Pectic Galactan Polysaccharide-Based Gene Delivery System for Targeting Neuroinflammation

Treating neuroinflammation-related injuries and disorders through manipulation of neuroinflammation functions is being heralded as a new therapeutic strategy. In this study, a novel pectic galactan (PG) polysaccharide based gene therapy approach is developed for targeting reactive gliosis in neuroinflammation. Galectin-3 (Gal-3) is a cell protein with a high affinity to β-galactoside sugars and is highly expressed in reactive gliosis. Since PG carries galactans, it can target reactive gliosis via specific carbohydrate interaction between galactan and Gal-3 on the cell membrane, and therefore can be utilized as a carrier for delivering genes to these cells. The carrier is synthesized by modifying quaternary ammonium groups on the PG. The resulting quaternized PG (QPG) is found to form complexes with plasmid DNA with a mean diameter of 100 nm and have the characteristics required for targeted gene therapy. The complexes efficiently condense large amounts of plasmid per particle and successfully bind to Gal-3. The in vivo study shows that the complexes are biocompatible and safe for administration and can selectively transfect reactive glial cells of an induced cortical lesion. The results confirm that this PG-based delivery system is a promising platform for targeting Gal-3 overexpressing neuroinflammation cells for treating neuroinflammation-related injuries and neurodegenerative diseases.     

Cholesterol and vascular disease. Study of pravastatin

Variations in lipid profile and incidence of vascular events were evaluated. Group 1 had a 29.3% reduction of total and a 38.3% reduction of LDL cholesterol as against reductions of 9% and 9.6% respectively in group 2. No significant difference was observed between the two groups as far as the vascular events considered were concerned. Pravastatin is an effective and safe drug. The lack of influence on the evolution of vascular disease would appear to be correlated to the small number of subjects studied and the short follow-up.     

Using optimistic atomic broadcast in transaction processing systems

Atomic broadcast primitives are often proposed as a mechanism to allow fault-tolerant cooperation between sites in a distributed system. Unfortunately, the delay incurred before a message can be delivered makes it difficult to implement high performance, scalable applications on top of atomic broadcast primitives. Recently, a new approach has been proposed for atomic broadcast which, based on optimistic assumptions about the communication system, reduces the average delay for message delivery to the application. We develop this idea further and show how applications can take even more advantage of the optimistic assumption by overlapping the coordination phase of the atomic broadcast algorithm with the processing of delivered messages. In particular, we present a replicated database architecture that employs the new atomic broadcast primitive in such a way that communication and transaction processing are fully overlapped, providing high performance without relaxing transaction correctness.     

Mechanochemical Processing of Mn and Co Oxides: An Alternative Way to Synthesize Mixed Spinels for Protective Coating

High‐Energy Ball Milling (HEBM) is proposed as a cost effective and environmental friendly technique to produce Co‐ and Mn‐ based oxides suitable for application as protective coating. Mixtures of manganese and cobalt oxides in different molar ratio (Co:Mn = 1:1 and Co:Mn = 2:1) were subjected to mechanochemical treatment up to 100 h and morpho‐structural evolution was evaluated. XRD analysis results show that the HEBM treatment promotes the solid‐state reaction of the starting compounds, with the formation of different crystalline phases when compared to high‐temperature solid‐state synthesis. SEM observations and N₂ adsorption measurements suggest that all processed powders are composed by aggregates of nanometric particles. While long milling time is required to complete the reaction, 10 hours are enough to activate the powders to obtain the desired phases after a mild thermal treatment, as evidenced by in situ thermal XRD analysis. Electrical conductivity measures performed with the Van der Pauw method on sintered pellets evidence a significant difference between the two compositions, related to the dual‐phase nature of Co:Mn = 1:1 material at intermediate temperatures (i.e., T < 700°C), Co:Mn = 2:1 sample showing higher conductivity values in the whole tested range (500°C–800°C).     

11C‐ and 18F‐Labeled Radioligands for P‐Glycoprotein Imaging by Positron Emission Tomography

P‐Glycoprotein (P‐gp) is an efflux transporter widely expressed at the human blood–brain barrier. It is involved in xenobiotics efflux and in onset and progression of neurodegenerative disorders. For these reasons, there is great interest in the assessment of P‐gp expression and function by noninvasive techniques such as positron emission tomography (PET). Three radiolabeled aryloxazole derivatives: 2‐[2‐(2‐methyl‐(¹¹C)‐5‐methoxyphenyl)oxazol‐4‐ylmethyl]‐6,7‐dimethoxy‐1,2,3,4‐tetrahydroisoquinoline ([¹¹C]‐ 5 ); 2‐[2‐(2‐fluoromethyl‐(¹⁸F)‐5‐methoxyphenyl)oxazol‐4‐ylmethyl]‐6,7‐dimethoxy‐1,2,3,4‐tetra‐hydroisoquinoline ([¹⁸F]‐ 6 ); and 2‐[2‐(2‐fluoroethyl‐(¹⁸F)‐5‐methoxyphenyl)oxazol‐4‐ylmethyl]‐6,7‐dimethoxy‐1,2,3,4‐tetrahydroisoquinoline ([¹⁸F]‐ 7 ), were tested in several in vitro biological assays to assess the effect of the aryl substituent in terms of potency and mechanism of action toward P‐gp. Methyl derivative [¹¹C]‐ 5 is a potent P‐gp substrate, whereas the corresponding fluoroethyl derivative [¹⁸F]‐ 7 is a P‐gp inhibitor. Fluoromethyl compound [¹⁸F]‐ 6 is classified as a non‐transported P‐gp substrate, because its efflux increases after cyclosporine A modulation. These studies revealed a promising substrate and inhibitor, [¹¹C]‐ 5 and [¹⁸F]‐ 7 , respectively, for in vivo imaging of P‐gp by using PET.     

Simulating Coxian phase-type distributions for patient survival

Coxian phase-type distributions are a special type of Markov model that can be used to represent survival times in terms of phases through which an individual may progress until they eventually leave the system completely. Previous research has considered the Coxian phase-type distribution to be ideal in representing patient survival in hospital. However, problems exist in fitting the distributions. This paper investigates the problems that arise with the fitting process by simulating various Coxian phase-type models for the representation of patient survival and examining the estimated parameter values and eigenvalues obtained. The results indicate that numerical methods previously used for fitting the model parameters do not always converge. An alternative technique is therefore considered. All methods are influenced by the choice of initial parameter values. The investigation uses a data set of 1439 elderly patients and models their survival time, the length of time they spend in a UK hospital.     

F-substituted hydroxyapatite nanopowders: Thermal stability,sintering behaviour and mechanical properties

Fluorine-substituted hydroxyapatites are considered promising materials for bone scaffolding. In this study a systematic investigation on F-half substituted hydroxyapatite (F-HAp, Ca₁₀(PO₄)₆OHF) obtained by precipitation is reported. Results on composition analysis, thermal behaviour, and sinterability are presented for a comparison with the respective pure hydroxyapatite. Samples were characterised by electron microscopy, induced coupled plasma-atomic emission spectroscopy, thermal analysis, infrared spectroscopy, N₂ adsorption measurements, X-ray diffraction and dilatometry. A semicrystalline F-substituted hydroxyapatite powder made up of needle-like nanoparticles was obtained. Notwithstanding that it was thermally stable up to 1300 °C, it was sintered at relatively low temperatures obtaining a very fine microstructure with a relevant nano-porosity, beneficial in view of cell adhesion and in-growth.Hardness, elastic modulus and toughness of produced samples were investigated by Vickers–Knoop microhardness testing. Significant improvements of the mechanical properties were observed for the F-substituted hydroxyapatite, in comparison with pure hydroxyapatite.