Control of neuronal ion channel function by glycogen synthase kinase-3: new prospective for an old kinase

Glycogen synthase kinase 3 (GSK-3) is an evolutionarily conserved multifaceted ubiquitous enzyme. In the central nervous system (CNS), GSK-3 acts through an intricate network of intracellular signaling pathways culminating in a highly divergent cascade of phosphorylations that control neuronal function during development and adulthood. Accumulated evidence indicates that altered levels of GSK-3 correlate with maladaptive plasticity of neuronal circuitries in psychiatric disorders, addictive behaviors, and neurodegenerative diseases, and pharmacological interventions known to limit GSK-3 can counteract some of these deficits. Thus, targeting the GSK-3 cascade for therapeutic interventions against this broad spectrum of brain diseases has raised a tremendous interest. Yet, the multitude of GSK-3 downstream effectors poses a substantial challenge in the development of selective and potent medications that could efficiently block or modulate the activity of this enzyme. Although the full range of GSK-3 molecular targets are far from resolved, exciting new evidence indicates that ion channels regulating excitability, neurotransmitter release, and synaptic transmission, which ultimately contribute to the mechanisms underling brain plasticity and higher level cognitive and emotional processing, are new promising targets of this enzyme. Here, we will revise this new emerging role of GSK-3 in controling the activity of voltage-gated Na(+), K(+), Ca(2+) channels and ligand-gated glutamate receptors with the goal of highlighting new relevant endpoints of the neuronal GSK-3 cascade that could provide a platform for a better understanding of the mechanisms underlying the dysfunction of this kinase in the CNS and serve as a guidance for medication development against the broad range of GSK-3-linked human diseases

Genetic and biotechnological approaches to preserve food quality against climate change

In this past decade, the bond between agriculture, food security, and climate change has become increasingly strong. Agriculture is recognized as one of the most endangered systems adversely affected by human activities and environmental issues. In particular, abiotic stress limits the quantity and quality of plant-based food. Heat stress, drought, and salinity impact plants at all different life stages, inducing morphological and physiological changes and provoking a reduction in their nutritional value. Accordingly, low-quality food results in a serious risk for the health of people worldwide. In this scenario, different genetic and biotechnological strategies have been investigated, including the use of New Plant Breeding Techniques (NBTs) and plant cell cultures. In this review, we describe how abiotic stresses alter the property and availability of nutritious food. In addition, we illustrate the advanced techniques that could be employed to address these issues and ameliorate the agricultural practices

Sulfur Starvation in Extremophilic Microalga Galdieria sulphuraria: Can Glutathione Contribute to Stress Tolerance?

This study reports the effects of sulfur (S) deprivation in cultures of Galdieria sulphuraria (Cyanidiophyceae). Galdieria is a unicellular red alga that usually grows, forming biomats on rocks, in S-rich environments. These are volcanic areas, where S is widespread since H2S is the prevalent form of gas. The glutathione content in Galdieria sulphuraria is much higher than that found in the green algae and even under conditions of S deprivation for 7 days, it remains high. On the other hand, the S deprivation causes a decrease in the total protein content and a significant increase in soluble protein fraction. This suggests that in the conditions of S starvation, the synthesis of enzy-matic proteins, that metabolically support the cell in the condition of nutritional stress, could be up regulated. Among these enzymatic proteins, those involved in cell detoxification, due to the accumulation of ROS species, have been counted

Changes upon the gluten-free diet of HLA-DQ2 and TRAFD1 gene expression in peripheral blood of celiac disease patients

Background: Celiac disease (CD) is a chronic immuno-mediated enteropathy caused by dietary gluten in genetically susceptible individuals carrying HLA (Human Leukocytes Antigen) genes that encode for DQ2.5 and DQ8 molecules. TRAFD1 (TRAF-type zinc finger domain 1) is a gene recently found associated with CD and defined as a master regulator of IFNγ signalling and of MHC class I antigen processing/presentation. There is no specific drug therapy and the only effective treatment is the gluten-free diet (GFD). The great majority of celiac patients when compliant with GFD have a complete remission of symptoms and recovery of gut mucosa architecture and function. Until now, very few studies have investigated molecular differences occurring in CD patients upon the GFD therapy. Methods: We looked at the expression of both HLA DQ2.5 and TRAFD1 risk genes in adult patients with acute CD at the time of and in treated patients on GFD. Specifically, we measured by qPCR the HLA-DQ2.5 and TRAFD1 mRNAs on peripheral blood mononuclear cells (PBMC) from the two groups of patients. Results: When we compared the HLA-DQ mRNA expression, we didn't find significant variation between the two groups of patients, thus indicating that GFD patients have the same capability to present gliadin antigens to cognate T cells as patients with active disease. Conversely, TRAFD1 was more expressed in PBMC from treated CD subjects. Notably, TRAFD1 transcripts significantly increased in the patients analyzed longitudinally during the GFD, indicating a role in the downregulation of gluten-induced inflammatory pathways. Conclusion: Our study demonstrated that HLA-DQ2.5 and TRAFD1 molecules are two important mediators of anti-gluten immune response and inflammatory process

Seismic vulnerability assessment of existing Italian hospitals: The case study of the national cancer institute “G. Pascale foundation” of Naples

Introduction: A large portion of the Italian built heritage is characterized by a significant seismic vulnerability since many structures were designed with outdated criteria, i.e., without accounting for seismic actions. This aspect is particularly relevant for strategic structures and infrastructures, whose functionalities are crucial in case of seismic events. Objective: The main aim of the present paper is to share the key findings related to the seismic vulnerability assessment of the National Institute for the Study and Treatment of Cancer (IRCCS) “Giovanni Pascale Foundation” in Naples. In particular, the main evidences could be easily extended to existing hospitals realized in the last century, with the main reference to: construction techniques, quality of constructional material, overt and convert seismic vulnerabilities and possible intervention strategies for risk mitigation. Methods: In the present paper, the assessment methodologies adopted for such a strategic hospital complex are provided, focusing in particular on: i. preliminary research of original design documents and on-site investigation for determining constructional details; ii. material tests on structural elements; iii. vulnerability seismic assessment by means of non-linear FE analyses (push-over and capacity spectrum method); iv. recommendations on retrofitting measures and cost estimations. Results: The conducted study puts into clear evidence the inadequacy of the investigated buildings to face the design seismic actions provided by the current Italian code and thus showed the significant seismic vulnerabilities affecting the Institute “G. Pascale Foundation” of Naples. Among these, particular attention has also been focused on the so-called intrinsic vulnerabilities, namely the ones not measurable explicitly and interesting non-structural elements (e.g., connection of shelves, stained glass windows, facilities, etc.). Conclusion: The presented case study highlights the strong seismic vulnerability affecting structures realized in the past century, despite their strategic functions. On the whole, the examined structures can be considered as representative of this building typology, and the adopted calculation criteria, as well as the assumptions of the assessment process, could be easily extended to similar case studies

Effect of Gliadin Stimulation on HLA-DQ2.5 Gene Expression in Macrophages from Adult Celiac Disease Patients

Macrophages play an important role in the pathogenesis of celiac disease (CD) because they are involved in both inflammatory reaction and antigen presentation. We analyzed the expression of CD-associated HLA-DQ2.5 risk alleles on macrophages isolated by two cohorts of adult patients, from the U.S. and Italy, at different stages of disease and with different genotypes. After isolating and differentiating macrophages from PBMC, we assessed the HLA genotype and quantified the HLA-DQ2.5 mRNAs by qPCR, before and after gliadin stimulation. The results confirmed the differences in expression between DQA1*05:01 and DQB1*02:01 predisposing alleles and the non-CD associated alleles, as previously shown on other types of APCs. The gliadin challenge confirmed the differentiation of macrophages toward a proinflammatory phenotype, but above all, it triggered an increase of DQA1*05:01 mRNA, as well as a decrease of the DQB1*02:01 transcript. Furthermore, we observed a decrease in the DRB1 genes expression and a downregulation of the CIITA transactivator. In conclusion, our findings provide new evidences on the non-coordinated regulation of celiac disease DQ2.5 risk genes and support the hypothesis that gliadin could interfere in the three-dimensional arrangement of chromatin at the HLA locus