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DNA damage response (DDR) is a term that includes a variety of highly sophisticated mechanisms that cells have evolved in safeguarding the genome from the deleterious consequences of DNA damage. It is estimated that every single cell receives tens of thousands of DNA lesions per day. Failure of DDR to properly respond to DNA damage leads to stem cell dysfunction, accelerated ageing, various degenerative diseases or cancer. The sole function of DDR is to recognize diverse DNA lesions, signal their presence, activate cell cycle arrest and finally recruit specific DNA repair proteins to fix the DNA damage and thus prevent genomic instability. DDR is composed of hundreds of spatiotemporally regulated and interconnected proteins, which are able to promptly respond to various DNA lesions. So it is not surprising that mutations in genes encoding various DDR proteins cause embryonic lethality, malignancies, neurodegenerative diseases and premature ageing. The importance of DDR for cell survival and genome stability is unquestionable, but how the sophisticated network of hundreds of different DDR proteins is spatiotemporally coordinated is far from being understood. In the last ten years ubiquitin (ubiquitination) and the ubiquitin-relative SUMO (sumoylation) have emerged as essential posttranslational modifications that regulate DDR. Beside a plethora of ubiqutin and sumo E1-activating enzymes, E2-conjugating enzymes, E3-ligases and ubiquitin/sumo proteases involved in ubiquitination and sumoylation, the complexity of ubiqutin and sumo systems is additionally increased by the fact that both ubiquitin and sumo can form a variety of different chains on substrates which govern the substrate fate, such as its interaction with other proteins, changing its enzymatic activity or promoting substrate degradation. The importance of ubiquitin/SUMO systems in the orchestration of DDR is best illustrated in patients with mutations in E3-ubiquitin ligases BRCA1 or RNF168. BRCA1 is essential for proper function of DDR and its mutations lead to triple-negative breast and ovarian cancers. RNF168 is an E3 ubiquitin ligase, which creates the ubiquitin docking platform for recruitment of different DNA damage signalling and repair proteins at sites of DNA lesion, and its mutations cause RIDDLE syndrome characterized by radiosensitivity, immunodeficiency and learning disability. In addition, recently discovered the ubiquitin receptor protein SPRTN is part of the DNA replication machinery and its mutations cause early-onset hepatocellular carcinoma and premature ageing in humans. Despite more than 700 different enzymes directly involved in ubiquitination and sumoylation processes only few of them are known to play a role in DDR. Therefore, we feel that the role of ubiquitin and the ubiquitin-related SUMO in DDR is far from being understood, and that this is the emerging field that will hugely expand in the next decade due to the rapid development of a new generation of technologies, which will allow us a more robust and precise analyses of human genome, transcriptome and proteome. In this Research Topic we provide a comprehensive overview of our current understanding of ubiquitin and SUMO pathways in all aspects of DDR, from DNA replication to different DNA repair pathways, and demonstrate how alterations in these pathways cause genomic instability that is linked to degenerative diseases, cancer and pathological ageing.

Priya

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Hephaestus Reloaded / Efesto Reloaded, presented in a bilingual (English/Italian) publication, and whose five authors are from Greece, Italy, and the US, invokes as its first inspiration the myth of Hephaestus who embodied a twofold entity: both disabled and technically capacious. The myth of Hephaestus has been passed across the centuries as an ancient metaphor signifying the idea of becoming-world, in which any distinction between the natural and the artificial, or the organic and the technical, is blurred. Human beings, by virtue of their physical vulnerabilities and limits, have enhanced their technological powers to the point of transcending their own given nature. At present, a variety of critical discourses in disciplines such as philosophy, history, aesthetics, and cognitive sciences pay attention to our becoming-hybrid (organic and mechanical beings) – unleashing a space for research that probes the concept of transcendence. Each of the contributions in this book addresses – through its own peculiar perspective, method and experimental style – a new way to approach the role of transcendence in socio-cultural life.In the Occidental history of ideas, the notion of transcendence has received at least three canonical articulations that are challenged by this book: religious (Judeo-Christian traditions), philosophical (Platonic-intellectual universality of ideas), and scientific (the objective and technological turn of knowledge). Nonetheless, it is with the rise of cybernetics, with its digital and virtual modalities of systems, networks, and knowledge, that our human environment emerges as a source of knowledge in itself -- not simply as an object but rather as an immersive agency in which nature, knowledge, technique merge. The transcendence of the actual and the virtual into a “third” element is construed and analyzed in this book through conceptual schemes that rely on a post-binary or non-binary understanding of coincidences, triangulations, hybrids, or post-human combinatorics. What is ultimately explored is how transcendence is ejected from strictly theological, philosophical, or scientific groundings and emerges as a germinating point of becoming (something else).

Dr. George Felfoldi

Music sheet from late 1969 called "There's A Change" by George Felfoldi & Lew Tobins from 5 Star Music Productions, Nashville, Tenn. USA

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"EPDF and EPUB available Open Access under CC-BY-NC-ND licence. Human service work is performed in many places – hospitals, shelters, households – and is characterised by a complex mixture of organising principles, relations and rules. Using ethnographic methods, researchers can investigate these site-specific complexities, providing multi-dimensional and compelling analyses. Bringing together both theoretical and practical material, this book shows researchers how ethnography can be carried out within human service settings. It provides an invaluable guide on how to apply ethnographic creativeness and offers a more humanistic and context-sensitive approach in the field of health and social care to generating valid knowledge about today’s service work."

One direction It

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This volume contains six essays that address the ""synoptic problem"" in the study of rabbinic literature. As a whole, they argue for the utility of recognizing that rabbinic documents are as much collections of traditions as they are well-crafted documents only to be considered in and of themselves.

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