Attenuation of muscle atrophy in a murine model of cachexia by inhibition of the dsRNA-dependent protein kinase

Atrophy of skeletal muscle is due to a depression in protein synthesis and an increase in degradation. Studies in vitro have suggested that activation of the dsRNA-dependent protein kinase (PKR) may be responsible for these changes in protein synthesis and degradation. In order to evaluate whether this is also applicable to cancer cachexia the action of a PKR inhibitor on the development of cachexia has been studied in mice bearing the MAC16 tumour. Treatment of animals with the PKR inhibitor (5 mg kg−1) significantly reduced levels of phospho-PKR in muscle down to that found in non-tumour-bearing mice, and effectively attenuated the depression of body weight, with increased muscle mass, and also inhibited tumour growth. There was an increase in protein synthesis in skeletal muscle, which paralleled a decrease in eukaryotic initiation factor 2α phosphorylation. Protein degradation rates in skeletal muscle were also significantly decreased, as was proteasome activity levels and expression. Myosin levels were increased up to values found in non-tumour-bearing animals. Proteasome expression correlated with a decreased nuclear accumulation of nuclear factor-κB (NF-κB). The PKR inhibitor also significantly inhibited tumour growth, although this appeared to be a separate event from the effect on muscle wasting. These results suggest that inhibition of the autophosphorylation of PKR may represent an appropriate target for the attenuation of muscle atrophy in cancer cachexia

Stat1 Phosphorylation Determines Ras Oncogenicity by Regulating p27Kip1

Inactivation of p27Kip1 is implicated in tumorigenesis and has both prognostic and treatment-predictive values for many types of human cancer. The transcription factor Stat1 is essential for innate immunity and tumor immunosurveillance through its ability to act downstream of interferons. Herein, we demonstrate that Stat1 functions as a suppressor of Ras transformation independently of an interferon response. Inhibition of Ras transformation and tumorigenesis requires the phosphorylation of Stat1 at tyrosine 701 but is independent of Stat1 phosphorylation at serine 727. Stat1 induces p27Kip1 expression in Ras transformed cells at the transcriptional level through mechanisms that depend on Stat1 phosphorylation at tyrosine 701 and activation of Stat3. The tumor suppressor properties of Stat1 in Ras transformation are reversed by the inactivation of p27Kip1. Our work reveals a novel functional link between Stat1 and p27Kip1, which act in coordination to suppress the oncogenic properties of activated Ras. It also supports the notion that evaluation of Stat1 phosphorylation in human tumors may prove a reliable prognostic factor for patient outcome and a predictor of treatment response to anticancer therapies aimed at activating Stat1 and its downstream effectors

Differential contribution of the m7G-cap to the 5′ end-dependent translation initiation of mammalian mRNAs

Many mammalian mRNAs possess long 5′ UTRs with numerous stem-loop structures. For some of them, the presence of Internal Ribosome Entry Sites (IRESes) was suggested to explain their significant activity, especially when cap-dependent translation is compromised. To test this hypothesis, we have compared the translation initiation efficiencies of some cellular 5′ UTRs reported to have IRES-activity with those lacking IRES-elements in RNA-transfected cells and cell-free systems. Unlike viral IRESes, the tested 5′ UTRs with so-called ‘cellular IRESes’ demonstrate only background activities when placed in the intercistronic position of dicistronic RNAs. In contrast, they are very active in the monocistronic context and the cap is indispensable for their activities. Surprisingly, in cultured cells or cytoplasmic extracts both the level of stimulation with the cap and the overall translation activity do not correlate with the cumulative energy of the secondary structure of the tested 5′ UTRs. The cap positive effect is still observed under profound inhibition of translation with eIF4E-BP1 but its magnitude varies for individual 5′ UTRs irrespective of the cumulative energy of their secondary structures. Thus, it is not mandatory to invoke the IRES hypothesis, at least for some mRNAs, to explain their preferential translation when eIF4E is partially inactivated

Measuring the impact of financial crisis on international markets: An application of the Financial Stress Index

The scope of paper is to examine whether the recent financial crisis has had any impact on international capital markets and more precisely on the 4 primary international stock markets of England, France, Japan, the United States and Greece. The research is based on the use of the Financial Stress Index (FSI) from July 2005 until December 2008 and August 2009. Research results showed that the recent financial crisis has had a negative impact on all examined markets, with the Tokyo stock exchange being the one mostly affected. It was, also, found increased variability of performances following the start of the financial crisis, a fact that is indicative of the presence of conditional heteroscedasticity. As far as the Greek market is concerned, the recent financial crisis has not affected in general the credit expansion towards enterprises and households; however, it has affected the credit expansion to enterprises and households on a case-to-case basis

Study of interaction between stabilized shear zone and twin road tunnels under construction

88 σ.Ο σχεδιασμός και η κατασκευή σηράγγων συνεχίζει να αποτελεί πρόκληση για τους μηχανικούς παγκοσμίως. Ο Ελλαδικός χώρος όντας μια περιοχή εξόχως ορεινή με έντονο ανάγλυφο καθιστά την κατασκευή και το σχεδιασμό ακόμα πιο δύσκολο εγχείρημα. Με αυτό το αντικείμενο ασχολείται η παρούσα εργασία η οποία εστιάζει το ενδιαφέρον της σε δίδυμη οδική σήραγγα, η οποία διατρέχει υφιστάμενη σταθεροποιημένη κατολίσθηση και είναι σχετικά αβαθής. Η Βόρεια Πελοπόννησος που αποτελεί την ευρύτερη περιοχή μελέτης παρουσιάζει επιπλέον ιδιαίτερο ενδιαφέρον δεδομένου του έντονου γεωλογικού και γεωτεκτονικού καθεστώτος της. Η παρουσία ρηγμάτων και κατολισθήσεων με την πολύ ασθενή και παραμορφώσιμη φύση υλικών παρουσιάζει ειδικές προκλήσεις στην κατασκευή σηράγγων επειδή μπορεί να οδηγήσει σε αιφνίδιες και μη ελεγχόμενες αστοχίες σε περίπτωση που δεν ληφθούν τα αναγκαία μέτρα. Προκειμένου να αξιολογήσουμε τη συμπεριφορά της βραχομάζας κατά τη διάνοιξη των κλάδων της σήραγγας διεξάγουμε γεωμετρική και παραμετρική ανάλυση με το λογισμικό SOFISTIK που βασίζεται στη μέθοδο πεπερασμένων στοιχείων. Οι προκαλούμενες συγκλίσεις εκσκαφής θα μας οδηγήσουν στην εκτίμηση των μέτρων προσωρινής υποστήριξης τα οποία είναι αναγκαία να ληφθούν και η μελέτη των επιφανειακών μετακινήσεων θα μας δείξει την επιρροή της εκσκαφής. Λαμβάνοντας υπόψη όλα τα προαναφερόμενα στοιχεία καταλήγουμε αιτιολογημένα στην διατύπωση συμπερασμάτων.The design and construction of tunnels continues to constitute a challenge for engineers globally. Because of the steep mountainous terrain of Greece the design and construction of tunnels is even more difficult venture. This paper is concerned with this matter focusing its interest in twin road tunnel, which crosses shear-zone and is relatively shallow. North Peloponnese which is the study area presents special interest because of its geological – geotectonic conditions. The presence of faults and shear zones with the very weak and highly deformable nature of materials is special challenge for tunneling because they can lead to sudden and uncontrolled collapses. In order to evaluate rock mass behaviour I am conducting a geometrical and parametric analysis with software SOFISTIK which is based on the method of finite elements. The occurring convergences on the excavation boundary will lead to an estimation of support system which is necessary to be taken and the study of grounds displacements will show us the boundary’s influence. Taking into consideration all these elements we come to the conclusion. Περίληψη (στα Αγγλικά) Αριθμός Σελίδων CD/DVD Φυσικό μέσο TXT Τύπος πόρου Koromilas_B_tunnels.pdfThe design and construction of tunnels continues to constitute a challenge for engineers globally. Because of the steep mountainous terrain of Greece the design and construction of tunnels is even more difficult venture. This paper is concerned with this matter focusing its interest in twin road tunnel, which crosses shear-zone and is relatively shallow. North Peloponnese which is the study area presents special interest because of its geological – geotectonic conditions. The presence of faults and shear zones with the very weak and highly deformable nature of materials is special challenge for tunneling because they can lead to sudden and uncontrolled collapses. In order to evaluate rock mass behaviour I am conducting a geometrical and parametric analysis with software SOFISTIK which is based on the method of finite elements. The occurring convergences on the excavation boundary will lead to an estimation of support system which is necessary to be taken and the study of grounds displacements will show us the boundary’s influence. Taking into consideration all these elements we come to the conclusion.Βασίλειος Χ. Κορομηλά

Experimentally-induced maternal hypothyroidism alters crucial enzyme activities in the frontal cortex and hippocampus of the offspring rat

Thyroid hormone insufficiency during neurodevelopment can result into significant structural and functional changes within the developing central nervous system (CNS), and is associated with the establishment of serious cognitive impairment and neuropsychiatric symptomatology. The aim of the present study was to shed more light on the effects of gestational and/or lactational maternal exposure to propylthiouracil (PTU)-induced hypothyroidism as a multilevel experimental approach to the study of hypothyroidism-induced changes on crucial brain enzyme activities of 21-day-old Wistar rat offspring in a brain region-specific manner. This experimental approach has been recently developed and characterized by the authors based on neurochemical analyses performed on newborn and 21-day-old rat offspring whole brain homogenates; as a continuum to this effort, the current study focused on two CNS regions of major significance for cognitive development: the frontal cortex and the hippocampus. Maternal exposure to PTU in the drinking water during gestation and/or lactation resulted into changes in the activities of acetylcholinesterase and two important adenosinetriphosphatases (Na+,K+- and Mg2+-ATPase), that seemed to take place in a CNS-region-specific manner and that were dependent upon the PTU-exposure timeframe followed. As these findings are analyzed and compared to the available literature, they: (i) highlight the variability involved in the changes of the aforementioned enzymatic parameters in the studied CNS regions (attributed to both the different neuroanatomical composition and the thyroid-hormone-dependent neurodevelopmental growth/differentiation patterns of the latter), (ii) reveal important information with regards to the neurochemical mechanisms that could be involved in the way clinical hypothyroidism could affect optimal neurodevelopment and, ultimately, cognitive function, as well as (iii) underline the need for the adoption of more consistent approaches towards the experimental simulation of congenital and early-age-occurring hypothyroidism. © 2014, Springer Science+Business Media New York