Інституціональна структура суспільства та економічна безпека держави

У статті розглядається взаємозв’язок між інституціональною структурою суспільства та економічною безпекою держави. Виділено інститути, які мають найбільший вплив на економічну безпеку держави.The article is concerned with institutional structure and economic state security and its correlation. It focus on institutes that it have potent influence on economic state security

The small heat shock protein B8 (HSPB8) modulates proliferation and migration of breast cancer cells

open12noBreast cancer (BC) is one of the major causes of cancer death in women and is closely related to hormonal dysregulation. Estrogen receptor (ER)-positive BCs are generally treated with anti hormone therapy using antiestrogens or aromatase inhibitors. However, BC cells may become resistant to endocrine therapy, a process facilitated by autophagy, which may either promote or suppress tumor expansion. The autophagy facilitator HSPB8 has been found overexpressed in some BC. Here we found that HSPB8 is highly expressed and differentially modulated by natural or synthetic selective ER modulators (SERMs), in the triple-positive hormone-sensitive BC (MCF-7) cells, but not in triple-negative MDA-MB-231 BC cells. Specific SERMs induced MCF-7 cells proliferation in a HSPB8 dependent manner whereas, did not modify MDA-MB-231 cell growth. ER expression was unaffected in HSPB8-depleted MCF-7 cells. HSPB8 over-expression did not alter the distribution of MCF-7 cells in the various phases of the cell cycle. Conversely and intriguingly, HSPB8 downregulation resulted in an increased number of cells resting in the G0/G1 phase, thus possibly reducing the ability of the cells to pass through the restriction point. In addition, HSPB8 downregulation reduced the migratory ability of MCF-7 cells. None of these modifications were observed, when another small HSP (HSPB1), also expressed in MCF-7 cells, was downregulated. In conclusion, our data suggest that HSPB8 is involved in the mechanisms that regulate cell cycle and cell migration in MCF-7 cells.openPiccolella, Margherita; Crippa, Valeria; Cristofani, Riccardo; Rusmini, Paola; Galbiati, Mariarita; Elena Cicardi, Maria; Meroni, Marco; Ferri, Nicola; Morelli, Federica F; Carra, Serena; Messi, Elio; Poletti, AngeloPiccolella, Margherita; Crippa, Valeria; Cristofani, Riccardo; Rusmini, Paola; Galbiati, Mariarita; Elena Cicardi, Maria; Meroni, Marco; Ferri, Nicola; Morelli, Federica F; Carra, Serena; Messi, Elio; Poletti, Angel

Aberrant Autophagic Response in The Muscle of A Knock-in Mouse Model of Spinal and Bulbar Muscular Atrophy

Spinal and bulbar muscular atrophy (SBMA) is characterized by loss of motoneurons and sensory neurons, accompanied by atrophy of muscle cells. SBMA is due to an androgen receptor containing a polyglutamine tract (ARpolyQ) that misfolds and aggregates, thereby perturbing the protein quality control (PQC) system. Using SBMA AR113Q mice we analyzed proteotoxic stress-induced alterations of HSPB8-mediated PQC machinery promoting clearance of misfolded proteins by autophagy. In muscle of symptomatic AR113Q male mice, we found expression upregulation of Pax-7, myogenin, E2-ubiquitin ligase UBE2Q1 and acetylcholine receptor (AchR), but not of MyoD, and of two E3-ligases (MuRF-1 and Cullin3). TGF beta 1 and PGC-1 alpha were also robustly upregulated. We also found a dramatic perturbation of the autophagic response, with upregulation of most autophagic markers (Beclin-1, ATG10, p62/SQSTM1, LC3) and of the HSPB8-mediated PQC response. Both HSPB8 and its co-chaperone BAG3 were robustly upregulated together with other specific HSPB8 interactors (HSPB2 and HSPB3). Notably, the BAG3: BAG1 ratio increased in muscle suggesting preferential misfolded proteins routing to autophagy rather than to proteasome. Thus, mutant ARpolyQ induces a potent autophagic response in muscle cells. Alteration in HSPB8-based PQC machinery may represent muscle-specific biomarkers useful to assess SBMA progression in mice and patients in response to pharmacological treatments

Development of a real options model to support utility investment strategy in power plant portfolio improvement

LAUREA MAGISTRALEQuesto lavoro si inserisce in un percorso di ricerca già avviato presso il Politecnico di Milano con la collaborazione dell’Università di Lincoln (UK) che ha portato allo sviluppo di un modello di applicazione delle Opzioni Reali (la Simulazione Ottimizzata con Soglie d’Esercizio) che supporti una utility nella decisione di investimento in centrali elettriche di base load. Il presente lavoro ha come scopo lo sviluppo ulteriore di quel modello per renderlo il più aderente possibile alla realtà con l’obiettivo di mantenerne tutti i vantaggi che lo caratterizzano rispetto agli altri metodi di applicazione delle opzioni reali e al metodo “discounted cash flow” (DCF). Le direzioni di miglioramento identificate e sviluppate sono tre: 1. La durata e il costo della fase pre – operativa di una centrale elettrica non sono determinati solo dalla fase di costruzione. Il tempo trascorso dal momento in cui la decisione d’investimento è presa a quando l’impianto effettivamente diventa operativo si differenzia notevolmente tra le tecnologie di base load. Primo obiettivo di questo lavoro è considerare nel modello differenti lead time tra decisione di investimento e inizio delle operazioni. 2. Mostrare come sia possibile sfruttare la flessibilità intrinseca alla fase pre – operativa di un impianto nucleare modellandola come successione di tre “compound options sequenziali”, modellando la possibilità di abbandonare o ritardare l’inizio di ogni fase al termine della precedente aggiunga valore all’investimento intero. 3. Un investimento in una centrale base load analizzato dal punto di vista di una utility è sempre un investimento in un portfolio di investimenti già esistente. Questo lavoro mira dunque a costruire un nuovo frame work che, integrando il metodo della Simulazione con Soglie d’Esercizio Ottimizzate (SOET) con il principale metodo per effettuare un’analisi di portfolio(la Mean Variance Portfolio Theory), tenga conto nella decisione di investimento del portfolio attualmente esistente. Attraverso l’analisi della letteratura verrà spiegato quali siano i vantaggi di questo approccio e come anche la principale debolezza che ha limitato l’uso della MVP Theory sia superata. Per utilizzare questo modello le variabili più critiche (prezzo dell’energia elettrica, costo del gas, costo del carbone, costo di costruzione, costo del design, costo dello studio e costo delle emissioni di CO2) sono state modellate tramite processi stocastici. Allo stesso tempo sono state implementate diversi tipi di opzioni reali e le compound options per modellare la fase pre – operativa di un impianto nucleare. Quindi, usando questo modello, quattro diverse tecnologie sono state confrontate: i reattori nucleari di taglia grande (LR), di taglia piccola (SMR), le centrali a gas (CCGT) e le centrali a carbone. Queste tecnologie sono state valutate in differenti case – study(accomunati dal fatto che si va a soddisfare il bisogno energetico di 1,5 GW) per mostrare uno alla volta i tre step di miglioramento inseriti. I case – study considerati sono: i. Scelta impianto più profittevole considerando l’intera durata della fase pre – operativa di una centrale e modellandola sia con che senza la successione di tre compound options, senza però considerare un portfolio attuale di investimenti già esistenti . ii. Scelta impianto più profittevole considerando l’intera durata della fase pre – operativa di una centrale modellandola sia con che senza la successione di tre compound options e considerando un fittizio portfolio attuale di investimenti già esistenti . iii. Scelta impianto più profittevole considerando l’intera durata della fase pre – operativa di una centrale modellandola sia con che senza la successione di tre compound options e considerando il portfolio attuale di investimenti già esistenti di EDF in UK.Implementando tale modello ogni portfolio nel piano E(NPV) – σ(NPV) non sarà più un singolo punto statico su di esso ma diverrà anche funzione del valore delle soglie d’esercizio che, facendo scattare le opzioni in condizioni differenti, modificano il valore atteso e il livello di rischio dell’intero portfolio. Ogni portfolio avrà dunque una propria frontiera efficiente per cui sarà possibile confrontarne gli andamenti e costruire una Frontiera Efficiente Ottimizzata che garantisca all’investitore di scegliere l’investimento addizionale e la condizione in cui effettuarlo affinché una definita funzione obiettivo venga massimizzata. Nel caso di applicazione di tale modello al caso di portfolio attuale di EDF in UK la tecnologia ottimale su cui investire per colmare una richiesta di 1,5 GW sono gli SMR.This work is part of a research project between the Politecnico di Milano and the University of Lincoln (UK), which has led to the development of an innovative real options approach (The Simulation with Optimized Exercise Thresholds) to support a utility in its decision of investment in base – load power plants. The aim of this work is the further development of the model to make it as close to reality as possible with the objective of maintaining all the advantages it has if compared with the others real options evaluation methods and with the “discounted cash flow method”(DCF). The steps of improvement we identify and develop in this work are: The length and the cost of the pre – operational phase of a power plant is not determined only by the construction phase. The time elapsed from the moment the decision to invest is taken and the moment in which the plant starts effectively to produce electricity is really different between the base – load technologies. First aim of this work is to consider in the model different lead time between the decision of investment and the moment in which the PP starts to produce electricity. To show how it is possible to use the intrinsic flexibility of the pre – operational phase of a nuclear PP modeling it as the succession of three sequential compound options and thus to show how the possibility to abandon or to delay the beginning of each phase at the end of the previous one add a great value to the overall investment. From the utility’s point of view, an investment in a base – load PP is always an investment in a wider portfolio of already existing investments. Hence, this work aims to build an innovative framework that, thanks to the integration between the Simulation with Optimized Thresholds (SOET) Method and the most important method to perform portfolio analysis(The Mean Variance Portfolio Theory), consider the actual portfolio of a utility in its decision of investment Through a literature review the advantages of this approach will be explained like for example how the main drawback that is limiting the use of the MVP Theory will be solved. With this method the most critical variables (including the price of electricity, the gas fuel cost, the coal fuel cost, the overnight cost, the study cost, the design cost and the cost of carbon emission) are modeled as stochastic processes. Furthermore several kind of real options has been implemented with the compound options to model the pre – operational phase of a nuclear PP. With this model four different technologies has been compared: the large nuclear reactor(LR), the small modular reactor(SMR), the gas plant(CCGT) and the coal plant. These technologies has been evaluated in different case – studies(in each of them the aim is to fulfill an additional request of 1,5 GWe) to show one at a time the three steps of improvement implemented. The study – cases considered are: The chosen of the “best” PP considering the whole length of the pre – operational phase of a PP modeling it both with and without the succession of three sequential compound options, without considering the actual portfolio of already existing investments. The chosen of the “best” PP considering the whole length of the pre – operational phase of a PP modeling it both with and without the succession of three sequential compound options, and considering a dummy actual portfolio of already existing investments. The chosen of the “best” PP considering the whole length of the pre – operational phase of a PP modeling it both with and without the succession of three sequential compound options, and considering the real actual portfolio of EDF’s already existing investments in UK. Implementing this model each portfolio in the plane E(NPV) – σ(NPV) will not a single static point on it anymore but it will be function of the value of the exercise thresholds too that, by triggering the investment in different conditions, influence the value of the expected NPV and of the level of risk of the overall portfolio. Thus, each possible portfolio will have its own efficient frontier and it will be then possible to compare them building an Optimized Efficient Frontier. In this way the model user will be able to choose the best additional investment and the best condition to perform it in order to maximize a specific objective function. At the end of this work the model developed here will be applied to the real actual portfolio of EDF in UK when an additional request of 1,5 GW is implemented. The technology obtained as optimal to build is the SMR’s one

The protein quality control system in motoneuron diseases

Spinal and bulbar muscular atrophy (SBMA) is a motoneuronal diseases caused by an elogated polyglutamine (polyQ) tract in the androgen receptor (AR). The polyQ expansion causes the AR protein to misfold and the binding with the ligand testosterone triggers a cascade of events, including ARpolyQ aggregation, that led to motoneuron death. The intracellular accumulation of misfolded ARpolyQ both altered the protein quality control system (PQC) and impaired the protective mechanisms deputed to refolding and clearance of misfolded proteins. In PQC, the molecular chaperones allow the refolding or the clearance of the misfolded proteins through the Ubiquitin Proteasome system (UPS) or the autophagic pathway. Moreover, emerging evidence reveal that ARpolyQ toxicity is not related only to motoneuron degeneration but also skeletal muscle damage plays a primary role in SBMA. AIM: The aim of the study was both to unravell the contribution of PQC in SBMA and to find molecular and pharmacological approaches for modulating PQC as potential therapeutic target. Methods: Western blot and filter retardation assay were used to analyse the biochemical properties of ARpolyQ and the protein level of PQC markers. RT-qPCR was used to quantify the mRNA expression of PQC genes in presence of ARpolyQ. Results: In SBMA motoneuronal cell line, we demonstrated that both UPS and autophagic pathway are impaired or blocked, leading to ARpolyQ accumulation into the aggregates. Moreover, analysis in SBMA animal model showed that in the spinal cord and in the skeletal muscle, the PQC could differ considerably in how degrading the mutant and misfolded ARpolyQ. In these conditions of PQC impairment we tested, in SBMA cell model, the overexpression of the small heat shock protein B8 (HspB8), involved in the autophagic pathway. HpB8 led to the autophagic removal of misfolded ARpolyQ, restorating the intracellular autophagic flux. Interestingly, we found that trehalose, a known autophagic stimulator, was able to induce the HspB8 expression and to facilitate the ARpolyQ clearance. Then, we tested the combined treatment of trehalose with Bicalutamide, an antiandrogen. Bicalutamide is able to slow down AR nuclear translocation and to retain it into the cytoplasm, where the autophagic pathway is active. Bicalutamide and trehalose showed synergic activity in the degradation of ARpolyQ. Conclusions: the PQC plays a crucial role in SBMA, the modulation of its activity with trehalose and Bicalutamide might be a promising approach for this no cure disease

Design hydrograph and routing scheme for flood mapping in a dense urban area

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Modeling and Monitoring Business Constraints of Non-conformant Choreographed Business Processes

A choreographed process defines the agreement between organizations with respect to the protocol that should be respected when the involved organizations interact with each other through their business processes. The resulting BPMN Choreographed Process that models this protocol can formalize business constraints. Although there are solutions that can monitor whether these constraints are satisfied, situations of non-conformance that have an impact on monitoring can arise. This happens especially when the involved parties are not equipped with a BPMS that can force business processes to align with the protocol. The purpose of this paper is twofold. First of all, it proposes the use of an extension of timed commitments to express business constraints. This extension takes into account situations of non-conformance that are not acceptable by the protocol, but are compatible with business objectives. In addition, it proposes a monitoring application solution that can support the proposed extension

Pregnancy and reproduction in autoimmune rheumatic diseases

Despite evidence for the important role of oestrogens in the aetiology and pathophysiology of chronic immune/inflammatory diseases, the previous view of an unequivocal beneficial effect of oestrogens on RA compared with a detrimental effect on SLE has to be reconsidered. Likewise, the long-held belief that RA remits in the majority of pregnant patients has been challenged, and shows that only half of the patients experience significant improvement when objective disease activity measurements are applied. Pregnancies in patients with SLE are mostly successful when well planned and monitored interdisciplinarily, whereas a small proportion of women with APS still have adverse pregnancy outcomes in spite of the standard treatment. New prospective studies indicate better outcomes for pregnancies in women with rare diseases such as SSc and vasculitis. Fertility problems are not uncommon in patients with rheumatic disease and need to be considered in both genders. Necessary therapy, shortly before or during the pregnancy, demands taking into account the health of both mother and fetus. Long-term effects of drugs on offspring exposed in utero or during lactation is a new area under study as well as late effects of maternal rheumatic disease on childre

Genomic analysis of the TRIM family reveals two groups of genes with distinct evolutionary properties

<p>Abstract</p> <p>Background</p> <p>The TRIM family is composed of multi-domain proteins that display the Tripartite Motif (RING, B-box and Coiled-coil) that can be associated with a C-terminal domain. TRIM genes are involved in ubiquitylation and are implicated in a variety of human pathologies, from Mendelian inherited disorders to cancer, and are also involved in cellular response to viral infection.</p> <p>Results</p> <p>Here we defined the entire human TRIM family and also identified the TRIM sets of other vertebrate (mouse, rat, dog, cow, chicken, tetraodon, and zebrafish) and invertebrate species (fruitfly, worm, and ciona). By means of comparative analyses we found that, after assembly of the tripartite motif in an early metazoan ancestor, few types of C-terminal domains have been associated with this module during evolution and that an important increase in TRIM number occurred in vertebrate species concomitantly with the addition of the SPRY domain. We showed that the human TRIM family is split into two groups that differ in domain structure, genomic organization and evolutionary properties. Group 1 members present a variety of C-terminal domains, are highly conserved among vertebrate species, and are represented in invertebrates. Conversely, group 2 is absent in invertebrates, is characterized by the presence of a C-terminal SPRY domain and presents unique sets of genes in each mammal examined. The generation of independent sets of group 2 genes is also evident in the other vertebrate species. Comparing the murine and human TRIM sets, we found that group 1 and 2 genes evolve at different speeds and are subject to different selective pressures.</p> <p>Conclusion</p> <p>We found that the TRIM family is composed of two groups of genes with distinct evolutionary properties. Group 2 is younger, highly dynamic, and might act as a <it>reservoir </it>to develop novel TRIM functions. Since some group 2 genes are implicated in innate immune response, their evolutionary features may account for species-specific battles against viral infection.</p