Οικο-Θεολογική διάσταση της προς Ρωμαίους επιστολή (ερμηνευτική και θεολογική προσέγγιση)

Η Οικολογική Κρίση αποτελεί τη συνέπεια ενός άκρατου υλισμού μέσα στον οποίο ζει ο σύγχρονος άνθρωπος. Η αδυναμία του ανθρώπου να προστατεύσει τη φύση δείχνει ότι ο άνθρωπος αντιλαμβάνεται τη θέση του μέσα στην δημιουργία όχι ως θέση ευθύνης για την προστασία του ίδιου και του φυσικού περιβάλλοντος, αλλά ως θέση εξουσίας της φύσης. Για τους Πατέρες της Εκκλησίας, η λύση του Οικολογικού προβλήματος βρίσκεται στη φιλική σχέση που πρέπει να αναπτύξει ο άνθρωπος με τη φύση. Με την έρευνα της Οικολογικής Κρίσης μέσα από την Αγία Γραφή, είναι δυνατόν να φωτιστούν πτυχές της διαφαινόμενης Οικολογικής καταστροφής, να αξιολογηθούν τα σχετικά προβλήματα και να βρεθεί η λύση των δεινών που απειλούν τον πλανήτη μας. Σύμφωνα, λοιπόν με τη θεώρηση της Ορθόδοξης Θεολογίας η Οικολογική Κρίση είναι πρώτιστα θεολογική. Ο απόστολος Παύλος διασώζει με πυκνό λόγο στην προς Ρωμαίους επιστολή του τη θέση του γύρω από τη σχέση του ανθρώπου και της Οικολογικής Κρίσης στον κόσμο. Η κτίση στο σύνολό της υφίσταται τις συνέπειες της ηθικής φθοράς και της αμαρτίας του ανθρώπου. Η οδυνηρή θέση της κτίσης περιγράφεται μέσα από την παρουσία των ωδίνων της που την κάνουν να στενάζει και να βιώνει, ως μη ώφειλε, συνέπειες τις οποίες η ίδια δεν δημιούργησε. Το κείμενο της προς Ρωμαίους επιστολής, αν και αναγνωρίζει ως υπαίτιο της Οικολογικής Κρίσης τον άνθρωπο, την ίδια στιγμή αναφέρεται στην ελπίδα ότι στο τέλος θα αλλάξουν όλα μέσα προς σωτηρία του ανθρώπου και του κόσμου.The ecological crisis is the consequence of an excessive materialism in which modern humans live. The inability of humans to protect nature shows that they perceive their position in creation not as a position of responsibility for the protection of themselves and the natural environment, but as a position of power over nature. According to the Church Fathers, the solution to the ecological problem lies in the friendly relationship that humans should develop with nature. By studying the Ecological Crisis through the Holy Scriptures, it is possible to shed light on aspects of the apparent ecological devastation, evaluate related problems, and find solutions to the dangers threatening our planet. Therefore, according to the perspective of Orthodox Theology, the Ecological Crisis is primarily theological. The apostle Paul, in his letter to the Romans, addresses the position of humans and the Ecological Crisis in the world through his dense discourse. The entire creation suffers the consequences of moral decay and human sin. The painful state of creation is described through the presence of its birth pangs, causing it to groan and experience consequences that it did not create itself. The text of the letter to the Romans acknowledges humans as responsible for the Ecological Crisis, while at the same time referring to the hope that everything will ultimately change towards the salvation of humans and the world

Impartiale découverte de cibles génomiques druggable par click-séquençage (Click-seq)

Durant ma thèse, mes études ont été axées sur le développement de nouvelles sondes et des protocoles chimiques pour l'élucidation des mécanismes d'action et de résistance pour les trois médicaments anticancéreux (cisplatine, le vorinostat, topotécan). L'idée de sondes chimiques qui peuvent être étiquetés post-traitement in cellulo avec des fluorophores par exemple Alexa Fluor 488 ou affinité des fragments par exemple biotine, nous a fasciné pour effectuer petite visualisation de molécule par microscopie confocale, ou pour développer des protocoles tirer vers le bas pour les petites cibles moléculaires d'isolement. Beaucoup d'attention a été accordée à catalysée par du cuivre 1, 3 dipolaire cycloaddition Huisgen, connu sous le nom ''click'' la chimie au cours de la dernière décennie, car il est l'une des premières réactions qui peuvent être considérés comme des bio-orthogonale. Toutes les sondes portent soit un alcyne ou groupement azoture stratégiquement positionnés qui leur permet de participer à la réaction de clic avec des fluorophores ou biotine alcyne ou azoture fonctionnalisés que countrparts, et dans le même temps de conserver le profil pharmacologique du médicament parental. Un certain nombre de défis synthétiques ont été overcomed pour la préparation d'une sonde chimique de base de cisplatine. Les efforts visant à synthétiser des analogues alcynes fonctionnalisés de cisplatine ont été infructueuses, la sonde chimique à base de cisplatine était donc fonctionnalisés azoture. La mise au point d'un protocole d'imagerie pour la visualisation de lésions de l'ADN platiné nous a permis de cribler une banque limitée de petites molécules en même temps que la sonde de cisplatine, afin d'identifier des médicaments qui peuvent moduler le cisplatine ciblage ayant des lésions de l'ADN platiné comme une lecture. Il est frappant, nous avons constaté que le vorinostat a eu un effet dramatique sur motif de coloration de la sonde de cisplatine. D'autres études ont démontré que le prétraitement des cellules avec vorinostat augmente charge de platine sur certains loci génomiques. En outre, une évaluation biologique plus approfondie a montré que la combinaison de vorinostat avec des médicaments de platine atténue les dommages à l'ADN synthèse voie de tolérance de translésionnelles (TLS), ainsi, ce qui conduit à la mort cellulaire. Enfin, je l'ai mis au point un protocole tirer vers le bas pour l'isolement de l'ADN qui est lié à la cisplatine en étiquetant la sonde en platine avec un fragment de biotine. Cartographie des interactions ADN-platine en utilisant le séquençage à haut débit profonde est en cours d'exécution. Vorinostat sonde chimique à base a été préparé dans une voie de synthèse en quatre étapes. Bien que le vorinostat est un médicament connu pour inhiber des histone désacétylases (HDAC), petite visualisation de molécule a indiqué d'abord un profil de coloration cytoplasmique. Les futures études dans notre laboratoire se concentrera sur le développement d'un protocole déroulant, afin de caractériser complètement le vorinostat interactome. Quoique, trois sondes chimiques à base de topotécan différents ont été préparés de la personne a été visualisé les succès par microscopie confocale. L'échec a été attribué à l'échec de la réaction "click" pour marquer la sonde avec le fluorophore. Le topotécan est une petite molécule qui agit comme un inhibiteur d'interface, formant ainsi un complexe ternaire avec l'ADN et la topoisomérase 1. L'encombrement stérique généré par le complexe ternaire autour de la sonde, dicte l'inaccessibilité de l'alcyne de la sonde de "click" réactifs.During my PhD, my studies have been focused on the development of novel chemical probes and protocols for the elucidation of the mechanisms of action and resistance for three anticancer drugs (cisplatin, vorinostat, topotecan). The idea of chemical probes that can be tagged post treatment in cellulo with fluorophores e.g. ALEXA FLUOR 488 or affinity moieties e.g. biotin, has fascinated us to perform small molecule visualization via confocal microscopy, or to develop pull down protocols for isolation small molecule targets. Much attention has been given to copper catalyzed 1, 3 dipolar Huisgen cycloaddition, known as ‘’click’’ chemistry over the past decade, since it is one of the first reactions that can be considered as bio-orthogonal. All the probes bear either an alkyne or azide moiety strategically positioned that allows them to participate in the click reaction with alkyne or azide functionalized fluorophores or biotin as countrparts, and at the same time to retain the pharmacological profile of the parental drug.A number of synthetic challenges have been overcomed for the preparation of a cisplatin based chemical probe. Efforts to synthesize alkyne functionalized analogues of cisplatin were unsuccessful, thus cisplatin based chemical probe was azide functionalized. The development of an imaging protocol for the visualization of platinated DNA lesions has enabled us to screen a limited library of small molecules along with the cisplatin probe, in order to identify drugs that can modulate cisplatin targeting having platinated DNA lesions as a readout. Strikingly, we found that vorinostat had a dramatic effect on cisplatin probe staining pattern. Further studies have demonstrated that pre-treatment of cells with vorinostat increases platinum loading on certain genomic loci. Furthermore, a more in depth biological evaluation has demonstrated that the combination of vorinostat with platinum drugs attenuates the DNA damage tolerance pathway translesion synthesis (TLS), thus, leading to cell death. Finally, I have developed a pull down protocol for the isolation of DNA that is bound to cisplatin by tagging the platinum probe with a biotin moiety. Mapping of DNA-platinum interactions using deep high throughput sequencing is currently running.Vorinostat based chemical probe has been prepared in a four step synthetic route. Although, vorinostat is a drug known to inhibit histone deacetylases (HDACs), small molecule visualization has indicated primarily a cytoplasmic staining pattern. Future studies in our laboratory will focus on the development of a pull down protocol, in order to fully characterize vorinostat interactome.Albeit, three different topotecan based chemical probes have been prepared none of the them has been successfully visualized by confocal microscopy. The failure has been attributed to the failure of the “click” reaction to tag the probe with the fluorophore. Topotecan is a small molecule that acts as an interfacial inhibitor, thus forming a ternary complex with DNA and topoisomerase 1. The steric hindrance generated by the ternary complex around the probe, dictates the inaccessibility of the alkyne moiety of the probe to “click” reagents

Energy efficiency tools for residential users

Residential energy consumption reserves a significant portion of the total energy consumption in modern cities. The rates of construction of new buildings as well as the rates of renovation on existing ones are generally very low. At the same time, unlike centrally operated large commercial buildings, the installation of energy management systems is a rather expensive solution leaving residential users with limited means to improve their energy efficiency as results are not evident. Considering that to drive energy efficient behaviour, we have to first raise awareness, then provide evidence through measurements and then support further, more elaborate, energy efficiency actions, we capitalise on ICT as soft measures towards reaching hard goals. We propose a novel incremental solution starting from a rather simple mobile application exploiting the sensors available in our smartphones and tablets to proceed to more intelligent advice provisioning towards energy efficiency. We present its implementation architecture and discuss certain market-wise challenges to prove its potential

Energy efficiency tools for residential users

Residential energy consumption reserves a significant portion of the total energy consumption in modern cities. The rates of construction of new buildings as well as the rates of renovation on existing ones are generally very low. At the same time, unlike centrally operated large commercial buildings, the installation of energy management systems is a rather expensive solution leaving residential users with limited means to improve their energy efficiency as results are not evident. Considering that to drive energy efficient behaviour, we have to first raise awareness, then provide evidence through measurements and then support further, more elaborate, energy efficiency actions, we capitalise on ICT as soft measures towards reaching hard goals. We propose a novel incremental solution starting from a rather simple mobile application exploiting the sensors available in our smartphones and tablets to proceed to more intelligent advice provisioning towards energy efficiency. We present its implementation architecture and discuss certain market-wise challenges to prove its potential

Inhibitors of BRAF dimers using an allosteric site

FDA-approved RAF inhibitors poorly inhibit BRAF dimers, which limits their clinical efficacy in tumors expressing BRAFV600E mutant monomers. Here the authors identify FDA-approved Ponatinib as an effective inhibitor of BRAF monomers and dimers and designed PHI1, an inhibitor with a unique mode of action and selectivity for oncogenic BRAF dimers

BMI1 nuclear location is critical for RAD51-dependent response to replication stress and drives chemoresistance in breast cancer stem cells

International audienceAbstract Replication stress (RS) has a pivotal role in tumor initiation, progression, or therapeutic resistance. In this study, we depicted the mechanism of breast cancer stem cells’ (bCSCs) response to RS and its clinical implication. We demonstrated that bCSCs present a limited level of RS compared with non-bCSCs in patient samples. We described for the first time that the spatial nuclear location of BMI1 protein triggers RS response in breast cancers. Hence, in bCSCs, BMI1 is rapidly located to stalled replication forks to recruit RAD51 and activate homologous-recombination machinery, whereas in non-bCSCs BMI1 is trapped on demethylated 1q12 megasatellites precluding effective RS response. We further demonstrated that BMI1/RAD51 axis activation is necessary to prevent cisplatin-induced DNA damage and that treatment of patient-derived xenografts with a RAD51 inhibitor sensitizes tumor-initiating cells to cisplatin. The comprehensive view of replicative-stress response in bCSC has profound implications for understanding and improving therapeutic resistance

Modulating mitofusins to control mitochondrial function and signaling

Mitofusins reside on the outer mitochondrial membrane and regulate mitochondrial fusion, a physiological process that impacts diverse cellular processes. Mitofusins are activated by conformational changes and subsequently oligomerize to enable mitochondrial fusion. Here, we identify small molecules that directly increase or inhibit mitofusins activity by modulating mitofusin conformations and oligomerization. We use these small molecules to better understand the role of mitofusins activity in mitochondrial fusion, function, and signaling. We find that mitofusin activation increases, whereas mitofusin inhibition decreases mitochondrial fusion and functionality. Remarkably, mitofusin inhibition also induces minority mitochondrial outer membrane permeabilization followed by sub-lethal caspase-3/7 activation, which in turn induces DNA damage and upregulates DNA damage response genes. In this context, apoptotic death induced by a second mitochondria-derived activator of caspases (SMAC) mimetic is potentiated by mitofusin inhibition. These data provide mechanistic insights into the function and regulation of mitofusins as well as small molecules to pharmacologically target mitofusins

Apoptotic stress causes mtDNA release during senescence and drives the SASP

Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP)1. Mitochondria are major regulators of the SASP; however, the underlying mechanisms have not been elucidated2. Mitochondria are often essential for apoptosis, a cell fate distinct from cellular senescence. During apoptosis, widespread mitochondrial outer membrane permeabilization (MOMP) commits a cell to die3. Here we find that MOMP occurring in a subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), requires BAX and BAK macropores enabling the release of mitochondrial DNA (mtDNA) into the cytosol. Cytosolic mtDNA in turn activates the cGAS–STING pathway, a major regulator of the SASP. We find that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan in aged mice. Our results reveal that apoptosis and senescence are regulated by similar mitochondria-dependent mechanisms and that sublethal mitochondrial apoptotic stress is a major driver of the SASP. We provide proof-of-concept that inhibition of miMOMP-induced inflammation may be a therapeutic route to improve healthspan