ATF4 couples MYC-dependent translational activity to bioenergetic demands during tumour progression.

The c-Myc oncogene drives malignant progression and induces robust anabolic and proliferative programmes leading to intrinsic stress. The mechanisms enabling adaptation to MYC-induced stress are not fully understood. Here we reveal an essential role for activating transcription factor 4 (ATF4) in survival following MYC activation. MYC upregulates ATF4 by activating general control nonderepressible 2 (GCN2) kinase through uncharged transfer RNAs. Subsequently, ATF4 co-occupies promoter regions of over 30 MYC-target genes, primarily those regulating amino acid and protein synthesis, including eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), a negative regulator of translation. 4E-BP1 relieves MYC-induced proteotoxic stress and is essential to balance protein synthesis. 4E-BP1 activity is negatively regulated by mammalian target of rapamycin complex 1 (mTORC1)-dependent phosphorylation and inhibition of mTORC1 signalling rescues ATF4-deficient cells from MYC-induced endoplasmic reticulum stress. Acute deletion of ATF4 significantly delays MYC-driven tumour progression and increases survival in mouse models. Our results establish ATF4 as a cellular rheostat of MYC activity, which ensures that enhanced translation rates are compatible with survival and tumour progression

A facile approach to hydrophilic oxidized fullerenes and their derivatives as cytotoxic agents and supports for nanobiocatalytic systems

A facile, environment-friendly, versatile and reproducible approach to the successful oxidation of fullerenes (oxC60) and the formation of highly hydrophilic fullerene derivatives is introduced. This synthesis relies on the widely known Staudenmaier’s method for the oxidation of graphite, to produce both epoxy and hydroxy groups on the surface of fullerenes (C60) and thereby improve the solubility of the fullerene in polar solvents (e.g. water). The presence of epoxy groups allows for further functionalization via nucleophilic substitution reactions to generate new fullerene derivatives, which can potentially lead to a wealth of applications in the areas of medicine, biology, and composite materials. In order to justify the potential of oxidized C60 derivatives for bio-applications, we investigated their cytotoxicity in vitro as well as their utilization as support in biocatalysis applications, taking the immobilization of laccase for the decolorization of synthetic industrial dyes as a trial case.Peer ReviewedPostprint (published version

Interactions of biologically active substances with electromagnetic fields: experimental study

The effects of electromagnetic fields (EMFs) have been proved by a large number of studies and specifically from epidemiological studies. A major “breakthrough” in EMFs research is to establish the mechanism by which EMFs cause alterations on biological systems. In this PhD thesis, the effects of the resonant electromagnetic spectrum of the SnMNA complex on in vitro, ex vivo and in vivo models and the possible synergistic phenomenon of the complex activity and its EMFs spectrum were studied. Furthermore, the effects of morphine’s resonant electromagnetic spectrum as analgesic in a series of in vivo experiments were studied. In vitro studies showed that SnMNA complex presented potent cytotoxic activity (200 times more potent than of cisplatin) on LMS and MCF-7 cells and let both cell lines to apoptosis. The percentage of apoptotic cells was increasing as the concentrations of SnMNA were increasing, while cells presented growth arrest at G2/M phase of cell cycle. In vivo studies showed that SnMNA complex caused total necrosis of tubules and glomeruli in kidneys and dilatation of sisunoids and vacuolation of liver hepatocytes at a single dose of 80mg/kg BW, while chronic administration (4 repeated times) of 5.4mg/kg BW presented mild toxicity. Moreover, SnMNA administration at 4x5.4mg/kg BW prolonged the Mean Survival Time (MST) at about 200% while 30% of these animals were cured. Data from aggregometer analysis revealed that SnMNA complex could also act as an antiplatelet agen, indicating its possible antimetastatic effects. Twenty seven resonant-electromagnetic frequencies (r-EMFs) were selected from the transformation of chemical shifts (in ppm) of NMR spectrum of SnMNA complex. Exposure of LMS and MCF-7 cells on these r-EMFs increased the cytotoxic activity, while the cytotoxic activity of the complex and its EMFs (synergy) was similar to that of SnMNA complex. Also, exposure of LMS cells to the r-EMFs caused apoptosis similar to that caused by complex, while cells presented growth arrest at G2/M phase of cell cycle. Exposure of tumor-bearing Wistar rats to r-EMFs prolonged the MST and 30% were cured, while no toxic effects were presented. Exposure of rats on 36 r-EMFs, derived from morphine’s NMR spectrum, increased by 50% the index of analgesic activity similar to that of morphine’s administration (10mg/kg BW). The latter indicates that the appropriate “information” of biologically active substance could be transferred by exposure of various targets to its resonant electromagnetic fields (energy fingerprint). This exposure can cause similar effects compared to those caused by the biological active substances. Concluding, the NMR spectrum and so the r-EMFS of active substances can be used to cause similar effects as those of the initial substances without any side effect.Η επίδραση των ηλεκτρομαγνητικών πεδίων στα βιολογικά συστήματα έχουν αποδειχθεί μέσω ενός μεγάλου αριθμού μελετών και πιο συγκεκριμένα από επιδημιολογικές μελέτες. Ένα σημαντικό βήμα στην έρευνα των ηλεκτρομαγνητικών πεδίων είναι να αποδειχθεί ο μηχανισμός με τον οποίο αυτά μπορούν να προκαλέσουν αλλαγές στα ζώντα συστήματα. Στην παρούσα διδακτορική διατριβή μελετήθηκε η επίδραση του φάσματος συντονισμού του SnMNA συμπλόκου σε in vitro, ex vivo και in vivo μοντέλα και η πιθανή εμφάνιση του φαινομένου της συνέργειας των δράσεων του συμπλόκου και του ηλεκτρομαγνητικού φάσματος συντονισμού αυτού. Επίσης, μελετήθηκε η επίδραση του φάσματος συντονισμού της μορφίνης σε in vivo μοντέλα στην αύξηση της αναλγητικής ικανότητας σε επίμυες Wistar. Τα in vitro πειράματα έδειξαν ότι το SnMNA παρουσιάζει ισχυρή κυτταροτοξική δράση (200 φορές ισχυρότερη από την πλατίνα) στα LMS και MCF-7 κύτταρα και οδηγεί τα κύτταρα σε αποπτωτικό θάνατο. Σε αυξανόμενες συγκεντρώσεις του SnMNA αυξάνεται το ποσοστό της απόπτωσης με το μεγαλύτερο ποσοστό των κυττάρων να βρίσκεται στη φάση G2/M. Τα in vivo πειράματα έδειξαν ότι προκαλεί νεφροτοξικότητα με ολική νέκρωση των σωληναρίων και των σπειραμάτων των νεφρών στην εφάπαξ δόση των 80mg/kg ΣΒ, ενώ στη χορήγηση 4x5.4mg/kg ΣΒ (χρόνια τοξικότητα) εμφανίστηκε ήπια τοξικότητα. Επίσης, αύξησε (4x5.4mg/kg ΣΒ) το μέσο χρόνο επιβίωσης των καρκινοπαθών πειραματόζωων της ομάδας πειράματος κατά 200%, ενώ το 30% αυτών επιβίωσε. Παράλληλα, το SnMNA λειτούργησε και ως αντιμεταστατικός παράγοντας βάσει των αποτελεσμάτων της αιμοπεταλιακής συσσώρευσης. Από το NMR φάσμα του SnMNA προέκυψαν 22 συχνότητες συντονισμού. Η έκθεση των LMS και MCF-7 κυττάρων σε αυτές τις συχνότητες οδήγησε σε αύξηση της κυτταροτοξικότητας, ενώ στην περίπτωση της συνέργειας η δράση αυτή ήταν ανάλογη της δράσης του συμπλόκου. Η έκθεση στις συχνότητες προκάλεσε απόπτωση αντίστοιχη του συμπλόκου, ενώ το μεγαλύτερο ποσοστό των εκτιθέμενων κυττάρων βρίσκεται στη φάση G2/M. Επίσης, δεν προκάλεσε τοξικότητα στους φυσιολογικούς επίμυες Wistar, ενώ επιμήκυνε το μέσο χρόνο επιβίωσης στους καρκινοπαθείς επίμυες και το 30% αυτών επιβίωσε. Η έκθεση των πειραματόζωων για 5 ώρες στο ηλεκτρομαγνητικό φάσμα 36 συχνοτήτων συντονισμού της μορφίνης οδήγησε σε αύξηση της αναλγησίας στο ήμισυ αυτής που προκαλεί η χορήγηση της μορφίνης σε δόση 10mg/kg ΣΒ. Είναι πιθανό ότι μέσω της εκπομπής των ΗΜΓΣΣ να μεταφέρεται η κατάλληλη «πληροφορία» του εκάστοτε μορίου (ενεργειακό αποτύπωμα) η οποία μπορεί να αναπαραγάγει παραπλήσια αποτελέσματα όπως το αρχικό μόριο. Η λήψη του NMR φάσματος οποιουδήποτε βιολογικά δραστικού μορίου και η χρησιμοποίηση των συχνοτήτων συντονισμού αυτού δίνει τη δυνατότητα προσομοίωσης της δράσης του τουλάχιστον σε πολύ μεγάλο βαθμό και χωρίς την εμφάνιση ανεπιθύμητων παρενεργειών

Context-Based, Predictive Access Control to Electronic Health Records

Effective access control techniques are in demand, as electronically assisted healthcare services require the patient’s sensitive health records. In emergency situations, where the patient’s well-being is jeopardized, different healthcare actors associated with emergency cases should be granted permission to access Electronic Health Records (EHRs) of patients. The research objective of our study is to develop machine learning techniques based on patients’ time sequential health metrics and integrate them with an Attribute Based Access Control (ABAC) mechanism. We propose an ABAC mechanism that can yield access to sensitive EHRs systems by applying prognostic context handlers where contextual information, is used to identify emergency conditions and permit access to medical records. Specifically, we use patients’ recent health history to predict the health metrics for the next two hours by leveraging Long Short Term Memory (LSTM) Neural Networks (NNs). These predicted health metrics values are evaluated by our personalized fuzzy context handlers, to predict the criticality of patients’ status. The developed access control method provides secure access for emergency clinicians to sensitive information and simultaneously safeguards the patient’s well-being. Integrating this predictive mechanism with personalized context handlers proved to be a robust tool to enhance the performance of the access control mechanism to modern EHRs System

Progressive Dehydration in Junior Laser Class Sailors During World Championship

The purpose of this manuscript is to assess hydration status of elite young sailing athletes during World Championship competition. 12 young elite male Laser Class sailors (age: 15.8±1.1 y, height: 1.74±0.1 m, weight: 65.1±1.5 kg, body fat: 12.5±3.1%, training experience: 7.0±1.2 y) participated in this descriptive study. After three-day baseline bodyweight measurements, hydration status was assessed via pre- and post-race body weights, urine specific gravity, and thirst ratings via a visual analog scale during 4 consecutive days of racing. Measurements and data collection took place at the same time each racing day, with mean environmental temperature, humidity, and wind speed at 23.0±0.8 oC, 64-70% and 9±1 knots, respectively. Average racing time was 130±9 min. Body weight was significantly decreased following each race-day as compared to pre-race values (day 1: -1.1±0.2, day 2: -2.5±0.1, day 3: -2.8±0.1, and day 4: -3.0±0.1% of body weight; P<0.05). The participants exhibited dehydration of -2.9±0.2 and -5.8±0.2% of body weight before and after the 4th racing day as compared to the 3-day baseline body weight. Urine specific gravity (pre – post day 1: 1.014-1.017; day 2: 1.019-1.024; day 3: 1.021-1.026; day 4: 1.022-1.027) and thirst (pre – post day 1: 2.0-5.2; day 2: 3.2-5.5; day 3: 3.7-5.7; day 4: 3.8-6.8) were also progressively and significantly elevated throughout the four days of competition. The data revealed progressive dehydration throughout four consecutive days of racing as indicated by decreased body weight, elevated urine concentration, and high thirst

Assessment of the PLAY integrated platform V2, Deliverable D5.2.2

This deliverable describes the second iteration of the PLAY integrated platform assessment. It presents the approach and discusses the findings of the overall evaluation

Collaborative Process Flexibility Using Multi-Criteria Decision Making

Part 23: Event-Driven Collaborative NetworkInternational audienceThe ability to deal with both foreseen and unforeseen changes in a collaborative process (also known as Collaborative Process flexibility) is considered critical for the business process management systems. In this paper, we present an approach that uses a modeling framework and engine called Situation Action Network (SAN), along with multi-criteria decision making methods and techniques (MCDM). Such combination introduces event-driven flexibility in collaborative processes. We discuss and implement appropriate notions and mechanisms in order to alleviate a part of the modeler’s effort during the design of hierarchical rules (i.e. SAN trees). This increases their run time flexibility and support the adaptation of collaborative business processes. We validate our approach using an illustrative scenario taken from the nuclear crisis management domain