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.

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

In this text, Georges Didi-Huberman responds, in letter-form, to the critical reflections about his work formulated by Jacques Rancière in “Images Re-read: Georges Didi-Huberman’s Method.” Didi-Huberman disagrees with Rancière’s analysis that images are “passive” and that the words which accompany them are “active.” Instead, he agrees with Merleau-Ponty’s view, which postulates that any analysis of images that seeks to disentangle its elements will render the image unintelligible. In opposition to Rancière’s presentation of his work, Didi-Huberman argues that his method is (...) one of tracing the mutually entangled implications of images. Furthermore, Didi-Huberman challenges Rancière to articulate what exactly “the sensible” means when he uses the phrase “distribution of the sensible.” While Rancière distrusts the reliance on pathos and emotions when it comes to analysing images, Didi-Huberman argues that “the sensible” will always involve the body with all its pathos, emotions and gestures. (shrink)

In this text, Jacques Rancière critically discusses the work of Georges Didi-Huberman on images. He disagrees with various claims seemingly made by Didi-Huberman about images, such as that they can “take position” or that they are “active.” Rancière argues that Didi-Huberman adds another form of dialectics to the simpler form of dialectics adopted by Bertolt Brecht and Harun Farocki in their works, namely one that also involves a layering of different temporalities. However, both in Brecht’s War Primer and in Didi-Huberman’s (...) analysis of it, all the potencies credited to images as such are actually potencies of the words that accompany the images. Rancière comes to the conclusion that to “put images in motion,” as Didi-Huberman wants to do, or to regard them as being “active,” he has to put words, his own poetic and extensive writings, in motion. (shrink)

Fichte assigns ‘intellectual intuition’ a new meaning after Kant. But in 1799, his doctrine of intellectual intuition is publicly deemed indefensible by Kant and nihilistic by Jacobi. I propose to defend Fichte’s doctrine against these charges, leaving aside whether it captures what he calls the ‘spirit’ of transcendental idealism. I do so by articulating three problems that motivate Fichte’s redirection of intellectual intuition from being to acting: (1) the regress problem, which states that reflecting on empirical facts of consciousness leads (...) only to further facts and so cannot yield a first principle; (2) the rhapsody problem, which states that the categories form a haphazard set and so lack necessity unless they derive from a first principle; and (3) the nihilism problem, which states that a first principle cannot lie outside our cognition of it, lest it be the cause of our cognition and, being first, the cause of all our actions, reducing us to machines. Crucially, Fichte’s three motivating problems are in fact aspects of a single problem. Leaving any aspect unsolved spoils putative solutions to the other two. Consequently, Fichte requires a single unified solution to all three, which his doctrine of intellectual intuition provides. (shrink)

In the Vocation of Man, Fichte makes the striking claim that life is eternal, rational, our true being, and the final cause of nature in general and of death in particular. How can we make sense of this claim? I argue that the public lectures that compose the Vocation are a popular expression of Fichte’s pre-existing commitment to what I call immortalism, the view that life is the unconditioned condition of intelligibility. Casting the I as an absolutely self-active or living (...) power enables his philosophical account of both the intelligibility of objects and of what it means to die. This explains his characterization of the Wissenschaftslehre as a system in which ‘all is act, movement, and life’. In Sect. 1, I explain the context of Jacobi’s use of ‘caput mortuum’ as a term for the thing in itself. In Sects. 2 and 3, I reconstruct two immortalist arguments from Fichte’s Jena period. The first is that the I’s self-activity rules out the existence of the thing in itself and thereby vanquishes ‘death’s head’. The second is that, insofar as the I charges us with the moral perfection of nature, it is the final cause of our entire life, including its end. This is to say that the I puts our every moment into question, even our last. In Sect. 4, I use these immortalist arguments to interpret the striking claim from the Vocation. (shrink)

We examine the role of religious identity in promoting strategic renewal in privately held founder family firms. Religious identity in these firms refers to their collective sense of being that reflects their founders’ and owner family members’ espoused religious values and beliefs, thereby distinguishing themselves from others in what is central, distinct, and enduring about their organization. We propose that such a religious identity determines family firms’ spiritual capital, which influences strategic renewal activities such as conflict resolution and resource allocation. (...) Specifically, we argue that spiritual capital can be a double-edged sword when family firms pursue strategic renewal. We discuss the implications of our work for future research. (shrink)

We examine the role of religious identity in promoting strategic renewal in privately held founder family firms. Religious identity in these firms refers to their collective sense of being that reflects their founders’ and owner family members’ espoused religious values and beliefs, thereby distinguishing themselves from others in what is central, distinct, and enduring about their organization. We propose that such a religious identity determines family firms’ spiritual capital, which influences strategic renewal activities such as conflict resolution and resource allocation. (...) Specifically, we argue that spiritual capital can be a double-edged sword when family firms pursue strategic renewal. We discuss the implications of our work for future research. (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)

Ethics in business and economics is often attacked for being too superficial. By elaborating the conclusions of two such critics of business ethics and welfare economics respectively, this article will draw the attention to the ethics behind these apparently well-intended, but not always convincing constructions, by help of the fundamental ethics of Emmanuel Levinas. To Levinas, responsibility is more basic than language, and thus also more basic than all social constructions. Co-operation relations in organizations, markets and value networks are generated (...) from personal relations and personal responsibilities. It is not sufficient to integrate ethics in an impersonal, rational system, neither in business organizations nor in the world economy. Ethics has its source not in rationality, but in the personal. (shrink)

Levinas did not present any new ethical theories; he did not even give any normative recommendations. But his phenomenological investigations help us to understand how the idea of ethics emerges and how we try to cope with it. The purpose of this paper is to suggest some implications from a reading of Levinas on how ethical challenges are handled within a management perspective. The paper claims that management, both in theory and in practice, is necessarily egocentric and thus ethically biased. (...) Therefore, ethics, defined as the idea that it is possible to do otherwise than pursue one's own interest, must have its source outside the scope of management. Levinas identifies this source as the call for responsibility from the Other, beyond the reach of managerial control. He also suggests how this idea of ethics is put into practice, especially in economic life: the existence of money makes it both possible and necessary to compare unique and incomparable others. Management tools may be used in the service of always more justice, as it also may be used for the opposite purpose. Instead of trying to draw a normative conclusion from Levinas, we may distinguish between two ways of experiencing reality: one through language and knowledge, covering both descriptive and normative knowledge, including business ethics, and the other through the particular events of encounters, from where this knowledge is continuously questioned through the call for responsibility, and thereby may provide possibilities for continuous improvements towards always more justice. (shrink)

Levinas did not present any new ethical theories; he did not even give any normative recommendations. But his phenomenological investigations help us to understand how the idea of ethics emerges and how we try to cope with it. The purpose of this paper is to suggest some implications from a reading of Levinas on how ethical challenges are handled within a management perspective. The paper claims that management, both in theory and in practice, is necessarily egocentric and thus ethically biased. (...) Therefore, ethics, defined as the idea that it is possible to do otherwise than pursue one's own interest, must have its source outside the scope of management. Levinas identifies this source as the call for responsibility from the Other, beyond the reach of managerial control. He also suggests how this idea of ethics is put into practice, especially in economic life: the existence of money makes it both possible and necessary to compare unique and incomparable others. Management tools may be used in the service of always more justice, as it also may be used for the opposite purpose. Instead of trying to draw a normative conclusion from Levinas, we may distinguish between two ways of experiencing reality: one through language and knowledge, covering both descriptive and normative knowledge, including ‘business ethics’, and the other through the particular events of encounters, from where this knowledge is continuously questioned through the call for responsibility, and thereby may provide possibilities for continuous improvements towards always more justice. (shrink)

Two attitudes are possible: one, that the world is an absolute jungle and that the exercise of coercive power by rulers is only a manifestation of this; and the other, that it is both necessary and right that there should be this exercise of power, that through it the world is much less of a jungle than it could possibly be without it, so that one should in principle be glad of the existence of such power, and only take exception (...) to its unjust exercise. (shrink)

The familiar issue of corporate social responsibility takes on a new topic. Added to the list of concerns from affirmative action and environmental integrity is their growing contributions to education. At first glance, the efforts may appear to be ordinary gestures of communal good will in terms of providing computers, sponsoring book covers, and interactive materials provided by Scholastic Magazine. A closer view reveals a targeted market of student life who are vulnerable to commercials placed in these formats. Among the (...) most effective corporate intervention is Channel One News. It offers a newsworthy show but with mandatory commercial viewing. This increasing trend of corporations intervening to assist schools that need more money and/or equipment is disingenuous.In this essay, I present the background of this commercialization of education and demonstrate the violations against student autonomy and integrity. Although there may be utilitarian merits to some interventions, I argue that these infringe upon the moral value of personhood. Advertising in schools in its current practice is immoral on deontological grounds. (shrink)

Kant’s critique/doctrine distinction tracks the difference between a canon for the understanding’s proper use and an organon for its dialectical misuse. The latter reflects the dogmatic use of reason to attain a doctrine of knowledge with no antecedent critique. In the 1790s, Fichte collapses Kant’s distinction and redefines dogmatism. He argues that deriving a canon is essentially dialectical and thus yields an organon: critical idealism is properly a doctrine of science or Wissenschaftslehre. Criticism is furthermore said to refute dogmatism, by (...) which Fichte means Spinozism. Schelling repudiates Fichte’s position in his Philosophical Letters by reviving Kant’s distinction. First, ‘critique’ for Schelling names a canon that is valid for all systems—including Spinozism—and thus favours none—not even the Wissenschaftslehre. Second, Schelling coins ‘dogmaticism’ to refer to what Kant calls ‘dogmatism’: reason’s uncritical claim to doctrine. Hence, he says all systems—even Fichte’s—are susceptible to the ‘enthusiasm’ of mistaking themselves for doctrines or ‘objects of knowledge’, instead of subjectively valid ‘objects of freedom’. I reconstruct Schelling’s argument for reviving Kant’s distinction, while noting two consequences for German idealism. First, if criticism favours no system, a system’s origin cannot be an act of knowledge, e.g., intellectual intuition, but only an act of endorsement. Second, if dogmaticism entails enthusiasm, a system’s goal cannot be absolute knowledge, but only infinite striving. Hence, by retrieving Schelling’s notion of dogmaticism, we can both gain a better understanding of the Letters and register the impact of a core Kantian distinction on the German idealist project. (shrink)

The concept of facticity denotes conditions of experience whose necessity is not logical yet whose contingency is not empirical. Although often associated with Heidegger, Fichte coins ‘facticity’ in his Berlin period to refer to the conclusion of Kant’s metaphysical deduction of the categories, which he argues leaves it a contingent matter that we have the conditions of experience that we do. Such rhapsodic or factical conditions, he argues, must follow necessarily, independent of empirical givenness, from the I through a process (...) of ‘genesis.’ I reconstruct Fichte’s argument by tracing the origin of his neologism, presenting his Jena critique of Kant’s rhapsodic appeal to the forms of judgment, and illustrating the Jena period’s continuity with the Berlin period’s genetic method, while noting a methodological shift whereby Fichte directs his critique against his own doctrine of intellectual intuition in order to eliminate its ‘factical terms.’. (shrink)

Fichte argues that the conclusion of Kant’s transcendental deduction of the categories is correct yet lacks a crucial premise, given Kant’s admission that the metaphysical deduction locates an arbitrary origin for the categories. Fichte provides the missing premise by employing a new method: a genetic deduction of the categories from a first principle. Since Fichte claims to articulate the same view as Kant in a different, it is crucial to grasp genetic deduction in relation to the sorts of deduction that (...) Kant offers. I propose to interpret genetic deduction as the simultaneous fulfillment of two tasks: answering the question quid facti by deriving the categories from the I and answering the question quid juris by establishing our entitlement to the categories as conditions of experience. While the second task represents Fichte’s agreement with Kant’s transcendental deduction, the first reflects his correction of Kant’s metaphysical deduction. (shrink)