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Synthesis and characterization of (cyclopentadienone)iron tricarbonyl complexes and their application to stereoselective catalytic transformations.
No full textIn recent years there has been a growing interest for developing efficient and selective homogeneous iron catalysts, thanks to the far lower cost and greater abundance of iron over the more precious metals.
During my PhD thesis, in order to improve the catalytic activities or achieve novel reactivity, we decided to modify the framework of the Knölker-type complex and to develop a small library of ten new chiral pre-catalysts, bearing a binaphthyl-derived backbone with different 3,3’-substituents, for the enantioselective hydrogenation of ketones (up to 52% ee). (Eur. J. Org. Chem., 2015, 5526-5536; Eur. J. Org. Chem., 2015, 1887-1893).
In addition to the ongoing development of chiral variants of the Knölker motif, our group was also interested in opening new vistas in catalyst design by accessing new catalyst structures easily to synthesize and with different reactivity profiles.
A new [bis(hexamethylene)cyclopentadienone]iron tricarbonyl complex was synthesized, which showed more stability and better reproducible results respect to the known Knölker-Casey catalyst underlined by TON, TOF and kinetic measurements.
Recently, we also developed a new generation of planar chiral (cyclopentadienone)iron tricarbonyl pre-catalyst, the results are promising but the research is still under investigation
Bene e male comune tra storia e filosofia. Le donne collaborazioniste processate a Milano dal 1945 al 1947.
No full textLa presente ricerca ha come obiettivo la creazione di nuove categorie interpretative relativamente alle donne collaborazioniste. Esse sono state analizzate non attraverso la storia di genere, ma per il ruolo svolto all’interno del contesto sociale. I fascicoli processuali e la ricostruzione della conseguente verità emersa sono stati i supporti per la riflessione che ha coinvolto storia e filosofia in uno stretto rapporto interpretativo. Il bene e il male sono affiorati attraverso le carte d’archivio. È stato possibile creare diverse tipologie di donne: la donna-ombra, la donna-grigia e la donna-libera.
Si è delineata l’opportunità di muovere la ricerca verso un’interpretazione fenomenologica tendente alla costruzione del bene comune e la definizione del male comune come bene di pochi.
Il male comune non può solo essere giustificato, agostinianamente, come assenza del bene, ma deve essere riconosciuto come libera estrinsecazione della volontà umana. Parafrasando un’espressione di Recalcati, il male comune diviene un “sistema pervasivo” che, gradualmente, si espande penetrando all’interno degli anditi più reconditi della mente umana in grado di pervenire alla fatale e permanente persecuzione dell’altro.
La donna è altresì, per antonomasia, l’estrinsecazione della positività, di colei che genera il buono, cioè il nuovo uomo, la vita, manifestazione di sicuro progresso. L’espressione “terra madre” è la sintomatica esplicitazione di un bene comune da proteggere e da tutelare. Il termine “madre” è non solo “un nome della memoria”, bensì “il” nome che contiene nella memoria ciascun uomo. Esso è l’intrinseca e necessaria volontà di ogni essere umano di possedere le radici della memoria che gli consentano di evolversi e di guardare al di là dell’orizzonte del tempo che ora c’è, ma che già cede il passo a quello che verrà.
This research has as its object the creation of new interpretative categories about the collaborationist women. They have been analysed not through gender history, but for their role performed within the social context. The processual dossier and the reconstruction of the consequent emerged truth have been the supports for critical analysis involving History and Philosophy in a close interpretative relationship. Good and evil have surfaced through archive papers. It has been possible to create different typologies of women: the shadow-woman, the grey-woman and the free-woman.
The research has proceeded toward a phenomenological interpretation which viewed the construction of common good and the definition of common evil as good for few.
The common evil cannot be justified only, in Augustinian way, as absence of good, but it must be recognized as a free expression of the human wish. Common evil, paraphrasing an expression from Recalcati’s, the common evil becomes a “pervasive system” that gradually expands penetrating inside the most secluded passages of human mind able to achieve the fatal and permanent persecution of the other.
The woman is also, utmost, the expression of the positiveness, the one who produces the good, that is the new man, the life, demonstration of sure progress. The expression “mother earth” it is the symptomatic explication of a common good to preserve and to protect. The term “mother” it is not only “a name of the memory”, on the contrary “the” name that contains in the memory every man. This name is the intrinsic and necessary wish of every human being to possess the roots of the memory that allow him to evolve and to look beyond the horizon of this time, but that already gives way to the time that will come
Multigrid methods and stationary subdivisions
No full textMultigridmethods are fast iterative solvers for sparse large ill-conditioned linear systems of equations derived, for instance, via discretization of PDEs in fluid dynamics, electrostatics and continuummechanics problems. Subdivision schemes are simple iterative algorithms for generation of smooth curves and surfaces with applications in 3D computer graphics and animation industry.
This thesis presents the first definition and analysis of subdivision based multigrid methods.
The main goal is to improve the convergence rate and the computational cost of multigrid taking advantage of the reproduction and regularity properties of underlying subdivision.
The analysis focuses on the grid transfer operators appearing at the coarse grid correction step in the multigrid procedure. The convergence of multigrid is expressed in terms of algebraic properties of the trigonometric polynomial associated to the grid transfer operator. We interpreter the coarse-to-fine grid transfer operator as one step of subdivision. We reformulate the algebraic properties ensuring multigrid convergence in terms of regularity and generation properties of subdivision. The theoretical analysis is supported by numerical experiments for both algebraic and geometric multigrid. The numerical tests with the bivariate anisotropic Laplacian ask for subdivision schemes with anisotropic dilation. We construct a family of interpolatory subdivision schemes with such dilation which are optimal in terms of the size of the support versus their polynomial generation properties. The numerical tests confirmthe validity of our theoretical analysis
UHRF1 coordinates DNA methylation and histone post-translational modifications in colon cancer .
No full textIn Colorectal cancer (CRC) genetic and epigenetic alterations are tightly connected, although these interactions on the patient’s outcome are not clearly understood.
A peculiar subclass of sporadic CRC tumors, is characterized by Microsatellite instability (MSI), due to hyper-methylated promoter of MHL1 gene and subsequent inactivation of the mismatch repair (MMR) mechanism, and the hypermethylation of CpG islands phenotype (CIMP), mediated by the hyper-methylation of promoter regions of several tumor suppressor genes (TSGs). This subclass carries a good prognosis and presents an inverse correlation with genomic and chromosome instability (CIN), together with a higher levels of DNA methylation at global level, compared to other CRCs. Among the epigenetic alterations, DNA methylation and histone modifications rearrangements are extremely important steps during tumorigenesis. UHRF1 is a key master epigenetic regulator that couples the maintenance of DNA methylation through the cell cycle with the histone-modification pattern. It monoubiquitinates H3K18/23 enabling the correct localization and activation of DNMT1 on the specific sites. UHRF1 is overexpressed in several cancer types mediating the hypermethylation of promoter regions of the TSGs and coordinating their heterochromatic silencing.
Relying on the idea that UHRF1 could play a crucial role in the modulation of DNA methylation changes, the overall aim of this PhD thesis was to evaluate the role of UHRF1 in the coordination of DNA methylation and histone post-translational modifications both at genome-wide and at locus specific level in CRCs.
Unexpectedly, we found that in CRC tissues UHRF1 was higher in tumors with microsatellite instability (MSI CRC), which have a better prognosis, compared to the stable ones (MSS CRC). MSI tumors were also characterized by higher levels of DNA methylation compared to the MSS. The UHRF1 knock-down in a MSI CRC cell line (RKO cells) induced an overall decrease in DNA methylation (RRB-seq analysis, pyrosequencing and MS-MLPA) both at global level and at gene promoters without affecting DNMTs levels, as observed by WB and RNA-seq analysis. ChIP experiments showed that UHRF1 depletion reduces DNMT1 binding to both repetitive elements (LINE-1) and specific gene promoters (MLH1, CDH1), decreasing H3K9me3 and increasing H3K4me3 on those hypo-methylated loci. RNA-seq data analysis showed that UHRF1 loss interferes with several important pathways, among others cell cycle, growth and proliferation. SILAC LC-MS/MS analysis showed that in RKO cells, UHRF1 loss decreases the overall presence of H3K23ub (» 30%) and H3K18ub (» 8%).
These results, together with the published findings, led us to hypothesize a model in which the loss of UHRF1 directly impairs the DNA methylation maintenance by reducing H3K18/K23ub and consequently DNMT1 activity and, indirectly, impairs the binding of Suv39H1, the histone methyl transferase (HMT) responsible for H3K9me3, to both genome-wide and promoter specific loci. These changes led to a severe chromatin rearrangement of heterochromatic signatures toward a more open and transcriptionally accessible structure, probably due to the disruption of the axis UHRF1-H3ub-DNMT1-HMTs. Our molecular data, together with the analysis performed on CRC samples, led us to speculate that the better prognosis correlated with MSI-CRC model, could reside in the UHRF1-high levels that result in a sort of protective condition for the genome integrity, maintaining the global DNA methylation level closer to the normal mucosae, and probably counteracting the hyper-methylation of TSGs
Metagenomic methods for the analysis of human microbiota towards a clinical application.
No full textSeveral microbial communities colonize different body areas constituting the human microbiota.
Recently, several researches suggested the involvement of these bacteria in maintaining omeostasis of the human body, highlighting as a microbial dysbiosis may be implicated in numerous inflammatory conditions and human diseases. The high-throughput sequencing technologies applicate to the study of human microbiome allowed to achieve important results about the interactions between microorganisms and the host. Moreover, metagenomics studies extended scientists’ knowledge about the human microbiota and its implications in numerous human diseases. Since the 16S rRNA gene sequencing was shown to be an effective method to investigate microbial communities, recently our laboratory adopted this molecular approach to characterize the interactions between bacteria and host. Therefore, the present PhD work describes our experience in samples collection, experimental procedures and data analysis in studying the human microbiota by means of a metagenomics approach. Indeed, our studies allowed us to understand that to achieve a complete overview of microbial communities involved in a specific fisio-pathological condition, a standardization of experimental protocols and data analysis should be adopted to carry out metagenomics surveys. Moreover, the taxonomic evaluations through 16S rRNA gene sequencing are just a first step for elucidating the roles of bacteria in the host’s health. Integrating the metagenomics data which those obtained by metatranscriptomic, metaproteomic, and metametabolomic represents a promising approach to develop new noninvasive bacterial-related diagnostic tools
Fine and ultrafine particulate: sampling, analysis and metal characterization for a risk assessment on human health.
No full textInformation about the size-distribution of airborne particulate matter (PM) and PM-bound toxic metals is a key knowledge in terms of health concern. The global aim of the project was to characterize the mass concentration, size-distribution and metal composition in different PM2.5 size ranges. The experimental design involved the collection of size-segregated particles at an outdoor urban background site in Como during a long-term monitoring campaign by means of a multistage low pressure impactor. The highest PM concentration levels were found during the heating period because of a joint influence of meteorological factors and variations in type and number of emission sources. In particular, the greatest and significant increase effect was registered for particles between 0.15 and 1.60 μm. For chemical analysis purposes, a novel and reliable Laser Ablation-Inductively Coupled Plasma-Mass Spectrometry (LA-ICP-MS) measurement protocol was properly developed and optimized, providing precise and accurate results. The proposed LA-ICP-MS method was then applied for the analysis of selected trace metals (Cr, Mn, Fe, Ni, Cu, Zn, Ba and Pb) on the extended set of size-segregated PM samples. Obtained findings revealed different and characteristic metal size-distributions in the fine, submicrometer and ultrafine fractions. The studied elements were variously enriched in the particulate sizes, suggesting that local emission sources may exist for these chemical species. Moreover, from a health and sanitary perspective, the estimated hazard quotient and index values suggested no non-carcinogenic health risks via the inhalation exposure route. Also the carcinogenic risks of Cr and Ni were within the acceptability range
The role of the long non coding RNA HAS2-AS1 in breast cancer cells
No full textExtracellular matrix (ECM) is a network made by proteins and proteoglycans, whose structure is essential to maintain tissue architecture and to provide molecules diffusion and cellular communications. A deregulated synthesis of ECM components is often associated to a pathological status. Among various glycosaminoglycans, hyaluronan (HA) is a ubiquitous ECM component with a remarkable structural importance. It is able to modulate cell adhesion, motility, growth and inflammation after the binding with cellular receptors (CD44 and RHAMM) and the activation of different cellular pathways. In tumour microenvironment, the up-regulation of HAS2 and the overproduction of HA are often associated with tumour progression and metastasis. This also applies to breast cancer, where the accumulation of HA and the overexpression of hyaluronan synthases (HASes) in stromal and tumoral cells correlate with tumor malignancy and patients survival.
The study of the regulation of HAS2, the main enzyme in the production of HA, is very important to understand the development and the progression of breast cancer. Recently, it has been discovered that the lncRNA HAS2-AS1 can modulate the expression of HAS2 and the production of hyaluronan in aortic smooth muscle cells via epigenetic modifications [1]. Although the role of HA and HAS2 in breast cancer is widely described, little is known about HAS2-AS1.
Given this considerations, the aim of this project is to study the role of HAS2-AS1 in breast cancer. In particular, we compared the behaviour of MDA-MB-231 and MCF-7 cells after the modulation of HAS2-AS1 expression with functional assays evaluating cell proliferation, migration and invasion. In the same conditions, we analysed the expression of HA related genes and receptors in MDA-MB-231 cells. This analysis revealed that HAS2-AS1 knockdown stimulated the presence of a malignant phenotype, as its abrogation increased cell motility and invasion, as well as the expression of several HA related genes and the receptor CD44. These evidences suggested that HAS2-AS1 plays an important role breast tumor progression through alteration of HA metabolism.
Further analysis were conducted to understand the molecular mechanisms at the basis of the changes observed. LncRNAs can orchestrate gene expression through a variety of mechanisms, regulating transcription and translation, chromatin remodelling and the interaction with other RNA species, i.e. miRNAs. HAS2-AS1 transcript contains a putative binding site for miRNA 186, a negative regulator of the pro-apoptotic receptor P2X7 [2]. In our results we demonstrated that the overexpression of HAS2-AS1 decreased the abundance of miR-186, while the transcript of P2X7 and other targets of miRNA 186 (involved in cell cycle and autophagy) raised.
All together, these data suggest that the “sponge effect” of HAS2-AS1 is able to antagonise the function of miRNA 186 on its downstream targets and could explain the presence of a malignant phenotype after HAS2-AS1 silencing in MDA-MB-231.
1. Vigetti D, Deleonibus S, Moretto P, Bowen T, Fischer JW, Grandoch M, et al. Natural antisense transcript for hyaluronan synthase 2 (HAS2-AS1) induces transcription of HAS2 via protein O-GlcNAcylation. J. Biol. Chem. 2014;289:28816–26.
2. Zhou L, Qi X, Potashkin JA, Abdul-Karim FW, Gorodeski GI. MicroRNAs miR-186 and miR-150 down-regulate expression of the pro-apoptotic purinergic P2X7 receptor by activation of instability sites at the 3ʹ-untranslated region of the gene that decrease steady-state levels of the transcript. J. Biol. Chem. 2008;283:28274–86
Pensare con Socrate. Per una didattica della filosofia con I bambini. Thinking with Socrates.For a didactics of philosophy with children
No full textThe research consists in two sections. The first is of a theoretical nature and is dedicated to the issue of philosophy as a common good. The second concerns the organization of philosophy didactic experimentation in primary school, with reference to the philosophical teaching project of the Giovani Pensatori of the Università dell’Insubria.
Following is an appendix including a number of philosophical paths with children, achieved within the project of Giovani Pensatori at the Università dell’Insubria in the period 2012 - 2016.
The analysis of philosophy as a common good fits in the context of the philosophical heritage of Kantian critical rationalism. Within this approach, the theoretical definition of the common good lies as a historical-critical transcendental idea whose objectivity is assessed within a practical and eschatological point of view.
Immanuel Kant's philosophical thinking allowed this reasoning development. However, it is in Giulio Preti's philosophy that this proposition achieves its highest speculative synthesis.
If philosophy is a common good, philosophizing as an application of historical-critical reason becomes a universal right of mankind that should be protected starting with primary school. This right is practically exemplified in the section dedicated to philosophy with children within the Giovani Pensatori project.
Goals, objectives and methodological-didactic indications of the philosophy with children are developed in this work, recognizing in Socrates and in Socratic dialogue its guiding principle, in order to ensure the exercise of those rational and critical abilities underlying each civilization
An integrative framework for cooperative production resources in smart manufacturing
No full textUnder the push of Industry 4.0 paradigm modern manufacturing companies are dealing with a significant digital transition, with the aim to better address the challenges posed by the growing complexity of globalized businesses (Hermann, Pentek, & Otto, Design principles for industrie 4.0 scenarios, 2016). One basic principle of this paradigm is that products, machines, systems and business are always connected to create an intelligent network along the entire factory’s value chain. According to this vision, manufacturing resources are being transformed from monolithic entities into distributed components, which are loosely coupled and autonomous but nevertheless provided of the networking and connectivity capabilities enabled by the increasingly widespread Industrial Internet of Things technology. Under these conditions, they become capable of working together in a reliable and predictable manner, collaborating among themselves in a highly efficient way. Such a mechanism of synergistic collaboration is crucial for the correct evolution of any organization ranging from a multi-cellular organism to a complex modern manufacturing system (Moghaddam & Nof, 2017). Specifically of the last scenario, which is the field of our study, collaboration enables involved resources to exchange relevant information about the evolution of their context. These information can be in turn elaborated to make some decisions, and trigger some actions. In this way connected resources can modify their structure and configuration in response to specific business or operational variations (Alexopoulos, Makris, Xanthakis, Sipsas, & Chryssolouris, 2016). Such a model of “social” and context-aware resources can contribute to the realization of a highly flexible, robust and responsive manufacturing system, which is an objective particularly relevant in the modern factories, as its inclusion in the scope of the priority research lines for the H2020 three-year period 2018-2020 can demonstrate (EFFRA, 2016). Interesting examples of these resources are self-organized logistics which can react to unexpected changes occurred in production or machines capable to predict failures on the basis of the contextual information and then trigger adjustments processes autonomously.
This vision of collaborative and cooperative resources can be realized with the support of several studies in various fields ranging from information and communication technologies to artificial intelligence. An update state of the art highlights significant recent achievements that have been making these resources more intelligent and closer to the user needs. However, we are still far from an overall implementation of the vision, which is hindered by three major issues. The first one is the limited capability of a large part of the resources distributed within the shop floor to automatically interpret the exchanged information in a meaningful manner (semantic interoperability) (Atzori, Iera, & Morabito, 2010). This issue is mainly due to the high heterogeneity of data model formats adopted by the different resources used within the shop floor (Modoni, Doukas, Terkaj, Sacco, & Mourtzis, 2016). Another open issue is the lack of efficient methods to fully virtualize the physical resources (Rosen, von Wichert, Lo, & Bettenhausen, 2015), since only pairing physical resource with its digital counterpart that abstracts the complexity of the real world, it is possible to augment communication and collaboration capabilities of the physical component. The third issue is a side effect of the ongoing technological ICT evolutions affecting all the manufacturing companies and consists in the continuous growth of the number of threats and vulnerabilities, which can both jeopardize the cybersecurity of the overall manufacturing system (Wells, Camelio, Williams, & White, 2014). For this reason, aspects related with cyber-security should be considered at the early stage of the design of any ICT solution, in order to prevent potential threats and vulnerabilities. All three of the above mentioned open issues have been addressed in this research work with the aim to explore and identify a precise, secure and efficient model of collaboration among the production resources distributed within the shop floor.
This document illustrates main outcomes of the research, focusing mainly on the Virtual Integrative Manufacturing Framework for resources Interaction (VICKI), a potential reference architecture for a middleware application enabling semantic-based cooperation among manufacturing resources. Specifically, this framework provides a technological and service-oriented infrastructure offering an event-driven mechanism that dynamically propagates the changing factors to the interested devices. The proposed system supports the coexistence and combination of physical components and their virtual counterparts in a network of interacting collaborative elements in constant connection, thus allowing to bring back the manufacturing system to a cooperative Cyber-physical Production System (CPPS) (Monostori, 2014). Within this network, the information coming from the productive chain can be promptly and seamlessly shared, distributed and understood by any actor operating in such a context. In order to overcome the problem of the limited interoperability among the connected resources, the framework leverages a common data model based on the Semantic Web technologies (SWT) (Berners-Lee, Hendler, & Lassila, 2001). The model provides a shared understanding on the vocabulary adopted by the distributed resources during their knowledge exchange. In this way, this model allows to integrate heterogeneous data streams into a coherent semantically enriched scheme that represents the evolution of the factory objects, their context and their smart reactions to all kind of situations. The semantic model is also machine-interpretable and re-usable. In addition to modeling, the virtualization of the overall manufacturing system is empowered by the adoption of an agent-based modeling, which contributes to hide and abstract the control functions complexity of the cooperating entities, thus providing the foundations to achieve a flexible and reconfigurable system. Finally, in order to mitigate the risk of internal and external attacks against the proposed infrastructure, it is explored the potential of a strategy based on the analysis and assessment of the manufacturing systems cyber-security aspects integrated into the context of the organization’s business model.
To test and validate the proposed framework, a demonstration scenarios has been identified, which are thought to represent different significant case studies of the factory’s life cycle. To prove the correctness of the approach, the validation of an instance of the framework is carried out within a real case study. Moreover, as for data intensive systems such as the manufacturing system, the quality of service (QoS) requirements in terms of latency, efficiency, and scalability are stringent, an evaluation of these requirements is needed in a real case study by means of a defined benchmark, thus showing the impact of the data storage, of the connected resources and of their requests
Critical role of CDKL5 in AMPA receptor composition: underlying mechanism and functional outcome.
No full textNeurological disorders associated with the X-linked kinase CDKL5 are characterized by the early onset of seizures, severe cognitive deficits and autistic traits. Loss of Cdkl5 affects spine density and stabilization as well as synaptic activity, but the underlying molecular mechanisms are still far from fully understood. Here we show several pieces of evidence linking Cdkl5-associated synaptic defects to AMPA receptor (R) expression and subunit composition. In particular, primary hippocampal neurons devoid of Cdkl5 have defective GluA2-subunit expression, as well as a hyper-phosphorylation of Serine 880 (S880). Moreover, Cdkl5-downregulation skews the composition of membrane-inserted AMPARs towards the GluA2-depleted calcium-permeable form. The depletion of membrane-inserted GluA2 is likely to rely on defective recycling. Indeed, at the molecular level, we find that CDKL5 interacts with GRASP-1, a neuron-enriched protein that coordinates the endosomal sorting of AMPARs towards the plasma membrane. Against this background, we assume that the resulting alterations can underlie, at least in part, the synaptic dysfunctions and cognitive deficits in CDKL5 disorder. Finally, we provide evidence that tianeptine, a promising drug previously reported to modulate AMPAR-mediated glutamatergic neurotransmission, is capable of restoring GluA2 expression and S880 phosphorylation in neurons devoid of CDKL5. These results places tianeptine as an interesting candidate drug for CDKL5-disorder