resveratrol-like Compounds as SIRT1 Activators

The sirtuin 1 (SIRT1) activator resveratrol has emerged as a promising candidate for the prevention of vascular oxidative stress, which is a trigger for endothelial dysfunction. However, its clinical use is limited by low oral bioavailability. In this work, we have applied a previously developed computational protocol to identify the most promising derivatives from our in-house chemical library of resveratrol derivatives. The most promising compounds in terms of SIRT1 activation and oral bioavailability, predicted in silico, were evaluated for their ability to activate the isolated SIRT1 enzyme. Then, we assessed the antioxidant effects of the most effective derivative, compound 3d, in human umbilical vein endothelial cells (HUVECs) injured with H₂O₂ 100 µM. The SIRT1 activator 3d significantly preserved cell viability and prevented an intracellular reactive oxygen species increase in HUVECs exposed to the oxidative stimulus. Such effects were partially reduced in the presence of a sirtuin inhibitor, sirtinol, confirming the potential role of sirtuins in the activity of resveratrol and its derivatives. Although 3d appeared less effective than resveratrol in activating the isolated enzyme, the effects exhibited by both compounds in HUVECs were almost superimposable, suggesting a higher ability of 3d to cross cell membranes and activate the intracellular target SIRT1.     

Impact of CFTR Modulators on the Impaired Function of Phagocytes in Cystic Fibrosis Lung Disease

Cystic fibrosis (CF), the most common genetically inherited disease in Caucasian populations, is a multi-systemic life-threatening autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In 2012, the arrival of CFTR modulators (potentiators, correctors, amplifiers, stabilizers, and read-through agents) revolutionized the therapeutic approach to CF. In this review, we examined the physiopathological mechanism of chronic dysregulated innate immune response in the lungs of CF patients with pulmonary involvement with particular reference to phagocytes, critically analyzing the role of CFTR modulators in influencing and eventually restoring their function. Our literature review highlighted that the role of CFTR in the lungs is crucial not only for the epithelial function but also for host defense, with particular reference to phagocytes. In macrophages and neutrophils, the CFTR dysfunction compromises both the intricate process of phagocytosis and the mechanisms of initiation and control of inflammation which then reverberates on the epithelial environment already burdened by the chronic colonization of pathogens leading to irreversible tissue damage. In this context, investigating the impact of CFTR modulators on phagocytic functions is therefore crucial not only for explaining the underlying mechanisms of pleiotropic effects of these molecules but also to better understand the physiopathological basis of this disease, still partly unexplored, and to develop new complementary or alternative therapeutic approaches.     

Of Mouse and Man: Cross-Species Characterization of Hypertensive Cardiac Remodeling

Hypertension is a major public health concern and poses a significant risk for sudden cardiac death (SCD). However, the characterisation of human tissues tends to be macroscopic, with little appreciation for the quantification of the pathological remodelling responsible for the advancement of the disease. While the components of hypertensive remodelling are well established, the timeline and comparative quantification of pathological changes in hypertension have not been shown before. Here, we sought to identify the phasing of cardiac remodelling with hypertension using post-mortem tissue from SCD patients with early and advanced hypertensive heart disease (HHD). In order to study and quantify the progression of phenotypic changes, human specimens were contrasted to a well-described angiotensin-II-mediated hypertensive mouse model. While cardiomyocyte hypertrophy is an early adaptive response in the mouse that stabilises in established hypertension and declines as the disease progresses, this finding did not translate to the human setting. In contrast, optimising fibrosis quantification methods and applying them to each setting identified perivascular fibrosis as the prevailing possible cause for overall disease progression. Indeed, assessing myocardial inflammation highlights CD45+ inflammatory cell infiltration that precedes fibrosis and is an early-phase event in response to elevated arterial pressures that may underscore perivascular remodelling. Along with aetiology insight, we highlight cross-species comparison for quantification of cardiac remodelling in human hypertension. As such, this platform could assist with the development of therapies specific to the disease phase rather than targeting global components of hypertension, such as blood pressure lowering.