Interactomic and Pharmacological Insights on Human Sirt-1

Sirt-1 is defined as a nuclear protein involved in the molecular mechanisms of inflammation and neurodegeneration through the de-acetylation of many different substrates even if experimental data in mouse suggest both its cytoplasmatic presence and nucleo-cytoplasmic shuttling upon oxidative stress. Since the experimental structure of human Sirt-1 has not yet been reported, we have modeled its 3D structure, highlighted that it is composed by four different structural regions: N-terminal region, allosteric site, catalytic core and C-terminal region, and underlined that the two terminal regions have high intrinsic disorder propensity and numerous putative phosphorylation sites. Many different papers report experimental studies related to its functional activators because Sirt-1 is implicated in various diseases and cancers. The aim of this article is (i) to present interactomic studies based human Sirt-1 to understand its most important functional relationships in the light of the gene–protein interactions that control major metabolic pathways and (ii) to show by docking studies how this protein binds some activator molecules in order to evidence structural determinants, physico-chemical features and those residues involved in the formation of complexes

The use of virtual environments for survey spatial ability evaluation in topographical disorientation

Due to their interactivity and to the sense of presence they afford, virtual environments constitute an interesting opportunity to study spatial cognition. In accordance with this perspective, we aimed to introduce a spatial test in virtual simulation in order to investigate the survey spatial ability in patients with topographical disorientation. To do this, we used the “planning in advance task” in a virtual environment that constitutes an effective procedure to experimentally evaluate survey maps. With this procedure we present the single case of a woman, with a right medial temporal lobe lesion, who shows a selective impairment in the acquisition of new spatial relationships. The patient’s performance in “planning in advance task” was compared with that of a control group made up of 40 female subjects matched for age and education. Results show how the patient revealed a significantly lower spatial performance when compared to the control group, demonstrating an inability to solve survey-type spatial tasks in complex virtual environments

Mitochondrial Abnormalities in Down Syndrome: Pathogenesis, Effects and Therapeutic Approaches

Down syndrome (DS) consists of a complex phenotype with constant features, such as mental retardation and hypotonia, and variable features, including heart defects and susceptibility to Alzheimer’s disease, type 2 diabetes, obesity and immune disorders. Overexpression of genes mapping to chromosome 21 (Hsa21) is directly or indirectly responsible for pathogenesis of DS phenotypic features, as overexpressed Hsa21 genes dysregulate several other genes mapping to different chromosomes. Many of these genes are involved in mitochondrial function. Recent studies highlight a link between mitochondrial dysfunction, consistently observed in DS subjects, and DS phenotype. In this review, we first provide a basic overview of mitochondrial alterations in DS in terms of mitochondrial bioenergetics, biogenesis and morphology. We then discuss how mitochondrial malfunction may contribute to the pathogenesis of clinical manifestations and how specific Hsa21 genes may cause the disruption of mitochondrial phenotype. Finally, we focus on drugs, which affect mitochondrial function and network to propose possible therapeutic approaches aimed at improving and/or preventing various aspects of the DS phenotype. Our working hypothesis is that correcting the mitochondrial defect might improve the neurological phenotype and prevent DS-associated pathologies, thus providing a better quality of life for DS individuals and their families

The Role of Molecular Chaperones in Virus Infection and Implications for Understanding and Treating COVID-19

The COVID-19 pandemic made imperative the search for means to end it, which requires a knowledge of the mechanisms underpinning the multiplication and spread of its cause, the coronavirus SARS-CoV-2. Many viruses use members of the hosts' chaperoning system to infect the target cells, replicate, and spread, and here we present illustrative examples. Unfortunately, the role of chaperones in the SARS-CoV-2 cycle is still poorly understood. In this review, we examine the interactions of various coronaviruses during their infectious cycle with chaperones in search of information useful for future research on SARS-CoV-2. We also call attention to the possible role of molecular mimicry in the development of autoimmunity and its widespread pathogenic impact in COVID-19 patients. Viral proteins share highly antigenic epitopes with human chaperones, eliciting anti-viral antibodies that crossreact with the chaperones. Both, the critical functions of chaperones in the infectious cycle of viruses and the possible role of these molecules in COVID-19 autoimmune phenomena, make clear that molecular chaperones are promising candidates for the development of antiviral strategies. These could consist of inhibiting-blocking those chaperones that are necessary for the infectious viral cycle, or those that act as autoantigens in the autoimmune reactions causing generalized destructive effects on human tissues

Overexpression of the Hsa21 Transcription Factor RUNX1 Modulates the Extracellular Matrix in Trisomy 21 Cells

Down syndrome is a neurodevelopmental disorder frequently characterized by other developmental defects, such as congenital heart disease. Analysis of gene expression profiles of hearts from trisomic fetuses have shown upregulation of extracellular matrix (ECM) genes. The aim of this work was to identify genes on chromosome 21 potentially responsible for the upregulation of ECM genes and to pinpoint any functional consequences of this upregulation. By gene set enrichment analysis of public data sets, we identified the transcription factor RUNX1, which maps to chromosome 21, as a possible candidate for regulation of ECM genes. We assessed that approximately 80% of ECM genes overexpressed in trisomic hearts have consensus sequences for RUNX1 in their promoters. We found that in human fetal fibroblasts with chromosome 21 trisomy there is increased expression of both RUNX1 and several ECM genes, whether located on chromosome 21 or not. SiRNA silencing of RUNX1 reduced the expression of 11 of the 14 ECM genes analyzed. In addition, collagen IV, an ECM protein secreted in high concentrations in the culture media of trisomic fibroblasts, was modulated by RUNX1 silencing. Attenuated expression of RUNX1 increased the migratory capacity of trisomic fibroblasts, which are characterized by a reduced migratory capacity compared to euploid controls

Cooperative Binding of the Cationic Porphyrin Tris-T4 Enhances Catalytic Activity of 20S Proteasome Unveiling a Complex Distribution of Functional States

The present study provides new evidence that cationic porphyrins may be considered as tunable platforms to interfere with the structural "key code" present on the 20S proteasome α-rings and, by consequence, with its catalytic activity. Here, we describe the functional and conformational effects on the 20S proteasome induced by the cooperative binding of the tri-cationic 5-(phenyl)-10,15,20-(tri N-methyl-4-pyridyl) porphyrin (Tris-T4). Our integrated kinetic, NMR, and in silico analysis allowed us to disclose a complex effect on the 20S catalytic activity depending on substrate/porphyrin concentration. The analysis of the kinetic data shows that Tris-T4 shifts the relative populations of the multiple interconverting 20S proteasome conformations leading to an increase in substrate hydrolysis by an allosteric pathway. Based on our Tris-T4/h20S interaction model, Tris-T4 is able to affect gating dynamics and substrate hydrolysis by binding to an array of negatively charged and hydrophobic residues present on the protein surface involved in the 20S molecular activation by the regulatory proteins (RPs). Accordingly, despite the fact that Tris-T4 also binds to the α3ΔN mutant, allosteric modulation is not observed since the molecular mechanism connecting gate dynamics with substrate hydrolysis is impaired. We envisage that the dynamic view of the 20S conformational equilibria, activated through cooperative Tris-T4 binding, may work as a simplified model for a better understanding of the intricate network of 20S conformational/functional states that may be mobilized by exogenous ligands, paving the way for the development of a new generation of proteasome allosteric modulators

High-Resolution Conformational Analysis of RGDechi-Derived Peptides Based on a Combination of NMR Spectroscopy and MD Simulations

The crucial role of integrin in pathological processes such as tumor progression and metastasis formation has inspired intense efforts to design novel pharmaceutical agents modulating integrin functions in order to provide new tools for potential therapies. In the past decade, we have investigated the biological proprieties of the chimeric peptide RGDechi, containing a cyclic RGD motif linked to an echistatin C-terminal fragment, able to specifically recognize αvβ3 without cross reacting with αvβ5 and αIIbβ3 integrin. Additionally, we have demonstrated using two RGDechi-derived peptides, called RGDechi1-14 and ψRGDechi, that chemical modifications introduced in the C-terminal part of the peptide alter or abolish the binding to the αvβ3 integrin. Here, to shed light on the structural and dynamical determinants involved in the integrin recognition mechanism, we investigate the effects of the chemical modifications by exploring the conformational space sampled by RGDechi1-14 and ψRGDechi using an integrated natural-abundance NMR/MD approach. Our data demonstrate that the flexibility of the RGD-containing cycle is driven by the echistatin C-terminal region of the RGDechi peptide through a coupling mechanism between the N- and C-terminal regions

Il Bilancio di Genere dell’Ateneo federiciano: dal rapporto di genere all’istituzionalizzazione del processo

[Italiano]:Le Università, in quanto enti di formazione e di ricerca, sono tenute a mettere in atto azioni e politiche volte a garantire la parità di genere e a rimuovere gli ostacoli che impediscono la piena realizzazione personale e professionale di uomini e donne. A tale scopo il Bilancio di Genere è lo strumento d’elezione per perseguire gli obiettivi di parità. Ma più che di un documento, si tratta di un vero e proprio articolato processo che richiede un significativo coinvolgimento della governance di Ateneo, attraverso un percorso di istituzionalizzazione dell’approccio alle questioni di genere. Il volume presenta gli esiti del secondo bilancio di genere della Federico II di Napoli, redatto secondo le Linee Guida elaborate dalla Conferenza dei Rettori delle Università Italiane. Oltre all’analisi di contesto, che consente di evidenziare i punti di forza e gli elementi di criticità dell’Ateneo federiciano rispetto alla parità di genere, il documento illustra il livello di integrazione della prospettiva di genere nei documenti strategici di Ateneo, la rete di organismi preposti alle tematiche di genere e il repertorio delle azioni messe in atto nel quinquennio precedente. L’analisi di genere degli impegni economico-finanziari, realizzata a partire dalla riclassificazione del bilancio, ha consentito inoltre di esplorare nel dettaglio le risorse espressamente destinate agli obiettivi di parità, identificando gli ambiti in cui è necessario investire maggiormente. Il documento include inoltre una prima analisi in ottica di genere dei questionari di rilevazione delle opinioni degli studenti e delle studentesse, che può essere adoperata come utile strumento per fornire spunti per la definizione di azioni positive destinate alla popolazione studentesca. Il quadro che emerge dall’analisi proposta è quello di un Ateneo che ha intrapreso un serio percorso di istituzionalizzazione dell’intero ciclo del Bilancio di Genere, attestato dall’impegno nella promozione di processi culturali ed organizzativi inclusivi volti a perseguire concretamente gli obiettivi di uguaglianza e di parità nella formazione, nella ricerca e nel lavoro. ./[English]:Universities, as training and research institutions, are required to implement actions and policies aimed at ensuring gender equality and at removing obstacles that prevent the full personal and professional fulfilment of men and women. To this end, the Gender Responsive Budgeting is the fundamental tool to pursue the objectives of equality. But more than a document, it is an articulated process that requires a significant involvement of the governance of the University, through a path of institutionalization of the approach to the gender issues. The volume presents the results of the second gender report of the University Federico II of Naples, drawn up according to the Conference of Rectors of Italian Universities Guidelines. In addition to the context analysis, which allows to highlight strengths and critical issues of the University with respect to gender equality, the document illustrates the level of integration of the gender perspective in the University's strategic documents, the network of bodies responsible for gender issues and the repertoire of actions implemented in the previous five years. The gender analysis of economic and financial commitments, carried out through the reclassification of the budget, has also made it possible to explore in detail the resources expressly allocated to the equality objectives, identifying the areas in which greatest investments are needed. The document also includes a preliminary gender analysis of student opinion questionnaires, which can be used as a useful tool to provide insights into the definition of positive actions for the student population. The picture that emerges from the proposed analysis is of a University that has embarked on a serious path of institutionalization of the gender budget process, attested by the commitment to promote inclusive cultural and organizational processes aimed at concretely pursuing equality objectives in training, research and work

Pro-Environmental Behaviors: Determinants and Obstacles among Italian University Students

The awareness of citizens concerning the health risks caused by environmental pollution is growing, but studies on determinants of pro-environmental behaviors have rarely examined health-related aspects. In this study, we investigated these determinants using data from a large survey among Italian university students (15 Universities: 4778 filled questionnaires). Besides the health-related aspects, represented by environmental health risk perception and functional health literacy, we considered social and demographic characteristics (gender, area of residence, sources of information, trust in institutional and non-institutional subjects, and students' capacity of positive actions, indicated as internal locus of control). The attitudes towards pro-environmental behaviors were positive for more than 70% of students and positively related with health risk perception, internal locus of control, and health literacy. The correspondence between the positive attitudes towards pro-environmental behaviors and the real adoption of such behaviors was approximately 20% for most behaviors, except for the separate collection of waste (60%). Such a discrepancy can be attributable to external obstacles (i.e., lack of time, costs, lack of support). The health-related aspects were linked to the pro-environmental attitudes, but to a lesser extent to pro-environmental behaviors, owing to the complexity of their determinants. However, they should be taken in account in planning education interventions