miRNA Expression Is Increased in Serum from Patients with Semantic Variant Primary Progressive Aphasia

Primary progressive aphasia (PPA) damages the parts of the brain that control speech and language. There are three clinical PPA variants: nonfluent/agrammatic (nfvPPA), logopenic (lvPPA) and semantic (svPPA). The pathophysiology underlying PPA variants is not fully understood, including the role of micro (mi)RNAs which were previously shown to play a role in several neurodegenerative diseases. Using a two-step analysis (array and validation through real-time PCR), we investigated the miRNA expression pattern in serum from 54 PPA patients and 18 controls. In the svPPA cohort, we observed a generalized upregulation of miRNAs with miR-106b-5p and miR-133a-3p reaching statistical significance (miR-106b-5p: 2.69 ± 0.89 mean ± SD vs. 1.18 ± 0.28, p < 0.0001; miR-133a-3p: 2.09 ± 0.10 vs. 0.74 ± 0.11 mean ± SD, p = 0.0002). Conversely, in lvPPA, the majority of miRNAs were downregulated. GO enrichment and KEGG pathway analyses revealed that target genes of both miRNAs are involved in pathways potentially relevant for the pathogenesis of neurodegenerative diseases. This is the first study that investigates the expression profile of circulating miRNAs in PPA variant patients. We identified a specific miRNA expression profile in svPPA that could differentiate this pathological condition from other PPA variants. Nevertheless, these preliminary results need to be confirmed in a larger independent cohort.     

Ex Vivo Evaluation of Ethosomes and Transethosomes Applied on Human Skin: A Comparative Study

In this study, the transdermal fate of vesicular nanosystems was investigated. Particularly, ethosomes based on phosphatidylcholine 0.9% w/w and transethosomes based on phosphatidylcholine 0.9 or 2.7% w/w plus polysorbate 80 0.3% w/w as an edge activator were prepared and characterized. The vesicle mean size, morphology and deformability were influenced by both phosphatidylcholine and polysorbate 80. Indeed, the mean diameters of ethosome were around 200 nm, while transethosome’s mean diameters were 146 or 350 nm in the case of phosphatidylcholine 0.9 or 2.7%, w/w, respectively. The highest deformability was achieved by transethosomes based on phosphatidylcholine 0.9%, w/w. The three types of vesicular nanosystems were applied on explanted human skin maintained in a bioreactor. Transmission electron microscopy demonstrated that all vesicles were able to enter the skin, keeping their structural integrity. Notably, the vesicle penetration capability was influenced by their physical-chemical features. Indeed, ethosomes reached keratinocytes and even the dermis, phosphatidylcholine 0.9% transethosomes were found in keratinocytes and phosphatidylcholine 2.7% transethosomes were found only in corneocytes of the outer layer. These findings open interesting perspectives for a differentiated application of these vesicles for transdermal drug delivery as a function of the cutaneous pathology to be addressed.     

Circulating Non-Coding RNA Levels Are Altered in Autosomal Dominant Frontotemporal Dementia

Frontotemporal Dementia (FTD) represents a highly heritable neurodegenerative disorder. Most of the heritability is caused by autosomal dominant mutations in the Microtubule-Associated Protein Tau (MAPT), Progranulin (GRN), and the pathologic exanucleotide expansion of C9ORF72 genes. At the pathological level, either the tau or the TAR DNA-binding protein (TDP-43) account for almost all cases of FTD. Pathogenic mechanisms are just arising, and the emerging role of non-coding RNAs (ncRNAs), such as microRNAs (miRNA) and long non-coding RNAs (lncRNAs), have become increasingly evident. Using specific arrays, an exploratory analysis testing the expression levels of 84 miRNAs and 84 lncRNAs has been performed in a population consisting of 24 genetic FTD patients (eight GRN, eight C9ORF72, and eight MAPT mutation carriers), eight sporadic FTD patients, and eight healthy controls. The results showed a generalized ncRNA downregulation in patients carrying GRN and C9ORF72 when compared with the controls, with statistically significant results for the following miRNAs: miR-155-5p (Fold Change FC: 0.45, p = 0.037 FDR = 0.52), miR-15a-5p (FC: 0.13, p = 0.027, FDR = 1), miR-222-3p (FC: 0.13, p = 0.027, FDR = 0.778), miR-140-3p (FC: 0.096, p = 0.034, FRD = 0.593), miR-106b-5p (FC: 0.13, p = 0.02, FDR = 0.584) and an upregulation solely for miR-124-3p (FC: 2.1, p = 0.01, FDR = 0.893). Conversely, MAPT mutation carriers showed a generalized robust upregulation in several ncRNAs, specifically for miR-222-3p (FC: 22.3, p = 7 × 10⁻⁶, FDR = 0.117), miR-15a-5p (FC: 30.2, p = 0.008, FDR = 0.145), miR-27a-3p (FC: 27.8, p = 6 × 10⁻⁶, FDR = 0.0005), miR-223-3p (FC: 18.9, p = 0.005, FDR = 0.117), and miR-16-5p (FC: 10.9, p = 5.26 × 10⁻⁵, FDR = 0.001). These results suggest a clear, distinctive pattern of dysregulation among ncRNAs and specific enrichment gene pathways between mutations associated with the TDP-43 and tau pathologies. Nevertheless, these preliminary results need to be confirmed in a larger independent cohort.     

Discovery of a Novel Inhibitor of Human Purine Nucleoside Phosphorylase by a Simple Hydrophilic Interaction Liquid Chromatography Enzymatic Assay

Human purine nucleoside phosphorylase (HsPNP) belongs to the purine salvage pathway of nucleic acids. Genetic deficiency of this enzyme triggers apoptosis of activated T-cells due to the accumulation of deoxyguanosine triphosphate (dGTP). Therefore, potential chemotherapeutic applications of human PNP inhibitors include the treatment of T-cell leukemia, autoimmune diseases and transplant tissue rejection. In this report, we present the discovery of novel HsPNP inhibitors by coupling experimental and computational tools. A simple, inexpensive, direct and non-radioactive enzymatic assay coupled to hydrophilic interaction liquid chromatography and UV detection (LC-UV using HILIC as elution mode) was developed for screening HsPNP inhibitors. Enzymatic activity was assessed by monitoring the phosphorolysis of inosine (Ino) to hypoxanthine (Hpx) by LC-UV. A small library of 6- and 8-substituted nucleosides was synthesized and screened. The inhibition potency of the most promising compound, 8-aminoinosine ( 4 ), was quantified through K_i and IC₅₀ determinations. The effect of HsPNP inhibition was also evaluated in vitro through the study of cytotoxicity on human T-cell leukemia cells (CCRF-CEM). Docking studies were also carried out for the most potent compound, allowing further insights into the inhibitor interaction at the HsPNP active site. This study provides both new tools and a new lead for developing novel HsPNP inhibitors.     

Potentiometric titration as a straightforward method to assess the number of functional groups on shortened carbon nanotubes

The conditions for oxidizing multi-walled carbon nanotubes to shorten them to a narrow length distribution have been optimized. One of the most difficult achievements is to fully characterize this material from a chemical point of view, and to find a good quantitative correlation among different techniques. Herein, we report on the combination of different methods to determine the number of functional groups generated during strong acid treatment and a further amidation reaction. A good correlation was found using the colorimetric Kaiser test, thermogravimetric analysis and potentiometric argentometric titration. The final technique, used for the first time in this field, is highly versatile and, being non-destructive, allows a complete recovery of the starting material. Short carbon nanotubes are particularly useful for applications in biomedicine, and the control and precise assessment of their functionalization is critical when used as carriers for therapeutic molecules.     

Silicone-coated non-woven polyester dressing enhances reepithelialisation in a sheep model of dermal wounds

Negative-pressure wound therapy (NPWT) also known as V.A.C.?(Vacuum-assisted closure), is widely used to manage various type of wounds and accelerate healing. NPWT has so far been delivered mainly via open-cell polyurethane (PU) foam or medical gauze. In this study an experimental setup of sheep wound model was used to evaluate, under NPWT conditions, the performance of a silicone-coated non-woven polyester (N-WPE) compared with PU foam and cotton hydrophilic gauze, used as reference materials. Animals were anesthetized with spontaneous breathing to create three 3?×?3?cm skin defects bilaterally; each animal received three different samples on each side (n?=?6 in each experimental group) and was subjected to negative and continuous 125?mmHg pressure up to 16?days. Wound conditions after 1, 8 and 16?days of treatment with the wound dressings were evaluated based on gross and histological appearances. Skin defects treated with the silicone-coated N-WPE showed a significant decrease in wound size, an increase of re-epithelialization, collagen deposition and wound neovascularisation, and a minimal stickiness to the wound tissue, in comparison with gauze and PU foam. Taken all together these findings indicate that the silicone-coated N-WPE dressing enhances wound healing since stimulates higher granulation tissue formation and causes minor tissue trauma during dressing changes.     

Easy obtainment of three-dimensional coordination polymer of zinc 1,2,4,5-benzenetetracarboxylate with para-amino-pyridinium cations

Within a wide study on coordination polymers coming from 1,2,4,5-benzenetetracarboxylate combined with aromatic amines and first row transition metal ions, we isolated and characterized a peculiar tridimensional coordination polymer made by an anionic mesoporous scaffold of Zn(II)-benzeneteracarboxylate whose charge is balanced by included p-aminopyridinium cations stacked up along two quasi-perpendicular crystallographic directions. The particular features of the solid state structure, easily obtained in standard conditions, prompts a wider research of possible related derivatives.     

Biomimetic Nanoparticles as a Theranostic Tool for Traumatic Brain Injury

Traumatic brain injury (TBI) triggers both central and peripheral inflammatory responses. Existing pharmacological drugs are unable to effectively and quickly target the brain inflamed regions, setting up a major roadblock towards effective brain trauma treatments. Nanoparticles (NPs) have been used in multiple diseases as drug delivery tools with remarkable success due to their rapid diffusion and specificity in the target organ. Here, leukocyte-based biomimetic NPs are fabricated as a theranostic tool to directly access inflamed regions in a TBI mouse model. This NP systemic delivery is visualized using advanced in vivo imaging techniques, including intravital microscopy and in vivo imaging system. The results demonstrate selective targeting of NPs to the injured brain and increased NPs accumulation among the peripheral organs 24 h after TBI. Interestingly, increased microglial proliferation, decreased macrophage infiltration, and reduced brain lesion following the NPs treatments compared to sham vehicle-treated mice are also found. In summary, the results suggest that NPs represent a promising future theranostic tool for TBI treatment.     

The DECIDE Science Gateway

The motivation of this work fits with the general vision to enable e-health for European citizens, irrespective of their social and financial status and their place of residence. Services to be provided include access to a high-quality early diagnostic and prognostic service for the Alzheimer Disease and other forms of dementia, based both on the European Research and Education Networks and the European Grid Infrastructure. The present paper reports on the architecture and services of a Science Gateway developed in the context of the DECIDE project, which aims to support the medical community in its daily duties of patients’ examination and diagnosis. The implementation of the Science Gateway is described with particular focus on the standard technologies adopted to ease the access by non IT-.expert users. The work leverages on an authentication and authorization infrastructure based on Identity Federations and robot certificates and on the adoption of the SAGA standard for middleware-independent Grid interaction. The architecture and the functionalities of the digital repository for medical image storage and analysis are also presented.     

Polymeric homogeneous composite membranes for separations in organic solvents

A new generation of organic solvent nanofiltration (NF) composite membranes was prepared combining a support layer with a selective layer made both from the same polymeric material (P84 copolyimide). These membranes, homogeneous in composition, but composite in structure, were defined as polymeric homogeneous composite (PHC) membranes. The composite membranes have the advantage over the asymmetric ones that each layer can be optimized independently. Moreover, the use of the same material for the preparation of both, the selective and the support layer, ensures a high affinity between the two layers and increases the long‐term stability of the composite membranes, reducing the possibility of delamination phenomena. In the design of the PHC membranes, a great attention was devoted to the support layer development. The effects of the composition of the casting solutions on the structure of porous P84 copolyimide membranes were investigated allowing to identify the conditions for the preparation of highly permeable, chemically, and mechanically stable P84 sponge like porous membranes. PHC membranes were prepared by coating and controlled solvent evaporation of a P84 solution on the optimized support crosslinked by reaction with a diamine (1,5‐diamino‐2‐methylpentane). Pure solvent permeation test and rejection experiments were carried out on the P84 supports and the corresponding PHC membranes in aggressive organic solvents like N‐methyl‐2‐pyrrolidone and N,N‐dimethyformamide, in which the original polymer was soluble. The PHC membrane resulted completely stable over long times (>96 h). © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013