High-throughput mutational screening adds clinically important information in myelodysplastic syndromes and secondary or therapy-related acute myeloid leukemia

Non peer reviewe

Study of the role of post-transcriptional factors in immunobiology and the development of IBD using conditional transgenic ablation systems

Innate immunity has evolved to recognize and respond rapidly to infection and tissue damage whilst maintaining inflammatory homeostasis and support to adaptive immunity. These complex responses depend on mechanisms controlling the expression of differentiation factors, cytokines, antigen presentation molecules and a hitherto of inflammatory mediators. Prior research has demonstrated that the biosynthesis of innate effector molecules is regulated at the post-transcriptional level which determines the utilization of the corresponding mRNAs. These post- transcriptional processes comprise a series of overlapping mechanisms controlling the subcellular localization, decay and translation of mRNA molecules via dynamic interactions with RNA binding proteins (RBPs). As has been demonstrated in animal models of acute and chronic inflammation (e.g. rheumatoid arthritis and Crohn’s disease), defects in post-transcriptional regulation may provide the impetus for the development of disease. The research presented focuses on the analysis of the functional role of RNA- binding proteins (RBPs) that interact with mRNA’s containing AU-rich elements. Such mRNAs are critical for innate immunity since the usually encode stress factors and inflammatory mediators. Specifically, we focus on the functions of the RBPs Elavll/HuR and hnRNPD/AUF1 during the development, induction and activity of innate immune cells. Our experimental approach involved the application of: novel transgenic systems of RBP deletion in hematopoietic cells, animal models of acute inflammation and Inflammatory Bowel Disease (IBD), and gene expression measurements.The comparison between HuR’s deletion in hematopoietic stem versus myelopoietic progenitor cells revealed HuR’s functions towards the regulation of hematopoietic differentiation of: (a) stem to progenitor cells and (b) myelopoietic progenitors to mature myeloid lineages, including innate effectors. The functions of HuR in these differentiation processes correlate with its functions in controlling cell cycle regulators and differentiation signals. Still, and in the case of myelopoietic deletions of HuR, the differentiation defect could be restored in the presence of high levels of differentiation factors or in the presence of inflammation. This, allowed us to dissect further the role of HuR in innate immune responses. From our data, it is clear that HuR controls the equilibrium in the production of pro- and anti- inflammatory mediators by organizing the RBP associations which control mRNA decay and translation. This property of HuR, render the outcome of its functions as immunomodulating and anti-inflammatory and was further revealed in animal models of endotoxemia and IBD. To validate the anti-inflammatory effects of HuR we also employed a drug-inducible HuR overexpression system that attenuated the development of acute IBD. This latest finding indicates the therapeutic potential of pharmaceutical modulation of HuR’s functions. Contrary to HuR, the myeloid restricted deletion of AUF1 revealed that it does not play a role in the development of innate cells but it does act as a pro- inflammatory RBP. Still its functions do not appear to relate to cytokine production, which against previous data and against AUF1’s role as an antagonist for HuR’s functions. Collectively our data demonstrate that HuR and AUF1 are involved in different responses and highlight HuR’s role as putative organizer of post- transcriptional networks.Τα κύτταρα της έμφυτης ανοσίας έχουν εξελιχθεί τόσο για να αναγνωρίζουν και να αντιδρούν άμεσα στη λοίμωξης και της ιστικής βλάβης όσο και για να ρυθμίζουν τη φλεγμονώδη ομοιόσταση και να υποστηρίζουν της αντιδράσεις της επίκτητης ανοσίας. Οι πολύπλοκες αυτές αντιδράσεις βασίζονται σε μηχανισμούς ρύθμισης της γονιδιακής έκφρασης παραγόντων διαφοροποίησης, κυτταροκινών, αντιγονοπαρουσιαστικών μορίων και άλλων παραγόντων της φλεγμονής. Είναι πλέον σαφές ότι η βιοσύνθεση μορίων που εμπλέκονται στις δράσεις της έμφυτης ανοσίας, ρυθμίζεται σε μεγάλο βαθμό από μεταμεταγραφικούς μηχανισμούς που καθορίζουν τη «χρήση» των αντίστοιχόν mRNA. Οι μεταμεταγραφικοί μηχανισμοί περιλαμβάνουν σειρά διαδικασιών οι οποίες καθορίζουν τα επιμέρους στάδια του μεταβολισμού του mRNA (σταθερότητα, υποκυτταρικός εντοπισμός, μετάφραση) και ελέγχονται από τις δυναμικές αλληλεπιδράσεις μορίων RNA με ειδικές ριβονουκλεοπρωτεΐνες (RBP) που τα αναγνωρίζουν. Όπως έχει αποδειχθεί σε περιπτώσεις οξείας και χρόνιας φλεγμονής (π.χ. ρευματοειδής αρθρίτιδα, νόσος Crohn), η απορρύθμιση των παραπάνω διεργασιών μπορεί να οδηγήσει σε μη φυσιολογικές κυτταρικές αντιδράσεις, οι οποίες με τη σειρά τους θα αποτελέσουν τη βάση για την ανάπτυξη παθολογίας. Αντικείμενο της παρούσας ερευνητικής εργασίας ήταν η ανάλυση του βιολογικού ρόλου ριβονουκλεοπρωτεϊνών που εμπλέκονται στη μεταμεταγραφική ρύθμιση των mRNA που περιέχουν αλληλουχίες αδενίνης και ουρακίλης (ARE) και που κωδικοποιούν παράγοντες του στρες και της φλεγμονής. Πιο συγκεκριμένα η εργασία επικεντρώθηκε στις δράσεις, πρωτίστως της RBP Elavll/HuR και δευτερευόντως της RBP hnRNPD/AUF1, στον καθορισμό της έμφυτης ανοσίας με εφαρμογή: καινοτόμων μεθοδολογιών διαγονιδιακής απαλοιφής των RBP από αρχέγονα αιμοποιητικά κύτταρα in vivo, πειραματικών προτύπων οξείας φλεγμονής και φλεγμονωδών νοσημάτων του εντέρου και μελετών γονιδιακής έκφρασης. Η απώλεια της HuR σε διαφορετικά αιμοποιητικά στάδια αποκάλυψε τον λειτουργικό της ρόλο στην ρύθμιση της αιμοποιητικής διαφοροποίησης: (α) των αρχεγόνων κυττάρων προς τα προγονικά και (β) των προγονικών μυελοποιητικών κυττάρων προς τα ώριμα μυελοειδή συμπεριλαμβανομένων και των κυττάρων μονοκυττάρων/μακροφάγων και των πολυμορφοπύρηνων. Ο αιμοποιητικός ρόλος της HuR συσχετίστηκε με τη ρύθμιση μορίων που εμπλέκονται στον κυτταρικό κύκλο των αρχέγονων και προγονικών κυττάρων καθώς και με τις δράσεις παραγόντων διαφοροποίησης. Παρά ταύτα και στην περίπτωση της μυελοειδικής απαλοιφής της HuR, ο φαινότυπος αυτός είναι αντιστρέψιμος είτε με την αυξημένη παρουσία παραγόντων διαφοροποίησης ή την παρουσία φλεγμονής γεγονός που επέτρεψε τη διαλεύκανση του ρόλου της HuR στις φλεγμονώδεις αντιδράσεις της έμφυτης ανοσίας. Από τα αποτελέσματα μας προκύπτει ότι η HuR παίζει σημαντικό ρόλο στη διατήρηση του ισοζυγίου προ- και αντι-φλεγμονωδών κυτταροκινών μέσα από την αλληλεπίδραση με τα mRNA που τις κωδικοποιούν και την διαφορική της δράση προς την οργάνωση των ριβονουκλεοπρωτεϊνικών συμπλόκων που καθορίζουν την σταθερότητα και την μεταφρασιμότητά τους. Η διατήρηση αυτού του ισοζυγίου προσδίδει στη HuR μια ανοσορρυθμιστική και αντιφλεγμονώδη δράση η οποία πιστοποιήθηκε τόσο στην ανάπτυξη πειραματικών προτύπων σηπτικής καταπληξίας όσο και σε πειραματικά πρότυπα Ιδιοπαθών Φλεγμονωδών Νοσημάτων του Εντέρου (ΙΦΝΕ). Για την πιστοποίηση της αντιφλεγμονώδους δράσης της HuR στην ανάπτυξη των ΙΦΝΕ, επιχειρήσαμε μια φαρμακο-διαγονιδιακή διαδικασία υπερ-έκφρασης της, η οποία κατέστειλε την ανάπτυξη της νόσου αναδεικνύοντας το θεραπευτικό δυναμικό φαρμακευτικών ρυθμίσεων των δράσεων της HuR. Αντίθετα τα αποτελέσματα μας για τις δράσεις της AUF1, όπως προκύπτουν από τη μυελοειδική απαλοιφή της έδειξαν ότι δεν σχετίζεται με τη ρύθμιση της αιμοποίησης αλλά δρα ως προφλεγμονώδης παράγοντας, χωρίς όμως να επηρεάζει τη βιοσύνθεση βασικών κυτταροκινών. Τα αποτελέσματά μας έρχονται σε αντίθεση με ένα πλήθος βιβλιογραφικών αναφορών που υποδεικνύουν ότι η HuR και ο AUF1 έχουν ανταγωνιστικές δράσεις στα ίδια mRNA και αναδεικνύουν τη HuR ως πιθανό κυρίαρχο διοργανωτή μεταμεταγραφικών δικτύων

Τεχνο-οικονομική αξιολόγηση συμπαραγωγικής μονάδας ORC μεσαίας κλίμακας με καύση βιομάζας

Εθνικό Μετσόβιο Πολυτεχνείο--Μεταπτυχιακή Εργασία. Διεπιστημονικό-Διατμηματικό Πρόγραμμα Μεταπτυχιακών Σπουδών (Δ.Π.Μ.Σ.) “Παραγωγή και Διαχείριση Ενέργειας

Visual Reconstruction of Ancient Coins Using Cycle-Consistent Generative Adversarial Networks

In this paper, our goal is to perform a virtual restoration of an ancient coin from its image. The present work is the first one to propose this problem, and it is motivated by two key promising applications. The first of these emerges from the recently recognised dependence of automatic image based coin type matching on the condition of the imaged coins; the algorithm introduced herein could be used as a pre-processing step, aimed at overcoming the aforementioned weakness. The second application concerns the utility both to professional and hobby numismatists of being able to visualise and study an ancient coin in a state closer to its original (minted) appearance. To address the conceptual problem at hand, we introduce a framework which comprises a deep learning based method using Generative Adversarial Networks, capable of learning the range of appearance variation of different semantic elements artistically depicted on coins, and a complementary algorithm used to collect, correctly label, and prepare for processing a large numbers of images (here 100,000) of ancient coins needed to facilitate the training of the aforementioned learning method. Empirical evaluation performed on a withheld subset of the data demonstrates extremely promising performance of the proposed methodology and shows that our algorithm correctly learns the spectra of appearance variation across different semantic elements, and despite the enormous variability present reconstructs the missing (damaged) detail while matching the surrounding semantic content and artistic style.</p

Comparison of iCOR and Rayleigh atmospheric correction methods on Sentinel-3 OLCI images for a shallow eutrophic reservoir

Remote sensing of inland waters is challenging, but also important, due to the need to monitor the ever-increasing harmful algal blooms (HABs), which have serious effects on water quality. The Ocean and Land Color Instrument (OLCI) of the Sentinel-3 satellites program is capable of providing images for the monitoring of such waters. Atmospheric correction is a necessary process in order to retrieve the desired surface-leaving radiance signal and several atmospheric correction methods have been developed through the years. However, many of these correction methods require programming language skills, or function as commercial software plugins, limiting their possibility of use by end users. Accordingly, in this study, the free SNAP software provided by the European Space Agency (ESA) was used to evaluate the possible differences between a partial atmospheric correction method accounting for Rayleigh scattering and a full atmospheric correction method (iCOR), applied on Sentinel-3 OLCI images of a shallow, highly eutrophic water reservoir. For the complete evaluation of the two methods, in addition to the comparison of the band reflectance values, chlorophyll (CHL) and cyanobacteria (CI) indices were also calculated and their values were intercompared. The results showed, that although the absolute values between the two correction methods did not coincide, there was a very good correlation between the two methods for both bands’ reflectance (r > 0.73) and the CHL and CI indices values (r > 0.95). Therefore, since iCOR correction image processing time is 25 times longer than Rayleigh correction, it is proposed that the Rayleigh partial correction method may be alternatively used for seasonal water monitoring, especially in cases of long time-series, enhancing time and resources use efficiency. Further comparisons of the two methods in other inland water bodies and evaluation with in situ chlorophyll and cyanobacteria measurements will enhance the applicability of the methodology

Chromatin maturation of the HIV-1 provirus in primary resting CD4+ T cells.

Human immunodeficiency virus type 1 (HIV-1) infection is a chronic condition, where viral DNA integrates into the genome. Latently infected cells form a persistent, heterogeneous reservoir that at any time can reactivate the integrated HIV-1. Here we confirmed that latently infected cells from HIV-1 positive study participants exhibited active HIV-1 transcription but without production of mature spliced mRNAs. To elucidate the mechanisms behind this we employed primary HIV-1 latency models to study latency establishment and maintenance. We characterized proviral transcription and chromatin development in cultures of resting primary CD4+ T-cells for four months after ex vivo HIV-1 infection. As heterochromatin (marked with H3K9me3 or H3K27me3) gradually stabilized, the provirus became less accessible with reduced activation potential. In a subset of infected cells, active marks (e.g. H3K27ac) and elongating RNAPII remained detectable at the latent provirus, despite prolonged proviral silencing. In many aspects, latent HIV-1 resembled an active enhancer in a subset of resting cells. The enhancer chromatin actively promoted latency and the enhancer-specific CBP/P300-inhibitor GNE049 was identified as a new latency reversal agent. The division of the latent reservoir according to distinct chromatin compositions with different reactivation potential enforces the notion that even though a relatively large set of cells contains the HIV-1 provirus, only a discrete subset is readily able to reactivate the provirus and spread the infection

Τεχνολογίες δέσμευσης και μετατροπής διοξειδίου το άνθρακα (CO2)

Summarization: The impending depletion of fossil resources combined with their most visible environmental consequences has led mankind to seek new methods to meet its energy needs in the direction of sustainable development. The latter implies the development of advanced energy production and storage technologies, which will be based on inexhaustible resources while being economical and environmentally friendly. In this direction, capturing and converting CO2 emissions (the most important of greenhouse gases) into alcohols (methanol and ethanol) can make the greatest contribution to meeting energy needs and protecting the environment. The present thesis examines the existing technologies for CO2 capture and conversion. The ways of producing and exploiting the derived fuels are presented. Particular emphasis is placed on the capture, storage and chemical conversion of carbon dioxide into methanol (CH3OH).Περίληψη: Η επικείμενη εξάντληση των ορυκτών πόρων σε συνδυασμό με τις ορατές πλέον περιβαλλοντικές τους συνέπειες, έχει οδηγήσει την ανθρωπότητα στην αναζήτηση νέων μεθόδων για να καλύψει τις ενεργειακές της ανάγκες προς την κατεύθυνση της αειφόρου ανάπτυξης. Το τελευταίο συνεπάγεται την ανάπτυξη προηγμένων τεχνολογιών παραγωγής/αποθήκευσης ενέργειας, οι οποίες θα βασίζονται σε ανεξάντλητους πόρους και παράλληλα θα είναι οικονομικές και φιλικές προς το περιβάλλον. Προς την κατεύθυνση αυτή, η δέσμευση και μετατροπή εκπομπών CO2 (το κατεξοχήν αέριο του θερμοκηπίου) σε αλκοόλες (μεθανόλη και αιθανόλη) δύναται να συμβάλλει τα μέγιστα στην κάλυψη των ενεργειακών αναγκών και στην προστασία του περιβάλλοντος. Η παρούσα εργασία εξετάζει τις υπάρχουσες τεχνολογίες για την δέσμευση και μετατροπή CO2. Παρουσιάζονται οι τρόποι παραγωγής και εκμετάλλευσής του παράγωγου καυσίμου. Ιδιαίτερη έμφαση δίνεται στη δέσμευση, αποθήκευση και χημική μετατροπή του διοξειδίου του άνθρακα σε μεθανόλη (CH3OH)

Female Entrepreneurship and Employability in the Digital Era: The Case of Greece

Given the increasing demand of skilled workers in the Information and Communication Technology (ICT) sector during the upcoming years in the European labour market, as well as the digital gap of Greece to the European average, as a result of the ongoing economic crisis, led us to search for innovative ways of dealing with the current situation, following the scientific perspective. Inclusion of an increasing proportion of the Greek population in the ICT sector could result in a reversal of the uncomfortable situation in Greece. The purpose of this study is to investigate the impact of ICT on women’s employability and entrepreneurship, as well as on career prospects in managerial positions in Greece, in order to map the existing situation, identify needs, and suggest training routes. Data from 1035 women were collected, via questionnaires and interviews, regarding ICT skills’ benefits on female employability and entrepreneurship. As revealed by the findings, although women believe that ICT skills are among the most crucial factors of success in the 21st century, however, they state that they feel underrepresented in the digital era

Transcriptomic Analysis of Pseudomonas aeruginosa Response to Pine Honey via RNA Sequencing Indicates Multiple Mechanisms of Antibacterial Activity

Pine honey is a unique type of honeydew honey produced exclusively in Eastern Mediterranean countries like Greece and Turkey. Although the antioxidant and anti-inflammatory properties of pine honey are well documented, few studies have investigated so far its antibacterial activity. This study investigates the antibacterial effects of pine honey against P. aeruginosa PA14 at the molecular level using a global transcriptome approach via RNA-sequencing. Pine honey treatment was applied at sub-inhibitory concentration and short exposure time (0.5× of minimum inhibitory concentration –MIC- for 45 min). Pine honey induced the differential expression (&gt;two-fold change and p ≤ 0.05) of 463 genes, with 274 of them being down-regulated and 189 being up-regulated. Gene ontology (GO) analysis revealed that pine honey affected a wide range of biological processes (BP). The most affected down-regulated BP GO terms were oxidation-reduction process, transmembrane transport, proteolysis, signal transduction, biosynthetic process, phenazine biosynthetic process, bacterial chemotaxis, and antibiotic biosynthetic process. The up-regulated BP terms, affected by pine honey treatment, were those related to the regulation of DNA-templated transcription, siderophore transport, and phosphorylation. Pathway analysis revealed that pine honey treatment significantly affected two-component regulatory systems, ABC transporter systems, quorum sensing, bacterial chemotaxis, biofilm formation and SOS response. These data collectively indicate that multiple mechanisms of action are implicated in antibacterial activity exerted by pine honey against P. aeruginosa

Gender-affirming hormone treatment and cognitive function in transgender young adults : a systematic review and meta-analysis

Background: Previous studies have examined whether steroid hormone treatment in transgender individuals may affect cognitive function; yet, their limited power does not allow firm conclusions to be drawn. We leveraged data from to-date literature aiming to explore the effect of gender-affirming hormone administration on cognitive function in transgender individuals. Methods: A search strategy of MEDLINE was developed (through June 1, 2019) using the key terms transgender, hormone therapy and cognitive function. Eligible were (i) cohort studies examining the longitudinal effect of hormone therapy on cognition, and (ii) cross-sectional studies comparing the cognitive function between treated and non-treated individuals. Standardized mean differences (Hedges' g) were pooled using random-effects models. Study quality was evaluated using the Newcastle-Ottawa Scale. Outcomes: Ten studies (seven cohort and three cross-sectional) were eligible representing 234 birth-assigned males (aM) and 150 birth-assigned females (aF). The synthesis of cohort studies (n = 5) for visuospatial ability following hormone treatment showed a statistically significant enhancement among aF (g = 0.55, 95% confidence intervals [CI]: 0.29, 0.82) and an improvement with a trend towards statistical significance among aM (g = 0.28, 95%CI: -0.01, 0.58). By contrast, no adverse effects of hormone administration were shown. No heterogeneity was evident in most meta-analyses. Interpretation: Current evidence does not support an adverse impact of hormone therapy on cognitive function, whereas a statistically significant enhancing effect on visuospatial ability was shown in aF. New longitudinal studies with longer follow-up should explore the long-term effects of hormone therapy, especially the effects on younger individuals, where there is greater scarcity of data