Nanoprobes to interrogate nonspecific interactions in lipid bilayers: from defect-mediated adhesion to membrane disruption

When a lipid membrane approaches a material/nanomaterial, nonspecific adhesion may occur. The interactions responsible for nonspecific adhesions can either preserve the membrane integrity or lead to its disruption. Despite the importance of the phenomenon, there is still a lack of clear understanding of how and why nonspecific adhesions may originate different resulting scenarios and how these interaction scenarios can be interrogated. This work aims at bridging this gap by investigating the interplay between cationic electrostatic and hydrophobic interactions in modulating the membrane stability during nonspecific adhesion phenomena. Here, the stability of the membrane has been studied employing anisotropic nanoprobes in zwitterionic lipid membranes with the support of coarse-grained molecular dynamics simulations to interpret the experimental observations. Lipid membrane electrical measurements and nanoscale visualization in combination with molecular dynamics simulations revealed the phenomena driving nonspecific adhesion. Any interaction with the lipidic bilayer is defect-mediated involving cationic electrostatically-driven lipid extractions and hydrophobicallydriven chains protrusion, whose interplay determines the existence of a thermodynamic optimum for the membrane structural integrity. These findings unlock unexplored routes to exploit nonspecific adhesion in lipid membranes. The proposed platform can act as a straightforward probing tool to locally interrogate interactions between synthetic materials and lipid membranes for the design of antibacterials, antivirals, and scaffolds for tissue engineering

Combining nitric oxide release with anti-inflammatory activity preserves nigrostriatal dopaminergic innervation and prevents motor impairment in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease

Background Current evidence suggests a role of neuroinflammation in the pathogenesis of Parkinson's disease (PD) and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of basal ganglia injury. Reportedly, nonsteroidal anti-inflammatory drugs (NSAIDs) mitigate DAergic neurotoxicity in rodent models of PD. Consistent with these findings, epidemiological analysis indicated that certain NSAIDs may prevent or delay the progression of PD. However, a serious impediment of chronic NSAID therapy, particularly in the elderly, is gastric, renal and cardiac toxicity. Nitric oxide (NO)-donating NSAIDs, have a safer profile while maintaining anti-inflammatory activity of parent compounds. We have investigated the oral activity of the NO-donating derivative of flurbiprofen, [2-fluoro-α-methyl (1,1'-biphenyl)-4-acetic-4-(nitrooxy)butyl ester], HCT1026 (30 mg kg-1 daily in rodent chow) in mice exposed to the parkinsonian neurotoxin MPTP. Methods Ageing mice were fed with a control, flurbiprofen, or HCT1026 diet starting ten days before MPTP administration and continuing for all the experimental period. Striatal high affinity synaptosomial dopamine up-take, motor coordination assessed with the rotarod, tyrosine hydroxylase (TH)- and dopamine transporter (DAT) fiber staining, stereological cell counts, immunoblotting and gene expression analyses were used to assess MPTP-induced nigrostriatal DAergic toxicity and glial activation 1-40 days post-MPTP. Results HCT1026 was well tolerated and did not cause any measurable toxic effect, whereas flurbiprofen fed mice showed severe gastrointestinal side-effects. HCT1026 efficiently counteracted motor impairment and reversed MPTP-induced decreased synaptosomal [3H]dopamine uptake, TH- and DAT-stained fibers in striatum and TH+ neuron loss in subtantia nigra pars compacta (SNpc), as opposed to age-matched mice fed with a control diet. These effects were associated to a significant decrease in reactive macrophage antigen-1 (Mac-1)-positive microglial cells within the striatum and ventral midbrain, decreased expression of iNOS, Mac-1 and NADPH oxidase (PHOX), and downregulation of 3-Nitrotyrosine, a peroxynitrite finger print, in SNpc DAergic neurons. Conclusions Oral treatment with HCT1026 has a safe profile and a significant efficacy in counteracting MPTP-induced dopaminergic (DAergic) neurotoxicity, motor impairment and microglia activation in ageing mice. HCT1026 provides a novel promising approach towards the development of effective pharmacological neuroprotective strategies against PD

Sprouty2 and Spred1-2 Proteins Inhibit the Activation of the ERK Pathway Elicited by Cyclopentenone Prostanoids

Sprouty and Spred proteins have been widely implicated in the negative regulation of the fibroblast growth factor receptor-extracellular regulated kinase (ERK) pathway. In considering the functional role of these proteins, we explored their effects on ERK activation induced by cyclopentenone prostanoids, which bind to and activate Ras proteins. We therefore found that ectopic overexpression in HeLa cells of human Sprouty2, or human Spred1 or 2, inhibits ERK1/2 and Elk-1 activation triggered by the cyclopentenone prostanoids PGA1 and 15d-PGJ2. Furthermore, we found that in HT cells that do not express Sprouty2 due to hypermethylation of its gene-promoter, PGA1-provoked ERK activation was more intense and sustained compared to other hematopoietic cell lines with unaltered Sprouty2 expression. Cyclopentenone prostanoids did not induce Sprouty2 tyrosine phosphorylation, in agreement with its incapability to activate tyrosine-kinase receptors. However, Sprouty2 Y55F, which acts as a defective mutant upon tyrosine-kinase receptor stimulation, did not inhibit cyclopentenone prostanoids-elicited ERK pathway activation. In addition, Sprouty2 did not affect the Ras-GTP levels promoted by cyclopentenone prostanoids. These results unveil both common and differential features in the activation of Ras-dependent pathways by cyclopentenone prostanoids and growth factors. Moreover, they provide the first evidence that Sprouty and Spred proteins are negative regulators of the ERK/Elk-1 pathway activation induced not only by growth-factors, but also by reactive lipidic mediators

Ti-rich precipitate evolution in vanadium-based alloys during annealing above 400C

We have assessed the plate-like TiO precipitate evolution in V-4Ti and V-4Ti-4Cr alloys during isochronal annealing above 400 °C, by combining Vickers hardness, positron lifetime and coincidence Doppler broadening measurements. Our results reveal the formation of additional TiO precipitates in both alloys at temperatures of 450–600 °C in both alloys. The implanted positrons become trapped at the nm-thick TiO/matrix interface, and act as effective probes of the concomitant annealing of vacancies taking place inside the TiO precipitates above 550 °C in V-4Ti alloy. The presence of Cr in the ternary alloy not only retards the recovery of dislocations, but also enhances the oxygen diffusivity and therefore decreases the vacancy content in the TiO precipitates. These results will impact the expected alloy stability and capacity to bind light elements in the operational temperature window of these alloys for fusion reaction applications.</p

Monolayer-thick TiO precipitation in V-4Cr-4Ti alloy induced by proton irradiation

We have characterised to atomic resolution the mono-layer thick TiO-type precipitate induced by proton irradiation in V-4Cr-4Ti alloy at a dose of 0.3 dpa and a temperature of 350 °C. Its formation coincides with the coarsening radiation-induced interstitial a/2〈111〉 dislocation loops that are already present at 300 °C. The dislocation network induced by prior cold work is mostly recovered at 300 °C and 0.3 dpa, and is therefore expected to exert a minimal effect on the precipitate formation. This monolayer-thick precipitate constitutes an early stage in the radiation-induced aging process of V-4Cr-4Ti at low temperatures, and can potentially absorb additional light elements in reactor environments.</p

COSMO-SkyMed Constellation Configurations: Current Status and Possible Evolutions

COSMO-SkyMed is an Earth Observation space programme funded by the Italian Ministry of Research and Italian Ministry of Defence (It-MoD) and conducted by the Italian Space Agency (ASI) in conjunction with It-MoD. In November 2010 the fourth and last COSMO-SkyMed satellite was successfully launched. It was integrated into the operational constellation after the positive conclusion of the commissioning phase in January 2011. The four satellites are placed in the same sun-synchronous dawn-dusk frozen orbit, designed in such a way to fulfil dual needs and to optimize the performances for a wide range of Civilian applications (e.g. risks management, agriculture/forestry, marine/coastal, geology) and Defence applications (surveillance, intelligence, crisis management, mission planning). The baseline four-satellite constellation configuration foresees that the satellites are placed on the same orbital plane with a difference of 90, 180, 270 and 360 deg in their respective anomalies. Currently the orbital configuration is composed of three satellites (namely PFM, FM#2 and FM#4) placed with a difference of 0, 180, and 270 deg in their respective anomalies, while a fourth satellite (namely FM#3) is placed in a tandem-like configuration with FM#2 (i.e. one-day temporal decorrelation). The aim of this paper is to analyze the orbital flexibility of COSMO-SkyMed constellation by performing a survey of the possible orbital interferometric configurations which could be achieved by the full COSMO-SkyMed constellation (e.g. tandem, tandem-like, double one-day tandem configuration, etc), focusing on their main features (e.g. temporal decorrelation, degradation of the temporal performances respect to the nominal equi-phased configuration, etc), highlighting the manoeuvres required for orbital configuration changes

Asthma in patients admitted to emergency department for COVID-19: prevalence and risk of hospitalization

Non