New insights into structural determinants of prion protein folding and stability

Prions are the etiological agent of fatal neurodegenerative diseases called prion diseases or transmissible spongiform encephalopathies. These maladies can be sporadic, genetic or infectious disorders. Prions are due to post-translational modifications of the cellular prion protein leading to the formation of a \u3b2-sheet enriched conformer with altered biochemical properties. The molecular events causing prion formation in sporadic prion diseases are still elusive. Recently, we published a research elucidating the contribution of major structural determinants and environmental factors in prion protein folding and stability. Our study highlighted the crucial role of octarepeats in stabilizing prion protein; the presence of a highly enthalpically stable intermediate state in prion-susceptible species; and the role of disulfide bridge in preserving native fold thus avoiding the misfolding to a \u3b2-sheet enriched isoform. Taking advantage from these findings, in this work we present new insights into structural determinants of prion protein folding and stability

In vitro evaluation of different organic matrices used to modulate silicon bioavailability.

Silicon (Si) has numerous health properties. It is an element of the extracellular matrix; it is involved in collagen synthesis, bone mineralization, and immune system modulation; and it reduces metal accumulation in Alzheimer's disease and the risk of atherosclerosis. Given its poor intestinal absorption, Si is ingested in the form of orthosilicic acid (OSA) to promote its bioavailability. The aim of this work was to compare different commercial dietary supplements containing stabilized OSA to ascertain their bioaccessibility, bioavailability, and safety in a model of human intestinal epithelium. Biocompatibility with the glycocalyx was also investigated. Supplements containing collagen, maltodextrins, and choline as OSA stabilizers were analyzed. Bioaccessibility was explored by means of an in vitro digestive process. Bioavailability was investigated using a Caco2 cell line alone, or co-culturing with a HT29-MTX cell line. The safety of the compounds tested (in terms of intestinal epithelium integrity) was judged on the grounds of MTS assay, transepithelial electrical resistance, and apparent permeability. The three formulations were also tested in a Caco2 cell model of intestinal glycocalyx Si retention. The choline-formulated OSA formulation outperformed the maltodextrin-stabilized supplement, with a Si bioavailability about 14 times higher (P < .05). The choline-formulated OSA formulation increased cell permeability, with consequent intestinal epithelium disruption. The supplements' absorption and bioavailability (and harmfulness) differed considerably, depending on the OSA stabilizer involved. Of the three formulations tested, the collagen-formulated OSA represents the best Si dietary supplement

Prion protein and copper cooperatively protect neurons by modulating NMDA receptor through S-nitrosylation

AIMS: Several neurodegenerative disorders show alterations in glutamatergic synapses and increased susceptibility to excitotoxicity. Mounting evidence suggests a central role for the cellular prion protein (PrP(C)) in neuroprotection. Therefore, the loss of PrP(C) function occurring in prion disorders may contribute to the disease progression and neurodegeneration. Indeed, PrP(C) modulates N-methyl-d-aspartate receptors (NMDAR), thus preventing cell death. In this study, we show that PrP(C) and copper cooperatively inhibit NMDAR through S-nitrosylation, a post-translational modification resulting from the chemical reaction of nitric oxide (NO) with cysteines. RESULTS: Comparing wild-type Prnp (Prnp(+/+)) and PrP(C) knockout (Prnp(0/0)) mouse hippocampi, we found that GluN1 and GluN2A S-nitrosylation decrease in Prnp(0/0). Using organotypic hippocampal cultures, we found that copper chelation decreases NMDAR S-nitrosylation in Prnp(+/+) but not in Prnp(0/0). This suggests that PrP(C) requires copper to support the chemical reaction between NO and thiols. We explored PrP(C)-Cu neuroprotective role by evaluating neuron susceptibility to excitotoxicity in Prnp(+/+) and Prnp(0/0) cultures. We found that (i) PrP(C)-Cu modulates GluN2A-containing NMDAR, those inhibited by S-nitrosylation; (ii) PrP(C) and copper are interdependent to protect neurons from insults; (iii) neuronal NO synthase inhibition affects susceptibility in wild-type but not in Prnp(0/0), while (iv) the addition of a NO donor enhances Prnp(0/0) neurons survival. INNOVATION AND CONCLUSIONS: Our results show that PrP(C) and copper support NMDAR S-nitrosylation and cooperatively exert neuroprotection. In addition to NMDAR, PrP(C) may also favor the S-nitrosylation of other proteins. Therefore, this mechanism may be investigated in the context of the different cellular processes in which PrP(C) is involved

Hallazgos histológico ultraestructurales característicos de las células madres (stem cell embriónico fetales). Primer reporte internacional

Se buscó la evidencia de crecimiento muscular o biogénesis que debería haberse iniciado a partir del transplante de Stem cell embriónico fetales de donantes con el propósito de observar los dos tipos de ADN distintos tanto del receptor como del donante. Materiales y métodos: esta investigación se realizó luego de recibir fragmentos de músculo cardiaco del ventrículo izquierdo en los cuales se implantaron dichas células directamente en el miocardio mediante 80 inyecciones de 1ml cada una en todas las paredes de ambos ventrículos, con especial énfasis en el izquierdo. Las biopsias fueron fijadas con glutaraldehido al 3%, post-fijazas con Tetraóxido de Osmio al 1%, deshidratadas en diversos gradientes ascendentes de alcohol etílico, preembedidas en Oxido de propileno, embebidas en resina Spurr para realizar los bloques, los cuales fueron cortados por ultramicrotomía, teñidas con acetato de uranilo y citrato de plomo, y finalmente observadas al Microscopio Electrónico de Transmisión JEOL- JEM 1010. Resultados: lo más relevante en esta investigación son los hallazgos encontrados en las mitocondrias que se presentaban hipertróficas, redondeadas con crestas vesiculares, siendo lo distintivo y el más importante hallazgo la presencia de una banda recta trilaminar con una estructura central electrondensa proteica, la misma que atraviesa perpendicularmente en toda la longitud de la mitocondria, formando una “Barra germinativa pluripotencial mitocondrial”, hallazgo propio distintivo de las células Madre. Conclusiones: siendo en la mitocondria esta inusual barra recta transversal electrondensa un importante aporte científico distintivo que identificaría plenamente a las células transplantadas del tipo de Stem cell embriónico fetales, diferentes a las mitocondrias con crestas cortas irregulares onduladas paralelas vacías, dando con esto una diferenciación característica que determinaría su capacidad de ser pluripotencial y de autorenovación

Pollutants monitoring and air quality evaluation in a confined environment: The ‘Majesty’ of Ambrogio Lorenzetti in the St. Augustine Church in Siena (Italy)

A monitoring campaign of the levels of some organic contaminants, such as polycyclic aromatic hydrocarbons (PAHs), perfluoro alkylated substances (PFASs), chlorinated pesticides (4 isomers of hexachlorocyclohexane, hexachlorobenzene, 6 isomers and metabolites of DDT and dieldrin), polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDEs), in different matrices (dust taken from the floor and under a wall painting and fragments of the 'Majesty' wall painting by Ambrogio Lorenzetti), was conducted in the historical museum of St. Augustine's church in Siena (Italy). Instrumental analyses were made by gas chromatography and liquid chromatography coupled with mass spectrometry. The results showed the presence of some organic pollutants (PAHs and PBDEs), whose interaction with the surfaces of works of art are not yet fully elucidated. The study was complemented by monitoring the air quality inside and outside the church for the detection of volatile organic compounds (VOCs); all the results showed low levels of air pollution. Copyright (C)2016 Turkish National Committee for Air Pollution Research and Control

functionalized multi wall carbon nanotubes tio2 composites as efficient photoanodes for dye sensitized solar cells

The incorporation of functionalized multi-wall carbon nanotubes into TiO2 mesoporous photoanodes for dye-sensitized solar cells leads to 30% enhancement in photoconversion efficiency of the optimized system

High Prevalence of Hepatitis C Virus Genotype 1b Infection in a Small Town of Argentina. Phylogenetic and Bayesian Coalescent Analysis

Previous studies in Argentina have documented a general prevalence of Hepatitis C Virus (HCV) infection close to 2%. In addition, a high prevalence of HCV has been recently reported in different Argentinean small rural communities. In this work, we performed a study aimed at analyzing the origins and diversification patterns of an HCV outbreak in Wheelwright, a small rural town located in Santa Fe province (Argentina)

Modulation of Alpha-Synuclein Aggregation by Dopamine Analogs

The action of dopamine on the aggregation of the unstructured alpha-synuclein (α-syn) protein may be linked to the pathogenesis of Parkinson's disease. Dopamine and its oxidation derivatives may inhibit α-syn aggregation by non-covalent binding. Exploiting this fact, we applied an integrated computational and experimental approach to find alternative ligands that might modulate the fibrillization of α-syn. Ligands structurally and electrostatically similar to dopamine were screened from an established library. Five analogs were selected for in vitro experimentation from the similarity ranked list of analogs. Molecular dynamics simulations showed they were, like dopamine, binding non-covalently to α-syn and, although much weaker than dopamine, they shared some of its binding properties. In vitro fibrillization assays were performed on these five dopamine analogs. Consistent with our predictions, analyses by atomic force and transmission electron microscopy revealed that all of the selected ligands affected the aggregation process, albeit to a varying and lesser extent than dopamine, used as the control ligand. The in silico/in vitro approach presented here emerges as a possible strategy for identifying ligands interfering with such a complex process as the fibrillization of an unstructured protein

Correction: Spatiotemporal distribution and speciation of silver nanoparticles in the healing wound.

Correction for 'Spatiotemporal distribution and speciation of silver nanoparticles in the healing wound' by Marco Roman et al., Analyst, 2020, 145, 6456–6469, DOI: 10.1039/D0AN00607F