Cholesterol impairment contributes to neuroserpin aggregation

Intraneural accumulation of misfolded proteins is a common feature of several neurodegenerative pathologies including Alzheimer's and Parkinson's diseases, and Familial Encephalopathy with Neuroserpin Inclusion Bodies (FENIB). FENIB is a rare disease due to a point mutation in neuroserpin which accelerates protein aggregation in the endoplasmic reticulum (ER). Here we show that cholesterol depletion induced either by prolonged exposure to statins or by inhibiting the sterol regulatory binding-element protein (SREBP) pathway also enhances aggregation of neuroserpin proteins. These findings can be explained considering a computational model of protein aggregation under non-equilibrium conditions, where a decrease in the rate of protein clearance improves aggregation. Decreasing cholesterol in cell membranes affects their biophysical properties, including their ability to form the vesicles needed for protein clearance, as we illustrate by a simple mathematical model. Taken together, these results suggest that cholesterol reduction induces neuroserpin aggregation, even in absence of specific neuroserpin mutations. The new mechanism we uncover could be relevant also for other neurodegenerative diseases associated with protein aggregation.Comment: 7 figure

Nuove prospettive nel monitoraggio biologico degli elementi metallici: l'esempio del cromo esavalente

L’industria galvanica è un settore importante su tutto il territorio nazionale, poiché i processi che la caratterizzano riguardano un gran numero di fabbricazioni industriali ed artigianali. Nella cromatura galvanica esiste un rischio chimico specifico dovuto all’esposizione a composti contenenti Cromo esavalente [Cr(VI)]. Il condensato dell’aria espirata (CAE) è stato usato per studiare l’esposizione acuta e a lungo termine a Cr(VI) in lavoratori addetti alla cromatura a spessore. Cr-CAE correla con specifici biomarcatori di stress ossidativo ed è possibile misurarne anche la frazione non ancora ridotta a Cr(III). Il CAE è quindi un fluido biologico promettente per il monitoraggio della dose assorbita a livello dell’organo bersaglio, della cinetica di riduzione polmonare di Cr(VI) e più in generale dei suoi effetti locali pneumotossici nelle lavorazioni galvaniche, con la possibilità di affiancare la sua raccolta e la sua analisi alle misure tradizionalmente fatte durante il monitoraggio biologico

Merging Continuous Flow Technology, Photochemistry and Biocatalysis to Streamline Steroid Synthesis

Since their structural elucidation in 1935, the introduction and substitution of functional groups and the modification of the steroidal scaffolds have been a fertile ground of research for synthetic and medicinal chemists. The discovery of steroids with hormonal and pharmacological activity has stimulated tremendous efforts to the development of highly selective and efficient synthetic procedures. Despite the progress made, steroid chemistry remains challenging and the preparation of steroidal compounds of pharmaceutical interests and in clinical practice, often requires long and elaborated synthesis. In recent years, a new impetus in the field came with the advent of enabling chemical technologies, such as continuous flow chemistry, which are exploited to overcome problems that arise from batch synthesis. Although it is still a niche sector, the use of flow technology in steroid synthesis and functionalization holds the premise to empower methodology development and to provide innovative tactics also for many hitherto uncharted chemistries. In this review, scientific contributions are reported and discussed in terms of flow set-up and advantages offered concerning process efficiency, optimization, waste minimization, safety improvement, easy scale-up and costs. We also highlight the main challenges, key improvements and the future trajectory in the application of continuous flow chemistry and its implementation to different disciplines such as photochemistry and biocatalysis with the ultimate goal of streamlining steroid synthesis

The three-body recombination of a condensed Bose gas near a Feshbach resonance

In this paper, we study the three-body recombination rate of a homogeneous dilute Bose gas with a Feshbach resonance at zero temperature. The ground state and excitations of this system are obtained. The three-body recombination in the ground state is due to the break-up of an atom pair in the quantum depletion and the formation of a molecule by an atom from the broken pair and an atom from the condensate. The rate of this process is in good agreement with the experiment on $^{23}$Na in a wide range of magnetic fields.Comment: 10 pages, 2 figures, to be published in Phys. Rev.

Bacterial Peroxidase on Electrochemically Reduced Graphene Oxide for Highly Sensitive H₂O₂ Detection

Peroxidase enzymes enable the construction of electrochemical sensors for highly sensitive and selective quantitative detection of various molecules, pathogens and diseases. Herein, we describe the immobilization of a peroxidase from Bacillus s. (BsDyP) on electrochemically reduced graphene oxide (ERGO) deposited on indium tin oxide (ITO) and polyethylene terephthalate (PET) layers. XRD, SEM, AFM, FT‐IR and Raman characterization of the sensor confirmed its structural integrity and a higher enzyme surface occupancy. The BsDyP‐ERGO/ITO/PET electrode performed better than other horseradish peroxidase‐based electrodes, as evinced by an improved electrochemical response in the nanomolar range (linearity 0.05–280 μM of H(2)O(2), LOD 32 nM). The bioelectrode was mechanically robust, active in the 3.5–6 pH range and exhibited no loss of activity upon storage for 8 weeks at 4 °C

Crystallization-based downstream processing of ω-transaminase- and amine dehydrogenase-catalyzed reactions

Biocatalytic synthesis is a powerful and frequently chosen method for the production of chiral amines. Unfortunately, these biocatalytic reactions often result in complex mixtures, bearing many components aside from the main product amine such as residual co-substrates, co-products, cofactors and buffer salts. This issue typically requires an additional effort during downstream processing towards the isolation of the desired chiral amine. For instance, transaminase- and amine dehydrogenase-catalyzed reactions, which often use high surpluses of amine or ammonia co-substrates, face complications in removing the residual amine donor or unreacted substrate and salts from the isolated amine products, thus complicating and increasing the costs of the process of product isolation and purification. This study explores the selective removal of chiral amines from model amine transaminase and amine dehydrogenase-catalyzed reactions via a salt-based specific crystallization step. The product amine is precipitated directly in one step from the reaction mixture as a product ammonium salt, which can easily be filtered from the reaction mixture, while the other reactants remain unchanged in solution for potential re-use.</p

Multi-fluid stratified shear flows in pipes. Part 2. Critical conditions in the development of interfacial profiles

Paper presented at the 5th International Conference on Heat Transfer, Fluid Mechanics and Thermodynamics, South Africa, 1-4 July, 2007.The focus of this paper is on mathematical formulation and computation of critical flow conditions in horizontal or nearly horizontal pipes. Continuity and momentum equations are derived considering an arbitrary number of fluids and then rearranged so as to yield a system of ordinary differential equations. It is shown that the matrix of the system needs to be invertible so as to compute interfacial profiles. Critical conditions are recognised as those for which the matrix becomes singular and the hypothesis of gradually varied flow fails. Some well known results of linear algebra are here used to define criteria capable of discerning between geometric and kinematic conditions of the flow which are certainly noncritical and others which may or may not be critical

Switching off malignant mesothelioma : exploiting the hypoxic microenvironment

Malignant mesotheliomas are aggressive, asbestos-related cancers with poor patient prognosis, typically arising in the mesothelial surfaces of tissues in pleural and peritoneal cavity. The relative unspecific symptoms of mesotheliomas, misdiagnoses, and lack of precise targeted therapies call for a more critical assessment of this disease. In the present review, we categorize commonly identified genomic aberrations of mesotheliomas into their canonical pathways and discuss targeting these pathways in the context of tumor hypoxia, a hallmark of cancer known to render solid tumors more resistant to radiation and most chemo-therapy. We then explore the concept that the intrinsic hypoxic microenvironment of mesotheliomas can be Achilles’ heel for targeted, multimodal therapeutic intervention

Anti-CTLA-4 therapy for malignant mesothelioma

Immunotherapy is an emerging therapeutic strategy with a promising clinical outcome in some solid tumors, particularly metastatic melanoma. One approach to immunotherapy is immune checkpoint inhibitors, such as blockage of CTLA-4 and PD-1/PD-L1. This special report aims to describe the state of clinical trials of tremelimumab in patients with unresectable malignant mesothelioma (MM) in particular with regard to the clinical efficacy, safety and tolerability. Criticism and perspective of this treatment are also discussed. Biological and clinical considerations rule out the use of tremelimumab as single agent for MM and, more generally, the use of immune checkpoint inhibitors for MM is still largely questionable and not supported by evidences