Implementazione e calibrazione di un modello di pressione massima in camera di combustione basato sulla misura della corrente di ionizzazione

L’obbiettivo dell’attività svolta presso il dipartimento di Sperimentazione Motopropulsori di Ferrari S.p.a. è sviluppare un modello in grado di stimare la pressione massima sviluppata dal motore, partendo dalla corrente di ionizzazione misurata in camera di combustione. Tale richiesta nasce dalla volontà di conoscere le condizioni in cui si trova il pistone durante il funzionamento in vettura, al fine di studiare il reale limite di detonazione. Oggigiorno, infatti, il limite di detonazione viene imposto attraverso convenzioni ingegneristiche. Queste convenzioni comportano limiti sull’anticipo di accensione che risultano troppo stringenti, andando così a perdere i vantaggi che una combustione ad alto anticipo di accensione produce. L’elaborato spiega i passaggi che hanno caratterizzato il processo di implementazione e calibrazione del modello di pressione massima. Nel primo capitolo vengono spiegati gli effetti delle principali grandezze motore sulla pressione massima, approfondendo quelli relativi alle tre grandezze scelte come input del modello: velocità di rotazione dell’albero motore, coefficiente di riempimento e MFB50 (50% mass fraction burnt). Il secondo capitolo spiega l’attività, svolta a monte, di implementazione di un modello in grado di identificare l’MFB50 a partire dalla corrente di ionizzazione misurata in camera di combustione. Nel terzo capitolo invece viene spiegato l’intero procedimento di calibrazione del modello di PMAX: dall’attività al banco prova fino ad arrivare al modello completamente calibrato. Infine il quarto capitolo mostra tutti i risultati ottenuti a valle dell’attività di validazione del modello, caratterizzata da una prima fase di confronto con un secondo modello sviluppato presso l’Università di Bologna e una seconda fase in cui è stato simulato il funzionamento di un motore controllato sulla base delle informazioni in uscita dal modello di PMAX

Targeting the Nerve Growth Factor Signaling Impairs the Proliferative and Migratory Phenotype of Triple-Negative Breast Cancer Cells.

Triple-negative breast cancer is a heterogeneous disease that still lacks specific therapeutic approaches. The identification of new biomarkers, predictive of the disease’s aggressiveness and pharmacological response, is a challenge for a more tailored approach in the clinical management of patients. Nerve growth factor, initially identified as a key factor for neuronal survival and differentiation, turned out to be a multifaceted molecule with pleiotropic effects in quite divergent cell types, including cancer cells. Many solid tumors exhibit derangements of the nerve growth factor and its receptors, including the tropomyosin receptor kinase A. This receptor is expressed in triple-negative breast cancer, although its role in the pathogenesis and aggressiveness of this disease is still under investigation. We now report that triple-negative breast cancer-derived MDAMB- 231 and MDA-MB-453 cells express appreciable levels of tropomyosin receptor kinase A and release a biologically active nerve growth factor. Activation of tropomyosin receptor kinase by nerve growth factor treatment positively affects the migration, invasion, and proliferation of triple-negative breast cancer cells. An increase in the size of triple-negative breast cancer cell spheroids is also detected. This latter effect might occur through the nerve growth factor-induced release of matrix metalloproteinase 9, which contributes to the reorganization of the extracellular matrix and cell invasiveness. The tropomyosin receptor kinase A inhibitor GW441756 reverses all these responses. Co-immunoprecipitation experiments in both cell lines show that nerve growth factor triggers the assembly of the TrkA/b1-integrin/FAK/Src complex, thereby activating several downstream effectors. GW441756 prevents the complex assembly induced by nerve growth factor as well as the activation of its dependent signaling. Pharmacological inhibition of the tyrosine kinases Src and FAK (focal adhesion kinase), together with the silencing of b1-integrin, shows that the tyrosine kinases impinge on both proliferation and motility, while b1-integrin is needed for motility induced by nerve growth factor in triple-negative breast cancer cells. The present data support the key role of the nerve growth factor/tropomyosin receptor kinase A pathway in triple-negative breast cancer and offer new hints in the diagnostic and therapeutic management of patients

Underage drinking on saturday nights, sociodemographic and environmental risk factors: a cross-sectional study

BACKGROUND: Excessive alcohol consumption in underage people is a rising phenomenon. A major proportion of the disease burden and deaths of young people in developed nations is attributable to alcohol abuse. The aim of this study was to investigate social, demographic and environmental factors that may raise the risk of Saturday night drinking and binge drinking among Italian school students. METHODS: The study was conducted on a sample of 845 Italian underage school students, by means of an anonymous, self-test questionnaire. Multivariate logistic regression was applied to identify independent risk factors for alcohol drinking and binge drinking. Ordered logistic regression was used to identify independent risk factors for harmful drinking patterns. RESULTS: The independent variables that confer a higher risk of drinking in underage students are older age classes, male sex, returning home after midnight, belonging to a group with little respect for the rules, or to a group where young people are not seen as leaders. The higher the perception of alcohol consumption by the group, the higher the risk. Spending time in bars or discos coincides with a two-fold or four-fold increase, respectively, in the risk of alcohol consumption. CONCLUSION: Our findings show that certain environmental and social risk factors are associated with underage drinking. The most important role for preventing young people's exposure to these factors lies with the family, because only parents can exert the necessary control and provide a barrier against potentially harmful situations

Communication between cells: exosomes as a delivery system in prostate cancer.

Despite the considerable efforts in screening and diagnostic protocols, prostate cancer still represents the second leading cause of cancer-related death in men. Many patients with localized disease and low risk of recurrence have a favourable outcome. In a substantial proportion of patients, however, the disease progresses and becomes aggressive. The mechanisms that promote prostate cancer progression remain still debated. Many findings point to the role of cross-communication between prostate tumor cells and their surrounding microenvironment during the disease progression. Such a connection fosters survival, proliferation, angiogenesis, metastatic spreading and drug-resistance of prostate cancer. Recent years have seen a profound interest in understanding the way by which prostate cancer cells communicate with the surrounding cells in the microenvironment. In this regard, direct cell-to-cell contacts and soluble factors have been identified. Increasing evidence indicates that PC cells communicate with the surrounding cells through the release of extracellular vesicles, mainly the exosomes. By directly acting in stromal or prostate cancer epithelial cells, exosomes represent a critical intercellular communication system. By querying the public database (https:// pubmed. ncbi. nlm. nih. gov) for the past 10 years, we have found more than four hundred papers. Among them, we have extrapolated the most relevant about the role of exosomes in prostate cancer malignancy and progression. Emerging data concerning the use of these vesicles in diagnostic management and therapeutic guidance of PC patients are also presented

Severe combined immunodeficiency-an update

Severe combined immunodeficiencies (SCIDs) are a group of inherited disorders responsible for severe dysfunctions of the immune system. These diseases are life-threatening when the diagnosis is made too late; they are the most severe forms of primary immunodeficiency. SCID patients often die during the first two years of life if appropriate treatments to reconstitute their immune system are not undertaken. Conventionally, SCIDs are classified according either to the main pathway affected by the molecular defect or on the basis of the specific immunologic phenotype that reflects the stage where the blockage occurs during the differentiation process. However, during the last few years many new causative gene alterations have been associated with unusual clinical and immunological phenotypes. Many of these novel forms of SCID also show extra-hematopoietic alterations, leading to complex phenotypes characterized by a functional impairment of several organs, which may lead to a considerable delay in the diagnosis. Here we review the biological and clinical features of SCIDs paying particular attention to the most recently identified forms and to their unusual or extra-immunological clinical features

DiGeorge-like Syndrome in a Child with a 3p12.3 Deletion Involving MIR4273 Gene Born to a Mother with Gestational Diabetes Mellitus

Chromosome 22q11.2 deletion is the most common chromosomal alteration associated with DiGeorge syndrome (DGS), even though this is not the only underlying cause of DGS. In rare patients, mutations in a single gene, TBX1, have been described resulting in a DGS phenotype. Recently, it has been reported that at least part of the TBX1 mutant phenotype is due to excessive bone morphogenetic proteins (BMP) signaling. Evidence suggests that miRNA may modulate the expression of critical T-box transcriptional regulators during midface development and Bmp-signaling. We report on a 7-year-old Caucasian male born to a mother affected with gestational diabetes (GDM) who had a 371Kb-interstitial deletion of 3p12.3 identified by array CGH, involving the ZNF717, MIR1243 and 4273 genes. The child presented with a DiGeorge anomaly (DGA) associated with unilateral renal agenesis and language delay. The immunological evaluation revealed a severe reduction and impairment of T lymphocytes. FISH analysis and TBX1 sequencing were negative. Among the miRNA-4273 predicted target genes, we found BMP3, which is involved in several steps of embryogenesisincluding kidney and lung organogenesis and in insulin gene expression. Since DGA is not commonly found in newborns of diabetic mothers, we hypothesize that the pathogenesis of DGA associated with GDM is multifactorial, involving both genetic and/or epigenetic cofactors

Assessing thermal maturity through a multi-proxy approach: a case study from the Permian Faraghan Formation (Zagros Basin, Southwest Iran)

This study focuses on the thermal maturity of Permian deposits from the Zagros Basin, Southwest Iran, employing both optical methods (Thermal Alteration Index, Palynomorph Darkness Index, Vitrinite Reflectance, UV Fluorescence) and geochemical analyses of organic matter (Rock Eval Pyrolysis and MicroRaman spectroscopy) applied to the Faraghan Formation along two investigated Darreh Yas and Kuh e Faraghan surface sections. Furthermore, an integrated palynofacies and lithofacies analysis was carried out in order to integrate the few studies on the depositional environment. The Faraghan Formation, which is widely distributed in the Zagros area, generally consists of shale intercalated with sandstones and pebble conglomerates in the lower part, followed by a succession of sandstone, siltstone and shaly intercalations and with carbonate levels at the top. The integrated palynofacies and lithofacies data confirm a coastal depositional setting evolving upwards to a shallow marine carbonate environment upwards. Rock Eval Pyrolysis and Vitrinite Reflectance analysis showed that the organic matter from samples of the Darreh Yas and Kuh e Faraghan sections fall in the mature to postmature range with respect to the oil to gas generation window, restricting the thermal maturity range proposed by previous authors. Similar results were obtained with MicroRaman spectroscopy and optical analysis such as Thermal Alteration Index and UV Fluorescence. Palynomorph Darkness Index values were compared with Rock Eval Pyrolysis and vitrinite reflectance values and discussed for the first time in the late stage of oil generation.This research was funded by PRIN (2017RX9XXXY-CIRILLI), by Fondo Ricerca di Base Department of Physics and Geology, University of Perugia (SPIRICBAS2018-SPINA), by the project “Paleontological Studies and Biozonation of Paleozoic Sediments in Central Iran and Zagros Basins” (coordinator R. Rettori) and MIUR grants-SORCI to PhD School of Science and Technology for Physics and Geology (XXXIV Cycle), University of Perugia; Project “Paleontological Studies and Biozonation of Paleozoic Sediments in Central Iran and Zagros Basins” (RETTORI).info:eu-repo/semantics/publishedVersio

H9c2 Cardiomyocytes under Hypoxic Stress: Biological Effects Mediated by Sentinel Downstream Targets

The association between diabetes and cardiovascular diseases is well known. Related diabetes macro- and microangiopathies frequently induce hypoxia and consequently energy failure to satisfy the jeopardized myocardium basal needs. Additionally, it is widely accepted that diabetes impairs endothelial nitric oxide synthase (eNOS) activity, resulting in diminished nitric oxide (NO) bioavailability and consequent endothelial cell dysfunction. In this study, we analyzed the embryonic heart-derived H9c2 cell response to hypoxic stress after administration of a high glucose concentration to reproduce a condition often observed in diabetes. We observed that 24 h hypoxia exposure of H9c2 cells reduced cell viability compared to cells grown in normoxic conditions. Cytotoxicity and early apoptosis were increased after exposure to high glucose administration. In addition, hypoxia induced a RhoA upregulation and a Bcl-2 downregulation and lowered the ERK activation observed in normoxia at both glucose concentrations. Furthermore, a significant cell proliferation rate increases after the 1400W iNOS inhibitor administration was observed. Again, hypoxia increased the expression level of myogenin, a marker of skeletal muscle cell differentiation. The cardiomyocyte gene expression profiles and morphology changes observed in response to pathological stimuli, as hypoxia, could lead to improper ventricular remodeling responsible for heart failure. Therefore, understanding cell signaling events that regulate cardiac response to hypoxia could be useful for the discovery of novel therapeutic approaches able to prevent heart diseases

The androgen receptor/filamin A complex as a target in prostate cancer microenvironment.

Prostate cancer represents the major cause of cancer-related death in men and patients frequently develop drug-resistance and metastatic disease. Most studies focus on hormone-resistance mechanisms related to androgen receptor mutations or to the acquired property of prostate cancer cells to over-activate signalling pathways. Tumour microenvironment plays a critical role in prostate cancer progression. However, the mechanism involving androgen/androgen receptor signaling in cancer associated fibroblasts and consequences for prostate cancer progression still remains elusive. We now report that prostate cancer associated fibroblasts express a transcriptional-incompetent androgen receptor. Upon androgen challenging, the receptor co-localizes with the scaffold protein filamin A in the extra-nuclear compartment of fibroblasts, thus mediating their migration and invasiveness. Cancer-associated fibroblasts move towards epithelial prostate cancer cells in 2D and 3D cultures, thereby inducing an increase of the prostate cancer organoid size. Androgen enhances both these effects through androgen receptor/filamin A complex assembly in cancer-associated fibroblasts. An androgen receptor-derived stapled peptide, which disrupts the androgen receptor/filamin A complex assembly, abolishes the androgen-dependent migration and invasiveness of cancer associated fibroblasts. Notably, the peptide impairs the androgen-induced invasiveness of CAFs in 2D models and reduces the overall tumour area in androgen-treated 3D co-culture. The androgen receptor in association with β1 integrin and membrane type-matrix metalloproteinase 1 activates a protease cascade triggering extracellular matrix remodeling. The peptide also impairs the androgen activation of this cascade. The present study offers a potential new marker, the androgen receptor/filamin A complex, and a new therapeutic approach targeting intracellular pathways activated by the androgen/androgen receptor axis in prostate cancer-associated fibroblasts. Such a strategy, alone or in combination with conventional therapies, may allow a more efficient treatment of prostate cancer

Expression Profiling and Functional Implications of a Set of Zinc Finger Proteins, ZNF423, ZNF470, ZNF521, and ZNF780B, in Primary Osteoarthritic Articular Chondrocytes

Articular chondrocytes are responsible for the maintenance of healthy articulations; indeed, dysregulation of their functions, including the production of matrix proteins and matrix-remodeling proteases, may result in fraying of the tissue and development of osteoarthritis (OA). To explore transcriptional mechanisms that contribute to the regulation of chondrocyte homeostasis and may be implicated in OA development, we compared the gene expression profile of a set of zinc finger proteins potentially linked to the control of chondrocyte differentiation and/or functions (ZNF423, ZNF470, ZNF521, and ZNF780B) in chondrocytes from patients affected by OA and from subjects not affected by OA. This analysis highlighted a significantly lower expression of the transcript encoding ZNF423 in chondrocytes from OA, particularly in elderly patients. Interestingly, this decrease was mirrored by the similarly reduced expression of PPARγ, a known target of ZNF423 with anti-inflammatory and chondroprotective properties. The ZNF521 mRNA instead was abundant in all primary chondrocytes studied; the RNAi-mediated silencing of this gene significantly altered the COL2A/COL1 expression ratio, associated with the maintenance of the differentiated phenotype, in chondrocytes cultivated in alginate beads. These results suggest a role for ZNF423 and ZNF521 in the regulation of chondrocyte homeostasis and warrant further investigations to elucidate their mechanism of action