Regional Policy in Greece of Tomorrow. The Perspectives of the Broader Regions

In the frame of the European Union’s enlargement and in the search for new more cohesive and functional standards for “administrative-spatial shapes†– under the pre-conditions of competitiveness, efficiency of urban and regional development and abolition of regional inequalities for sustainable development, - noteworthy is the examination of the reconstruction of the administrative system of Regions through the introduction of the proposed institution of the broader region in Greece. In the present article, we present the needs of the above administrative reconstruction, we investigate the economic form and the land-planning determination of the broader region; we set the directive lines towards the formation of its developmental pattern, while not omitting provisions with regards to the development impacts upon the natural environment. The final administrative shape which will be adaptable to the particular conditions of each broader region will contribute substantially, to the viable or sustainable development and to the worthy to be experienced development. Fundamental question among others is the formation of an administrative shape with explicit answers on the optimization of the European cooperation. Case study of the present article constitutes the proposed broader region of Epirus- Macedonia -Thrace, given the important influence that will exert one such organizational department on the Balkan country and on the European Union and vice versa. The example of the proposed broader region constitutes a characteristic case of an administrative reconstruction, with the parallel objective of rearrangement and upgrade of vital issues of spatial, environmental, socioeconomic and developmental importance.

Regional Policy in Greece of Tomorrow. The Perspectives of the Broader Regions

In the frame of the European Union's enlargement and in the search for new more cohesive and functional standards for "administrative-spatial shapes" – under the pre-conditions of competitiveness, efficiency of urban and regional development and abolition of regional inequalities for sustainable development, - noteworthy is the examination of the reconstruction of the administrative system of Regions through the introduction of the proposed institution of the broader region in Greece. In the present article, we present the needs of the above administrative reconstruction, we investigate the economic form and the land-planning determination of the broader region; we set the directive lines towards the formation of its developmental pattern, while not omitting provisions with regards to the development impacts upon the natural environment. The final administrative shape which will be adaptable to the particular conditions of each broader region will contribute substantially, to the viable or sustainable development and to the worthy to be experienced development. Fundamental question among others is the formation of an administrative shape with explicit answers on the optimization of the European cooperation. Case study of the present article constitutes the proposed broader region of Epirus- Macedonia -Thrace, given the important influence that will exert one such organizational department on the Balkan country and on the European Union and vice versa. The example of the proposed broader region constitutes a characteristic case of an administrative reconstruction, with the parallel objective of rearrangement and upgrade of vital issues of spatial, environmental, socioeconomic and developmental importance

Conceptualising ‘macro-regions’: Viewpoints and tools beyond NUTS classification

Definitions are imposed but properties not. The basic question addressed by this paper is how to ‘detect’ objective socio-economic spatial structures instead of ‘defining’ them arbitrarily. The NUTS classification model is rather arbitrary. Not only have the administrative units been structured through ‘accidental’ historical conditions but the reliability of the measurement of the population in an area is disputable as long as the mobility is strengthened and the ‘usual residence’ becomes more and more vague. Concerning the auxiliary criteria, they are also heterogeneous and are rather perceptions imposed by decision makers than physical entities. The quantitative network analysis (QNA) approach is suggested as a tool to detect macro-structures regarded as socio-economic and natural infrastructure of a ‘macro-region’. This is based on algebraic analysis of a number of variables such as flows of people migration, financial means, information, commodities, bio-diversity elements and parameters of the new relationship between urban and rural areas. In this paper, by using algorithms of QNA, such as Density of flows or Betweenness centrality of places, ‘denser’ networks of flows among places or more ‘central’ places can be differentiated from others, and thus can be used for a more substantial demarcation of ‘macro-regions’

Internal and External Sources of Regional Growth

AbstractThis paper examines the pattern of regional growth due to their ability to adopt technology. Whether regions exhibit a ‘high’ or ‘low’ path of growth depends on the adoption of technological improvements. Technology adoption can be either ‘internal’ or ‘external’ to the region. This approach is tested empirically using data for 247 European regions. The results suggest that adoption of technology has a significant and positive effect in regional growth in Europe

Overcoming phenotypic switching: targeting protein-protein interactions in cancer

Alternative protein-protein interactions (PPIs) arising from mutations or post-translational modifications (PTMs), termed phenotypic switching (PS), are critical for the transmission of alternative pathogenic signals and are particularly significant in cancer. In recent years, PPIs have emerged as promising targets for rational drug design, primarily because their high specificity facilitates targeting of disease-related signaling pathways. However, obstacles exist at the molecular level that arise from the properties of the interaction interfaces and the propensity of small molecule drugs to interact with more than one cleft surface. The difficulty in identifying small molecules that act as activators or inhibitors to counteract the biological effects of mutations raises issues that have not been encountered before. For example, small molecules can bind tightly but may not act as drugs or bind to multiple sites (interaction promiscuity). Another reason is the absence of significant clefts on protein surfaces; if a pocket is present, it may be too small, or its geometry may prevent binding. PS, which arises from oncogenic (alternative) signaling, causes drug resistance and forms the basis for the systemic robustness of tumors. In this review, the properties of PPI interfaces relevant to the design and development of targeting drugs are examined. In addition, the interactions between three tyrosine kinase inhibitors (TKIs) employed as drugs are discussed. Finally, potential novel targets of one of these drugs were identified in silico

The chicken ovalbumin upstream promoter-transcription factors modulate genes and pathways involved in skeletal muscle cell metabolism

The chicken ovalbumin upstream promoter-transcription factors ( COUP-TFs) are orphan members of the nuclear hormone receptor ( NR) superfamily. COUP-TFs are involved in organogenesis and neurogenesis. However, their role in skeletal muscle ( and other major mass tissues) and metabolism remains obscure. Skeletal muscle accounts for similar to 40% of total body mass and energy expenditure. Moreover, this peripheral tissue is a primary site of glucose and fatty acid utilization. We utilize small interfering RNA ( siRNA)-mediated attenuation of Coup-TfI and II ( mRNA and protein) in a skeletal muscle cell culture model to understand the regulatory role of Coup-Tfs in this energy demanding tissue. This targeted NR repression resulted in the significant attenuation of genes that regulate lipid mobilization and utilization ( including Ppar alpha, Fabp3, and Cpt-1). This was coupled to reduced fatty acid beta-oxidation. Additionally we observed significant attenuation of Ucp1, a gene involved in energy expenditure. Concordantly, we observed a 5-fold increase in ATP levels in cells with siRNA-mediated repression of Coup-TfI and II. Furthermore, the expression of classical liver X receptor ( LXR) target genes involved in reverse cholesterol transport ( Abca1 and Abcg1) were both significantly repressed. Moreover, we observed that repression of the Coup-Tfs ablated the activation of Abca1, and Abcg1 mRNA expression by the selective LXR agonist, T0901317. In concordance, Coup-Tf-siRNA-transfected cells were refractory to Lxr-mediated reduction of total intracellular cholesterol levels in contrast to the negative control cells. In agreement Lxr-mediated activation of the Abca1 promoter in Coup-Tf-siRNA cells was attenuated. Collectively, these data suggest a pivotal role for Coup-Tfs in the regulation of lipid utilization/cholesterol homeostasis in skeletal muscle cells and the modulation of Lxr-dependent gene regulation

A bioinformatics approach for the characterization of recombination structures and how they are affected by transposable element sequences in genetic instability

In the beginning of the 20th century, the experiments conducted by Thomas Hunt Morgan set the foundation for the creation of a new field in biology, namely the field of genetics as we know it today. Correlating the process of transferring a chromosome with the process of transferring characters from parental generations to their progeny, led to the discovery of many important phenomena that occur during the stages of meiosis, the most important of which, is possibly the existence of recombination events between homologous pairs of chromosomes. In this paper, bioinformatic tools and recombination datasets from genetic maps were utilized, in order to estimate the average distance between a recombination hotspot and its subsequent, along the genome. The first purpose of this research, was the validation of T. H Morgan's theory of recombination, as it was developed in 1911, with contemporary methods that were unavailable at the time. By combining data sets, recombination events have collected from meioses and sex-specific genetic maps have constructed. It was shown that, a substantial fraction of the genome shows some degree of sexually-specific variated recombination frequency. More specificaly the vast majority of male hotspots are clustered in small genetic distances as long as the female hotspots are disturbuted uniformly along the chromosomes. Recombination is occurred in Holliday junctions (HJs) that constitute important intermediate structures for many cell functions such as DNA recombination and DNA repair. The second stage of the research was conducted in order to characterize Holliday junctions that derive from a 10-nt degenerate iverted repeat sequence, with a 3-nt core motif. Inverted repeats are present in abundance in both prokaryotic and eukaryotic genomes and can form DNA secondary structures – hairpins and cruciforms that are involved in many important biological processes such as DNA replication, DNA transition and DNA methylation. In this study, the human genome was explored whether the IRs-HJ degenerate sequence associates with transposable elements (TEs) and mainly with those of the active and inactive ALU, LINE, SVA and HERV families. Six different forms of the IRs-HJs sequence motif were identified, and located the genomic coordinates of sequences containing both IRs-HJs and TEs. From 2982 total HJs, a significant number of 1319 TE-associated HJs were found, with a median distribution of 1 per 2.4 Mb. The HJs with higher GC content were observed more frequently at the genome. A high percentage of HJs were associated with all main TE families, with specificity for particular active or inactive elements: DNA elements and the retroelements ALUs, LINEs and HERVs up to 41.94%, 72.72%, 42.94% and 84.5%, respectively. Phylogenetic analysis revealed that HJs occur in both active and inactive TEs. Furthermore, the TE-associated HJs were almost exclusively found within a distance less than 1 Mb from human genes, while only 23 were not associated with any genes. This is the first report associating human HJs, with mobile elements. These data pinpoint that particular HJ forms show preference for specific active retrotransposon families of ALUs and LINEs, suggesting that retrotransposon-incorporated HJs may relocate or replicate in the genome through retrotransposition, contributing to recombination, genome plasticity and DNA repair. The third stage of this research was conducted in order to characterize sequences that promote genomic instability through particular Microdeletion and Microduplication Syndromes (MMS). MMS are rare recombinations, but cumulatively they represent a significant group of genetic abnormalities almost equal to aneuploidies. Some of them and in particular Di George Microdeletion can be found in frequencies second only to trisomy 21. Based on our database of MMS it was found that almost all MMS span in length less than 5Mbs which is the cut-off point of resolution in standard cytogenetics. Furthermore, a significant percentage of them are in length less than 0.5Mbs and all together, short and long MMS, have a high probability to harbor TE-associated and non-TE associated HJs-IRs. More importantly, gene proximity bioinformatics analysis revealed that a significantly high number of MMS associated IRs are proximal to regions of genes that control key developmental processes and transcription factors in humans. Collectively, it is proposed that IRs and other recombination primers such as TEs that exist in regions spanning MMS hotspots underlie a possible mechanism for their occurrence during gametogenesis. The final stage of the research was conducted in order to discover variations of PRDM9 sequence motif (CCNCCNTNNCCNC) which are responsible for the generation of breast invasive carcinoma (BRC), head and neck squamous cell carcinoma (HN) as well as for lung adenocarcinoma (LUAD). The final results showed a preference for specific PRDM9 sequences that reside within the boundaries of Double Strand Breaks and are responsible for the generation of specific types of cancer after proving by bioinformatics analysis the statistical significance of each PRDM9 sequence variation inside the BRC, HN and LUAD. For the first time, an immediate correlation between the PRDM9 sequence motif d(CCACCATCACCAC) and the emergence of breast invasive carcinoma (BRC), lung adenocarcinoma (LUAD) and head and neck squamous cell carcinoma (HN) is proved.Η συγκεκριμένη ερευνητική εργασία διεκπεραιώθηκε σε 4 στάδια. Στο πρώτο στάδιο χρησιμοποιήθηκαν βιοπληροφορικά εργαλεία για την ανάλυση δεδομένων ανασυνδυασμού από γενετικούς χάρτες, προκειμένου να εκτιμηθεί η μέση απόσταση μεταξύ ενός hotspot ανασυνδυασμού και των επόμενων, κατά μήκος του γονιδιώματος. Ο πρωταρχικός σκοπός αυτής της έρευνας ήταν η επικύρωση της θεωρίας του ανασυνδυασμού του T. H Morgan. Συνδυάζοντας σύνολα δεδομένων από γεγονότα ανασυνδυασμού που έχουν συγκεντρωθεί από μειώσεις κατασκευάστηκαν γενετικοί χάρτες ειδικοί για το κάθε φύλο. Αποδείχθηκε ότι υπάρχει διαφορική εκδήλωση της συχνότητας του ανασυνδυασμού στα 2 φύλα. Πιο συγκεκριμένα, η μεγάλη πλειοψηφία των hotspots στους άρρενες συγκεντρώνεται σε μικρές γενετικές αποστάσεις, αντιθέτως με τα hotspots των θήλεων τα οποία κατανέμονται ομοιόμορφα κατά μήκος των χρωμοσωμάτων.Στο δεύτερο στάδιο της έρευνας χαρακτηρίστηκαν ενδιάμεσες δομές ανασυνδυασμού, οι δομές Holliday οι οποίες προέρχονται από αλληλουχιακά μοτίβα ανεστραμμένων επαναλήψεων. Οι ανεστραμμένες επαναλήψεις είναι παρούσες σε αφθονία τόσο σε προκαρυωτικά όσο και σε ευκαρυωτικά γονιδιώματα και μπορούν να σχηματίσουν δευτερογενείς δομές του DΝΑ που εμπλέκονται σε πολλές σημαντικές βιολογικές διεργασίες όπως η αντιγραφή και η μεθυλίωση του DNA. Σε αυτό τα στάδιο, διερευνήθηκε κατά πόσο οι αλληλουχίες των IRs-HJs συνδέονται με μεταθετά στοιχεία (TEs) και κυρίως με ALUs, LINEs, SVAs και HERVs. Έξι διαφορετικές μορφές του αλληλουχιακού μοτίβου των IRs-HJs ταυτοποιήθηκαν και εντοπίστηκαν οι γονιδιωματικές συντεταγμένες αλληλουχιών που περιέχουν τόσο IRs-HJs όσο και ΤΕs. Από τα 2982 συνολικά HJs, βρέθηκε ένας σημαντικός αριθμός 1319 HJs που σχετίζονται με ΤΕs, με μέση κατανομή 1 HJ ανά 2,4 Mb. Ένα υψηλό ποσοστό IRs-HJs συσχετίστηκε με όλες τις κύριες οικογένειες ΤΕs, με ειδικότητα για συγκεκριμένα ενεργά ή ανενεργά μεταθετά στοιχεία: τα DNA μεταθετά και τα μεταγενέστερα στοιχεία των οικογενειών των ALUs, LINEs και HERVs έως 41,94%, 72,72%, 42,94% και 84,5% αντίστοιχα. Η φυλογενετική ανάλυση αποκάλυψε ότι τα HJs εμφανίζονται τόσο σε ενεργά όσο και σε αδρανή ΤΕs. Επιπλέον, οι σχετιζόμενες με ΤΕs IRs-HJs αλληλουχίες εντοπίστηκαν σχεδόν αποκλειστικά σε απόσταση μικρότερη από 1 Mb από τα ανθρώπινα γονίδια, ενώ μόνο 23 δεν συσχετίστηκαν με κανένα γονίδιο. Αυτή είναι η πρώτη αναφορά που συνδέει τα ανθρώπινα HJs με μεταθετά στοιχεία. Από τα παραπάνω δεδομένα προκύπτει ότι συγκεκριμένες αλληλουχιακές μορφές των HJs δείχνουν προτίμηση για συγκεκριμένα ενεργά στοιχεία των οικογενειών των ALUs και LINEs, αποδεικνύοντας ότι τα ενσωματωμένα σε ρετρομεταθετά IRs-HJs μπορούν να μεταφερθούν στο γονιδίωμα μέσω της ρετρομετάθεσης, συμβάλλοντας στον ανασυνδυασμό, στην πλαστικότητα του γονιδιώματος και στην επιδιόρθωση του DNA. Στο 3ο στάδιο της έρευνας χαρακτηρίστηκαν αλληλουχίες με ανασυνδυαστική δράση που ενοχοποιούνται για την εμφάνιση γονιδιωματικής αστάθειας ειδικότερα μέσω των συνδρόμων μικροελλείψεων και μικροδιπλασιασμών (MMS). Τα MMS προέρχονται από σπάνια γεγονότα ανασυνδυασμού, αλλά αθροιστικά αντιπροσωπεύουν μια σημαντική ομάδα γενετικών ανωμαλιών σχεδόν ισοδύναμων με ανευπλοειδίες. Από τις προσωπικές βάσεις δεδομένων των MMS διαπιστώθηκε ότι σχεδόν όλα τα MMS έχουν μήκος μικρότερο από 5 Mbs. Επιπλέον, ένα σημαντικό ποσοστό αυτών έχει μήκος μικρότερο από 0.5Mbs και όλα μαζί εμφανίζουν μεγάλη πιθανότητα να φιλοξενούν TEs και HJs-IR. Πιο σημαντικά, η βιοπληροφορική ανάλυση εγγύτητας γονιδίων αποκάλυψε ότι ένας σημαντικά υψηλός αριθμός IRs-HJs που σχετίζονται με MMS εντοπίζονται σε περιοχές γονιδίων που ελέγχουν βασικές αναπτυξιακές διεργασίες της εμβρυογένεσης και της μορφογένεσης οργάνων. Συνολικά, προτείνεται ότι τα IRs-HJs και άλλες μονάδες ανασυνδυασμού, όπως τα ΤΕs που εντοπίζονται σε περιοχές των MMS, ίσως δηλώνουν έναν πιθανό μηχανισμό για την εμφάνισή των συγκεκριμένων συνδρόμων κατά τη διάρκεια της γαμετογένεσης. Στο τελικό στάδιο της έρευνας εντοπίστηκαν παραλλαγές του μοτίβου αλληλουχίας PRDM9 (CCNCCNTNNCCNC) οι οποίες ενοχοποιούνται για τη εμφάνιση καρκίνου του μαστού (BRC), κεφαλής και τραχήλου (HN) καθώς και για το αδενοκαρκίνωμα του πνεύμονα LUAD). Τα τελικά αποτελέσματα έδειξαν την ύπαρξη συγκεκριμένων αλληλουχιών PRDM9 που βρίσκονται εντός των ορίων των δίκλωνων θραύσεων που είναι υπεύθυνες για τη δημιουργία ειδικών τύπων καρκίνου αφού αποδείχθηκε με βιοπληροφορική ανάλυση η στατιστική σημασία της παρουσίας κάθε αλληλουχίας PRDM9 εντός των BRC, HN και LUAD . Για πρώτη φορά, αποδεικνύεται άμεση συσχέτιση μεταξύ του αλληλουχιακού μοτίβου d(CCACCATCACCAC) και της εμφάνισης του καρκίνου του μαστού (BRC), του αδενοκαρκινώματος του πνεύμονα (LUAD) και του καρκίνου κεφαλής και τραχήλου(HN)