Η σεργλυκίνη (SG) είναι η κύρια πρωτεογλυκάνη που εκφράζεται από τα αιμοποιητικά κύτταρα και συμμετέχει στη ρύθμιση διαφόρων παραγόντων που εμπλέκονται στις αντιδράσεις φλεγμονής. Επιπλέον, φαίνεται ότι διαδραματίζει σημαντικό ρόλο στη βιολογία του πολλαπλού μυελώματος αφού αναστέλλει τη δραστικότητα της κλασικής οδού και της λεκτινικής οδού του συμπληρώματος και προάγει την προσκόλληση των μυελωματικών κυττάρων στο κολλαγόνο τύπου Ι. Παράλληλα, η αυξημένη έκφρασή της σχετίζεται με τον επιθετικό φαινότυπο των κυττάρων καρκίνου του ρινοφάρυγγα. Στην παρούσα διατριβή μελετήθηκε η έκφραση της SG σε κακοήθειες. Τα αποτελέσματά μας αναδεικνύουν την έντονη παρουσία της σε συμπαγείς όγκους λόγω της αυξημένης έκφρασή της είτε από τα καρκινικά κύτταρα είτε από τα κύτταρα φλεγμονής και τα κύτταρα του στρώματος τα οποία επιστρατεύονται κατά την ανάπτυξη του όγκου. Επιπλέον, η αυξημένη έκφρασή της και η έκκρισή της σχετίσθηκαν με το μεταστατικό δυναμικό των κυτταρικών σειρών διαφόρων τύπων καρκίνου. Παράλληλα, ταυτοποιήθηκε η έκφραση του μεταγράφου της SG που προκύπτει από εναλλακτικό μάτισμα με απαλοιφή του εξωνίου 2. Επιπροσθέτως, μελετήθηκε ο βιολογικός ρόλος της SG σε επιθετικά καρκινικά κύτταρα μαστού. Βρέθηκε ότι η SG αλληλεπιδρά με πρωτεΐνες που διαδραματίζουν σημαντικό ρόλο σε κυτταρικές λειτουργίες όπως η αναδιοργάνωση του κυτταροσκελετού, η μεταφορά και ανακύκλωση μορίων από και προς την κυτταρική επιφάνεια και η γονιδιακή ρύθμιση. Η ίδια πρωτεογλυκάνη εκκρίνεται ιδιοσυστατικά από αυτά τα κύτταρα. Τόσο η γλυκοζαμινογλυκανική της σύσταση όσο και η ανασταλτική της δράση έναντι της ενεργοποίησης του συστήματος του συμπληρώματος είναι παρόμοιες με τη SG που εκκρίνεται από τα μυελωματικά κύτταρα. Η συμβολή της SG στον επιθετικό φαινότυπο των καρκινικών κυττάρων επιβεβαιώθηκε με την υπερέκφρασή της σε χαμηλής επιθετικότητας κύτταρα καρκίνου του μαστού. Λειτουργίες όπως ο κυτταρικός πολλαπλασιασμός, η μετανάστευση και η διήθηση των καρκινικών κυττάρων σχετίσθηκαν θετικά με την αυξημένη έκφραση και έκκριση της SG από αυτά τα κύτταρα. Οι επαγωγικές της ιδιότητες καταργήθηκαν με την απαλοιφή των θέσεων πρόσδεσης των γλυκοζαμινογλυκανών από τον πρωτεϊνικό της κορμό. Επιπλέον, διερευνήθηκε το πρωτεολυτικό δυναμικό αυτών των κυττάρων με τη μελέτη της έκφρασης πρωτεολυτικών ενζύμων του εξωκυττάριου χώρου, όπως οι tPA, uPA, MMP-1, MMP-2, MMP-3, MMP-9, MT1-MMP και του αναστολέα των μεταλλοπρωτεϊνασών TIMP-1. Παρουσιάσθηκε ότι η υπερέκφραση του πλήρους μορίου της SG αλλά και της μη γλυκοζυλιωμένης της μορφής οδηγούν στη διαφοροποίηση της έκφρασης και της ενεργότητας των μορίων αυτών με τρόπο που ποικίλει ανάλογα με την κυτταρική πυκνότητα. Παρόλα αυτά, τα δεδομένα που προέκυψαν από τη μελέτη της έκφρασης του uPA και της MT1-MMP συσχέτισαν την αυξημένη τους ενεργότητα με την υπερέκφραση της γλυκοζυλιωμένης μορφής της SG και ανέδειξαν την πιθανή συμβολή τους στην επιθετικότητα των καρκινικών κυττάρων μαστού. Συμπερασματικά, η παρουσία της SG είναι έντονη σε πληθώρα συμπαγών όγκων και καρκινικών κυτταρικών σειρών και φαίνεται να σχετίζεται με το μεταστατικό δυναμικό των κυττάρων. Η συμβολή της στον επιθετικό φαινότυπο των καρκινικών κυττάρων περιλαμβάνει τόσο ενδοκυττάριες όσο και εξωκυττάριες δράσεις που μεσολαβούνται από τη γλυκοζυλιωμένη της μορφή. / Serglycin (SG) is the major proteoglycan of hematopoietic origin cells and contributes to the regulation of several inflammatory proteins. Moreover, SG has a significant role in the biology of Multiple Myeloma; It inhibits the activation of the classical and the lectin pathway of complement system. Enhanced SG expression is correlated with the aggressive phenotype of nasopharyngeal cancer cells. In the present study, the expression of SG in several malignancies was investigated. The strong presence of SG in solid tumors due to its elevated expression either by cancer cells or by inflammatory and stomal cells was revealed. Furthermore, SG elevated expression and secretion was correlated with the high metastatic potential of several cancer cell lines. The expression of the alternatively spliced SG mRNA (variant 2) was identified. This variant lacks exon 2. The role of SG in the biology of aggressive breast cancer cells was studied. SG interacts with significant mediators of actin cytoskeleton reorganization, protein transport and regulation of gene expression. This proteoglycan is constitutively secreted by aggressive breast cancer cells and shares the same glycosaminoglycan (GAG) moieties and inhibitory effects torward complement system activation as the secreted SG by myeloma cells. SG contribution in the aggressive phenotype of cancer cells was studied via the overexpression of the moleclule in the low aggressive breast cancer cells. Cellular functions such as proliferation, migration and invasion of cancer cells were positively correlated with the elevated expression and secretion of SG. These properties were abolished by the deletion of GAG binding sites from SG core protein. Moreover, the proteolytic potential of the overexpressing cells was examined via the expression of ECM degrading molecules, such as tPA, uPA, MMP-1, MMP-2, MMP-3, MMP-9, MT1-MMP, and TIMP-1 MMP inhibitor. Altered expression and activity rates of these enzymes correlated with the overexpression of either the full length or the truncated form of SG in a manner which depends on the cellular density. Interestingly, enhanced MT1-MMP activity followed only the overexpression of the full length molecule indicating the contribution of this MMP in breast cancer cell aggressiveness. The data above revealed the intense presence of SG in several solid tumors and cancer cell lines and the correlation of SG expression with the metastatic potential of cancer cells. Its contribution to cancer cells aggressive phenotype includes both intracellular and extracellular functions which are mediated by the glycanated form of SG.

No description available.

No description available.

Prostate cancer is one of the leading causes of cancer-related deaths in men worldwide, with 10,000 new cases/year diagnosed in Sweden. In this context, there is an urgent need to identify new biomarkers to detect prostate cancer at an initial stage for earlier treatment intervention. Although how prostate cancer develops has not been fully established, the male sex hormone testosterone is a known prerequisite for prostate cancer development. High levels of transforming growth factor-β (TGFβ) are prognostically unfavorable in prostate cancer patients. TGFβ is a multifunctional cytokine that regulates a broad range of cellular responses. TGFβ signals through either the canonical Smad or the non-Smad signaling cascade. Cancerous cells develop different strategies to evade defense mechanisms and metastasize to different parts of the body. This thesis unveils one such novel mechanism related to TGFβ signaling. The first two articles provide evidence that TGFβ receptor type I (TβRI) is ubiquitinated by tumor necrosis factor receptor-associated factor 6 (TRAF6) and is cleaved at the ectodomain region by tumor necrosis factor alpha converting enzyme (TACE) in a protein kinase C zeta type-dependent manner. After TβRI is shed from the ectodomain, it undergoes a second cleavage by presenilin 1 (PS1), a γ-secretase catalytic subunit, which liberates the TβRI intracellular domain (TβRI-ICD) from the cell membrane. TRAF6 promotes TGFβ-dependent Lys63-linked polyubiquitination and recruitment of PS1 to the TβRI complex, and facilitates the cleavage of TβRI by PS1 to generate a TβRI-ICD. The TβRI-ICD then translocates to the nucleus, where it binds with the transcriptional co-activator p300 and regulates the transcription of pro-invasive target genes such as Snail1. Moreover, the nuclear translocated TβRI-ICD cooperates with the Notch intracellular domain (NICD), a core component in the Notch signaling pathway, to drive the expression of invasive genes. Interestingly, treatment with g-secretase inhibitors was able to inhibit cleavage of TβRI and inhibit the TGFβ-induced oncogenic pathway in an in vivo prostate cancer xenograft model. In the third article, we identified that Lysine 178 is the acceptor lysine in TβRI that is ubiquitinated by TRAF6. The TβRI K178R mutant was neither ubiquitinated nor translocated to the nucleus, and prevented transcriptional regulation of invasive genes in a dominant negative manner. In the fourth article, we show that TGFβ utilizes the E3-ligase TRAF6 and the p38 mitogen-activated protein kinase to phosphorylate c-Jun. In turn, the phosphorylated c-Jun activates p21 and Snail1 in a non-canonical Smad-independent pathway, and thereby promotes invasion in cancerous cells. In summary, we elucidate a new mechanism of TGFβ-induced oncogenic signal transduction in cancer cells in which TRAF6 plays a fundamental role. This opens a new avenue in the field of TGFβ signaling.

Habitat fragmentation and biological invasions are widely considered to be the most significant threats to global biodiversity, and synergistic interactions between these processes have the potential to cause even greater biodiversity loss than either acting alone. The objective of my study was to investigate the effects of fragmentation on plant communities in native forest fragments, and to examine potential interactions between these effects and invasions by exotic plants at multiple spatial scales. I examined edge, area and landscape effects on plant invasions using empirical data from fragmented landscapes on the West Coast of New Zealand. My research revealed significant interactions between the amount of native forest cover in the landscape and the strength of edge and area effects on plant communities in forest fragments. The dominance of exotic plants in the community was highest at forest edges and decreased towards fragment interiors, however the interiors of very small fragments were relatively more invaded by exotic plants than those in larger fragments, reflecting a significant interaction between edge and area effects. Similarly, exotic dominance increased in more heavily deforested landscapes, but this effect was only apparent in very small fragments (<2 ha). The combined effects of small fragment size and low forest cover in the landscape appear to have promoted invasions of exotic plants in very small remnants. I explored the mechanisms underlying edge-mediated invasions in forest fragments and examined whether propagule availability and/or habitat suitability may be limiting invasions into fragments. Experimental addition of exotic plant propagules revealed that landscape forest cover interacted with edge effects on germination, growth and flowering rates of two short-lived, herbaceous species, and this appeared to be driven by elevated light and soil phosphorus levels at edges in heavily deforested landscapes. I also examined the role of traits in influencing plant responses to forest fragmentation. Different traits were associated with exotic invasiveness in edge and interior habitats of forest fragments, indicating that the traits promoting invasiveness were context dependent. Traits also had a major influence on responses of native plants to forest fragmentation, with generalist species appearing to benefit from fragmentation, as they can utilise both forest and open habitats, whereas native forest specialists have been negatively impacted by fragmentation.

The invasive pathways, InlA- and InB-mediated uptake and M cell transcytosis, that Listeria monocytogenes uses to invade the intestine have mainly been studied using infection models that do not truly replicate what occurs during a natural infection. Recently, our lab has developed an oral infection model that is more physiolocally relevant to what occurs during food borne listeriosis. We have sought to evaluate the relative roles of the previously defined invasive pathways, in our oral model of infection. We have done this by utilizing an InlAmCG Lm strain that is able to bind murine E-cadherin, knockout Lm strains, ΔinlA Lm, and ΔinlAΔinlB Lm. We also took advantage of a knockout mice strain CD137-/-that has M cells that are deficient in M cell transcytosis. We were able to show that these invasive pathways are relevant in our oral infection model, that M cell transcytosis is a compensatory pathway for InlA-mediated uptake, and that there might be another mechanism that L. monocytogenes uses to invade the intestines. To confirm this, it is necessary though that the M cell transcytosis deficiency be confirmed in the CD137-/- mice.

Widespread anthropogenic invasions have prompted concerns that naturalized organisms could threaten biodiversity. In particular, invasive weeds can negatively affect native biota through a variety of means, including disrupting mutualisms. This thesis was designed to observe and test dispersal mutualisms in a native forest during autumn when the majority of plant species are fruiting. In this thesis I examined whether the invasive plant barberry (Berberis glaucocarpa) was influencing the behaviour of a native frugivore bellbird (Anthornis melanura) and a range of dispersal related services in a native forest, Kowhai Bush near Kaikoura. To test these 18 banded bellbirds were followed through autumn 2011. These observe bellbirds were split between control and test bird. Barberry fruit was removed from the test bird territories. I recorded whether bellbirds changed their territory sizes, foraging and daily behaviours. During 52 hours of observations, bellbirds were never observed feeding on barberry fruit. No significant changes to bellbird behaviour or territories were observed after the removal of barberry fruit. Bellbird diet overall was dominated by invertebrates (83% of foraging observations), with smaller contributions from fruit (16%, nearly all on Coprosma robusta), nectar and honeydew. Since bellbirds did not eat barberry fruit, removal of this weed is unlikely to negatively affect bellbirds during autumn. Which other bird species were dispersing barberry was recorded. I recorded 242 hours of videotape footage on 24 fruiting plants. A total of 101 foraging events were recorded of 4 different bird species: silvereyes (Zosterops lateralis) 42 visits, blackbirds (Turdus merula) 27 visits, song thrush (Turdus philomelos) 29, and starlings (Sturnus vulgaris) 3 visits. The species differed in the mean length of time they spent in plants, so the overall contribution to barberry fruit removal was 32.6% silvereyes, 24.3% blackbirds, 42.9% song thrush and 0.1% starlings. To find out the relative contribution of exotic and native birds to dispersal of fruits in Kowhai Bush, I mist-netted 221 birds of 10 species and identified any seeds in the 183 faeces they deposited. A total of 21 plant species were observed fruiting in Kowhai Bush during this time. A total of 11 different plant species were identified from 1092 seeds. Birds were further observed feeding on 3 other plant species which were not observed in faecal samples. This left 7 plants with unobserved dispersal vectors. There were likely four main dispersers, bellbirds, silvereyes, song thrush and blackbirds and five minor, brown creeper (Mohoua novaeseelandiae), tui (Prosthemadera novaeseelandiae), fantails (Rhipidura fuliginosa), dunnock (Prunella modularis) and starlings. However there was considerable variability between these bird species dispersal abilities. Introduced birds’ song thrush and blackbirds were observed dispersing naturalized plant seeds at higher than expected rates in comparison to native frugivores bellbirds and silvereyes. I also measured the gape sizes on mist netted birds and on samples of fruit from Kowhai Bush. Both silvereyes and bellbirds were found to be eating fruit larger than their gape, but despite this two native (Hedycarya arborea and Ripogonum scandens) and three exotic plants (Vitis vinifera, Taxus baccata and Crataegus monogyna) had large fruit that were probably mainly dispersed by song thrush and blackbirds. Hence, introduced birds were important seed dispersers for large fleshy fruited seeds in Kowhai Bush. Demonstrating that interactions among native and exotic flesh fruited plants and frugivores is important within forest communities.

Les inégalités sociales et les politiques menées par les pouvoirs publics ont contribué à l'expansion de l'habitat précaire et spontané au Brésil. A Rio de Janeiro, les formes d'habitat populaire montrent une évolution au fil du temps, en s'adaptant aux différentes politiques urbaines et au développement urbain de la ville. L'habitat populaire, malgré son caractère spontané, accompagne ainsi les transformations urbaines. Depuis 2000, une nouvelle forme d'habitat populaire et spontané surgit aux abords d'une ancienne autoroute industrielle de la ville de Rio de Janeiro, l'Avenida Brasil. Il s'agit de l'invasion d'anciens terrains d'usines abandonnées par des habitants des favelas. Le processus d'occupation des terrains, la conversion de l'espace en habitat, et les règles établies à l'intérieur de celui-ci révèlent que les invasions présentent un nouveau cas de figure dans le cadre de l'habitat populaire spontané à Rio de Janeiro, que l'on dénomme " copropriété de fait ". Ce travail de recherche pose la question de la représentation de ce nouveau type d'habitat dans la ville et dans la société actuelle. Nous avons étudié le développement du territoire de la ville et de la favela d'origine des occupants, ainsi que les différentes politiques publiques concernant l'habitat précaire pour comprendre la production des " copropriétés de fait " et leur rapport avec l'évolution urbaine à Rio de Janeiro. L'analyse de l'espace construit de l'invasion se développe en relation avec l'espace social communautaire et révèle des nouvelles pratiques, issues de la forme d'habitat populaire en copropriété

Ce travail offre une révision sociohistorique du processus de formation étatique fondé sur les prémisses du marxisme politique. C'est une relecture des thèses de Robert Brenner et sa théorie des relations sociales de propriété (TRSP) permettant de résoudre les limites internalistes de son approche. Inspiré des travaux de Benno Teschke et de Justin Rosenberg, ce travail élargit le spectre analytique de la TRSP à l'égard des régimes d'appropriation politique. Le concept d'hybridité interactive y est élaboré de manière à attribuer à la médiation géopolitique un rôle causal central dans le procès de formation de l'État. À la différence de Teschke et de Rosenberg, le concept positionne ce processus dans une perspective interrégionale plutôt qu'internationale, une subtilité analytique primordiale dans l'analyse historique de régimes prénationaux. Il permet ainsi de considérer la limite typifiante d'une conceptualisation sous forme de régimes d'appropriation et de souligner la diversité qualitative des régimes d'accumulations politiques. Empiriquement, ce travail extirpe le contexte de formation étatique de l'Angleterre de l'analyse strictement centrée sur la relation anglo-normande - à l'issue de l'invasion normande de l'île en 1066 -. L'unicité politique de l'Angleterre est plutôt resituée dans une perspective régionale, un point démontré par l'entremise d'une analyse de l'impact géopolitique des invasions vikings sur le processus de formation étatique en Angleterre entre le 9e et 11e siècle. Il est postulé ici que les stratégies d'accumulations scandinaves, avec ses expéditions vikings en Europe, ont eu un impact nécessaire sur la trajectoire de développement étatique anglais. Sans les multiples débalancements des relations sociales que leur présence a provoqués en Angleterre, l'invasion normande subséquente n'aurait pas pu avoir un effet politique aussi centralisateur. ______________________________________________________________________________ MOTS-CLÉS DE L’AUTEUR : sociologie historique, marxisme, accumulation politique, État, féodalisme, viking, Angleterre, Danelaw, Scandinavie, international, capitalisme

La fusariosi della spiga è tra le malattie del grano più distruttive e diffuse al mondo. Alcune specie responsabili di questa malattia sono micotossigene. Ci sono state segnalazioni della presenza di nivalenolo (NIV) e tossine T-2 e HT-2 nel nord Italia, micotossine prodotte da Fusarium poae, F. sporotrichioides e F. langsethiae. I limiti massimi di T-2 e HT-2 ammessi nei cereali non trasformati e nei prodotti a base di cereali non sono ancora stati individuati (Regolamento CE 856/2005). Il programma di dottorato del candidato è inserito in questa linea di ricerca. Sono stati condotti studi in vitro sulla biologia ed ecologia dei funghi produttori di NIV, T-2 e HT-2, considerando quattro isolati di F. poae, due di F. sporotrichioides e due di F. langsethiae. Le prove hanno riguardato la crescita delle colonie, la produzione di spore, la loro germinazione e la produzione di micotossine. La gravità dell'infezione, l'invasione (quantità di DNA nelle spighe), la resa in granella e la produzione di tossine sono state misurate a diversi tempi, temperature (in planta) e stadi fenologici (in campo) dopo l'inoculazione artificiale. Al fine di verificare l'attendibilità dei dati, tutti gli esperimenti in planta e in campo sono stati ripetuti per due anni. / The Fusarium head blight is one of the most destructive diseases of wheat in different parts of the world. Some of the species responsible for Fusarium head blight are potentially mycotoxigenic. There are reports of nivalenol (NIV), T-2 toxin and HT-2 in northern Italy. These are metabolites produced by F. poae, F. sporotrichioides, and F. langsethiae. The maximum limits of T-2 and HT-2 permitted in unprocessed cereals and cereal-based products, included in EC Regulation 856/2005 has not been identified. The PhD program of the candidate is placed in this line of the research. In vitro studies conducted on the biological and ecological of pathogenic fungi producer NIV, T-2 and HT-2 including four isolates of F. poae, two of F. sporotrichioides and two isolate of F. langsethiae. Tests were carried out to investigate the conidia germination, colony growth, spore production and mycotoxins production. The infection severity, invasion (amount of DNA in spikes), grain yield and toxin production were measured at different temperatures, different time (in planta) and different growth stages (in field) after artificial inoculation.