Here, the emerging data on DNA G‐quadruplexes (G4s) as epigenetic modulators are reviewed and integrated. This concept has appeared and evolved substantially in recent years. First, persistent G4s (e.g., those stabilized by exogenous ligands) were linked to the loss of the histone code. More recently, transient G4s (i.e., those formed upon replication or transcription and unfolded rapidly by helicases) were implicated in CpG island methylation maintenance and de novo CpG methylation control. The most recent data indicate that there are (...) direct interactions between G4s and chromatin remodeling factors. Finally, multiple findings support the indirect participation of G4s in chromatin reshaping via interactions with remodeling‐related transcription factors (TFs) or damage responders. Here, the links between the above processes are analyzed; also, how further elucidation of these processes may stimulate the progress of epigenetic therapy is discussed, and the remaining open questions are highlighted. (shrink)

The concept of a G‐quartet, a unique structural arrangement intrinsic to guanine‐rich DNA, was first introduced by Gellert and colleagues1 over 40 years ago. For decades, it has been uncertain whether the G‐quartet and the structure that it gives rise to, the G‐quadruplex, are purely in vitro phenomena. Nevertheless, the presence of signature G‐rich motifs in the eukaryotic genome, and the plethora of proteins that bind to, modify or resolve this nucleic acid structure in vitro have provided circumstantial evidence for (...) its physiological relevance. More recently, direct visualisation of G‐quadruplex DNA at native telomeres was achieved, bolstering the evidence for its existence in the cell. Furthermore, G‐quadruplex folded telomeric DNA has been found to perturb telomere function and to impede the action of telomerase, an enzyme overexpressed in >85% of human cancers, hence opening up a novel avenue for cancer therapy in the form of G‐quadruplex stabilising agents. BioEssays 29: 155–165, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

In this study a combination of computer tools for coupling and virtual screening is detailed, in 108 active molecules and 3620 decoys to find stabilizers for G quadruplex. To have more precise results, combinations of coupling programs with fifteen energy scoring functions were applied. The validation and evaluation of the metrics was done with the CompScore genetic algorithm. The results showed an increase in BEDROC and EF of 50% compared to other strategies, as well as reflecting early recognition of active (...) molecules. From these results it is possible to work with the molecules that showed a good early recognition and evaluate their effect as G4 stabilizers. This ensures more efficient and accurate results in the preclinical stage for the development of anticancer drugs. Keywords: Enrichment metrics; telomere; G quadruplex ; CompScore. References [1]M. Porru, P. Zizza, M. Franceschin, C. Leonetti and A. Biroccio. «EMICORON: A multi-targeting G4 ligand with a promising preclinical profile» 2017. Biochimica et Biophysica Acta - General Subjects, 1861, 1362–1370. [Online]. Available: https://doi.org/10.1007/s00294-018-0836-6. [2]K. Tomita. «How long does telomerase extend telomeres? Regulation of telomerase release and telomere length homeostasis». Current Genetics, 64, 1177–1181. 2018. [Online]. Available: https://doi.org/10.1016/j.bbagen. 2016.11.010. [3]M. Jafri, S. Ansari, M. Alqahtani and J. Shay. «Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies. Genome Medicine., 2016. [Online]. Available: https://doi.org/10.3390/ijms19020482. [4]J. Huppert and S. Balasubramanian. «G-quadruplexes in promoters throughout the human genome». 35, 406–413. 2007. [Online]. Available: https://doi.org/10.1016/j.bbapap.2017.06.012. [5]S. Joy, Vijayakumar, S. Choi and H. Sunhye. «Role of computer-aided drug design in modern drug discovery». Archives of Pharmacal Research. 2015. [Online]. Available: https://doi.org/10.1007/s12272-015-0640-5. [6]S. Asamitsu, S. Obata, Z. Yu, T. Bando and H. Sugiyama. «Recent Progress of Targeted G-Quadruplex-Preferred Ligands Toward Cancer Therapy». Molecules, 24, 429. 2019. [En línea]. Available: https://doi.org/10.3390/molecules24030429. [7]R. Monsen and J. Trent. «Biochimie G-quadruplex virtual drug screening : A review». Biochimie, 152, 134–148. 2018. [Online]. Available: https://doi.org/10.1039/c9cc06748e. [8]J. Beauvarlet, P. Bensadoun, E. Darbo, G. Labrunie, E. Richard, I. Draskovic and M. Djavaheri-mergny. «Modulation of the ATM / autophagy pathway by a G-quadruplex ligand tips the balance between senescence and apoptosis in cancer cells». 1–18. 2019. [Online]. Available: https://doi.org/10.1093/nar/gkz095. [9].Z. Crees, J. Girard, Z. Rios, G. Botting, K. Harrington and C. Shearrow. « Oligonucleotides and G-quadruplex stabilizers: targeting telomeres and telomerase in cancer therapy».2014. [Online]. Available: https://doi.org/10.2174/1381612820666140630100702. [10].M. Meier, A. Moya-torres, N. Krahn, M. Mcdougall, L. Orriss, E. Mcrae and T. Patel. «Structure and hydrodynamics of a DNA Gquadruplex with a cytosine bulge»., 1–13. 2018. [Online]. Available: https://doi.org/10.1093/nar/gky307. (shrink)

In vertebrates, single cell analyses of replication timing patterns brought to light a very well controlled program suggesting a tight regulation on initiation sites. Mapping of replication origins with different methods has revealed discrete preferential sites, enriched in promoters and potential G‐quadruplex motifs, which can aggregate into initiation zones spanning several tens of kilobases (kb). Another characteristic of replication origins is a nucleosome‐free region (NFR). A modified yeast strain containing a humanized origin recognition complex (ORC) fires new origins at NFRs (...) revealing their regulatory role. In cooperation with NFRs, the histone variant H2A.Z facilitates ORC loading through di‐methylation of lysine 20 of histone H4. Recent studies using genome editing methods show that efficient initiation sites associated with transcriptional activity can synergize over several tens of kb by establishing physical contacts and lead to the formation of early domains of DNA replication demonstrating a co‐regulation between replication initiation and transcription. (shrink)

Abstract3′ untranslated regions (3′ UTRs) of mRNAs have many functions, including mRNA processing and transport, translational regulation, and mRNA degradation and stability. These different functions require cis‐elements in 3′ UTRs that can be either sequence motifs or RNA structures. Here we review the role of secondary structures in the functioning of 3′ UTRs and discuss some of the trans‐acting factors that interact with these secondary structures in eukaryotic organisms. We propose potential participation of 3′‐UTR secondary structures in cytoplasmic polyadenylation in (...) the model organism Drosophila melanogaster. Because the secondary structures of 3′ UTRs are essential for post‐transcriptional regulation of gene expression, their disruption leads to a wide range of disorders, including cancer and cardiovascular diseases. Trans‐acting factors, such as STAU1 and nucleolin, which interact with 3′‐UTR secondary structures of target transcripts, influence the pathogenesis of neurodegenerative diseases and tumor metastasis, suggesting that they are possible therapeutic targets. (shrink)

In this book William G. Lycan offers an epistemology of philosophy itself, a partial method for philosophical inquiry. The epistemology features three ultimate sources of justified philosophical belief. First, common sense, in a carefully restricted sense of the term-the sorts of contingentpropositions Moore defended against idealists and skeptics. Second, the deliverances of well confirmed science. Third and more fundamentally, intuitions about cases in a carefully specified sense of that term. The first half of On Evidence in Philosophy expounds a version (...) of Moore's method and applies it to each of several issues. This version is shown to resist all the standard objections to Moore; most of them do not even apply. It is argued, in Chapters 5 and 6, that philosophical method is far lesspowerful than most have taken it to be. In particular, deductive argument can accomplish very little, and hardly ever is an opposing position refuted except by common sense or by science. The final two chapters defend the evidential status of intuitions and the Goodmanian method of reflectiveequilibrium; it is argued that philosophy always and everywhere depends on them. The method is then set within a more general explanatory-coherentist epistemology, which is shown to resist standard forms of skepticism.In sum, William G. Lycan advocates a picture of philosophy as a very wide explanatory reflective equilibrium incorporating common sense, science, and our firmest intuitions on any topic-and nothing more, not ever. (shrink)

First published in 2000. Routledge is an imprint of Taylor & Francis, an informa company.

Many defenders of the possibility of time travel into the past also hold that such time travel places no restrictions on what said time travelers can do. Some hold that it places at least a few restrictions on what time travelers can do. In attempting to resolve this dispute, I reached a contrary conclusion. Time travelers to the past cannot do other than what they in fact do. Using a very weak notion of can, I shall argue that the correspondingly (...) strong cannot do otherwise applies in the case of backwards time travel. I defend this result from objections. (shrink)

This book traces the intellectual revolution initiated by Thales in the sixth century BC to its culmination in the metaphysics of Parmenides.

This book traces the intellectual revolution initiated by Thales in the sixth century BC to its culmination in the metaphysics of Parmenides.

In questo volume sono raccolti gli scritti frutto della ricerca effettuata nell’ambito del Progetto: “Ontologia Formale e Ontologie: uno Strumento per il Dialogo Interdisciplinare e Interculturale”. Scopo del progetto è mostrare al pubblico intellettuale italiano, sia di estrazione scientifica che umanistica, le potenzialità dello strumento dell’ontologia in generale, e dell’ontologia formale in particolare, per il dialogo costruttivo interdisciplinare e interculturale. Dialogo interdisciplinare per il rapporto fra discipline scientifiche e umanistiche, dialogo interculturale per il rapporto fra le diverse culture e religioni (...) in una società globalizzata. (shrink)

El informe sobre el estado de la democracia liberal de 2022 elaborado por el Instituto de investigación V-Dem de la Universidad de Gothenburg constata la existencia de un claro declive global en el apoyo a este sistema de gobierno que baja a los niveles de 1989.

This compilation of student research papers and analysis of important historical legal papers attempts to compare the experience of the past political-legal issues with the present.

La noticia de la inauguración en mayo de este año del Global Hub for Pandemic and Epidemic Intelligence en Berlín pasó un tanto desapercibida. Esta fue una de las últimas jugadas maestras de estrategia política de la fulgurante carrera ciertamente no académica de la canciller alemana Angela Merkel, quien anunció que Alemania aportará una financiación anual de treinta millones de euros.