The human ARF tumor suppressor senses blastema activity and suppresses epimorphic tissue regeneration.

The control of proliferation and differentiation by tumor suppressor genes suggests that evolution of divergent tumor suppressor repertoires could influence species regenerative capacity. To directly test that premise, we humanized the zebrafish p53 pathway by introducing regulatory and coding sequences of the human tumor suppressor ARF into the zebrafish genome. ARF was dormant during development, in uninjured adult fins, and during wound healing, but was highly expressed in the blastema during epimorphic fin regeneration after amputation. Regenerative, but not developmental signals resulted in binding of zebrafish E2f to the human ARF promoter and activated conserved ARF-dependent Tp53 functions. The context-dependent activation of ARF did not affect growth and development but inhibited regeneration, an unexpected distinct tumor suppressor response to regenerative versus developmental environments. The antagonistic pleiotropic characteristics of ARF as both tumor and regeneration suppressor imply that inducing epimorphic regeneration clinically would require modulation of ARF -p53 axis activation

Εκτίμηση Βιομηχανικού Κινδύνου σε Εγκαταστάσεις SEVESO και Σχεδιασμός Χρήσεων Γης. Η Περίπτωση του Δήμου Κορδελιού – Ευόσμου

Σκοπός της παρούσας Μεταπτυχιακής Διπλωματικής Εργασίας αποτελεί η διερεύνηση των της επικινδυνότητας των βιομηχανικών ατυχημάτων, τα οποία με την ανάπτυξη της βιομηχανικής δραστηριότητας έχουν αυξηθεί ραγδαία και μπορούν να επηρεάσουν αρνητικά τις παρακείμενες χρήσεις γης και γενικότερα τις οικιστικές ζώνες. Ειδικότερα, τις τελευταίες δεκαετίες έχουν προκληθεί βιομηχανικά ατυχήματα μεγάλης έκτασης τα οποία αποτέλεσαν σημεία καμπής για την αρχή της ανθρώπινης προσπάθειας για τη μείωση της επικινδυνότητας από εγκαταστάσεις που διαχειρίζονται επικίνδυνες ουσίες. Στα πλαίσια της παρούσας εργασίας, αρχικά πραγματοποιείται μια βιβλιογραφική επισκόπηση των τεχνολογικών ατυχημάτων με σαφή επικέντρωση στις κατηγορίες ατυχημάτων που μπορούν να λάβουν χώρα συγκεκριμένα σε βιομηχανικές εγκαταστάσεις που διαχειρίζονται ή/και αποθηκεύουν επικίνδυνες χημικές ουσίες. Στην συνέχεια αναλύονται οι επιπτώσεις των βιομηχανικών ατυχημάτων μεγάλης έκτασης (ΒΑΜΕ), και δίνονται μερικά σύντομα παραδείγματα βιομηχανικών μεγάλων ατυχημάτων που συνέβησαν τόσο στην Ελλάδα όσο και Διεθνώς. Αναλύονται οι Οδηγίες Seveso, οι οποίες αποτελούν την Ευρωπαϊκή προσπάθεια για την προφύλαξη των ανθρώπων, του περιβάλλοντος αλλά και των βιομηχανικών εγκαταστάσεων από τις επιπτώσεις που ενέχουν αυτά τα ατυχήματα, ενώ έμφαση δίνεται στο Ελληνικό Νομοθετικό Πλαίσιο που ενσωματώνει την τελευταία Οδηγία Seveso III και των διατάξεων που αυτή εφαρμόζει. Έμφαση δίνεται επίσης, στις διατάξεις τόσο της Ευρωπαϊκής Οδηγίας όσο και την Ελληνικής Νομοθεσίας σε ζητήματα που αφορούν το χωροταξικό σχεδιασμό, τη πολεοδομία και τις χρήσεις γης. Μελέτη Περίπτωσης της παρούσας εργασίας αποτελεί ο Δήμος Κορδελιού – Ευόσμου ο οποίος συνορεύει με τις εγκαταστάσεις της Ελληνικά Πετρέλαια Α.Ε., εταιρεία η οποία υπάγεται στην Οδηγία Seveso. Σε συνέχεια της περιγραφής τόσο των χαρακτηριστικών του Δήμου (π.χ. πληθυσμιακά στοιχεία κ.α.) όσο και την εταιρείας (π.χ. οριοθέτηση, αποστάσεις, ύπαρξη Ειδικού ΣΑΤΑΜΕ κ.α.), διερευνάται καταρχάς η ύπαρξη προβλέψεων κυρίως στο ζήτημα των χρήσεων γης – βιομηχανικών ατυχημάτων, τόσο από άποψη του ισχύοντος ρυθμιστικού σχεδιασμού του Δήμου (π.χ. Γενικά Πολεοδομικά Σχέδια κ.α.) και άλλων Προγραμμάτων (π.χ. Επιχειρησιακό Πρόγραμμα), όσο και από τον Υπερκείμενο Χωροταξικό Σχεδιασμό (π.χ. ΠΠΧΣΑΑ Κεντρικής Μακεδονίας κ.α.). Στην συνέχεια, πραγματοποιούνται και οπτικοποιούνται σενάρια ατυχημάτων από την εν λόγω εγκατάσταση μέσω του λογισμικού ALOHA και εξετάζονται οι αρνητικές επιπτώσεις κυρίως σε σύγκριση με τις χρήσεις γης ενώ, εντοπίζονται ευπαθείς χρήσεις (π.χ. σχολεία, ΚΑΠΗ κ.α.) εντός των ζωνών αρνητικών επιπτώσεων. Τέλος, η εργασία καταλήγει σε σύντομες προτάσεις στη πολεοδομική κλίμακα, με σκοπό την εξεύρεση χρονικά σύντομων και εφικτών δράσεων για τη μείωση της βιομηχανικής επικινδυνότητας και της ευπάθειας των χρήσεων γης, σε μια χαρακτηριστική περιοχή γειτνίασης βιομηχανίας Seveso και οικιστικού χώρου.The purpose of this Master's Thesis is to investigate the risk of industrial accidents which with the development of industrial activity have increased rapidly and can adversely affect adjacent land uses and residential areas in general. In particular, large-scale industrial accidents have occurred in recent decades, which have been turning points for the beginning of the human effort to reduce the risk from hazardous substances management facilities. In the context of the present work, a bibliographic review of technological accidents is initially carried out with a clear focus on the categories of accidents that may occur specifically in industrial facilities that manage and / or store hazardous chemicals. Then the effects of large-scale industrial accidents are analyzed, and some brief examples of major industrial accidents that occurred both in Greece and internationally are given. The Seveso Directives are analyzed, which are the European effort to protect people, the environment and industrial facilities from the effects of these accidents, while emphasis is placed on the Greek Legislative Framework that incorporates the latest Seveso Directive III and the provisions which it applies. Emphasis is placed on the provisions of both the European Directive and the Greek Legislation on issues related to spatial planning, urban planning and land uses. Case Study of the present work is the Municipality of Kordelio - Evosmos which borders the facilities of Hellenic Petroleum SA, a company which is subject to the Seveso directive. Following the description of both the characteristics of the Municipality (e.g. land uses, population data, etc.) and the company (e.g. demarcation, distances, existence of Special SATAME, etc.), the existence is first investigated forecasts mainly on the issue of land uses, both in terms of the current regulatory planning of the Municipality (e.g. General Urban Plans, etc.) and other Programs (e.g. Operational Plan), as well as the Superior Spatial Planning ( e.g. PPXSAA of Central Macedonia etc.). Then, accident scenarios are performed and visualized from this installation through the ALOHA software and the negative effects are examined mainly in comparison with the land uses while, vulnerable uses are identified (e.g. schools, KAPI etc.) within the zones adverse effects. Finally, the work concludes with short proposals on the urban scale, with the aim of finding short-term and feasible actions to reduce industrial risk and land use vulnerability, in a typical neighborhood of Seveso industry and residential space

Periplakin, a novel component of cornified envelopes and desmosomes that belongs to the plakin family and forms complexes with envoplakin

The cornified envelope is a layer of transglutaminase cross-linked protein that is assembled under the plasma membrane of keratinocytes in the outermost layers of the epidermis. We have determined the cDNA sequence of one of the proteins that becomes incorporated into the cornified envelope of cultured epidermal keratinocytes, a protein with an apparent molecular mass of 195 kD that is encoded by a mRNA with an estimated size of 6.3 kb. The protein is expressed in keratinizing and nonkeratinizing stratified squamous epithelia and in a number of other epithelia. Expression of the protein is upregulated during the terminal differentiation of epidermal keratinocytes in vivo and in culture. Immunogold electron microscopy was used to demonstrate an association of the 195-kD protein with the desmosomal plaque and with keratin filaments in the differentiated layers of the epidermis. Sequence analysis showed that the 195-kD protein is a member of the plakin family of proteins, to which envoplakin, desmoplakin, bullous pemphigoid antigen 1, and plectin belong. Envoplakin and the 195-kD protein coimmunoprecipitate. Analysis of their rod domain sequences suggests that the formation of both homodimers and heterodimers would be energetically favorable. Confocal immunofluorescent microscopy of cultured epidermal keratinocytes revealed that envoplakin and the 195-kD protein form a network radiating from desmosomes, and we speculate that the two proteins may provide a scaffolding onto which the cornified envelope is assembled. We propose to name the 195-kD protein periplakin

Rhomboid family member 2 regulates cytoskeletal stress-associated Keratin 16.

Keratin 16 (K16) is a cytoskeletal scaffolding protein highly expressed at pressure-bearing sites of the mammalian footpad. It can be induced in hyperproliferative states such as wound healing, inflammation and cancer. Here we show that the inactive rhomboid protease RHBDF2 (iRHOM2) regulates thickening of the footpad epidermis through its interaction with K16. K16 expression is absent in the thinned footpads of irhom2-/- mice compared with irhom2+/+mice, due to reduced keratinocyte proliferation. Gain-of-function mutations in iRHOM2 underlie Tylosis with oesophageal cancer (TOC), characterized by palmoplantar thickening, upregulate K16 with robust downregulation of its type II keratin binding partner, K6. By orchestrating the remodelling and turnover of K16, and uncoupling it from K6, iRHOM2 regulates the epithelial response to physical stress. These findings contribute to our understanding of the molecular mechanisms underlying hyperproliferation of the palmoplantar epidermis in both physiological and disease states, and how this 'stress' keratin is regulated

Desmosome structure, composition and function

AbstractDesmosomes are intercellular junctions of epithelia and cardiac muscle. They resist mechanical stress because they adopt a strongly adhesive state in which they are said to be hyper-adhesive and which distinguishes them from other intercellular junctions; desmosomes are specialised for strong adhesion and their failure can result in diseases of the skin and heart. They are also dynamic structures whose adhesiveness can switch between high and low affinity adhesive states during processes such as embryonic development and wound healing, the switching being signalled by protein kinase C. Desmosomes may also act as signalling centres, regulating the availability of signalling molecules and thereby participating in fundamental processes such as cell proliferation, differentiation and morphogenesis. Here we consider the structure, composition and function of desmosomes, and their role in embryonic development and disease