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)

Ese artículo presenta una síntesis de las teorías normativas de la guerra justa, mostrando los consensos teóricos existentes en las tres categorías de la ius ad bellum (la justicia de la guerra), ius in bello (la justicia en la guerra) y ius postbelum (justicia de la postguerra). Posteriormente, se desarrollan estos conceptos para el caso de una guerra real.

El concepto de 'legitimidad' que introduce Weber tiene que ver con el grado de aceptación que los gobernados confieren a sus gobernantes. Filósofos, como Habermas, han contestado esta concepción señalando que la aceptación debe estar enmarcada en un sistema normativo que garantice los derechos en uso de esa comunidad y estipule las reglas que el gobernante ha de cumplir para acceder al ejercicio del gobierno. Puede discutirse si la concepción de Weber es tal como la describe Habermas o si ella (...) da cuenta de los aspectos que aquí se señalan. Pero el hecho es que el concepto de 'legitimidad' se disocia, entonces, en dos: legitimidad de origen (aceptabilidad) y legitimidad funcional (el objeto del ejercicio del poder y la manera como se accede a este). [Fragmento]. (shrink)

Ese artículo presenta una síntesis de las teorías normativas de la guerra justa, mostrando los consensos teóricos existentes en las tres categorías de la ius ad bellum (la justicia de la guerra), ius in bello (la justicia en la guerra) y ius postbelum (justicia de la postguerra). Posteriormente, se desarrollan estos conceptos para el caso de una guerra real.

Se aplica la idea perelmaniana de valor como una noción que, aunque confusa, permite el acuerdo del auditorio universal (el conjunto de individuos adultos y razonables), con el propósito de presentar una ética que, de una parte, supere las limitaciones del liberalismo rawlsiano fundamentado en el constructivismo kantiano, y de la otra, critique por limitadamente practicable el modelo puramente dialógico de Habermas. Todo esto, no obstante, salvando las contribuciones que estos dos pensadores aportan para resolver conflictos éticos y políticos en (...) el mundo actual. La ética argumentativa aquí presentada defiende el acuerdo entre pretensiones rivales de justicia como resultado de la acción estratégica tanto como de la acción comunicativa, sobre la base de un concepto de progreso moral entendido como un punto de no retomo encamado en la concepción de los derechos humanos y su desarrollo en la sociedad contemporánea. (shrink)

La idea perelmaniana de valor como noción confusa pero posibilitadora del acuerdo del auditorio universal (conjunto de los individuos adultos y razonables de la época actual) se aplica aquí para hacer una propuesta de ética que supere, de un lado, las limitaciones de la línea de fundamentación monológica inaugurada por Kant y defendida en la actualidad por Rawls; y que critique, del otro, el modelo puramente dialógico habermasiano por impracticable.

l. "Los axiomas de un sistema axiomático deben ser autoevidentes". ¿Cómo son, entonces, autoevidentes? ¿Qué ocurre si dijera: así es como lo encuentro mas fácil de imaginar. Y aquí imaginar no es un proceso mental particular en el cual uno cierra sus ojos o los cubre con las manos.

Normal propositional modal systems This first chapter has two main aims. One is to give a general account of the propositional modal systems that we shall ...

An examination of verbal hallucinations and thought insertion as examples of "alienated self-consciousness.".

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

This entirely new work guides the reader through the most basic systems of modal propositional logic up to systems of modal predicate with identity, dealing with both technical developments and discussing philosophical applications.

Biological evolution is a complex blend of ever changing structural stability, variability and emergence of new phe- notypes, niches, ecosystems. We wish to argue that the evo- lution of life marks the end of a physics world view of law entailed dynamics. Our considerations depend upon dis- cussing the variability of the very ”contexts of life”: the in- teractions between organisms, biological niches and ecosys- tems. These are ever changing, intrinsically indeterminate and even unprestatable: we do not know ahead of (...) time the ”niches” which constitute the boundary conditions on selec- tion. More generally, by the mathematical unprestatability of the ”phase space”, no laws of mo- tion can be formulated for evolution. We call this radical emergence, from life to life. The purpose of this paper is the integration of variation and diversity in a sound concep- tual frame and situate unpredictability at a novel theoretical level, that of the very phase space. Our argument will be carried on in close comparisons with physics and the mathematical constructions of phase spaces in that discipline. The role of symmetries as invariant preserving transformations will allow us to under- stand the nature of physical phase spaces and to stress the differences required for a sound biological theoretizing. In this frame, we discuss the novel notion of ”enablement”. Life lives in a web of enablement and radical emergence. This will restrict causal analyses to differential cases. Mutations or other causal differ- ences will allow us to stress that ”non conservation princi- ples” are at the core of evolution, in contrast to physical dynamics, largely based on conservation principles as sym- metries. Critical transitions, the main locus of symmetry changes in physics, will be discussed, and lead to ”extended criticality” as a conceptual frame for a better understanding of the living state of matter. (shrink)

Hume's Reception in Early America: Expanded Edition brings together the original American responses to one of Britain's greatest men of letters, David Hume. Now available as a single volume paperback, this new edition includes updated further readings suggestions and dozens of additional primary sources gathered together in a completely new concluding section. From complete pamphlets and booklets, to poems, reviews, and letters, to extracts from newspapers, religious magazines and literary and political journals, this book's contents come from a wide variety (...) of sources published in colonial America and the early United States between 1758 and 1850. As well as classics by Thomas Jefferson, John Adams and Alexander Hamilton, it contains scores of unknown and hard-to-locate items, many of which have not been reprinted since their original publication. These responses are divided into four parts covering Hume's Essays; his Philosophical Writings; his History of England; and his Character and Death. Each of those parts has a separate introductory essay, and every selection is introduced by a short headnote that sets the piece in its historical context and provides bibliographical references. Packed with new insights into Hume and American thought and culture, Hume's Reception in Early America reveals the relevance and impact of Hume on American political, philosophical, historical, religious, and aesthetic debates. (shrink)

Editor James Fetzer presents an analytical and historical introduction and a comprehensive bibliography together with selections of many of Carl G. Hempel's most important studies to give students and scholars an ideal opportunity to appreciate the enduring contributions of one of the most influential philosophers of science of the 20th century.

One of Hume's most well-known works and a masterpiece of philosophy, A Treatise of Human Nature is indubitably worth taking the time to read.

This is a welcome reprint of a book that continues to grow in importance.

Lycan not only uses the numerous arguments against materialism, and functionalist theories of mind in particular, to gain a more detailed positive view of the ..

The author presents and defends three theses: (1) "the first is that it is not profitable for us at present to do moral philosophy; that should be laid aside at any rate until we have an adequate philosophy of psychology." (2) "the second is that the concepts of obligation, And duty... And of what is morally right and wrong, And of the moral sense of 'ought', Ought to be jettisoned if this is psychologically possible...." (3) "the third thesis is that (...) the differences between the well-Known english writers on moral philosophy from sidgwick to the present day are of little importance." (staff). (shrink)

Throughout his career, Schelling assigns knowledge of the absolute first principle of philosophy to intellectual intuition. Schelling's doctrine of intellectual intuition raises two important questions for interpreters. First, given that his doctrine undergoes several changes before and after his identity philosophy, to what extent can he be said to “hold onto” the same “sense” of it by the 1830s, as he claims? Second, given that his doctrine of intellectual intuition restricts absolute idealism to what he calls a “science of reason”, (...) which he says cannot prove the absolute’s existence, what other doctrine does he require in order to prove this? I will answer these questions by tracing the shifts in Schelling’s doctrine of intellectual intuition from the 1790s to the 1830s and drawing out its evolving methodological role within his science of intelligibility. (shrink)