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Background Alzheimer’s disease (AD) is the major age-related form of dementia in which dysfunctional ubiquitin-proteasome system (UPS) and autophagy represent primary mechanisms leading to accumulation of misfolded proteins, dysfunction of astroglial cells, neuroinflammation and neurodegeneration. Alterations of the endoplasmic reticulum (ER)-mitochondria contact sites (MERCS), specifically the shortening of the distance between the organelles, was proposed as a key mechanism of cell dysfunction in AD. However, its link to the impairment of the proteolytic system in AD remains unexplored. Methods We used, as a model, hippocampal astrocytes from 3xTg-AD mice expressing either control plasmid or synthetic linkers stabilizing ER-mitochondrial interaction at 10 nm (10 nm-EML) or at 20 nm (20 nm-EML). Alternatively, astrocytes were treated with mitochondrial Ca 2+ uptake inhibitor benzethonium chloride or activator amorolfine. We used Western blot to assess protein expression and specific enzymatic activity tests for the analysis of proteasomal, autophagic and lysosomal activities. Single cell fluorescent Ca 2+ imaging, using 4mtD3cpv probe targeted to the mitochondrial matrix, was used to assess mitochondrial Ca 2+ uptake. Results Stabilization of MERCS at 20 nm (20 nm-MERCS), which promotes mitochondrial Ca 2+ uptake, rescued protein ubiquitination, UPS composition and activity. Immunoproteasome components β2i and β5i, upregulated in AD astrocytes, and INFγ, a master-regulator of UPS remodelling in inflammatory conditions, were also rescued. Autophagic markers beclin 1, LC3II and p62, and lysosome-related marker cathepsin B, all upregulated in AD astrocytes, were significantly reduced, while autophagic flux was rescued, by stabilizing 20 nm-MERCS. Furthermore, stabilization of 20 nm-MERCS fully rescued previously reported deficit of mitochondrial Ca 2+ uptake. Strikingly, application of a mitochondrial Ca 2+ uptake positive modulator, amorolfine, partially rescued pathological remodelling of UPS and autophagy, suggesting that both mitochondrial Ca 2+ -related and Ca 2+ -unrelated mechanisms play a role in the beneficial effect of 20 nm-MERCS stabilization on protein dyshomeostasis. Conclusions Our results suggest that disruption of ER-mitochondrial interaction is a key factor for AD-related dysregulation of protein degradation and provide a proof that stabilization of MERCS at a defined distance and/or pharmacological rescue of mitochondrial Ca 2+ uptake represent valuable strategies for the development of future anti-AD therapy.

Engineering amorphous dielectric films with tunable thermal conductivity is advantageous for the thermal management of semiconductor devices and thermal insulation of aerospace applications. Here, we demonstrate that incorporating dense dispersed amorphous Al(Ti)N (~1 nm or above) nanoparticles having phase volume fractions from 6 to 70 %, has a negligible effect on the intrinsic thermal conductivity of the amorphous Si 3 N 4 matrix (~2 W m −1 K −1 ), in which the wave-like ‘propagons’ in Allen-Feldmann theory are believed to be unsupressed and non-tuned. By contrast, incorporating (5–15 nm) crystalline TiN phases significantly increases the thermal conductivity (up to 15 W m −1 K −1 ). Critically, the micrometre-thick Si 3 N 4 /AlN and Si 3 N 4 /TiN amorphous matrix dual-phase nanocomposite coatings exhibit excellent thermal stability upon exposure to ambient air at 1000 °C for 50 h. These findings shed light on the phonon transport mechanism regarding the effects of the second phase and pave a design pathway for engineering amorphous coatings displaying unprecedented high thermal conductivity and excellent thermal stability. Amorphous films with tunable thermal conductivity are needed for semiconductor/aerospace fields. Amorphous Al(Ti)N nanoparticles have negligible effect on thermal conductivity of Si 3 N 4 2 W m −1 K −1 , while incorporating crystal TiN phases increases to 15 W m −1 K −1 .

IP 3 receptor (IP 3 R)-mediated Ca 2+ transfer at the mitochondria-endoplasmic reticulum (ER) contact sites (MERCS) drives mitochondrial Ca 2+ uptake and oxidative metabolism and is linked to different pathologies, including Parkinson’s disease (PD). The dependence of Ca 2+ transfer efficiency on the ER-mitochondria distance remains unexplored. Employing molecular rulers that stabilize ER-mitochondrial distances at 5 nm resolution, and using genetically encoded Ca 2+ indicators targeting the ER lumen and the sub-mitochondrial compartments, we now show that a distance of ~20 nm is optimal for Ca 2+ transfer and mitochondrial oxidative metabolism due to enrichment of IP 3 R at MERCS. In human iPSC-derived astrocytes from PD patients, 20 nm MERCS were specifically reduced, which correlated with a reduction of mitochondrial Ca 2+ uptake. Stabilization of the ER-mitochondrial interaction at 20 nm, but not at 10 nm, fully rescued mitochondrial Ca 2+ uptake in PD astrocytes. Our work determines with precision the optimal distance for Ca 2+ flux between ER and mitochondria and suggests a new paradigm for fine control over mitochondrial function. The distance-dependence analysis of ER-mitochondria Ca 2+ transfer suggests that a distance of ∼20 nm between the organelles ensures maximal efficiency of mitochondrial Ca 2+ uptake and OXPHOS and rescues Ca 2+ uptake in Parkinson’s disease mitochondria.

Alterations of endoplasmic reticulum (ER)-mitochondrial interaction have been associated with different pathological conditions, including neurodegenerative diseases, characterized by dysregulation of protein homeostasis. However, little is known about how enhanced ER-mitochondrial tethering affects cellular proteostatic machinery. Here, we transiently overexpressed synthetic ER-mitochondrial linkers (EMLs), stabilizing the ER-mitochondrial distance at ≤5 nm (denominated as 5 nm-EML) and ∼10 nm (10 nm-EML), in HeLa cells. No alterations were found in cell growth, although metabolic activity and total ATP were significantly reduced. In EML-expressing cells, global protein synthesis was significantly reduced, accompanied by a reduction of total PERK and eIF2α protein levels, but increased p-eIF2α. Unfolded protein response (UPR) markers ATF4 and ATF6 were upregulated, suggesting that enhanced ER-mitochondrial tethering deranges protein synthesis and induces a low-grade ER stress/UPR. To further investigate ER-mitochondrial tethering-induced protein dyshomeostasis, we performed shotgun mass spectrometry proteomics followed by bioinformatic analysis. Analysis of highly changed proteins and the most significantly overrepresented gene ontology (GO) terms revealed that ≤5 nm tethering preferentially affected the expression of proteins involved in RNA processing and splicing and proteasomal protein degradation, while ∼10 nm tethering preferentially affected protein translation. Both EMLs affected expression of proteins involved in mitochondrial bioenergetics and metabolism, defense against oxidative stress, ER protein homeostasis, signaling and secretion. Finally, lipidomic analysis suggests that 5 nm-EML and 10 nm-EML differentially affect lipid homeostasis. Altogether, our results suggest that enhanced ER-mitochondrial tethering leads to a profound remodeling of cellular protein homeostasis, which may play a key role in pathogenesis of Alzheimer's and other neurodegenerative diseases.

The aim of the study was to determine the stability and heat resistance of extra premium olive oil. The study material consisted of six extra virgin olive oils (EVOO) obtained from Spain. Four samples were single-strain olive oils: Arbequina, Picual, Manzanilla, and Cornicabra. Two samples were a coupage of Arbequina and Picual varieties: Armonia (70% Arbequina and 30% Picual) and Sensation (70% Picual and 30% Arbequina). Olive oil samples were heated at 170 °C and 200 °C in a pan (thin layer model). In all samples, changes in indexes of lipid nutritional quality (PUFA/SFA, index of atherogenicity, index of thrombogenicity, and hypocholesterolemic/hypercholesterolemic ratio), changes in tocopherol, total polar compounds content, and triacylglycerol polymers were determined. Heating olive oil in a thin layer led to its degradation and depended on the temperature and the type of olive oil. Increasing the temperature from 170 to 200 °C resulted in significantly higher degradation of olive oil. At 200 °C, deterioration of lipid nutritional indices, total tocopherol degradation, and formation of triacylglycerol polymers were observed. A twofold increase in the polar fraction was also observed compared to samples heated at 170 °C. The most stable olive oils were Cornicabra and Picual.

Background/Objectives: Methyltransferase EZH2-mediated H3K27me3 is involved in liver inflammation and fibrosis, but its role in hepatic metabolic derangements is not yet clearly defined. We investigated if a high-fat diet (HFD) induced early changes in EZH2 expression and H3K27 me3 in the liver of mice. Methods: Five-week-old mice were fed an HFD or a low-fat diet (Control) for 2 weeks (2 W) or 8 weeks (8 W). Body weight was recorded weekly. Glycemia and oral glucose tolerance were assessed at baseline and after 2 W–8 W. Finally, livers were collected for further analysis. Results: As expected, mice that received 8 W HFD showed an increase in body weight, glycemia, and liver steatosis and an impairment in glucose tolerance; no alterations were observed in 2 W HFD mice. Eight weeks of HFD caused hepatic EZH2 nuclear localization and increased H3 K27me3; surprisingly, the same alterations occurred in 2 W HFD mice livers, even before overweight onset. We demonstrated that selective EZH2 inhibition reduced H3K27me3 and counteracted lipid accumulation in HUH-7 cells upon palmitic acid treatment. Conclusions: In conclusion, we point to EZH2/H3K27me3 as an early epigenetic event occurring in fatty-acid-challenged livers both in vivo and in vitro, thus establishing EZH2 as a potential pharmacological target for metabolic derangements.

Engineering amorphous dielectric films with tunable thermal conductivity is advantageous for the thermal management of semiconductor devices and thermal insulation of aerospace applications. Here, we demonstrate that incorporating dense dispersed amorphous Al(Ti)N (~1 nm or above) nanoparticles having phase volume fractions from 6 to 70 %, has a negligible effect on the intrinsic thermal conductivity of the amorphous Si N matrix (~2 W m K ), in which the wave-like 'propagons' in Allen-Feldmann theory are believed to be unsupressed and non-tuned. By contrast, incorporating (5-15 nm) crystalline TiN phases significantly increases the thermal conductivity (up to 15 W m K ). Critically, the micrometre-thick Si N /AlN and Si N /TiN amorphous matrix dual-phase nanocomposite coatings exhibit excellent thermal stability upon exposure to ambient air at 1000 °C for 50 h. These findings shed light on the phonon transport mechanism regarding the effects of the second phase and pave a design pathway for engineering amorphous coatings displaying unprecedented high thermal conductivity and excellent thermal stability.

IP receptor (IP R)-mediated Ca transfer at the mitochondria-endoplasmic reticulum (ER) contact sites (MERCS) drives mitochondrial Ca uptake and oxidative metabolism and is linked to different pathologies, including Parkinson's disease (PD). The dependence of Ca transfer efficiency on the ER-mitochondria distance remains unexplored. Employing molecular rulers that stabilize ER-mitochondrial distances at 5 nm resolution, and using genetically encoded Ca indicators targeting the ER lumen and the sub-mitochondrial compartments, we now show that a distance of ~20 nm is optimal for Ca transfer and mitochondrial oxidative metabolism due to enrichment of IP R at MERCS. In human iPSC-derived astrocytes from PD patients, 20 nm MERCS were specifically reduced, which correlated with a reduction of mitochondrial Ca uptake. Stabilization of the ER-mitochondrial interaction at 20 nm, but not at 10 nm, fully rescued mitochondrial Ca uptake in PD astrocytes. Our work determines with precision the optimal distance for Ca flux between ER and mitochondria and suggests a new paradigm for fine control over mitochondrial function.

Titanium dioxide thin films are durable, chemically stable, have a high refractive index and good electro/photochemical proprieties. Consequently, they are widely used as anti-reflective layers in optical devices and large area glazing products, dielectric layers in microelectronic devices and photo catalytic layers in self-cleaning surfaces. Titania coatings may have amorphous or crystalline structures, where three crystalline phases of TiO2 can be obtained: anatase, rutile and brookite, although the latter is rarely found. It is known, however, that the structure of TiO2 coatings is sensitive to deposition conditions and can also be modified by post-deposition heat treatments. In this study, titania coatings have been deposited onto soda-lime glass substrates by reactive sputtering from a metallic target. The magnetron was driven in mid-frequency pulsed DC mode. The as-deposited coatings were analysed by micro Raman spectroscopy, X-ray diffraction (XRD), atomic force microscopy (AFM) and scanning electron microscopy (SEM). Selected coatings were annealed at temperatures in the range 200–700 °C and re-analysed. Whilst there was weak evidence of a nanocrystallinity in the as-deposited films, it was observed that these largely amorphous low temperature structures converted into strongly crystalline structures at annealing temperatures above 400 °C.

Low emissivity (Low-E) coatings are applied to large area architectural glazing to reduce heat losses from buildings. They combine high visible transparency with high reflectance in the far-infrared region. To achieve this combination of properties, Low-E coatings generally consist of dielectric-silver-dielectric multi-layer systems or stacks, where the thin (~10 nm) silver layer reflects long wavelength IR back into the building and the dielectric layers both protect the silver and act as anti-reflectance layers. The dielectric layers are commonly TiO2, SnO2 or ZnO, and all the layers are usually deposited by magnetron sputtering. The market for Low-E coatings has grown considerably in recent years due to environmental legislation and increased energy costs. To further expand the market, the next generation of Low-E coatings are increasingly being deposited onto toughenable glass, which is post-deposition annealed at temperatures of up to 650oC. However, under these conditions, silver atoms are highly mobile and can rapidly diffuse through the other constituent layers of the coating stack, which can have a detrimental impact on the performance of the coating. Diffusion in polycrystalline films occurs much faster than in bulk samples and by different mechanisms. This is caused by the physical properties of thin films, which may contain a high density of defects such as dislocations, vacancies and grain boundaries that can act as pathways for diffusion processes. The aim of this project therefore is to carry out a detailed study of diffusion processes in dielectric-silver coating systems deposited under industrially relevant conditions (i.e. using commercially available magnetron designs and power deliver modes). TiO2 coatings have been deposited onto float glass substrates by reactive pulsed magnetron sputtering and characterised using Raman spectroscopy, scanning electron microscopy, energy-dispersive X-ray spectroscopy, atomic force microscopy and X-ray diffraction. The coatings have been annealed at temperatures in the range of 100oC to 800oC and re-analysed to determine the effect of annealing on the film structures. An interesting transition from a weakly crystalline rutile-like structure with very small grain sizes to a strongly crystalline anatase structure or mixed-phase structure with much larger grains was observed as annealing temperature was increased. Selected coatings were over coated with silver and annealed for a second time. These coatings were analysed by X-ray photoelectron spectroscopy and secondary ion mass spectrometry to determine the diffusion profiles of silver through the titania layer and the reverse diffusion of sodium from the glass substrates. Little difference in the diffusion rate of silver was observed with annealing temperature, but sodium was observed to diffuse significantly faster through samples annealed at higher temperature range. Similar studies have been performed for Al-doped ZnO, Zn2SnO4 and Si3N4 coatings. These films have been post-deposition annealed at 650oC then over coated with silver and re-annealed at 250oC. Diffusion profiles for both Ag and Na atoms were measured using secondary ion mass spectrometry. Finally dielectric/Ag/dielectric layers were deposited to investigate the behaviour of silver and sodium after annealing at 250oC. The basic models of diffusion mechanisms in thin films have been developed using Fick’s second diffusion law. Analytical modelling was used to fit the experimental data into a concentration dependent curve that represents the solution to Fick’s second law. Moreover selected dielectric/Ag/dielectric stacks were subjected to temperature dependency of silver diffusion studies using Arrhenius diffusion principle. Samples were post-deposition annealed at the temperature range of 200-650oC for 5 minutes to investigate silver diffusion at different heat treatment conditions and diffusivity values were used to find activation energies and frequency factors from Arrhenius plot. Overall findings from the diffusion studies are that from dielectric materials investigated in this work Al-doped ZnO coatings have the best barrier properties for silver atoms diffusion and show relatively low values for sodium diffusion, when not annealed at relatively high temperatures. Zinc stannate, on the other hand, was found to be the material through which atoms investigated here diffuse fairly easily. Both silver and sodium atoms were found to have the highest diffusion rates through zinc stannate films relative to the other coatings investigated in this work.