Network-based approaches to explore complex biological systems towards network medicine

Network medicine relies on different types of networks: from the molecular level of protein–protein interactions to gene regulatory network and correlation studies of gene expression. Among network approaches based on the analysis of the topological properties of protein–protein interaction (PPI) networks, we discuss the widespread DIAMOnD (disease module detection) algorithm. Starting from the assumption that PPI networks can be viewed as maps where diseases can be identified with localized perturbation within a specific neighborhood (i.e., disease modules), DIAMOnD performs a systematic analysis of the human PPI network to uncover new disease-associated genes by exploiting the connectivity significance instead of connection density. The past few years have witnessed the increasing interest in understanding the molecular mechanism of post-transcriptional regulation with a special emphasis on non-coding RNAs since they are emerging as key regulators of many cellular processes in both physiological and pathological states. Recent findings show that coding genes are not the only targets that microRNAs interact with. In fact, there is a pool of different RNAs—including long non-coding RNAs (lncRNAs) —competing with each other to attract microRNAs for interactions, thus acting as competing endogenous RNAs (ceRNAs). The framework of regulatory networks provides a powerful tool to gather new insights into ceRNA regulatory mechanisms. Here, we describe a data-driven model recently developed to explore the lncRNA-associated ceRNA activity in breast invasive carcinoma. On the other hand, a very promising example of the co-expression network is the one implemented by the software SWIM (switch miner), which combines topological properties of correlation networks with gene expression data in order to identify a small pool of genes—called switch genes—critically associated with drastic changes in cell phenotype. Here, we describe SWIM tool along with its applications to cancer research and compare its predictions with DIAMOnD disease genes

Insulin signaling in insulin resistance states and cancer: A modeling analysis

Insulin resistance is the common denominator of several diseases including type 2 diabetes and cancer, and investigating the mechanisms responsible for insulin signaling impairment is of primary importance. A mathematical model of the insulin signaling network (ISN) is proposed and used to investigate the dose-response curves of components of this network. Experimental data of C2C12 myoblasts with phosphatase and tensin homologue (PTEN) suppressed and data of L6 myotubes with induced insulin resistance have been analyzed by the model. We focused particularly on single and double Akt phosphorylation and pointed out insulin signaling changes related to insulin resistance. Moreover, a new characterization of the upstream signaling of the mammalian target of rapamycin complex 2 (mTORC2) is presented. As it is widely recognized that ISN proteins have a crucial role also in cell proliferation and death, the ISN model was linked to a cell population model and applied to data of a cell line of acute myeloid leukemia treated with a mammalian target of rapamycin inhibitor with antitumor activity. The analysis revealed simple relationships among the concentrations of ISN proteins and the parameters of the cell population model that characterize cell cycle progression and cell death

Insulin signaling network: mathematical modeling and parameter estimation from experimental data

The insulin signaling network (ISN) is an important metabolic network that, upon the insulin binding to its receptor at the cell surface, triggers the glucose uptake into the cell. The study of this mechanism within muscle cells, hepatocytes and cells of the adipose tissue is of major interest since it is crucial for understanding more clearly the factors that may induce the insulin resistance. However, the structure and the behaviour of the insulin signaling network are only partially known and the current research on this topic is fragmented into various lines of investigation. Because of the high degree of complexity of the ISN, it is diffcult to understand, without a theoretical framework, how the network responses evidenced from the experimental data determine the cell behaviour. In the present thesis, we proposed a detailed mathematical model of the ISN in order to investigate the factors that affect the basal concentrations and the dose-response curves (i.e., the steady state concentrations at given insulin levels) of the main components of the whole network. Our model concentrated particularly on single and double phosphorylation of Akt protein, and hypothesized the existence of a putative factor released by the small intestine that induces insulin resistance by activating the mammalian target of rapamycin complex 2 (mTORC2) in an insulin-independent manner and possibly operating through the IGF-1 receptor. Such hypothesis is based on clinical and experimental observations. The parameters of the ISN model were estimated from the experimental data of two skeletal muscle cell lines using a least squares approach. As the available data consisted in the equilibrium concentrations of many of the known signaling components at given values of the insulin, we derived the concentrations of the chemicals at the steady-state from the kinetic equations and then we implemented an algorithm that minimizes the distance between the model outputs and the data. For the numerical solution, we used a local optimization routine based on a derivative-free algorithm for bound constrained optimization. The ISN model was able to adequately fit the available experimental data. The model could thus become a useful tool to generate and test hypotheses, leading to a deeper understanding of the molecular mechanisms underlying insulin resistance and, in future perspective, to find drugs able to counterbalance the effects of this disease. Finally, as it is now widely recognized that Akt and mTOR complexes have a major role also in the regulation of cell proliferation, and then in cancer development, we combined the ISN model with a mathematical model that described the evolution of a AML (acute myeloid leukemia) cell population in order to investigate the effects of mTOR inhibitors with antitumor activity on the ISN and on the cell population response. Based on literature data of AML cell response to mTOR inhibitors with antitumor activity (the dual ATP-competitive mTOR inhibitor AZD8055), the two models provided simple relationships between the concentrations of proteins of the ISN and parameters representative of cell cycle progression and cell death

La tutela della vittima nelle fonti europee e nel sistema processuale penale italiano

2011 - 2012Il presente lavoro, prendendo le mosse dall’analisi delle fonti interne e sovranazionali che contribuiscono alla tutela della vittima del reato, mira a verificare in che misura l’ordinamento italiano abbia recepito le indicazioni provenienti dai provvedimenti adottati sul tema, nel tentativo di delineare quello che è stato definito lo “statuto” della vittima del reato. Lo scenario sovranazionale che si presenta all’interprete racchiude una pluralità di livelli: ONU, Unione europea e Consiglio d’Europa, Corte di giustizia dell’Unione europea e Corte europea dei diritti dell’uomo. Il tema è affrontato con riferimento a numerosi aspetti, che abbracciano l’istituto del risarcimento del danno da parte dello Stato, la tutela delle vittime della tratta di esseri umani e della criminalità organizzata, nonché i possibili sviluppi del paradigma mediativo in ambito penale. In una prospettiva diacronica, l’Unione europea ha intrapreso il cammino verso il formale riconoscimento dei diritti della vittima del reato al fine di realizzare uno spazio di libertà, sicurezza e giustizia. In tale ottica, la protezione delle vittime costituisce la “piattaforma comune” da cui devono trarre fondamento ed ispirazione tutti gli altri strumenti funzionali al raggiungimento dell’obiettivo. La tutela delle vittime è stata a lungo messa in disparte dal legislatore italiano che, concentrandosi sul momento repressivo, ne ha trascurato i problemi e le reali istanze. Soltanto a partire dai primi anni ottanta si è fatta strada un’analisi del crimine che, senza pregiudicare i diritti dell’imputato, ha posto l’accento su un’ottica Opfer-orientiert (orientata alla vittima), traducendosi in scelte di politica criminale più attente alla prospettiva vittimologica. Ciò nonostante, in molti punti la nostra legislazione appare non completamente rispettosa degli obblighi imposti dall’ordinamento sovranazionale. Nella prospettiva attuale si avverte l’esigenza di rafforzamento delle politiche socio-assistenziali in favore delle vittime del reato, al fine di scongiurare i rischi di vittimizzazione secondaria che sovente si palesano nella fase del post-crimen. In futuro, il processo di ristrutturazione del sistema processuale penale dovrà necessariamente passare attraverso il potenziamento dei poteri processuali riconosciuti alla persona offesa e degli istituti ispirati ai temi della restorative justice e della composizione del conflitto ingenerato dal reato. [a cura dell'autore]This piece of work, starting from the analysis of the inner and supranational sources which contribute to the tutelage of the victim of the offence, aims to check how the Italian rules have caught the suggestions coming from the measures which are adopted for this theme, with the attempt to delineate what has been defined the “statute” of the victim of the offence. The supranational scenery which is in front of the expert includes a plurality of levels: ONU, European Union and European Council, Court of Justice of the European Union and European Court of the rights of man. The theme has been discussed referring to many aspects, including the Institute of the Compensation by the State, the tutelage of the victims of the human beings trade and the organized crime and also about the probable developments of the meditative paradigm in the penal laws. In a diachronic perspective, the course of the European Union towards the formal recognition of the rights of the victim of the offence has been faced with the aim to create a space of freedom, safety and justice. According to this point of view, the safety of the victims characterizes the “common platform” from which all the other functional instruments, to reach the goal, have to take grounding and inspiration. The tutelage of the victims has been put aside for many years by the Italian legislator who, concentrated on the repressive moment, has neglected the problems and the real petitions of the victims. Only since the early eighties an analysis of the crime has been taken into consideration which, without compromising the rights of the defendant, has focused on a line Opfer-orientert (victim oriented), revealing in choices of criminal policy more careful towards the victim oriented perspective. In spite of this, in many points, our legislation looks like not totally respectful of the duties imposed by the supranational rules. In the current perspective it’s possible to notice the need to strengthen the social-charitable policies in favor of the victims of the offence, in order to avoid the risks of the secondary victimization which, often, are revealed in the postcrime phase. Furthermore, the reorganization phase of the procedural penal system should, necessarily, go through the procedural laws strengthening which are recognized for the offended person and of the Institutes inspired to the restorative justice and of the composition of the conflict caused by the offence. [edited by author]XI n.

SAveRUNNER: a network-based algorithm for drug repurposing and its application to COVID-19

The novelty of new human coronavirus COVID-19/SARS-CoV-2 and the lack of effective drugs and vaccines gave rise to a wide variety of strategies employed to fight this worldwide pandemic. Many of these strategies rely on the repositioning of existing drugs that could shorten the time and reduce the cost compared to de novo drug discovery. In this study, we presented a new network-based algorithm for drug repositioning, called SAveRUNNER (Searching off-lAbel dRUg aNd NEtwoRk), which predicts drug-disease associations by quantifying the interplay between the drug targets and the disease-specific proteins in the human interactome via a novel network-based similarity measure that prioritizes associations between drugs and diseases locating in the same network neighborhoods. Specifically, we applied SAveRUNNER on a panel of 14 selected diseases with a consolidated knowledge about their disease-causing genes and that have been found to be related to COVID-19 for genetic similarity, comorbidity, or for their association to drugs tentatively repurposed to treat COVID-19. Focusing specifically on SARS subnetwork, we identified 282 repurposable drugs, including some the most rumored off-label drugs for COVID-19 treatments, as well as a new combination therapy of 5 drugs, actually used in clinical practice. Furthermore, to maximize the efficiency of putative downstream validation experiments, we prioritized 24 potential anti-SARS-CoV repurposable drugs based on their network-based similarity values. These top-ranked drugs include ACE-inhibitors, monoclonal antibodies, and thrombin inhibitors. Finally, our findings were in-silico validated by performing a gene set enrichment analysis, which confirmed that most of the network-predicted repurposable drugs may have a potential treatment effect against human coronavirus infections.Comment: 42 pages, 9 figure

How do we choose whom to trust? The effect of social networks on trust

Our social lives are governed by trust. But how do we choose whom to trust? In this work, based on a laboratory experiment, we explore whether building relationships in a social network increases individuals' level of trust. We find that social interactions direct trust, but their impulse is not sufficiently strong to result beneficial

A Sustainable Improvement of ω-Bromoalkylphosphonates Synthesis to Access Novel KuQuinones

Owing to the attractiveness of organic phosphonic acids and esters in the pharmacological field and in the functionalization of conductive metal-oxides, the research of effective synthetic protocols is pivotal. Among the others, ω-bromoalkylphosphonates are gaining particular attention because they are useful building blocks for the tailored functionalization of complex organic molecules. Hence, in this work, the optimization of Michaelis–Arbuzov reaction conditions for ω-bromoalkylphosphonates has been performed, to improve process sustainability while maintaining good yields. Synthesized ω-bromoalkylphosphonates have been successfully adopted for the synthesis of new KuQuinone phosphonate esters and, by hydrolysis, phosphonic acid KuQuinone derivatives have been obtained for the first time. Considering the high affinity with metal-oxides, KuQuinones bearing phosphonic acid terminal groups are promising candidates for biomedical and photo(electro)chemical applications

3-morpholino-7-[N-methyl-N-(4′-carboxyphenyl)amino]phenothiazinium chloride

The synthesis of 3-morpholino-7-[N-methyl-N-(4′-carboxyphenyl)amino]phenothiazinium chloride is reported here. Interestingly, non-symmetric phenothiazinium salt is functionalized with a carboxylic acid group that allows the easy and stable anchoring on metal oxides. In addition, the morpholine unit reduces the dye aggregation tendency; thus, improving its potential applications in the biomedical and photo-electrocatalytic field

The Site of Lesion in Hearing Loss: Advances in Otoneuroradiology

The last decade has witnessed significant advances in imaging of the middle and inner ear and the auditory pathways. High resolution computerized tomography (CT) scanners and new magnetic resonance (MR) sequences have been implemented in clinical practice as valuable supportive tools for the Audiologist in the identification of the site of lesion and for the surgical planning by the Otologist. The purpose of this chapter is to review the current advanced methods of neuroradiological evaluation of patients with sensorineural hearing loss (SNHL), either congenital or acquired, especially focusing on the assessment of candidates to cochlear implantation (CI), with plenty of explicative images

Physical and Thermal Evaluation of Olive Oils from Minor Italian Cultivars

Authentication of extra virgin olive oils is a key strategy for their valorization and a way to preserve olive biodiversity. Physical and thermal analysis have been proposed in this study as fast and green techniques to reach this goal. Thirteen extra virgin olive oils (EVOOs) obtained from minor olive cultivars, harvested at three different ripening stages, in four Italian regions (Abruzzo, Apulia, Sardinia, and Calabria) have been studied. Thermal properties, viscosity and color, as influenced by fatty acid composition and chlorophyll content, have been investigated. The thermal curves of EVOOs, obtained by differential scanning calorimetry, were mostly influenced by the oleic acid content: a direct correlation with the cooling and heating enthalpy and an indirect correlation with the cooling transition range were observed. The minor fatty acids, and particularly arachidic acid, showed an influence, mostly on the heating thermograms. Viscosity and color showed respectively a correlation with fatty acids composition and chlorophyll content, however they didn’t result able to discriminate between the samples. Thanks to the principal component analysis, the most influencing thermal parameters and fatty acids were used to cluster the samples, based on their botanical and geographical origin, resulting instead the harvesting time a less influential variable