Gold Embroidery: A Sophisticated Technique for Early Mycenaean Swords and Daggers

One of the advanced decorative techniques of the Late Bronze Age Aegean is so-called gold embroidery, restricted only to luxurious weapons of the Early Mycenaean period. The technique consists in the dense placement of minute twisted gold filaments next to each other in order to give the impression of a mosaic. In the final stage, the craftsman decorated the whole with engraved designs, usually spirals. The present paper presents a detailed discussion on the history of research, the context, chronology and typology of the known examples, and a technical analysis based on archaeometric and experimental data. It is suggested that the use of the technique, which extends across the LH I–IIIA1 period, was reserved for burials of the highest status and was associated with other exclusive metal-working techniques, like inlaid decoration. The technique is unknown in Minoan Crete and the Eastern Mediterranean and, so far, the only possible parallels are to be found in the Wessex and Armorican cultures

Data Stream Clustering for Real-Time Anomaly Detection: An Application to Insider Threats

Insider threat detection is an emergent concern for academia, industries, and governments due to the growing number of insider incidents in recent years. The continuous streaming of unbounded data coming from various sources in an organisation, typically in a high velocity, leads to a typical Big Data computational problem. The malicious insider threat refers to anomalous behaviour(s) (outliers) that deviate from the normal baseline of a data stream. The absence of previously logged activities executed by users shapes the insider threat detection mechanism into an unsupervised anomaly detection approach over a data stream. A common shortcoming in the existing data mining approaches to detect insider threats is the high number of false alarms/positives (FPs). To handle the Big Data issue and to address the shortcoming, we propose a streaming anomaly detection approach, namely Ensemble of Random subspace Anomaly detectors In Data Streams (E-RAIDS), for insider threat detection. E-RAIDS learns an ensemble of p established outlier detection techniques [Micro-cluster-based Continuous Outlier Detection (MCOD) or Anytime Outlier Detection (AnyOut)] which employ clustering over continuous data streams. Each model of the p models learns from a random feature subspace to detect local outliers, which might not be detected over the whole feature space. E-RAIDS introduces an aggregate component that combines the results from the p feature subspaces, in order to confirm whether to generate an alarm at each window iteration. The merit of E-RAIDS is that it defines a survival factor and a vote factor to address the shortcoming of high number of FPs. Experiments on E-RAIDS-MCOD and E-RAIDS-AnyOut are carried out, on synthetic data sets including malicious insider threat scenarios generated at Carnegie Mellon University, to test the effectiveness of voting feature subspaces, and the capability to detect (more than one)-behaviour-all-threat in real-time. The results show that E-RAIDS-MCOD reports the highest F1 measure and less number of false alarm = 0 compared to E-RAIDS-AnyOut, as well as it attains to detect approximately all the insider threats in real-time

TP63 and TP73 in cancer, an unresolved “family” puzzle of complexity, redundancy and hierarchy

AbstractTP53 belongs to a small gene family that includes, in mammals, two additional paralogs, TP63 and TP73. The p63 and p73 proteins are structurally and functionally similar to p53 and their activity as transcription factors is regulated by a wide repertoire of shared and unique post-translational modifications and interactions with regulatory cofactors. p63 and p73 have important functions in embryonic development and differentiation but are also involved in tumor suppression. The biology of p63 and p73 is complex since both TP63 and TP73 genes are transcribed into a variety of different isoforms that give rise to proteins with antagonistic properties, the TA-isoforms that act as tumor-suppressors and DN-isoforms that behave as proto-oncogenes. The p53 family as a whole behaves as a signaling “network” that integrates developmental, metabolic and stress signals to control cell metabolism, differentiation, longevity, proliferation and death. Despite the progress of our knowledge, the unresolved puzzle of complexity, redundancy and hierarchy in the p53 family continues to represent a formidable challenge

A Rule-based Skyline Computation over a dynamic database

Skyline query which relies on the notion of Pareto dominance filters the data items from a database by ensuring only those data items that are not worse than any others are selected as skylines. However, the dynamic nature of databases in which their states and/or structures change throughout their lifetime to incorporate the current and latest information of database applications, requires a new set of skylines to be derived. Blindly computing skylines on the new state/structure of a database is inefficient, as not all the data items are affected by the changes. Hence, this paper proposes a rule-based approach in tackling the above issue with the main aim at avoiding unnecessary skyline computations. Based on the type of operation that changes the state/structure of a database, i.e. insert/delete/update a data item(s) or add/remove a dimension(s), a set of rules are defined. Besides, the prominent dominance relationships when pairwise comparisons are performed are retained; which are then utilised in the process of computing a new set of skylines. Several analyses have been conducted to evaluate the performance and prove the efficiency of our proposed solution

KDM1A microenvironment, its oncogenic potential, and therapeutic significance

The lysine-specific histone demethylase 1A (KDM1A) was the first demethylase to challenge the concept of the irreversible nature of methylation marks. KDM1A, containing a flavin adenine dinucleotide (FAD)-dependent amine oxidase domain, demethylates histone 3 lysine 4 and histone 3 lysine 9 (H3K4me1/2 and H3K9me1/2). It has emerged as an epigenetic developmental regulator and was shown to be involved in carcinogenesis. The functional diversity of KDM1A originates from its complex structure and interactions with transcription factors, promoters, enhancers, oncoproteins, and tumor-associated genes (tumor suppressors and activators). In this review, we discuss the microenvironment of KDM1A in cancer progression that enables this protein to activate or repress target gene expression, thus making it an important epigenetic modifier that regulates the growth and differentiation potential of cells. A detailed analysis of the mechanisms underlying the interactions between KDM1A and the associated complexes will help to improve our understanding of epigenetic regulation, which may enable the discovery of more effective anticancer drugs

Data mining and query processing methods in data streams

This thesis studies the problem of data management in data streams in order to reduce the response time and therefore to improve quality of services taking account the memory requirements which is a major limitation in data streams. More specifically, we study data mining problems such as clustering and classification in data streams and we develop incremental algorithm with low memory requirements. We examine similarity queries between different data streams and we propose an indexing scheme suitable for dynamic data. We also propose algorithms for continuous preference queries evaluation problems in sensor networks. We introduce queries for knowledge discovery and we propose algorithms for their evaluation.Η παρούσα διατριβή μελετά προβλήματα διαχείρισης δεδομένων σε ροές δεδομένων με σκοπό την ελάττωση του χρόνου απόκρισης και κατά συνέπεια τη βελτίωση εξυπηρέτησης των χρηστών λαμβάνοντας υπόψη τις απαιτήσεις μνήμης που αποτελεί βασικό περιορισμό στις ροές δεδομένων. Συγκεκριμένα, μελετάμε προβλήματα εξόρυξης δεδομένων όπως ομαδοποίηση και κατηγοριοποίηση σε ροές δεδομένων και αναπτύσσουμε επαυξητικούς αλγορίθμους με χαμηλές απαιτήσεις μνήμης. Εξετάζουμε ερωτήματα ομοιότητας μεταξύ διαφορετικών ροών δεδομένων και προτείνουμε ένα σχήμα δεικτοδότησης κατάλληλο για δυναμικά δεδομένα. Προτείνουμε επίσης αλγόριθμους για την αποτίμηση συνεχών ερωτημάτων προτίμησης σε ροές δεδομένων. Τέλος, μελετάμε προβλήματα διαχείρισης δεδομένων σε δίκτυα αισθητήρων. Παρουσιάζουμε ερωτήματα για την εξαγωγή γνώσης και προτείνουμε αλγορίθμους για την αποτίμησή τους

Regulation of immune response in inflammatory bowel disease and experimental colitis models

Inflammatory bowel disease (IBD) is a chronic remittent or progressive inflammation of the gastrointestinal tract that affects millions of people worldwide. This inflammatory condition encompasses two major forms known as Crohn’s disease (CD) and ulcerative colitis (UC). The onset of IBD typically occurs in the second and third decades of life, with the majority of patients progressing to a relapsing and chronic disease. Although the precise cause of IBD has not yet been fully elucidated, recent advances in the understanding of the molecular pathogenesis of IBD have been made owning to three related lines of investigation. First, IBD has been amenable to the discovery of susceptibility genes. Secondly, it appears that commensal pathogens or their products rather than conventional flora, play a pivotal role in the dysregulated immunity typically observed in IBD cases. Thirdly, murine models that exhibit many of the features of UC seem to be driven bacterially and have helped to unravel the pathogenic mechanisms underlying IBD. Overall, it appears that an imbalance of the mucosal immune system leads to the overproduction of inflammatory cytokines, release of reactive oxygen metabolites and infiltration of immune cells into the intestine, resulting in uncontrolled intestinal inflammation and tissue damage. Myeloid-derived suppressor cells (MDSCs) constitute a diverse cell population made up of immature myeloid cells (IMCs), consisting of mostly progenitor cells of macrophages, granulocytes, dendritic cells and myeloid cells at early stages of differentiation. In mice, MDSCs are characterized by the co-expression of Gr-1 and CD11b markers, and are further divided into granulocytic and monocytic subset, defined as CD11b+Ly6G+Ly6Clow and CD11b+Ly6GlowLy6C+ cells, respectively. In humans, phenotypic characterization of MDSCs is challenging, due to lack of uniform criteria. Nevertheless, they are most commonly characterized by the expression of the myeloid marker CD33 and the lack of expression of the major histocompatibility complex (MHC) class-II molecule, human leukocyte antigen (HLA-DR) and several other lineage markers. Although most of our knowledge on the role of MDSCs in immune responses has been based on tumor bearing mice and cancer patients, increasing evidence has suggested their role in many pathological conditions, such as infections, transplantation and autoimmunity. Traditionally, MDSCs are considered as potent suppressors of immune responses through different mechanisms. However, recent literature highlighted their plasticity, denoting proinflammatory potential of specific subsets emerging in specific microenvironment. Despite the well-defined suppressive effects of MDSCs on T cell responses, their function in autoimmune diseases, like IBD, is controversial. In particular, the immunosuppressive function of MDSCs was suggested by several reports showing that CD11b+Gr1+ MDSCs are increased during intestinal inflammation. As is the case for murine colitis models, CD14+HLA-DRlow MDSCs with suppressive properties were also reported to be increased in the peripheral blood (PB) of IBD patients. On the other hand, recent studies supported a proinflammatory role of myeloid cells in experimental colitis, demonstrated that adoptively transferred colonic Ly6Chigh cells differentiated into inflammatory cells, contributing to intestinal inflammation. In this PhD thesis, we investigated the immunomodulatory properties of MDSCs in experimental inflammatory colitis and T cell-mediated immune responses in IBD patients.MDSCs (defined as CD14+HLA-DR-/lowCD33+CD15+ cells) numbers were determined in PB from IBD patients. PB MDSCs function was assessed in vitro. Experimental colitis was induced upon 2,4,6-trinitrobenzene sulfonic acid (TNBS) treatment and MDSCs were characterized by flow cytometry. The in vivo suppressive potential of bone marrow (BM)-derived MDSCs (BM-MDSCs) was tested by using both depleting and adoptive transfer strategies. MDSCs were enriched in the periphery of IBD patients during active disease. TNBS colitis induced amplification of MDSCs, particularly of the granulocytic (Ly6G+) subset during the effector phase of disease. Of interest, BM-MDSCs potently suppressed CD4+ T cell responses under steady state but failed to control colitis- associated immune responses in vivo. Mechanistically, under the colonic inflammatory milieu MDSCs switched phenotype (decreased proportion of Gr1high and increased numbers of Gr1low) and downregulated CCAAT/enhancer-binding protein beta (CEBPβ) expression, a critical transcription factor for the suppressive function of MDSCs. In accordance with the murine data, human CD33+CD15+MDSCs from PB of IBD patients not only failed to suppress autologous T cell responses but instead enhanced T cell proliferation in vitro. Our findings demonstrate an aberrant function of MDSCs in experimental inflammatory colitis and in IBD-associated immune responses in vitro. Delineation of the mechanisms that underlie the loss of MDSCs function in IBD may provide novel therapeutic targets.Οι Ιδιοπαθείς Φλεγμονώδεις Νόσοι του Εντέρου (ΙΦΝΕ) είναι χρόνιες φλεγμονώδεις παθήσεις του πεπτικού σωλήνα, με υποτροπίαζοντα ή προοδευτικό χαρακτήρα που επηρρεάζουν εκατομμύρια ανθρώπων παγκοσμίως. Ο όρος ΙΦΝΕ περιλαμβάνει τη νόσο του Crohn και την ελκώδη κολίτιδα. Η ηλικία εμφάνισης της νόσου τοποθετείται συνήθως στη δεύτερη και τρίτη δεκαετία της ζωής, με την πλειονότητα των ασθενών να εμφανίζουν κλινική πορεία χαρακτηριζόμενη από υφέσεις και εξάρσεις. Αν και η ακριβής αιτιολογία των ΙΦΝΕ δεν έχει πλήρως αποσαφηνιστεί, θεωρείται νόσος πολυπαραγοντική. Φαίνεται ότι υπάρχει γενετική προδιάθεση, με υπεύθυνα συγκεκριμένα γονίδια που πιθανώς είναι ο πλέον σπουδαίος παράγοντας κινδύνου εμφάνισης των ΙΦΝΕ. Επιπλέον, η αλλαγή του μικροβιώματος δημιουργεί δυσβίωση μεταξύ ξενιστή και μικροβιώματος του εντέρου και αποτελεί σημαντικό παράγοντα του ξενιστή για την αιτιολογία της νόσου. Δεδομένα από πειραματικά μοντέλα κολίτιδας έχουν βοηθήσει σημαντικά στην κατανόηση των ανοσολογικών μηχανισμών που εμπλέκονται στην έναρξη και την εξέλιξη της νόσου. Συνολικά, φαίνεται ότι μία διαταραχή στο ανοσολογικό σύστημα του εντερικού βλεννογόνου οδηγεί σε υπερπαραγωγή φλεγμονωδών κυτταροκινών, απελευθέρωση μεσολαβητών οξειδωτικού στρες και διήθηση του εντέρου από φλεγμονώδη κύτταρα με αποτέλεσμα φλεγμονή του εντέρου και ιστική καταστροφή. Τα κατασταλτικά κύτταρα μυελικής προέλευσης (Myeoid-derived suppressor cells- MDSCs) αποτελούν έναν ετερογενή πληθυσμό κυττάρων που περιλαμβάνει μακροφάγα, κοκκιοκύτταρα, δενδριτικά κύτταρα και κύτταρα μυελικής σειράς σε πρώιμα στάδια διαφοροποίησης. Στα ποντίκια, τα MDSCs χαρακτηρίζονται από την έκφραση των Gr-1 και CD11b δεικτών και περιλαμβάνουν δύο υποομάδες κυττάρων: αυτά με μορφολογία παρόμοια με εκείνη των κοκκιοκυττάρων και φαινότυπο CD11b+Ly6G+Ly6Clow και αυτά με μορφολογία παρόμοια με εκείνα των μονοκυττάρων και φαινότυπο CD11b+Ly6GlowLy6C+. Στους ανθρώπους, ο φαινοτυπικός προσδιορισμός των MDSCs συνιστά πρόκληση, λόγω της έλλειψης ενιαίων κριτηρίων. Συνηθέστερα, χαρακτηρίζονται απο την έκφραση του δείκτη CD33 της μυελικής σειράς και την έλλειψη έκφρασης τόσο του μορίου τάξης ΙΙ του μείζονος συμπλέγματος ιστοσυμβατότητας (MHC-ΙΙ), HLA-DR, όσο και άλλων δεικτών που χαρακτηρίζουν τις υπόλοιπες κυτταρικές σειρές του μυελού των οστών. Αν και ο ρόλος των MDSCs έχει κυρίως μελετηθεί σε πειραματικά μοντέλα καιασθενείς με καρκίνο, πρόσφατες μελέτες αναδεικνύουν το ρόλο αυτών σε πληθώρα παθολογικών καταστάσεων, όπως οι λοιμώξεις, η μεταμόσχευση και η αυτοανοσία. Παραδοσιακά, τα εν λόγω κύτταρα θεωρείται ότι καταστέλλουν την ανοσιακή απάντηση μέσω ποικίλων μηχανισμών. Ωστόσο, η πρόσφατη βιβλιογραφία επισημαίνει την πλαστικότητα αυτών των κυττάρων, δεδομένου ότι το εκάστοτε φλεγμονώδες περιβάλλον μπορεί να τους προσδώσει προφλεγμονώδεις ιδιότητες. Αν και οι κατασταλτικές ιδιότητες των MDSCs στις διαμεσολαβούμενες απο Τ κύτταρα ανοσιακές απαντήσεις είναι καλώς καθορισμένες, ο ρόλος αυτών στα αυτοάνοσα νοσήματα, όπως οι ΙΦΝΕ, είναι αμφιλεγόμενος. Πιο συγκεκριμένα, η ανοσοκατασταλτική δράση των MDSCs υποστηρίζεται από πολλές εργασίες που αναδεικνύουν την αύξηση των CD11b+Gr1+ MDSCs σε πειραματικά μοντέλα κολίτιδας. Παρομοίως, αύξηση των κατασταλτικών CD14+HLA-DRlow MDSCs περιγράφεται και στο περιφερικό αίμα ασθενών με ΙΦΝΕ. Ωστόσο, πρόσφατες μελέτες επισημαίνουν τον προφλεγμονώδη ρόλο των κυττάρων της μυελικής σειράς σε πειραματικά μοντέλα κολίτιδας, καθώς αυτόλογη μεταφορά Ly6Chigh κυττάρων εντερικού βλεννογόνου οδηγεί σε διαφοροποίηση των τελευταίων σε κύτταρα που προάγουν τη φλεγμονή του εντέρου. Στην παρούσα διδακτορική διατριβή, το ενδιαφέρον εστιάστηκε στον ανοσορυθμιστικό ρόλο των MDSCs σε πειραματικά μοντέλα κολίτιδας, καθώς και στις ανοσιακές απαντήσεις που διαμεσολαβούνται από τα Τ κύτταρα σε ασθενείς με ΙΦΝΕ. Ο αριθμός των MDSCs (ταυτοποιούμενα ως CD14+HLA-DR-/lowCD33+CD15+ κύτταρα) προσδιορίστηκε στο περιφερικό αίμα ασθενών με ΙΦΝΕ, ενώ η δράση αυτών αξιολογήθηκε με in vitro δοκιμασίες. Το πειραματικό μοντέλο που χρησιμοποιήθηκε ήταν αυτό της χημικά 2,4,6-trinitrobenzene sulfonic acid (TNBS) επαγόμενης κολίτιδας. Τα MDSCs χαρακτηρίστηκαν με τη μέθοδο της κυτταρομετρία ροής. Η in vivo ανοσοκατασταλτική δράση των MDSCs που καλλιεργήθηκαν από μυελό των οστών υγιών ποντικιών (BM-MDSCs) ελέγχθηκε τόσο με δοκιμασίες απαλοιφής όσο και αυτόλογης μεταφοράς. Η μελέτη σε ανθρώπινα δείγματα ασθενών με ΙΦΝΕ, ανέδειξε αύξηση του αριθμού των MDSCs στο περιφερικό αίμα ασθενών με ενεργό νόσο. Παρομοίως, τα MDSCs, ιδιαίτερα ο υποπληθυσμός που χαρακτηρίζεται ως Ly6G+, αυξήθηκε στα περιφερικά λεμφικά όργανα ποντικών με TNBS επαγόμενη κολίτιδα κατά την ενεργό φάση της νόσου. Αντίθετα με τις αρχικές προσδοκίες, η αυτόλογη μεταφορά BM-MDSCs σε ποντίκια με TNBS κολίτιδα απέτυχε να ελέγξει τη φλεγμονή in vivo. Περαιτέρω μελέτη του μηχανισμού δράσης των MDSCs, έδειξε ότι η έκθεση των εν λόγω κυττάρων στο φλεγμονώδες περιβάλλον της κολίτιδας οδηγεί σε αλλαγή του φαινότυπου (μείωση των Gr1high και αύξηση των Gr1low κυττάρων) αυτών, καθώς και σε μειωμένη έκφραση της πρωτεΐνης CCAAT/enhancer-binding protein beta (CEBPβ), η οποία αποτελεί μεταγραφικό παράγοντα κλειδί στην ανοσοκατασταλτική δράση των MDSCs. Σε συμφωνία με τα αποτελέσματα της μελέτης στο πειραματικό μοντέλο κολίτιδας, MDSCs τα οποία απομονώθηκαν από περιφερικό αίμα ασθενών με ενεργό νόσο όχι μόνο δεν κατέστειλαν αλλά αντιθέτως ενίσχυσαν τον πολλαπλασιασμό αυτόλογων CD4+ Τ κυττάρων ex vivo. Συνολικά, τα δεδομένα αυτά αναδεικνύουν μια παράδοξη λειτουργία των MDSCs σε πειραματικά μοντέλα κολίτιδας, καθώς και στην in vitro ανοσιακή απάντηση ασθενών με ΙΦΝΕ. Η περαιτέρω κατανόηση των μηχανισμών που οδηγούν στην απώλεια του βασικού χαρακτηριστικού των MDSCs, που συνίσταται στην καταστολή των ανοσιακών απαντήσεων, θα μπορούσε να υποβοηθήσει στο σχεδιασμό νέων θεραπευτικών στόχων

Efficient Incremental Subspace Clustering in Data Streams

Performing data mining tasks in streaming data is considered a challenging research direction, due to the continuous data evolution. In this work, we focus on the problem of clustering streaming time series, based on the sliding window paradigm. More specifically, we use the concept of α-clusters in each time instance separately. A subspace αcluster consists of a set of streams, whose value difference is less than α in a consecutive number of time instances (dimensions). The clusters can be continuously and incrementally updated as the streaming time series evolve. The proposed technique is based on a careful examination of pair-wise stream similarities for a subset of dimensions and then, it is generalized for more streams per cluster. Performance evaluation results show that the proposed pruning criteria are important for search space reduction, and that the cost of incremental cluster monitoring is computationally more efficient than reclustering.

Transcription factor regulation trhough lysine methylation

Recent studies revealed that histone lysine-methyltransferases, in addition to their function on chromatin, can also regulate specific gene expression programs through methylation of transcription factors. The emerging field of lysine methylation encouraged us to extend our studies on identifying new substrates for Set9, Smyd2 and Smyd3, which is presented in the first part of my thesis. It was found that Set9 efficiently methylates E2F1. Both Set9 and Smyd2 methylate the tumor-suppressor protein Rb, the transcription factor HNF4 and the linker histone H1o. Smyd2 also methylates the heat shock protein HSP90 and Set9 methylates the methyltransferase Smyd2. Histone modifying enzymes can regulate various cellular processes through the methylation of transcription factors. The most characteristic example is the regulation of DNA damage-induced apoptosis through modulation of p53 function. In particular, the studies identified a pro-apoptotic function of the histone methyltransferase Set9 and an anti-apoptotic role of the histone demethylase LSD1, through mechanisms that involve methylation and demethylation of two different residues of p53, respectively. In the second part of my thesis we study the role of Set9 and LSD1 in DNA damage-induced cell death in the p53-deficient cell line H1299 (human lung carcinoma cell line). The two enzymes regulate DNA damage-induced cell death in a manner opposite to that observed in p53+/+ cells (U2OS). The anti-apoptotic role of Set9 and the pro-apoptotic role of LSD1 emerges through modulation of E2F1. The Set9-mediated methylation of E2F1 at lysine-185 destabilizes the protein and negatively influences E2F1-mediated cell death, as opposed to its stabilizing function on p53, which promotes apoptosis. LSD1 is required for DNA damage induced accumulation of E2F1 and activation of pro-apoptotic targets, while its enzymatic action inhibits p53 transcriptional activity. In the third part of my thesis we aimed to characterize the genomic locations bound by the methyltransferase Set9, the demethylase LSD1 and the transcription factor E2F1. The processing of the results provided information regarding their distribution profile on their target genes. Furthermore, we performed comparative analysis preparative to locate co-recruitment of these factors on common sites