Drug discovery for age-related diseases and their targets

Insight into biological pathways, identification of new targets and appropriate biomarkers are the prerequisites for drug discovery & development. This PhD thesis addresses the role of fundamental research in drug discovery in age-related Alzheimer’s disease (AD), and a cancer-related target, the cell cycle. The large economic impact of AD, exponentially increasing in the ageing societies of industrialised countries strongly urges for discovery and development of drugs and therapy-related tools. As a consequence, the interest for retinoids based on their confirmed involvement in the regulation of disease-related genes in neurodegenerative ailments including AD has been revived, even though details of their molecular modes of action remain to be elucidated. The first project described in this PhD thesis focuses on the regulation of alpha-, beta-, and gamma-secretases mediated by all-trans-retinoic acid (ATRA), the main metabolite of retinoids. Our findings support the hypothesis that ATRA is capable of regulating secretases in the anti-amyloidogenic sense at the levels of transcription, translation, and activation. Apart from increased alpha-secretase activity, we show a complex chain of regulatory events, resulting in impaired beta-secretase trafficking and its membranal localisation due to protein kinase C (PKC) activation by ATRA, resulting in enhanced secretion of soluble APPalpha. ATRA also affected activity, transcription and localisation of Presenilin 1, the functional core of the gamma-secretase, but had no effect on Presenilin 2. The experiments were performed in three neuronal and non-neuronal cell lines of human and murine origin, which allowed us to determine general mechanisms and cell line-specific differences in the ATRA-mediated regulation of secretases. Although control of gene expression by retinoids occurs mainly via genomic regulation of target genes, anti-amyloidogenic effects of retinoids have been attributed to their PKC-stimulating ability and subsequent activation of alpha-secretases only. Therefore, contribution of genomic and non-genomic control mechanisms to the regulation of BACE1, the main beta-secretase, by ATRA was examined in the second project. Our findings corroborated the role of PKC stimulation in the down-regulation of BACE1 at the transcriptional and translational levels, resulting in decrease of Abeta42 in the human embryonic kidney HEK 293 cell line. ATRA induced DNA-binding activity of its receptors RARbeta-RXR, and showed PKC- dependent activation of the transcription factors NFkB and AP-1, as revealed by electrophoretic mobility shift assay (EMSA). We show disruption of a PKC-modulated decrease of BACE1 mRNA and Abeta levels, when NFkB or AP-1 activity was blocked by BAY11-7082, NFkB inhibitor, or by the transfection of inhibitory DNA-oligonucleotides. For the first time PKC-signalling induced by retinoids could be linked to the transcriptional control of BACE1 regulation. The last project described in this PhD studied the role of ADAM17 in the the cell cycle. ADAM17 is gaining attention in the field of clinical research as a potential outcome biomarker in breast cancer and adenocarcinoma. However, a possible implication of ADAM17 in the cell cycle has not been investigated, since its role in cancer is usually considered in the context of epidermal growth factor receptor signalling. First, through a combination of mass spectrometry and biochemical methods, we identified alpha- and beta-tubulins as binding partners of ADAM17. This interaction was confirmed bidirectionally in the murine neuroblastoma N2a cell line, and the ADAM17 fragments involved in tubulin-binding were identified. Additionally, we showed co-localisation of ADAM17 and tubulins in the spindle of mitotic cells. Furthermore, we were able to show a cell cycle-dependent regulation of ADAM17 by over-expression of either full length or mature ADAM17 versions in N2a cell line and observed significantly increased invasiveness due to over-expression of mature ADAM17 form. Still, biological significance of the interaction between ADAM17 and tubulins remains to be discovered. Altogether, these studies examined existing theories, raised new hypothesis, and contributed to the identification of new targets and a clearer understanding of fundamental mechanisms

Promotion of cell death or neurite outgrowth in PC-12 and N2a cells by the fungal alkaloid militarinone A depends on basal expression of p53

The fungal alkaloid militarinone A (MiliA) was recently found to stimulate neuronal outgrowth in PC-12 cells by persistant activation of pathways that are also involved in NGF-mediated differentiation, namely the PI3-K/PKB and the MEK/ERK pathways. Application of equal concentrations of MiliA to other cells such as the murine neuroblastoma cell line N2a resulted in immediate onset of apoptosis by nuclear translocation of apoptosis inducing factor (AIF), activation of caspases and c-Jun/AP-1 transcription factor without an intermediate differentiated phenotype, although minor transient phosphorylation of PKB and MAPK as well as activation of NF-κB were also observed. Translocation of AIF was preceded by p53 phosphorylation at Ser15 and blocked by pifithrin α, a known inhibitor of p53-transcriptional activity. We here show that both cell types activate the same pathways albeit in different time scales. This is mainly due to contrasting basal expression levels of p53, which in turn regulates expression of AIF. In PC-12 cells, continuous activation of these pathways after prolonged treatment with 40μM MiliA first led to up-regulation of p53, phosphorylation of p53, release of AIF from mitochondria and its translocation into the nucleus. Additionally, also activation of the c-Jun/AP-1 transcription factor was observed, and PC-12 cells subsequently underwent apoptosis 48-72h post-treatment. We report that similar pathways working on different levels are able to initially shape very divergent cellular response

Multidisciplinary approach for a new vision of urban requalification. Multi-scale strategies of social innovation, economic improvement and environmental sustainability practices

Ponència presentada a: Session 7: Participación en planeamiento / Participation in planning. Environmental and hermeneutic plannin

Multidisciplinary approach for a new vision of urban requalification. Multi-scale strategies of social innovation, economic improvement and environmental sustainability practices

Ponència presentada a: Session 7: Participación en planeamiento / Participation in planning. Environmental and hermeneutic plannin

Multidisciplinary approach for a new vision of urban requalification. Multi-scale strategies of social innovation, economic improvement and environmental sustainability practices.

This work is an operative best practice of new methodological approach that connects three disciplines - Planning, Design and Environmental Technological Design – in a holistic project. A multidisciplinary approach is necessary to understand the complexity of urban phenomena meeting social, economic and environmental needs. It is very important boosting virtuous mechanisms for urban regeneration spreading innovation, guiding and shaping spontaneous social-change initiatives, starting from local traditions. The work team was involved in an international workshop, called “Urban Village and Renovation Design”, took between Rome and Shanghai, within May and November 2016, in collaboration with the School of Design and Arts, East China Normal University of Shanghai. Our research team composed by planners, architects and designers has drawn up a methodology in order to apply it in a small rural village requalification project in China. The town, named XibinZhen (Fujian Region) is undergoing in an economic and social contraction process which is bringing it to an incessant depopulation. We recognize landscape aspects, in our case the Youxi River, like a key resources to improve the urban area and the identity related with the context. The methodology is composed in this way: 1) research and analyses in order to know places and ongoing multiscale phenomena; 2) collection of international best practices and references applicable in the specific case study; 3) brainstorming in which different disciplinary figures, local stakeholders and citizens are involved; 4) design strategies considering different stakeholders needs and different cultural approach or points of view: 5) starting from those strategies, definition of specific goals for a design concept and a sub sequential project propose. Our proposal is composed by multi-scale strategies of social innovation, economic improvement, environmental sustainable practices, through a new setting of spaces and uses. Our new vision of Xibin Town runs around three key words for development: “new”, that is to have a “for change” approach; “river”, that is to recognize what we may call “genius loci”; “town”, that is to recognize the urban character of Xibin and its role in a broader context. The three themes on which we set up the project strategy are: · ENVIRONMENT: two linear promenades (the Urban Promenade and the Green Promenade), of new public space for the town with different characters related to the different nature of the waterfronts, north and south. The implementation of landscape qualities (industries on the facing coasts) · URBAN LIFE: two axes: the Urban Axis that consolidates and upgrades the vital core of the collective life, organizing places and activities from the city gate by the Boulevard to the Market Street, to administration and public services (the Civic Street and the Civic Center); the Heritage Path that works between tradition and innovation, organizing step by step from culture to nature (traditional ateliers street, green street, educational theme park) · Functional to these themes is the MOBILITY SYSTEM, re-organized fundamentally in an Urban Ring that distributes the main traffic. The final output is a masterplan which collects and coordinates all the specific project actions redefining spaces, the use of them and architecture, starting from a reinterpretation of traditional technology and local material

Rationalized kitchen in Germany and Russia: the social support of the new way of life

The authors compare two design-concepts of functional organization of the space of the kitchen: Weienhofsiedlung and design of the sectional kitchen in the house-commune, the influence of the ideas of standardization and rationalization on the mode of life is analyzed

Lomografia

La Lomografia è un nuovo stile di fotografia artistica sperimentale nata nel 1991, quando due studenti di Vienna in gita a Praga, avendo dimenticato le loro macchine fotografiche, comprano in un mercatino dell’usato una Lomo Kompakt Automat, una piccola, enigmatica macchina fotografica russa, analogica e compatta. Tornati a casa e dopo aver sviluppato i rullini, restano impressionati dalle immagini uniche, colorate e talvolta sfocate prodotte da 35 millimetri Lomo LC-A. Nel corso degli anni a partire dal 1991 e dal viaggio a Praga dei due studenti austriaci, la lomografia si è fatta fautrice di una nuova filosofia estetica, fondata sul motto “Non pensare, scatta!”. Nella filosofia Lomo, infatti, il momento giusto non si attende, ma si manifesta da solo, spontaneamente, per il fatto stesso che l’operatore lo seleziona e lo definisce come tale. Nella filosofia lomo non esiste il momento giusto perché ogni momento è (potenzialmente) quello giusto. L’atteggiamento tipico del lomoamatore è quello di chi ricerca la bellezza in maniera casuale. E’ un osservatore “laterale” del quotidiano che si lascia stupire ed emozionare dalle manifestazioni fortuite di senso estetico che il quotidiano custodisce. Tutti possono fare una lomografia, e con una certa pratica, chiunque può farlo bene. In questo senso è un fenomeno molto democratico. Tuttavia il fenomeno Lomo non risiede solo nella filosofia di chi la pratica, ma anche nello stile espressivo della lomografia, e nell’imperfezione che ne scaturisce. Un’imperfezione che più che mancanza, è esagerazione, saturazione, enfasi, eccesso. La scarsa qualità delle macchine Lomo (in primo luogo la LC-A da cui tutto partì) genera in fase di stampa infiltrazioni di luce, macchie di ombra e la cosiddetta “vignettatura”, tratto distintivo della Lomografia. Quanto più una foto è “vignettata”, tanto più è riconoscibile e classificabile come lomografia. Le sfocatura, le eccessive saturazioni di colore sono ben tollerate, anzi vengono addirittura enfatizzate tramite l’uso di pellicole scadute. Anche sul piano dei soggetti scelti da fotografare domina la casualità, l’instabilità, l’asimmetria, la deformazione della prospettiva. A completare il quadro della “filosofia Lomo” c’è il tratto identitario e comunitario. I lomoamatori si sentono parte di una comunità la cui logica, paradossalmente, è digitale, fondata sui social network, sui forum di discussione, sulle centinaia di Lomowall che si trovano in rete. Una comunità che si sente e riconosce come “alternativa”, nella stessa posizione “laterale” rispetto alle logiche dominanti, che è propria dello stile fotografico. Le Lomografie sono le immagini scattate con la minima dose di razionalità. Preferibilmente durante la notte. Preferibilmente dal fianco. L'intento di Lomography come filosofia è quella di lasciar andare tutte le sovrastrutture teoriche della fotografia tradizionale, e catturare la vita così com'è, nel modo più diretto possibile. Per tradurre la libertà in immagini. Per essere liberi, selvaggi, e giovani. Per essere spontaneo. E impressionare gli altri con la propria spontaneità, tramite i vari forum ed il Lomowall del sito ufficiale.Lomography is a new experimental artistic photography style born in 1991, when two students in Vienna on a trip to Prague, having forgotten their cameras, bought in a flea market a Lomo Kompakt Automat, a small, enigmatic Russian camera , analog and compact. They returned home and after having developed the rollers, were impressed by the unique pictures, colorful, and sometimes blurry produced 35mm Lomo LC-A. Over the years since 1991 and the trip to Prague of the-two Austrian students, Lomography has become an advocate of a new aesthetic philosophy, founded on the motto "Do not think, shoot!". In Lomo philosophy, in fact, the right moment does not expect, but it manifests itself, spontaneously, by the very fact that the operator selects and defines it as such. In Lomo philosophy it does not exist for the right moment because each moment is (potentially) the right one. The typical attitude of lomoamateurs is to those who seek randomly beauty. It 'a "lateral" observer of the newspaper that you let surprise and excite the aesthetic sense of fortuitous events that daily guards. Anyone can make a lomo-picture, and with some practice, anyone can do it well. In this sense it is a very democratic phenomenon. However, the Lomo phenomenon lies not only in the philosophy of those who practice it, but also in the expressive style of Lomography, and imperfection that emerges. An imperfection that rather than failing, it is exaggeration, saturation, focus, excess. The poor quality of the machines Lomo (primarily the LC-A from which everything went) generates during light leaks Printing, shadow spots and the so-called "vignetting", hallmark of Lomography. The more a picture is "vignetting", the more is recognizable and classifiable as lomography. The blur, excessive color saturations are well tolerated, indeed they are even emphasized by the use of expired film. Even on the floor of the subjects chosen by photographing the randomness dominates, the instability, the asymmetry, the deformation of perspective. To complete the picture of "Lomo philosophy" is the identity tract and community. The lomoamatori feel part of a community whose logic, paradoxically, is digital, based on social networks, on the discussion forums, the hundreds of Lomowall found in the network. A community that feels and recognizes as "alternative", the same "side position" with respect to the dominant logic, which is characteristic of the photographic style. The Lomografie have pictures taken with the minimum dose of rationality. Preferably overnight. Preferably from the side. The intent of Lomography as philosophy is to let go of all the theoretical superstructure of traditional photography, and capture life as it is, in the most direct way possible. To translate freedom into images. To be free, wild, and young. To be spontaneous. And impress others with their spontaneity, through various forums and Lomowall the official site

Communal flats in Moscow and Petrograd in literature of Michail Bulgakov, Joseph Brodsky, Anna Akhmatova

The article represents fragment of the author’s research «The Soviet design 1920–1987. Contexts, types, interiors, furniture and other domestic space appliances», where the main topics are: dwelling construction, domestic interior, design of home appliances. During 1920–1987 the author discusses parallels between economic and political situation in the country, appearance of the new types of dwelling and design innovations

Multidisciplinary approach for a new vision of urban requalification. Multi-scale strategies of social innovation, economic improvement and environmental sustainability practices.

For us Design for Next means linking people to places in a straight connection to the complexity of urban condition. Improving the quality of urban places means to work on the relationship between: people, places, traditions and cultural identity. The relationships involve also the link between building; environment and landscape system. A multidisciplinary approach is necessary to understand the complexity of urban phenomena meeting social, economic and environmental needs. It is very important boosting virtuous mechanisms for urban regeneration spreading innovation, guiding and shaping spontaneous social-change initiatives, starting from local traditions. Our research team composed by planners, architects and designers has drawn up a methodology in order to apply it in a small rural village requalification project in China. The town, named XibinZhen (Fujian Region) is undergoing in an economic and social contraction process, which is bringing it to an incessant depopulation. We recognize landscape aspects, in our case the Youxi River, like a key resource to improve the urban area and the identity related with the context. We also have identified a heritage path, which connects the two waterfronts and defines a cultural itinerary to understand and develop lifestyles, traditions and local production. The methodology is composed in this way: 1) research and analyses in order to know places and ongoing multiscale phenomena; 2) collection of international best practices and references applicable in a specific case study; 3) brainstorming in which different disciplinary figures, local stakeholders and citizens are involved; 4) design strategies considering different stakeholders needs and different cultural approach or points of view. Our proposal is composed by multi-scale strategies of social innovation, economic improvement, environmental sustainable practices, through a new setting of spaces and uses. Our new vision of Xibin Town runs around three key words for development: “new”, that is to have a “for change” approach; “river”, that is to recognize what we may call “genius loci”; “town”, that is to recognize the urban character of Xibin and its role in a broader context

Weissenhofsiedlung Stoccarda 1927 - 2017. Approfondimenti e interpretazioni.

Il libro è il risultato di una ricerca e di un workshop internazionale che hanno avuto come esito una mostra, organizzata con il contributo del Goethe-Institut, da Embrice2030, dal Dipartimento di Architettura dell’Università Roma Tre e dal Dipartimento di Pianificazione Design Tecnologia dell’Architettura di Sapienza Università di Roma. La Mostra è stata curata da Milena Farina, Giovanni Longobardi, Giovanna Spadafora e Giuliano Valeri per Roma Tre; da Federica Dal Falco e Sabrina Lucibello per l’Università Sapienza; da Vittorio Giusepponi, Diana Giaisa Rinaldi e Carla Scura per Embrice2030. I materiali esposti costituiscono i risultati del Workshop tenutosi nell’ottobre 2017 presso la sede del Goethe-Institut al quale hanno partecipato studenti di architettura di Roma Tre e dottorandi e studenti di Design della Sapienza insieme a ricercatori e giovani artisti facenti capo alla APS Embrice2030. La mostra presenta un lavoro di approfondimento e interpretazione, coordinato da Carlo Severati e A lberto Giuliani, di alcuni aspetti della Weissenhofsiedlung di Stoccarda: un piccolo quartiere sperimentale costruito ad opera di alcuni fra i maggiori architetti europei del ’900 sotto la direzione di Ludwig Mies van der Rohe. Il quartiere faceva parte di una grande Esposizione programmata per il 1927, da luglio a settembre, dal Deutscher Werkbund, anche come risposta alla celebre Exposition des Arts décoratifs et industriels modernes svoltasi a Parigi nel 1925. Gli alloggi erano in tutto 60, nella maggior parte diversi uno dall’altro, con l’eccezione di quelli progettati dagli architetti olandesi Oud e Stam. Solo 11 dei 21 edifici di abitazione sono sopravvissuti nelle loro forme originali. Il quartiere, e l’intera Esposizione, sono stati il punto di incontro di artisti di varie tendenze progressiste, tedeschi ed europei, dopo la difficile fase di post-bellica culminata con la Repubblica di Weimar nel 1919. Il catalogo è stato concepito in tre sezioni: architettura, design, arti. I progetti pubblicati sono accompagnati da descrizioni e illustrazioni. La seconda parte del catalogo presenta saggi e approfondimenti degli autori. La sezione Design è per la cura scientifica di Federica Dal Falco. The book is the result of an international research and workshop and an exhibition, organized with the contribution of the Goethe-Institut, by Embrice2030, the Department of Architecture of the Roma Tre University and the Department of Planning Design Technology of Architecture of Sapienza University of Rome. The exhibition was curated by Milena Farina, Giovanni Longobardi, Giovanna Spadafora and Giuliano Valeri for Roma Tre; by Federica Dal Falco and Sabrina Lucibello for Sapienza University; by Vittorio Giusepponi, Diana Giaisa Rinaldi and Carla Scura for Embrice2030. The projects and research exhibited constitute the results of the Workshop held in October 2017 at the Goethe-Institut in Rome which was attended by students of architecture from Roma Tre and PhD students and students of Design from Sapienza together with researchers and young artists from the APS Embrice2030. The exhibition presents an in-depth study and interpretation, coordinated by Carlo Severati and A lberto Giuliani, of some aspects of the Weissenhofsiedlung in Stuttgart: a small experimental neighborhood built by some of the greatest European architects of the twentieth century under the direction of Ludwig Mies van der Rohe. The neighborhood was part of a large exhibition scheduled for 1927, from July to September, by the Deutscher Werkbund, also as a response to the famous Exposition des Arts décoratifs et industriels modernes held in Paris in 1925. The buildings were mostly different from one another, with the exception of those designed by Dutch architects Oud and Stam. Only 11 of the 21 residential buildings have survived in their original forms. The neighborhood, and the entire Exhibition, were the meeting point for artists of various progressive trends, German and European, after the difficult post-war phase that culminated with the Weimar Republic in 1919. The catalog was conceived in three sections: architecture, design, arts. The published projects are accompanied by descriptions and illustrations. The second part of the catalog presents essays and insights by the authors. The scientific responsible of the Design section is Federica Dal Falco.Il libro concerne studi, ricerche e interpretazioni interdisciplinari tra arti, design e architettura sulla Weissenhofsiedlung di Stoccarda del 1917 presentati sotto forma di saggi e come progetti e opere esposti in occasione della Mostra "Abitare la Weissenhofsiedlung di Stoccarda 1927-2017. Approfondimenti e interpretazioni" tenuta dal 9 maggio al 17 giugno 2018 presso il Goethe Institut Rom sede di Roma. I materiali oggetto della Mostra costituiscono i risultati del Workshop internazionale e interdisciplinare tenuto presso la sede del Goethe-Institut curato e organizzato da docenti di Roma tre Università degli studi - Dipartimento di Architettura, Sapienza Università di Roma - Dipartimento di Pianificazione Design Tecnologia dell’Architettura Sapienza Università di Roma - Dottorato in Pianificazione, Design, Tecnologie dell'Architettura, Associazione Embrice 2030, Goethe-Institut Rom. Al workshop hanno partecipato studenti e dottorandi delle due Istituzioni universitarie, artisti e membri dell'Associazione culturale Embrice 2030. Il quartiere sperimentale della Weissenhofsiedlung venne costruito ad opera dei maggiori architetti europei del Novecento sotto la guida di Mies van der Rohe. Il quartiere faceva parte di una grande Esposizione programmata per il 1927, da luglio a settembre, dal Deutscher Werkbund, e rappresentò il punto di incontro tra artisti, architetti progressisti e designer uniti nella diversità delle espressioni progettuali da un comune sentire, volto alla ricerca di una nuova dimensione dell'abitare aderente ai principi della modernità. Le ricerche e i progetti realizzati durante il workshop, tra arti, design e architettura, hanno interpretato nella contemporaneità forme e tecnologie secondo un approccio che considera il progetto quale risultato di un'evoluzione dinamica, considerando le opere del passato come un patrimonio di forme e idee programmatiche che si proiettano nel presente e nel futuro. La sezione Design (p. 20-29; p. 96-114), per la cura scientifica di Dal Falco, si pone in continuità con l'esperienza svolta nel 2014 che ha prospettato con analoghe metodologie - workshop di product design e di Design della comunicazione visiva e multimediale- la reinterpretazione dell'Esposizione del Werkbund (1914) di Colonia. Lo specifico contributo di dal Falco, dal titolo “Weissenhofsiedlung 1927. La questione tecnologica della modernità tra architettura e design” (p. 65-83), riguarda la questione tecnologica, il concetto di tipo e la produzione in serie che costituirono uno degli aspetti più rilevanti nel rapporto tra architettura e design.The book concerns studies, research and interdisciplinary interpretations between arts, design and architecture on the Stuttgart Weissenhofsiedlung of 1917. The studies are presented in the form of essays and as projects and works that are exhibited on the occasion of the "Abitare la Weissenhofsiedlung in Stuttgart 1927-2017. Insights and interpretations" held from 9 May to 17 June 2018 at the Goethe Institut Rom in Rome. The materials of the Exhibition are the results of the international and interdisciplinary Workshop held at the Goethe-Institut, which is curated and organized by professors from Rome - Department of Architecture, Sapienza University of Rome - Department of Planning, Architectural Technology Sapienza University of Rome - PhD in Planning, Design, Architectural Technologies, Embrice 2030 Association, Goethe-Institut Rom. Students and PhD students of the two university institutions, artists and members of the Embrice 2030 cultural association took part in the workshop. Weissenhofsiedlung was built by the greatest European architects of the twentieth century, coordinated by Mies van der Rohe. The neighborhood was part of a large Exhibition which was held from July to September 1927 by the Deutscher Werkbund, and represented the meeting point between artists, progressive architects and designers united in the diversity of design expressions from a common feeling, aimed at the search for a new dimension of living adhering to the principles of modernity. The research and projects carried out during the workshop, between arts, design and architecture, have interpreted contemporary forms and technologies according to an approach that considers the project as the result of a dynamic evolution and the past as a heritage of forms and ideas that are projected in the present and in the future. The Design section (p. 20-29; p. 96-114), edited by Dal Falco, is in continuity with the experience carried out in 2014 which presented similar methodologies - product design and visual communication design workshops and multimedia) the reinterpretation of the Werkbund Exhibition (1914) in Cologne. The specific contribution of dal Falco, entitled “Weissenhofsiedlung 1927. The technological question of modernity between architecture and design” (p. 65-83), concerns the technological question, the concept of type and mass production which constituted one of the aspects more relevant in the relationship between architecture and design