Genom att använda folktro och religion skapade den Japanska regimen under två eror, Meji och Showa, ett instrument för att tygla folket och ge obehindrad makt till toppskiktet i samhället. Man underströk kejsarfamiljens gudomliga arv som släkting till dem mäktigaste kamin i gudavärlden solgudinnan Amaterasu. Som släkting till henne var han att betrakta som gud och fick aldrig ifrågasättas. Det Japanska folket var inte heller vilket folk som helst utan ett härskarfolk som även det hade gudomlig härkomst. När folket sedan genom mängder av propaganda från skolväsendet upp igenom hela samhället indoktrinerats om sin och kejsarens överhöghet var det dags att visa resten av världen sin gudomlighet. Genom att besegra sina fiender i krig blev övertygelsen än större på hemmafronten och Kokka Shinto tycktes mer och mer sitta inne med sanningen. Japan var riktigt nära att slå ut den amerikanska flottan under andra världskriget, men en serie förluster satte stopp för framgångarna och Japan besegrades. Den amerikanska ockupationsmakten identifierade Kokka Shinto som skyldig till aggressionerna på samma sätt som nazismen var för Tyskland. Kokka Shinto hjälpte till att göra Japan till en fascistisk stat precis som syftet var med den. Från början av Mejirestorationen till slutet av Andra Världskriget var Kokka Shinto en framgångssaga för ultranationalisterna men de allierades seger krossades Statsshinto. Det finns dock kvarlämningar av Statsshinto i Japan och när en Japansk premiärminister kan besöka Yasukuni-templet utan att tvingas avgå visar landet att man ännu har en bit att vandra innan man helt har kastat av sig sitt nationalistiska och fascistiska ok. Slutsatsen blir därför att jag inte anser att Kokka Shinto är en religion utan snarare mäktiga mäns sluga utnyttjande av folktro och vidskeplighet i syfte att ta över ett land. Kokka Shinto är en veritabel våldtäkt på en legitim religion men genom att använda samma mytologi och historia köper man sig legitimitet. Man måste som utomstående vara mycket distinkt i att skilja på Shinto och Kokka Shinto ungefär på samma sätt som man skiljer på Socialism från Nationalsocialism. Fram till 1868 var Shinto en mycket tolerant religion och efter 1945 är det så återigen, det finns dock ett nationellt tema i Shinto som onda krafter kan utnyttja.

Disputats. Rheinische Friedrich-Wilhelms-Universität, 2001. / Haves kun i elektronisk udg.

Οι όγκοι εγκεφάλου του ανθρώπου είναι φαινοτυπικά και γονοτυπικά ετερογενείς. Υπάρχουν σημαντικά κενά στην κατανόηση των μοριακών οδών που εμπλέκονται στην γένεση και ανάπτυξη των νεοπλασμάτων αυτών, καθώς και στη βιολογική και κλινική συμπεριφορά τους. Δεδομένου ότι: α) υπάρχει ένας αυξανόμενος όγκος πληροφοριών σχετικά με την εμπλοκή των υποδοχέων νευροτροφινών Trks (υποδοχείς κινάσης τυροσίνης) στην παθογένεια των νεοπλασμάτων του ΚΝΣ, β) οι νευροτροφίνες μπορούν να ρυθμίζουν τη γονιδιακή έκφραση στο νευρικό σύστημα μέσω του μεταγραφικού παράγοντα STAT-5 με μηχανισμό ανεξάρτητο της ενεργοποίησης της κινάσης JAK-2, γ) η οδός μεταγωγής σήματος JAK-2/STAT-5 ενεργοποιείται από την ερυθροποιητίνη (Epo) (μέσω δέσμευσής της με τον υποδοχέα της EpoR) η οποία πρόσφατα έχει θεωρηθεί ως παράγοντας-κλειδί της αύξησης των όγκων λόγω των αντιαποπτωτικών και αγγειογενετικών ιδιοτήτων και δυνητικός στόχος ογκολογικών θεραπευτικών στρατηγικών, δ) η Epo διαντιδρά με τον παράγοντα αγγειογένεσης VEGF ενδυναμώνοντας την αγγειοδραστικότητά του και συχνά οι δύο αυτοί αναπτυξιακοί παράγοντες συνεκφράζονται, ε) ερευνητικά δεδομένα υποδεικνύουν ένα δυνητικό ρόλο του άξονα VEGF/JAK-2/ STAT-5 στην αγγειογένεση στον καρκίνο και στ) σε πολλά νεοπλάσματα, τα κύτταρα του όγκου καθώς και τα μακροφάγα του στρώματος εκφράζουν τους παράγοντες λεμφαγγειογένεσης VEGF-C και VEGF-D οι οποίοι μέσω του υποδοχέα τους VEGFR-3 (υποδοχέας κινάσης τυροσίνης) έχει βρεθεί ότι προάγουν την αγγειογένεση στα νεοπλάσματα αυτά, ο στόχος της παρούσας εργασίας είναι η μορφολογική μελέτη της έκφρασης των υποδοχέων κινάσης τυροσίνης Trks (υποδοχείς νευροτροφινών) και VEGFR-3 και η συσχέτισή τους με την οδό μεταγωγής σήματος EpoR/ JAK-2/ STAT-5 στα νεοπλάσματα του εγκεφάλου στον άνθρωπο. Για την ανίχνευση των Trks, EpoR, JAK-2, STAT-5 και VEGFR-3, χρησιμοποιήθηκε η ανοσοϊστοχημική μέθοδος σε διαδοχικές τομές ιστού πάχους 4μm, μονιμοποιημένου σε φορμόλη και εγκλεισμένου σε παραφίνη. Χρησιμοποιήθηκαν ειδικά αντισώματα έναντι των προς μελέτη πρωτεϊνών. Εξετάσθηκαν συνολικά 92 όγκοι εγκεφάλου (50 αστροκυτώματα: 5 πιλοκυτταρικά αστροκυττώματα WHO grade I, 6 διάχυτα αστροκυττώματα WHO grade II, 10 αναπλαστικά αστροκυττώματα. WHO grade III και 29 πολύμορφα γλοιοβλαστώματα. WHO grade IV, 8 ολιγοδενδρογλοιώματα, 6 επενδυμώματα, 5 μυελοβλαστώματα και 23 μηνιγγιώματα). Επιπλέον, στη μελέτη συμπεριλήφθηκαν τομές ιστού φυσιολογικού εγκεφάλου. Στην παρούσα εργασία, η πλειονότητα των αστροκυττωμάτων ανεξαρτήτως βαθμού κακοήθειας, έδειξε μέτρια έως έντονη κυτταροπλασματική ανοσοδραστικότητα για τους υποδοχείς TrkA (57%), TrkB (56%) και TrkC (46%). Όλα τα ολιγοδενδρογλοιώματα και τα επενδυμώματα που εξετάσθηκαν ήταν αρνητικά για τους υποδοχείς Trk ενώ έκφραση των υποδοχέων ανιχνεύθηκε σε μικρό ποσοστό των μυελοβλαστωμάτων. Στις ανοσοθετικές περιοχές των όγκων, το τοίχωμα των αγγείων ήταν έντονα θετικό για τον υποδοχέα TrkB. Σε ένα σημαντικό ποσοστό αστροκυττωμάτων (41%), επενδυμωμάτων (33%) και μηνιγγιωμάτων (48%) ανιχνεύθηκε έκφραση του EpoR, ενώ τα ολιγοδενδρογλοιώματα και τα μυελοβλαστώματα που εξετάσθηκαν ήταν αρνητικά. Συνέκφραση των JAK-2/STAT-5 ανιχνεύθηκε στο 39% των αστροκυττωμάτων, στο 43% των ολιγοδενδρογλοιωμάτων, στο 50% των επενδυμωμάτων και σε όλα (100%) τα μυελοβλαστώματα που συμπεριλήφθηκαν στη μελέτη. Η πλειονότητα των μηνιγγιωμάτων έδειξε ασθενή έως μηδενική έκφραση των πρωτεινών JAK-2 και STAT-5. Σε κάποιους όγκους, ανιχνεύθηκε έκφραση της πρωτείνης STAT-5 ενώ ήταν αρνητικοί για την κινάση JAK-2. Επίσης, βρέθηκαν όγκοι JAK-2- ανοσοθετικοί/ EpoR-ανοσοαρνητικοί. Στα ενδοθηλιακά κύτταρα των αγγείων των όγκων ανιχνεύθηκε έκφραση των EpoR, JAK-2 και/ή STAT-5. Η μελέτη της έκφρασης του VEGFR-3 έδειξε την καθολική σχεδόν έκφραση του υποδοχέα στο ενδοθήλιο των αγγείων, στους όγκους εγκεφάλου που εξετάσθηκαν, καθώς και στο τοίχωμα μεγαλύτερων αγγείων εκτός της περιοχής των όγκων. Επίσης, σε κάποιες περιπτώσεις, παρατηρήθηκε έκφραση του υποδοχέα σε νεοπλασματικά κύτταρα. Στα αστροκυτταρικά γλοιώματα, η έκφραση των pan-Trk, TrkB και TrkC σχετίζεται στατιστικά σημαντικά με την έκφραση STAT-5 ενώ δεν υπάρχει στατιστικά σημαντική συσχέτιση της έκφρασης του υποδοχέα TrkA με την έκφραση των JAK-2 και STAT-5, καθώς και της έκφρασης των Trks με την έκφραση της κινάσης JAK-2. Στα αστροκυτταρικά γλοιώματα, η έκφραση JAK-2 σχετίζεται στατιστικά σημαντικά με την έκφραση STAT-5, ενώ η έκφραση των JAK-2 και STAT-5 δεν σχετίζεται σημαντικά με την έκφραση EpoR. Στα επενδυμώματα υπάρχει στατιστικά σημαντική συσχέτιση μεταξύ της έκφρασης JAK-2, STAT-5 και EpoR. Επίσης, στα μυελοβλαστώματα υπάρχει στατιστικά σημαντική συσχέτιση μεταξύ της έκφρασης JAK-2 και STAT-5. Σε σημαντικό ποσοστό των εξετασθέντων όγκων –ιδιαίτερα των γλοιωμάτων- συνεκφράζονται οι υποδοχείς EpoR και VEGFR-3 στο ενδοθήλιο και στα λεία μυικά κύτταρα των αγγείων. Συγκεκριμένα, έκφραση και των δύο υποδοχέων στο τοίχωμα των αγγείων του όγκου, ανιχνεύθηκε, στο 58% των αστροκυτταρικών γλοιωμάτων, στο 67% των ολιγοδενδρογλοιωμάτων, στο 50% των επενδυμωμάτων, στο 20% των μυελοβλαστωμάτων και στο 33% των μηνιγγιωμάτων. Επίσης συνέκφραση των υποδοχέων TrkB και VEGFR-3 στο ενδοθήλιο των αγγείων των όγκων ανιχνεύθηκε στο 57% των αστροκυτταρικών γλοιωμάτων. Η έκφραση στο ενδοθήλιο των αγγείων των όγκων (α) του υποδοχέα TrkB στην πλειονότητα των TrkB-ανοσοθετικών όγκων, (β) των EpoR, JAK-2 και/ή STAT-5 σε αρκετούς όγκους ανεξάρτητα της ανοσοθετικότητας των νεοπλασματικών κυττάρων για τις πρωτεΐνες αυτές και (γ) του VEGFR-3 σχεδόν σε όλους του εξετασθέντες όγκους, οδηγεί στο συμπέρασμα ότι οι παραπάνω παράγοντες πιθανόν συνεργάζονται στην αγγειογενετική διαδικασία στους όγκους εγκεφάλου. Η παρούσα μελέτη απέδειξε την παρουσία των: Trks, EpoR, JAK-2, STAT-5 και VEGFR-3 σε σημαντικό ποσοστό των όγκων εγκεφάλου στον άνθρωπο. Είναι απαραίτητο να διενεργηθούν λειτουργικές μελέτες των σηματοδοτικών οδών που προκύπτουν από την ενεργοποίηση των Trks, EpoR και VEGFR-3, προκειμένου να αποσαφηνισθούν οι πιθανές διαντιδράσεις αυτών των οδών στη διαδικασία της ογκογένεσης, γεγονός που θα μπορούσε να οδηγήσει στο σχεδιασμό νέων θεραπευτικών στρατηγικών για την αποτελεσματική αντιμετώπιση των όγκων εγκεφάλου στον άνθρωπο. / Brain tumors are phenotypically and genotypically heterogeneous. Significant gaps exist in current understanding of the molecular pathways involved in the genesis, progression, and biological and clinical behavior of brain tumors. Considering that : a) there is a growing amount of evidence implicating the neurotophin receptors Trks (receptor tyrosine kinases) in the pathogenesis of CNS tumors, b) neurotrophins may regulate neuronal gene expression via transcription factor STAT-5 in a JAK-2 independent manner, c) the JAK-2/STAT-5 signaling pathway is activated by Epo (recently characterized as a key factor for tumor growth) through its receptor EpoR, d) Epo is known to interact synergistically with vascular endothelial growth factor (VEGF), a potent angiogenic factor, and enhance its vascular activity, and these two growth factors, are often co-expressed, e) recent data suggest a potential role for a VEGF/JAK-2/STAT-5 axis in tumor angiogenesis and f) in many tumors, VEGF-C and -D are produced by tumor cells as well as by tumor-associated macrophages and through their receptor VEGFR-3 are involved in tumor angiogenesis and growth, the aim of this thesis is the morphological study of the expression patterns of the receptor tyrosine kinases Trks (neurotrophin receptors) and VEGFR-3 and their correlation with the EpoR/ JAK-2/ STAT-5 signaling pathway in human brain tumors. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded, 4μm thick serial sections using the anti-Mouse/ Rabbit Poly HRP IHC Detection kit (CHEMICON International, Inc.). Antibodies against the Trk receptors, EpoR, JAK-2, STAT-5 and VEGFR-3, were used. A total of 92 brain tumors (50 astrocytic gliomas: 5 pilocytic astrocytomas; WHO grade I, 6 diffuse fibrillary astrocytomas; WHO grade II, 10 anaplastic astrocytomas; WHO grade III and 29 glioblastomas multiforme; WHO grade IV, 8 oligodendrogliomas, 6 ependymomas, 5 medulloblastomas, and 23 meningiomas) were included in this study. Normal human brain tissue was obtained postmortem (2 males). The present study demonstrated moderate to strong, granular cytoplasmic immunoreactivity in the majority of astrocytomas, for TrkA (57%), TrkB (56%) and TrkC receptors (46%), independently of grade. All the oligodendrogliomas and the ependymomas examined, were Trk immunonegative while a small percentage of medulloblastomas exhibited Trk immunopositivity. The endothelium of tumor vessels, in the immunopositive areas of the tumors, showed conspicuous immunoreactivity for TrkB receptor. A significant percentage of astrocytomas (41%), ependymomas (33%) and meningiomas (48%) displayed EpoR immunoreactivity. Oligodendrogliomas and medulloblastomas were EpoR- immunonegative. JAK-2/STAT-5 co-expression was detected in 39% of astrocytomas, 43% of oligodendrogliomas, 50% of ependymomas and in all (100%) the medulloblastomas examined. In contrast, most of the meningiomas showed weak or no immunoreactivity for JAK-2 and STAT-5 proteins. Some tumors exhibited STAT-5 immunoreactivity being JAK-2-immunonegative and others were JAK-2-immunopositive being EpoR- immunonegative. In some tumors - independently of EpoR immunoreactivity in tumors cells- the endothelium of tumor capillaries as well as florid angioproliferative changes and/or proliferations of smooth muscle cells showed conspicuous immunoreactivity for EpoR. Furthermore, endothelial cells of some tumor vessels showed JAK-2 and/or STAT-5 immunoreactivity. The present study demonstrated the almost catholic VEGFR-3 expression in the endothelium of tumor vessels in the brain tumor specimens examined, as well as in the smooth muscle cells in peritumoral vessels. In some tumors, the tumor cells expressed VEGFR-3receptor. In astrocytic gliomas, pan-Trk, TrkB and TrkC expression was significantly correlated with STAT-5 expression but not with JAK-2 whereas TrkA expression was not significantly correlated with either JAK-2 or STAT-5 expression. In astrocytic gliomas, JAK-2 expression was significantly correlated with STAT-5 expression whereas JAK-2 and STAT-5 expression were not significantly correlated with EpoR expression. In ependymomas, strong relationship between JAK-2, STAT-5 and EpoR expression was confined. Furthermore, in medulloblastomas, strong relationship between JAK-2 and STAT-5 expression was detected. A significant percentage of astrocytomas (58%), oligodendrogliomas (67%), ependymomas (50%), medulloblastomas (20%) and meningiomas (33%), displayed EpoR and VEGFR-3 co-expression in tumor vessels. Additionally, TrkB and VEGFR-3 co-expression was detected in the endothelium of tumor capillaries in 57% of the astrocytomas examined. The above results indicate the existence of a ligand (other than Epo)-dependent or independent JAK-2 activation that leads to the constitutive activation of STAT-5 as well as the existence of at least one mechanism, other than the Trk - dependent gene induction by STAT-5 that results to the latter’s constitutive activation in these tumors. Furthermore, the finding of EpoR, JAK-2 and/or STAT-5 immunoreactivity in endothelial cells of tumor vessels, supports the ongoing notion of an angiogenic role of Epo in tumor neovascularization. The presence of TrkB, EpoR, JAK-2, STAT-5 and VEGFR-3 in the endothelium of tumor vessels in the brain tumors specimens included in this study, implicate these factors as possible critical players in the process of angiogenesis. The present study demonstrates the expression of Trks, EpoR, JAK-2, STAT-5 and VEGFR-3 in a significant percentage of human brain tumors. Functional studies of the Trks, EpoR and VEGFR-3-activated signaling pathways, are necessary in order to clarify the meaning of a possible cross-talking between these pathways in the process of oncogenesis, the deep understanding of which, could lead to innovative new strategies for drug targeting to human brain tumors.

No description available.

The Chronic Myeloid Leukemia (CML) is a clonal hematopoietic stem cell disorder characterized by the t(9:22) genetic translocation and expression of the oncogenic tyrosine kinase BCR-ABL . A first BCR-ABL Tyrosine Kinase Inhibitor (TKI), Imatinib (IM), was identified that inhibits proliferation of BCR-ABL expressing hematopoietic cells and leads to disease remission. However, BCR-ABL mRNA remains detectable in the most immature HSCs and discontinuation of IM results in clinical relapse. STAT5 factors play a crucial role in the CML pathogenesis of human primary CML cells. However, the contribution of the two related STAT5 genes, STAT5A and STAT5B, was unknown. We used an RNAinterference based strategy to analyze STAT5A or STAT5B roles in normal and CML cells. We showed that STAT5A/5B double knock-down (KD) triggers normal and CML cell apoptosis and suppressed long-term clonogenic potential of immature hematopoietic stem and progenitor cells known to be resistant to TKI treatment and responsible for residual disease. STAT5A loss alone was ineffective at impairing growth of both normal and CML cells under standard conditions. In contrast, STAT5A loss was sufficient to enhance Reactive Oxygen Species (ROS) which correlated with enhanced DNA damages in both normal and leukemic cells. We reported that STAT5A regulates oxidative stress through unconventional mechanisms, in a non-transcriptional-dependent manner. We further showed that, in contrast to primary cells at diagnosis, IM-resistant cells exhibited enhanced STAT5A dependence, by being sensitive to STAT5A single KD. To investigate the molecular basis of STAT5A activity in TKI-resistance and oxidative stress, we performed a transcriptomic analysis of STAT5 regulated genes. We identified Axl, which encodes a receptor tyrosine kinase, recently shown to be crucial in TKI-resistant CML cells. Specifically, Axl expression is enhanced by STAT5A. We investigated the role of Axl and we found that Axl KD did not affect survival of IM-sensitive CML cells. However, Axl KD decreased survival of IM-resistant cells, miming the activity of STAT5A. Moreover, Axl loss increased ROS levels in CML cells, promoting STAT5A anti-oxidant activity. We further sought to determine the expression of the Axl ligand, Gas6. Gas6 expression is dramatically reduced in CML primary cells at diagnosis compared to healthy cells. The strong and consistent down-regulation of Gas6 in CML cells suggested a possible role in the pathophysiology. Collectively, our findings highlight the pro-survival, stress protection and drug resistance roles of STAT5 factors, providing new understanding for medical treatment of CML patients. We suggest that STAT5A acts in synergy with Axl to face exogenous insults and propose a new mechanism by which CML cells increase their proliferation and reduce their motility by down-regulating Gas6 expression.

[Truncated abstract] Fibrosis is a feature of many pulmonary conditions, including idiopathic pulmonary fibrosis (IPF), which is characterised by the accumulation of fibroblasts/myofibroblasts and excessive deposition of collagen. IPF is a disease of unknown aetiology that is unresponsive to current therapy and is typically fatal. The inflammatory cytokine interleukin (IL)-6 is elevated in patients with IPF and recent studies have shown that IL-6-induced signalling is altered in lung fibroblasts from patients with IPF. IL-6 belongs to the gp130 cytokine family, which is a group of ten structurally related cytokines, that all require the membrane bound glycoprotein gp130 to activate intracellular signalling pathways. Gp130 activates intracellular signalling through the Shp2-ERK1/2 and STAT1/3 pathways to mediate cellular activities. This thesis tests the hypothesis that gp130-mediated signalling is dysregulated in the development and progression of pulmonary fibrosis. To address this hypothesis, I assessed the role of gp130-mediated signalling in a mouse model of bleomycin-induced lung fibrosis. This thesis utilised two novel gp130 mutant mice strains with directed and enhanced gp130-mediated Shp2-ERK1/2 (gp130¿STAT/¿STAT) or STAT1/3 (gp130757F/757F) signalling. I observed complete protection from fibrosis in gp130¿STAT/¿STAT mice up to 60 days after bleomycin treatment and profound fibrosis in gp130757F/757F mice compared to wt controls. The enhanced fibrosis observed in gp130757F/757F mice was diminished by monoallelic deletion of STAT3 (gp130757F/757F;STAT3+/-), identifying gp130-STAT3 signalling as a novel promoter of lung fibrosis. ... In addition, IL-6/11 activation of gp130-mediated signalling modulated transforming growth factor (TGF)-ß-induced effects on adult fibroblast proliferation and myofibroblast differentiation. Interaction between IL-6/11 and TGF-ß1 on fibroblast proliferation was dependent on both the gp130-ERK1/2 and gp130-STAT1/3 pathways. Loss of either pathway abrogated the effects of IL-6 and IL-11 on TGF-ß1- 4 induced fibroblast proliferation. However, it was clear that gp130-STAT3 signalling inhibited TGF-ß1-induced myofibroblast differentiation of primary lung fibroblasts. The inhibition of myofibroblast differentiation was associated with gp130-STAT3 dependent inhibition of TGF-ß1-induced Smad3 phosphorylation. These results indicate that IL-6 and IL-11 promote myofibroblastic differentiation of lung fibroblasts, while gp130-STAT3 signalling inhibits TGF-ß1-induced Smad3 phosphorylation and myofibroblastic differentiation of lung fibroblasts While the pathogenesis of IPF is unknown, it is believed that excessive collagen deposition, aberrant fibroblast behaviour and an inflammatory response are critical to the progression of this disease. It has been shown here that IL-6 family cytokines mediate the development and progression of bleomycin-induced lung fibrosis by increasing collagen synthesis, fibroblast proliferation, myofibroblast differentiation and inflammation through gp130-STAT3 signalling. This thesis has demonstrated that differential activation of cytoplasmic signalling pathways by a membrane bound receptor can have a profound effect on pulmonary responses to injury. Furthermore, this thesis is the first study to identify the gp130-STAT3 pathway as a therapeutic target in the treatment of IPF.

[Truncated abstract] The innate ability of the heart to compensate for an increase in workload as a result of disease or injury, through an increase in size and mass is known as cardiac hypertrophy. The hypertrophy of the heart compensates for an increase in workload with an increase in cardiac output. However, excessive hypertrophy can result in cardiac dysfunction and substantially increases the risk of cardiac failure and mortality. The molecular mechanisms that regulate the development of cardiac hypertrophy and cardiac failure are not entirely understood. Traditionally, the G-protein Coupled Receptor (GPCR) and the downstream Mitogen-Activated Protein Kinase (MAPK) family of proteins have been implicated. However, elevated circulating and ventricular levels of several classes of cytokines also suggested that signaling by the downstream effectors of cytokine receptors, such as the Signal Transducers and Activators of Transcription (STATs), may be important. The aim of this thesis was, therefore, to characterize the involvement of MAPK and STAT pathways in regulating cardiac hypertrophy and cardiac failure. A function for MAPK and STAT signaling in regulating cardiac hypertrophy stimulated by the inflammatory cytokine IL-1Β was initially defined in primary cultures of neonatal rat cardiac myocytes. In this study, it was demonstrated that the chemical inhibition of ERK or p38MAPK was sufficient to inhibit IL-1Β-stimulated ANF expression. In contrast, simultaneous inhibition of both ERK and p38MAPK was required to ablate the hypertrophic morphology of cardiac myocytes treated with IL-1Β. These results demonstrated differential signaling from the MAPK isoforms in regulating the gene expression and morphological components of cardiac hypertrophy. In addition, it was revealed that IL-1Β treatment resulted in a delayed response (>60 min) in STAT3α tyrosine phosphorylation, which was subsequently shown to require the initial rapid activation of either ERK or p38MAPK. IL-1Β-stimulated STAT3 phosphorylation was also dependent on the de novo synthesis of secondary signaling molecules. The ablation of the STAT3 tyrosine phosphorylation by the inhibition of ERK or p38MAPK activity, correlated with the attenuation of IL-1Β-stimulated ANF expression, suggesting that signaling through STAT3α may be involved in regulating gene expression associated with IL-1Β cardiac hypertrophy

Resumo: A expressão de citocinas inflamatórias é um processo estritamente regulado por mecanismos variados, incluindo o controle da sinalização intracelular e da atividade transcricional por inibidores endógenos, os quais são pouco estudados e compreendidos. Três grupos de proteínas: SHP, PIAS e SOCS inibem de maneira distinta e específica a transdução de sinais pela via JAK/STAT, bem como a atividade dos fatores de transcrição, eventos que modulam a expressão de diversas citocinas. As doenças periodontais estão associadas à inflamação persistente, com elevados níveis de citocinas proinflamatórias, no entanto praticamente não existem informações sobre a participação destes mecanismos de regulação nas diferentes condições clínicas periodontais. Os objetivos deste projeto incluíram avaliar a cinética de expressão das proteínas SOCS1 e SOCS3 e suas proteínas-alvo, STAT1 e STAT3, respectivamente, durante a evolução da doença periodontal. Foram utilizados 36 ratos Wistar divididos em 2 grupos: DP - doença periodontal induzida por 2 métodos: ligaduras ao redor dos 1os molares inferiores e injeções de 60 μg de LPS de E. coli no tecido gengival palatino dos molares superiores, 3x/semana; Grupo controle negativo - recebeu apenas injeções de PBS (veículo). Os ratos foram sacrificados 7, 15 e 30 dias após a indução da doença periodontal para avaliação histológica e análise macroscópica da perda óssea alveolar. A expressão de SOCS1 e SOCS3 e a ativação de STAT1 e STAT3 foram avaliadas nas biópsias gengivais por PCR em tempo real e Western blot. Ambos os modelos apresentaram significante e progressiva perda óssea dos 7 aos 30 dias. A inflamação foi evidente já no período de 7 dias em ambos os modelos, porém enquanto manteve-se similar nos demais períodos no modelo de indução por LPS, apresentou uma diminuição na severidade da inflamação... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Inflammatory cytokine gene expression is a process strictly regulated by various mechanisms, including the negative regulation of signaling of cytokine receptors and of the activity of transcription factors such as STATs. These mechanisms involve endogenous proteins and are largely unknown, especially in periodontal diseases. Three groups of proteins, SHP, PIAS and SOCS modulate in a fairly specific manner JAK/STAT signaling and/or STAT activity. Periodontal diseases are infectious-inflammatory conditions of the supporting tissues of the teeth associated with increased levels of proinflammatory cytokines, but there are no information regarding the role of these endogenous mediators of JAK/STAT during its course. The aims of this study included the evaluation of the expression kinetics of inducible negative regulators and their target proteins during the course of experimentally induced periodontal disease. 36 Wistar rats were divided into two groups: PD - experimental periodontal disease induced by two methods: ligature placement around the first mandibular molars and E. coli lipopolysaccharide (LPS) injections into the palatal gingival tissues of the maxillary molars, 3x/week, and Negative Control group. Rats were sacrificed 07, 15 and 30 days after disease induction for histological evaluation of periodontal inflammation and macroscopic analysis of alveolar bone loss. SOCS expression and the activation status of STAT1 and STAT3 were evaluated in gingival biopsies by real time PCR and Western Blot. Both disease models presented significant progressive bone loss from 7 to 30 days. Inflammation was evident and similar for all the periods in LPS injected sites; however, a decrease on severity at the end of the experimental period was observed in the ligature model. There was a significant (p<0.05) increase on SOCS1 and SOCS3 gene expression in PD compared to control... (Complete abstract click electronic access below) / Orientador: Joni Augusto Cirelli / Coorientador: Carlos Rossa Junior / Banca: Carlos Ferreira dos Santos / Banca: Paulo Sergio Cerri / Mestre

Syftet med undersökningen var att med hjälp av lämpliga statistiska metoder testa det så kallade ”Första petropolitiska lagen” med vilket menas en negativ korrelation mellan priset på råolja och graden av friheten hos petropolitiska länder. Med stöd av ett lämplig teoretisk referensram och diskussion över de kausala mekanismerna, har en hypotes över sambandet tagits fram. Trettio tre petropolitiska stater har identifierats vilket omfattar hela populationen. Demokratiska friheter och priset på råolja har definierats och omvandlats till en kvantifierbar form och sedan testats statistiskt. Samtliga variabler har kodats i form av tidsserieobservationer och en paneldata har konstruerats innehållande totalt 939 årliga observationer för de trettio tre petropolitiska länder. Den aggregerade sambandet över hela populationen har testats med en OLE regressionsanalys med så kallad ”first-order” autokorrelation med panelspecifika standardavvikelser. Den första petropolitiska lagen har även testats individuellt för varje petropolitisk land som ingick i urvalet. Erhållen resultat från aggregerat regressionsanalys tyder på att det föreligger ett svagt, med 95 % statistiskt signifikant, positiv samband mellan den beroende och den oberoende variabeln. När sambandet testades enskilt för varje land, har endast 16 av 33 länder fått signifikanta korrelationsnivåer. Fem av länder visade en negativ samband medan elva länder visade en positiv samband mellan beroende och oberoende variabler. Hypotesen har därmed kunnat falsifieras. Förklaringsgraden, samt autokorrelationsproblem tyder dock på att en mer omfattande analys krävs för att kunna säkerställa erhållna resultat. / The purpose of this study was to, with proper statistical methods, investigate so called ”The First Law of Petropolitics”. The First Law of Petropolitics postulates that there exists a negative correlation between price of oil and pace of freedom in the oil-rich petrolist states. A hypothesis has been formulated based on appropriate theoretical references and a discussion about its causal mechanisms. Thirty three petropolist states have been identified which comprises the whole population. The pace of freedom and the price of oil has been defined and transformed into a quantifiable measure and tested statistically. Variables were coded into a time-series panel-data form which included 939 annual observations for those thirty three petrolist states. The aggregated correlation between dependent and independent variables has been tested with an OLE regression analysis with so called “first-order autocorrelation with panel-specific standard errors”. The first law of petropolitics also has been individually tested for each petrolist state. The results from the aggregate regression suggest that there exists a weak, with 95 % statistically significant, positive correlation between a dependent and an independent variables. When each petrolist state has been regressed individually the results showed that only 16 of 33 states had significant levels of correlation. Five of those states had a negative correlation, while other eleven states had a positive correlation. The hypothesis has therefore been falsified. The low R2 –value obtained in both tests and autocorrelation problems suggest that a further investigation of the First Law of Petropolitics is necessary in order to secure the obtained results.

This essay aims to explore the difference in the political system between the Ukrainian regime in the period 2010-2014 and the regime that emerged out of the euromaidan protests in 2014. Through this the essay will determine if there has been any democratical progress between both of the timelines and if any of the periods achieved the status of democracy. Democracy is defined as polyarchy which gives a clear structure to study both periods and compare them to the criteria’s that this type of democracy offers. The areas that will be studied are: Free and Fair Elections, Universal Suffrage, Elected Representatives, the Right to Candidate in Elections, the Right to Organize, Freedom of Speech and Alternative Sources of Information. The essay is a Theory Consuming Case Study with both descriptive questions and a descriptive approach to answer the questions. The framework that is used to analyze the information is of a qualitative nature. This essay concludes that both periods have had large democratic problems. Although the problems for both periods differ, in the first problem there are several events with rigged elections, crime against journalists and restraints of freedom of speech. The second period saw several improvements in several areas but issues with universal suffrage emerged. This caused both periods to not being able to fulfill the criteria’s of polyarchy which, in this study, is the benchmark for a democracy. Instead, both periods achieved the criteria’s for a hybrid regime which in many ways are equivalent of a flawed democracy.