Vasoactivity of Rucaparib, a PARP-1 Inhibitor, is a Complex Process that Involves Myosin Light Chain Kinase, P2 Receptors, and PARP Itself

Therapeutic inhibition of poly(ADP-ribose) polymerase (PARP), as monotherapy or to supplement the potencies of other agents, is a promising strategy in cancer treatment. We previously reported that the first PARP inhibitor to enter clinical trial, rucaparib (AG014699), induced vasodilation in vivo in xenografts, potentiating response to temozolomide. We now report that rucaparib inhibits the activity of the muscle contraction mediator myosin light chain kinase (MLCK) 10-fold more potently than its commercially available inhibitor ML-9. Moreover, rucaparib produces additive relaxation above the maximal degree achievable with ML-9, suggesting that MLCK inhibition is not solely responsible for dilation. Inhibition of nitric oxide synthesis using L-NMMA also failed to impact rucaparib's activity. Rucaparib contains the nicotinamide pharmacophore, suggesting it may inhibit other NAD+-dependent processes. NAD+ exerts P2 purinergic receptor-dependent inhibition of smooth muscle contraction. Indiscriminate blockade of the P2 purinergic receptors with suramin abrogated rucaparib-induced vasodilation in rat arterial tissue without affecting ML-9-evoked dilation, although the specific receptor subtypes responsible have not been unequivocally identified. Furthermore, dorsal window chamber and real time tumor vessel perfusion analyses in PARP-1-/- mice indicate a potential role for PARP in dilation of tumor-recruited vessels. Finally, rucaparib provoked relaxation in 70% of patient-derived tumor-associated vessels. These data provide tantalising evidence of the complexity of the mechanism underlying rucaparib-mediated vasodilation.

Sentimento e reflexão : crítica da identidade nos «Fichte-studien» de Novalis

Tese de doutoramento, Estudos de Literatura e de Cultura (Estudos de Literatura e de Cultura de Expressão Alemão), Universidade de Lisboa, Faculdade de Letras, 2016

Does companionate love express itself unequally in different organizational forms (private companies, hybrid and non-governmental organizations)?

Although, the word “Love” in organizations is seen as a rare concept, but it has gained importance in management theoretical foundation. This study seeks to explore the companionate love in distinct of organizational forms (Private companies; Social organizations; NGO and IPSS) through interviews. The results propose that it is a tensional concept with a complex dynamic: tension of personal behavior, tension of professional behavior; tension of individual impact and tension of community impact. The love dynamic has common points to all organizations, but its expression depends on the specific form of the organization.

Husserl's approach to transcendental intersubjectivity

It is our intention in the course of the development of this thesis to give an account of how intersubjectivity is "eidetically" constituted by means of the application of the phenomenological reduction to our experience in the context of the thought of Edmund Husserl; contrasted with various representative thinkers in what H. Spiegelberg refers to as "the wider scene" of phenomenology. That is to say, we intend to show those structures of both consciousness and the relation which man has to the world which present themselves as the generic conditions for the possibility of overcoming our "radical sol itude" in order that we may gain access to the mental 1 ife of an Other as other human subject. It is clear that in order for us to give expression to these accounts in a coherent manner, along with their relative merits, it will be necessary to develop the common features of any phenomenological theory of consdousness whatever. Therefore, our preliminary inquiry, subordinate to the larger theme, shall be into some of the epistemological results of the application of the phenomenological method used to develop a transcendental theory of consciousness. Inherent in this will be the deliniation of the exigency for making this an lIintentional ll theory. We will then be able to see how itis possible to overcome transcendentally the Other as an object merely given among other merely given objects, and further, how this other is constituted specifically as other ego. The problem of transcendental intersubjectivity and its constitution in experience can be viewed as one of the most compelling, if not the most polemical of issues in phenomenology. To be sure, right from the beginning we are forced to ask a number of questions regarding Husserl's responses to the problem within the context of the methodological genesis of the Cartesian Meditations, and The Crisis of European Sciences and Transcendental Phenomenology. This we do in order to set the stage for amplification. First, we ask, has Husserl lived up to his goal, in this connexion, of an apodictic result? We recall that in his Logos article of 1911 he adminished that previous philosophy does not have at its disposal a merely incomplete and, in particular instances, imperfect doctrinal system; it simply has none whatever. Each and every question is herein controverted, each position is a matter of individual conviction, of the interpretation given byaschool, of a "point of view". 1. Moreover in the same article he writes that his goal is a philosophical system of doctrine that, after the gigantic preparatory work. of generations, really be- . gins from the ground up with a foundation free from doubt and rises up like any skilful construction, wherein stone is set upon store, each as solid as the other, in accord with directive insights. 2. Reflecting upon the fact that he foresaw "preparatory work of generations", we perhaps should not expect that he would claim that his was the last word on the matter of intersubjectivity. Indeed, with 2. 'Edmund Husserl, lIPhilosophy as a Rigorous Science" in Phenomenology and theCrisis6fPhilosophy, trans". with an introduction by Quentin Lauer (New York.: Harper & Row, 1965) pp. 74 .. 5. 2Ibid . pp. 75 .. 6. 3. the relatively small amount of published material by Husserl on the subject we can assume that he himself was not entirely satisfied with his solution. The second question we have is that if the transcendental reduction is to yield the generic and apodictic structures of the relationship of consciousness to its various possible objects, how far can we extend this particular constitutive synthetic function to intersubjectivity where the objects must of necessity always remain delitescent? To be sure, the type of 'object' here to be considered is unlike any other which might appear in the perceptual field. What kind of indubitable evidence will convince us that the characteristic which we label "alter-ego" and which we attribute to an object which appears to resemble another body which we have never, and can never see the whole of (namely, our own bodies), is nothing more than a cleverly contrived automaton? What;s the nature of this peculiar intentional function which enables us to say "you think just as I do"? If phenomenology is to take such great pains to reduce the takenfor- granted, lived, everyday world to an immanent world of pure presentation, we must ask the mode of presentation for transcendent sub .. jectivities. And in the end, we must ask if Husserl's argument is not reducible to a case (however special) of reasoning by analogy, and if so, tf this type of reasoning is not so removed from that from whtch the analogy is made that it would render all transcendental intersubjective understandtng impos'sible? 2. HistoticalandEidetic Priority: The Necessity of Abstraction 4. The problem is not a simple one. What is being sought are the conditions for the poss ibili:ty of experi encing other subjects. More precisely, the question of the possibility of intersubjectivity is the question of the essence of intersubjectivity. What we are seeking is the absolute route from one solitude to another. Inherent in this programme is the ultimate discovery of the meaning of community. That this route needs be lIabstract" requires some explanation. It requires little explanation that we agree with Husserl in the aim of fixing the goal of philosophy on apodictic, unquestionable results. This means that we seek a philosophical approach which is, though, not necessarily free from assumptions, one which examines and makes explicit all assumptions in a thorough manner. It would be helpful at this point to distinguish between lIeidetic ll priority, and JlhistoricallJpriority in order to shed some light on the value, in this context, of an abstraction.3 It is true that intersubjectivity is mundanely an accomplished fact, there havi.ng been so many mi.llions of years for humans to beIt eve in the exi s tence of one another I s abili ty to think as they do. But what we seek is not to study how this proceeded historically, but 3Cf• Maurice Natanson;·TheJburne in 'Self, a Stud in Philoso h and Social Role (Santa Cruz, U. of California Press, 1970 . rather the logical, nay, "psychological" conditions under which this is possible at all. It is therefore irrelevant to the exigesis of this monograph whether or not anyone should shrug his shoulders and mumble IIwhy worry about it, it is always already engaged". By way of an explanation of the value of logical priority, we can find an analogy in the case of language. Certainly the language 5. in a spoken or written form predates the formulation of the appropriate grammar. However, this grammar has a logical priority insofar as it lays out the conditions from which that language exhibits coherence. The act of formulating the grammar is a case of abstraction. The abstraction towards the discovery of the conditions for the poss; bi 1 ity of any experiencing whatever, for which intersubjective experience is a definite case, manifests itself as a sort of "grammar". This "grammar" is like the basic grammar of a language in the sense that these "rulesil are the ~ priori conditions for the possibility of that experience. There is, we shall say, an "eidetic priority", or a generic condition which is the logical antecedent to the taken-forgranted object of experience. In the case of intersubjectivity we readily grant that one may mundanely be aware of fellow-men as fellowmen, but in order to discover how that awareness is possible it is necessary to abstract from the mundane, believed-in experience. This process of abstraction is the paramount issue; the first step, in the search for an apodictic basis for social relations. How then is this abstraction to be accomplished? What is the nature of an abstraction which would permit us an Archimedean point, absolutely grounded, from which we may proceed? The answer can be discovered in an examination of Descartes in the light of Husserl's criticism. 3. The Impulse for Scientific Philosophy. The Method to which it Gives Rise. 6. Foremost in our inquiry is the discovery of a method appropriate to the discovery of our grounding point. For the purposes of our investigations, i.e., that of attempting to give a phenomenological view of the problem of intersubjectivity, it would appear to be of cardinal importance to trace the attempt of philosophy predating Husserl, particularly in the philosophy of Descartes, at founding a truly IIscientific ll philosophy. Paramount in this connexion would be the impulse in the Modern period, as the result of more or less recent discoveries in the natural sciences, to found philosophy upon scientific and mathematical principles. This impulse was intended to culminate in an all-encompassing knowledge which might extend to every realm of possible thought, viz., the universal science ot IIMathexis Universalis ll •4 This was a central issue for Descartes, whose conception of a universal science would include all the possible sciences of man. This inclination towards a science upon which all other sciences might be based waS not to be belittled by Husserl, who would appropriate 4This term, according to Jacab Klein, was first used by Barocius, the translator of Proclus into Latin, to designate the highest mathematical discipline. . 7. it himself in hopes of establishing, for the very first time, philosophy as a "rigorous science". It bears emphasizing that this in fact was the drive for the hardening of the foundations of philosophy, the link between the philosophical projects of Husserl and those of the philosophers of the modern period. Indeed, Husserl owes Descartes quite a debt for indicating the starting place from which to attempt a radical, presupositionless, and therefore scientific philosophy, in order not to begin philosophy anew, but rather for the first time.5 The aim of philosophy for Husserl is the search for apodictic, radical certitude. However while he attempted to locate in experience the type of necessity which is found in mathematics, he wished this necessity to be a function of our life in the world, as opposed to the definition and postulation of an axiomatic method as might be found in the unexpurgated attempts to found philosophy in Descartes. Beyond the necessity which is involved in experiencing the world, Husserl was searching for the certainty of roots, of the conditi'ons which underl ie experience and render it pOssible. Descartes believed that hi~ MeditatiOns had uncovered an absolute ground for knowledge, one founded upon the ineluctable givenness of thinking which is present even when one doubts thinking. Husserl, in acknowledging this procedure is certainly Cartesian, but moves, despite this debt to Descartes, far beyond Cartesian philosophy i.n his phenomenology (and in many respects, closer to home). 5Cf. Husserl, Philosophy as a Rigorous Science, pp. 74ff. 8 But wherein lies this Cartesian jumping off point by which we may vivify our theme? Descartes, through inner reflection, saw that all of his convictions and beliefs about the world were coloured in one way or another by prejudice: ... at the end I feel constrained to reply that there is nothing in a all that I formerly believed to be true, of which I cannot in some measure doubt, and that not merely through want of thought or through levity, but for reasons which are very powerful and maturely considered; so that henceforth I ought not the less carefully to refrain from giving credence to these opinions than to that which is manifestly false, if I desire to arrive at any certainty (in the sciences). 6 Doubts arise regardless of the nature of belief - one can never completely believe what one believes. Therefore, in order to establish absolutely grounded knowledge, which may serve as the basis fora "universal Science", one must use a method by which one may purge oneself of all doubts and thereby gain some radically indubitable insight into knowledge. Such a method, gescartes found, was that, as indicated above by hi,s own words, of II radical doubt" which "forbids in advance any judgemental use of (previous convictions and) which forbids taking any position with regard to their val idi'ty. ,,7 This is the method of the "sceptical epoche ll , the method of doubting all which had heretofor 6Descartes,Meditations on First Philosophy, first Med., (Libera 1 Arts Press, New York, 1954) trans. by L. LaFl eur. pp. 10. 7Husserl ,CrisiS of Eliroeari SCiences and Trariscendental Phenomenology, (Northwestern U. Press, Evanston, 1 7 ,p. 76. 9. been considered as belonging to the world, including the world itself. What then is left over? Via the process of a thorough and all-inclusive doubting, Descartes discovers that the ego which performs the epoche, or "reduction", is excluded from these things which can be doubted, and, in principle provides something which is beyond doubt. Consequently this ego provides an absolute and apodictic starting point for founding scientific philosophy. By way of this abstention. of bel ief, Desca'rtes managed to reduce the worl d of everyday 1 ife as bel ieved in, to mere 'phenomena', components of the rescogitans:. Thus:, having discovered his Archimedean point, the existence of the ego without question, he proceeds to deduce the 'rest' of the world with the aid of innate ideas and the veracity of God. In both Husserl and Descartes the compelling problem is that of establ ishing a scientific, apodictic phi'losophy based upon presuppos itionless groundwork .. Husserl, in thi.s regard, levels the charge at Descartes that the engagement of his method was not complete, such that hi.S: starting place was not indeed presupositionless, and that the validity of both causality and deductive methods were not called into question i.'n the performance of theepoche. In this way it is easy for an absolute evidence to make sure of the ego as: a first, "absolute, indubitablyexisting tag~end of the worldll , and it is then only a matter of inferring the absolute subs.tance and the other substances which belon.g to the world, along with my own mental substance, using a logically val i d deductive procedure. 8 8Husserl, E.;' Cartesian 'Meditation;, trans. Dorion Cairns (Martinus Nijhoff, The Hague, 1970), p. 24 ff.

Hubert Aquin et la Gnose

Reprendre contact avec les réalités de l’âme, rouvrir la source où l’être rejaillit éternellement : tel est l’idéal occulte, inavouable, d’où procède la poétique d’Hubert Aquin. Depuis sa jeunesse, Aquin s’emploie clandestinement à défaire les mailles de la conscience et à rebrousser chemin vers les arrière-plans ténébreux du Moi, vers le Plérôme de la vie nue. Il manœuvre pour se mettre au service de l’intentionnalité impersonnelle inscrite au plus profond de sa psyché, pour devenir l’instrument du vouloir aveugle « qui opère en lui comme une force d’inertie ». Son œuvre ne s’accomplit pas dans le texte, mais à rebours du texte, voire à rebours du langage ; elle se déploie sur le terrain d’une confrontation enivrée avec le Négatif — avec la Parole sacrée issue de l’abîme. En d’autres termes, elle prend la forme d’une Gnose, c’est-à-dire d’un exercice de dé-subjectivation, de destruction de soi, consistant à réaliser la connaissance participative de l’empreinte imaginale scellée derrière les barreaux de la finitude. Essentiellement consacrée à l’analyse de la dimension gnostique de l’œuvre d’Hubert Aquin, cette thèse vise à montrer que la connaissance du hiéroglyphe mystérieux gravé au fond de l’âme n’est pas une sinécure. Il s’agit plutôt d’un opus contra naturam qui comporte bien des risques (en tout premier lieu celui d’une inflation psychique). Pourtant, ce travail est aussi, aux yeux de l’auteur, le seul véritablement digne d’être accompli, celui qui donne à l’homme le moyen de se soustraire à l’engloutissement de la mort et la possibilité de renaître. Comme l’écrit Aquin dans un texte de jeunesse, l’ouverture inconditionnelle au Négatif (la destruction de soi) est « une façon privilégiée d’expérimenter la vie et un préalable à toute entreprise artistique » ; elle correspond à « un mode supérieur de connaissance », à un savoir « impersonnel » qui offre immédiatement le salut.

A poetics of apprehension : indeterminacy in Gertrude Stein, Emily Dickinson and Caroline Bergvall

Ce mémoire examine les poétiques de trois poètes très différentes, mais dont les œuvres peuvent être qualifiées d'indéterminées et de radicales : Emily Dickinson (1830-1886), Gertrude Stein (1874-1946) et Caroline Bergvall (née en 1962). Dickinson et Stein sont anglo-américaines, tandis que Bergvall est d’origine franco-norvégienne, bien qu'elle choisisse d’écrire en anglais. Toutes les trois rompent la structure syntaxique conventionnelle de l’anglais par leurs poétiques, ce qui comporte des implications esthétiques et politiques. Dans ce qui suit, j’analyse l’indétermination de leurs poétiques à partir de la notion, décrite par Lyn Hejinian, de la description comme appréhension qui présente l’écriture comme un mode de connaissance plutôt qu'un moyen d’enregistrer ce que le poète sait déjà. La temporalité de cette activité épistémologique est donc celle du présent de l’écriture, elle lui est concomitante. J'affirme que c'est cette temporalité qui, en ouvrant l’écriture aux événements imprévus, aux vicissitudes, aux hésitations, aux erreurs et torsions de l’affect, cause l'indétermination de la poésie. Dans le premier chapitre, j'envisage l'appréhension chez Gertrude Stein à travers son engagement, tout au long de sa carrière, envers « le présent continu » de l’écriture. Le deuxième chapitre porte sur le sens angoissé de l’appréhension dans la poésie de Dickinson, où le malaise, en empêchant ou en refoulant une pensée, suspend la connaissance. Le langage, sollicité par une expérience qu'il ne peut lui-même exprimer, donne forme à l'indétermination. Un dernier chapitre considère l’indétermination linguistique du texte et de l’exposition Say Parsley, dans lesquels Bergvall met en scène l’appréhension du langage : une appréhension qui survient plutôt chez le lecteur ou spectateur que chez la poète.

El extravío del poeta: notas sobre la escritura de Roberto Bolaño (Crítica)

El autor reflexiona sobre una constante en la narrativa del escritor chileno Roberto Bolaño: sus personajes poetas –de muy diversa índole moral y ocupacional– se desplazan de un lugar a otro, en exilio o peregrinaje, en busca de un escritor ausente, nunca lo encuentran, o éste muere antes de que se establezca la comunicación. La práctica de la escritura, problemática por sí misma, convierte al poeta en un ser perdido o en tránsito, extraviado, un ser vacío que escribe «bajo hipnosis», un secretario que toma nota de los sueños y pesadillas de otro, que únicamente discute con algún fantasma sobre la pertinencia de los párrafos que se repiten. El acto de escribir se convierte, en la obra de Bolaño, en un escenario marcado por el vacío y el exilio.

A escrita do texto acadêmico na graduação: modos de utilização de conceitos teóricos de uma área de conhecimento

In this study we have developed a discussion about academic text production in the undergraduate course of Literature and Languages. Specifically, we are going to analyze the monographic text writing in order to verify the meaning effects created from the ways of showing other s discourses that constitute a written production. As a means to do that, we are going to answer the following question: How does a young researcher make use of a theory in order to be part of a particular scientific community? We aim to: 1) analyze the linguistic resources, like quotations and signs of cohesion that demonstrate the other s voice presence in academic writing; 2) observe the meaning effects produced through the ways that the one who writes shows the other s voice in the written text. Firstly, we have selected 23 (twentythree) monographs produced in the last five years by students from a Literature and Languages undergraduate course in a determined public university. However, in this study, we have analyzed just 02 (two) different monographic texts. To develop such an investigation, we have inquired Kuhn s concept of science, which shows the existence of different meanings of science production in the course of the centuries. It allows us to define academic writing as science production that develops and contributes to knowledge production. With the purpose of restricting the meaning of writing conception, we have relied on Coracini, who assumes that all writing production is the registration of the self, in other words, writing comes from the subject s intervention, it is to say that only an imposition of the self guarantees the subject as author of what he writes. We have as theoretical basis the following concepts: 1-) Authier-Revus s enunciative heterogeneity, that allowed us to analyze the written marks of the other in the monographic writing; 2-) Pêcheux s reformulation-paraphrase and Orlandi s polysemy and paraphrase, concepts that present notions of productivity and creativity as ways of meaning production, and allows us to observe how the process of language production in academic writing is established; 3-) Rossi-Landi s concept of exchange-value and use-value, which consider language as a linguistic work, allowing us to verify the differences between use and social functionality in a determined theory; and 4-) Possenti s notion of authorship indicia, with which we have identified attitudes that make the one who writes author of his own text. We have verified that writing characterized for repetition and reproduction may develop a meaning effect that constructs the idea that writing production promotes an author, a concept or a theory. We have also realized that a written text that restricts itself to reproduce other authors discourses and does not articulate a theory with data analysis or with work methodology, when evaluated is approved and legitimates itself as scientific production. That demonstrates the existence of academic productions that do not develop any functionality of the employed theory. The text works as a means to promote its theoretical concepts, and theory. It is to say that the theoretical foundantion, which usually is a way to argue and sustain scientific production, does not have any function. Thus, we consider that the way someone shows the other s discourse in academic writing may work as a way to underline what the other asserts to the detriment of the researcher s words. This fact allows us to comprehend that a way of writing may evidence a meaning effect of the author s, theory s or theoretical concepts promotion

Fragmentos de um modelo: pequenas lavouras de café e acumulação de capitais. Franca/São Paulo 1890-1914

Este artigo versa sobre a importância da pequena cafeicultura no complexo cafeeiro entre 1890 e 1914. Discutimos aqui as relações de trabalho, as formas de financiamento e o modo como a pequena propriedade se insere neste universo. Utilizamos como fontes prioritárias os contratos de trabalho que envolviam a formação e/ou o trato de cafeeiros e as escrituras de dívidas hipotecárias, ambas lavradas nos Livros Cartoriais, fontes estas ainda não trabalhadas pela historiografia de forma mais sistemática. Desviamos nosso olhar para uma região marcada predominantemente pelas pequenas e médias fazendas produtoras de café, observando a dinâmica da acumulação em um período de expansão e de crise da cafeicultura.

Crédito e pequena cafeicultura no oeste paulista: Franca/SP 1890-1914

This article turns on the importance of the small coffee production in the coffee complex economy between 1890 and 1914. We argue here the relations of work, the forms of financing and the way as the small coffee production inserts itself in this universe. We use as priority sources the employment contracts that involved the formation and/or the treatment of coffee trees and the Writes of mortgage debts, both recorded in Notarial Books, documents not used by historiography in a systematical way. We turns our look for a region marked predominantly for small and the middle producing farms of coffee, observing the dynamics of the accumulation in a period of expansion and crisis of the coffee economy.