High-Fat Diet Leads to Reduced Protein O-GlcNAcylation and Mitochondrial Defects Promoting the Development of Alzheimer’s Disease Signatures

The disturbance of protein O-GlcNAcylation is emerging as a possible link between altered brain metabolism and the progression of neurodegeneration. As observed in brains with Alzheimer’s disease (AD), flaws of the cerebral glucose uptake translate into reduced protein O-GlcNAcylation, which promote the formation of pathological hallmarks. A high-fat diet (HFD) is known to foster metabolic dysregulation and insulin resistance in the brain and such effects have been associated with the reduction of cognitive performances. Remarkably, a significant role in HFD-related cognitive decline might be played by aberrant protein O-GlcNAcylation by triggering the development of AD signature and mitochondrial impairment. Our data support the impairment of total protein O-GlcNAcylation profile both in the brain of mice subjected to a 6-week high-fat-diet (HFD) and in our in vitro transposition on SH-SY5Y cells. The reduction of protein O-GlcNAcylation was associated with the development of insulin resistance, induced by overfeeding (i.e., defective insulin signaling and reduced mitochondrial activity), which promoted the dysregulation of the hexosamine biosynthetic pathway (HBP) flux, through the AMPK-driven reduction of GFAT1 activation. Further, we observed that a HFD induced the selective impairment of O-GlcNAcylated-tau and of O-GlcNAcylated-Complex I subunit NDUFB8, thus resulting in tau toxicity and reduced respiratory chain functionality respectively, highlighting the involvement of this posttranslational modification in the neurodegenerative process.     

Evidence for a Negative Correlation between Human Reactive Enamine-Imine Intermediate Deaminase A (RIDA) Activity and Cell Proliferation Rate: Role of Lysine Succinylation of RIDA

Reactive intermediate deaminase (Rid) proteins are enzymes conserved in all domains of life. UK114, a mammalian member of RidA subfamily, has been firstly identified as a component of liver perchloric acid-soluble proteins (L-PSP). Although still poorly defined, several functions have been attributed to the mammalian protein UK114/RIDA, including the reactive intermediate deamination activity. The expression of UK114/RIDA has been observed in some tumors, arousing interest in this protein as an evaluable tumor marker. However, other studies reported a negative correlation between UK114/RIDA expression, tumor differentiation degree and cell proliferation. This work addressed the question of UK114/RIDA expression in human non-tumor HEK293 cell lines and in some human tumor cell lines. Here we reported that human RIDA (hRIDA) was expressed in all the analyzed cell line and subjected to lysine (K-)succinylation. In HEK293, hRIDA K-succinylation was negatively correlated to the cell proliferation rate and was under the control of SIRT5. Moreover, K-succinylation clearly altered hRIDA quantification by immunoblotting, explaining, at least in part, some discrepancies about RIDA expression reported in previous studies. We found that hRIDA was able to deaminate reactive enamine-imine intermediates and that K-succinylation drastically reduced deaminase activity. As predicted by in silico analysis, the observed reduction of deaminase activity has been related to the drastic alterations of hRIDA structure inferred by K-succinylation. The role of hRIDA and the importance of its K-succinylation in cell metabolism, especially in cancer biology, have been discussed.     

Photo-Polymerization Damage Protection by Hydrogen Sulfide Donors for 3D-Cell Culture Systems Optimization

Photo-polymerized hydrogels are ideally suited for stem-cell based tissue regeneration and three dimensional (3D) bioprinting because they can be highly biocompatible, injectable, easy to use, and their mechanical and physical properties can be controlled. However, photo-polymerization involves the use of potentially toxic photo-initiators, exposure to ultraviolet light radiation, formation of free radicals that trigger the cross-linking reaction, and other events whose effects on cells are not yet fully understood. The purpose of this study was to examine the effects of hydrogen sulfide (H₂S) in mitigating cellular toxicity of photo-polymerization caused to resident cells during the process of hydrogel formation. H₂S, which is the latest discovered member of the gasotransmitter family of gaseous signalling molecules, has a number of established beneficial properties, including cell protection from oxidative damage both directly (by acting as a scavenger molecule) and indirectly (by inducing the expression of anti-oxidant proteins in the cell). Cells were exposed to slow release H₂S treatment using pre-conditioning with glutathione-conjugated-garlic extract in order to mitigate toxicity during the photo-polymerization process of hydrogel formation. The protective effects of the H₂S treatment were evaluated in both an enzymatic model and a 3D cell culture system using cell viability as a quantitative indicator. The protective effect of H₂S treatment of cells is a promising approach to enhance cell survival in tissue engineering applications requiring photo-polymerized hydrogel scaffolds.     

Molecular Biomarkers in Idiopathic Pulmonary Fibrosis: State of the Art and Future Directions

Idiopathic pulmonary fibrosis (IPF), the most lethal form of interstitial pneumonia of unknown cause, is associated with a specific radiological and histopathological pattern (the so-called “usual interstitial pneumonia” pattern) and has a median survival estimated to be between 3 and 5 years after diagnosis. However, evidence shows that IPF has different clinical phenotypes, which are characterized by a variable disease course over time. At present, the natural history of IPF is unpredictable for individual patients, although some genetic factors and circulating biomarkers have been associated with different prognoses. Since in its early stages, IPF may be asymptomatic, leading to a delayed diagnosis. Two drugs, pirfenidone and nintedanib, have been shown to modify the disease course by slowing down the decline in lung function. It is also known that 5–10% of the IPF patients may be affected by episodes of acute and often fatal decline. The acute worsening of disease is sometimes attributed to identifiable conditions, such as pneumonia or heart failure; but many of these events occur without an identifiable cause. These idiopathic acute worsenings are termed acute exacerbations of IPF. To date, clinical biomarkers, diagnostic, prognostic, and theranostic, are not well characterized. However, they could become useful tools helping facilitate diagnoses, monitoring disease progression and treatment efficacy. The aim of this review is to cover molecular mechanisms underlying IPF and research into new clinical biomarkers, to be utilized in diagnosis and prognosis, even in patients treated with antifibrotic drugs.     

Long-Term Efficacy of Intranasal Esketamine in Treatment-Resistant Major Depression: A Systematic Review

Esketamine (ESK) has been approved as a rapid-acting intranasal treatment for treatment-resistant depression (TRD). Although existing studies have investigated the efficacy of ESK in the 4-week induction phase, our knowledge about long-term ESK efficacy remains poor. The aim of this systematic review was to summarize the available data on long-term ESK efficacy for TRD. A systematic search was performed including articles in English, up to 31 March 2021. The search found 7 relevant studies, involving 1024 adult TRD patients. Continuing treatment with ESK after the 4-week induction phase may be associated with stable efficacy in relapse prevention among TRD patients. Conversely, the long-term antidepressant effectiveness upon discontinuation of ESK might be limited, although data from three studies had a moderate to high risk of bias. Overall, the results on the effectiveness of this compound in the long term are mixed. According to our findings, ESK treatment should be continued following the induction phase to reach a stable efficacy in relapse prevention, while the long-term antidepressant and anti-suicidal effects of ESK after discontinuation are inconsistent. Currently, the level of proof of ESK efficacy in long-term TRD treatment remains low and more RCTs with larger sample sizes and active comparators are needed.     

Ultrathin hydroxyapatite coating on pure magnesium substrate prepared by pulsed electron ablation technique

Magnesium (Mg) as a potential material for biodegradable implants is attractive due to its mechanical similarity to the bone tissue and nontoxic corrosion products. However, the rapid corrosion rate of bare magnesium is associated with hydrogen release, which may complicate the healing process. The corrosion rate may be reduced by suitable alloying, but concurrently the biocompatibility of such alloy might be deteriorated. Another way of reduction of the corrosion rate is coating. Hydroxyapatite (HA)-based coating is considered to improve biocompatibility as well as decrease the corrosion rate by the barrier effect. In this study, ultrathin (150 nm) HA and HA containing Sr coatings are deposited via pulsed electron ablation technique on pure Mg. The microstructure of the coating was assessed by scanning electron microscopy. Electrochemical methods were used to investigate the corrosion properties of prepared coatings. The materials covered by this layer were characterized by superior corrosion behavior, with corrosion rates of coated samples up to five times lower as compared with the uncoated ones. Such coating is the thinnest coating found in the literature sources.     

Scouring at Bed Sills as a Response to Flash Floods

The temporal development of clear-water local scour depth at bed sills in uniform gravel beds is considered. Experiments are presented on the development of scour holes under unsteady hydraulic conditions, with the triangular-shaped hydrographs tested being of different durations and different rates of flow variation. Based on the experimental results and a theoretical framework, a method is given for the definition and prediction of the scouring process under unsteady flows in terms of a dimensionless temporal parameter. A “flash flood” is here defined as an event for which the scour doesn’t attain its potential magnitude, i.e., the equilibrium value for the peak hydrograph flow rate. This flood nature is dependent on both the characteristics of the flood event itself and the characteristics of the stream. A quantitative measure of what constitutes a flash flood is given in terms of the identified temporal parameter. Results show that the ratio between the final scour depth and the potential scour depth at a bed sill for a given hydrograph can be estimated as a function of the identified temporal parameter.     

Nuclear reactor dynamics on-line estimation by Locally Recurrent Neural Networks

In this paper, the Causal Recursive Back-Propagation (CRBP) algorithm is employed to train on-line an Infinite Impulse Response–Locally Recurrent Neural Network (IIR–LRNN) for modelling the dynamics of a next-generation nuclear reactor. The results demonstrate the advantages of the on-line training over the batch-mode learning in the reconstruction of complex nonlinear dynamic relationships.     

Rawseeds ground truth collection systems for indoor self-localization and mapping

A trustable and accurate ground truth is a key requirement for benchmarking self-localization and mapping algorithms; on the other hand, collection of ground truth is a complex and daunting task, and its validation is a challenging issue. In this paper we propose two techniques for indoor ground truth collection, developed in the framework of the European project Rawseeds, which are mutually independent and also independent on the sensors onboard the robot. These techniques are based, respectively, on a network of fixed cameras, and on a network of fixed laser scanners. We show how these systems are implemented and deployed, and, most importantly, we evaluate their performance; moreover, we investigate the possible fusion of their outputs.