In accordance with Leo Strauss’s ingenious suggestion, the Athenian Stranger of Plato’s Laws is best understood as an alternative ‘Socrates’, fleeing from the hemlock to Crete. Situated between Crito and Phaedo, Laws effectively tests the reader’s loyalty to the real Socrates who obeys Athenian law and dies cheerfully in Athens. Having separated Plato from the Stranger, a nuanced defence of Karl Popper’s suspicions about Laws confronts the apologetic readings of both Strauss and Christopher Bobonich. As hinted by his preference for (...) wine, the antidote for hemlock, the Athenian Stranger repeatedly proves himself the opposite of Socrates, particularly with respect to piety. Once the Stranger is recognized as ‘an unreliable narrator’, this apparently ponderous product of Plato’s senility becomes the taut thriller of an innovative teacher at the peak of his powers. (shrink)

This book is a translation of W.V. Quine's Kant Lectures, given as a series at Stanford University in 1980. It provide a short and useful summary of Quine's philosophy. There are four lectures altogether: I. Prolegomena: Mind and its Place in Nature; II. Endolegomena: From Ostension to Quantification; III. Endolegomena loipa: The forked animal; and IV. Epilegomena: What's It all About? The Kant Lectures have been published to date only in Italian and German translation. The present book is filled out (...) with the translator's critical Introduction, "The esoteric Quine?" a bibliography based on Quine's sources, and an Index for the volume. (shrink)

The current study is a pilot trial to examine the effects of a nonelective, classroom-based, teacher-implemented, mindfulness meditation intervention on standard clinical measures of mental health and affect in middle school children. A total of 101 healthy sixth-grade students (55 boys, 46 girls) were randomized to either an Asian history course with daily mindfulness meditation practice (intervention group) or an African history course with a matched experiential activity (active control group). Self-reported measures included the Youth Self Report (YSR), a modified (...) Spielberger State-Trait Anxiety Inventory, and the Cognitive and Affective Mindfulness Measure –Revised. Both groups decreased significantly on clinical syndrome subscales and affect but did not differ in the extent of their improvements. Meditators were significantly less likely to develop suicidal ideation or thoughts of self-harm than controls. These results suggest that mindfulness training may yield both unique and non-specific benefits that are shared by other novel activities. (shrink)

This chapter describes the potential far‐reaching consequences of contemplative higher education for the fields of science and medicine.

The purpose of this article is to show a structural relationship in Dutch between sentences with the main verb "duren" (last) and specifying complements such as een week (a week) or "drie kwartier" (three quarters of an hour) on the one hand, and sentences with Duration Measuring Adverbials such as "gedurende een week" (for a week), "gedurende die week" (lit: for that week) on the other.

Special issue in honour of Landon Rabern. This special issue of Discrete Mathematics is dedicated to his memory, as a tribute to his many research achievements. It contains 10 new articles written by his collaborators, friends, and colleagues that showcase his interests.

Metaphors for describing the introduction, impacts, and management of non-native species are numerous and often quite outspoken. Policy-makers have adopted increasingly disputed metaphorical terms from scientific discourse. We performed a critical analysis of the use of strong metaphors in reporting scientific findings to policy-makers. Our analysis shows that perceptions of harm, invasiveness or nativeness are dynamic and inevitably display multiple narratives in science, policy or management. Improving our awareness of multiple expert and stakeholder narratives that exist in the context of (...) non-native species management, as well as metaphorical alternatives, is critical. (shrink)

This edited volume illustrates the central importance of diversity of human values throughout healthcare. The readings are organised around the main stages of the clinical encounter from the patient's perspective. This introductory chapter opens up crucial issues of methodology and of practical application in this highly innovative approach to the role of ethics in healthcare.

Mindfulness training has been used to improve emotional wellbeing in early adolescents. However, little is known about treatment outcome moderators, or individual differences that may differentially impact responses to treatment. The current study focused on gender as a potential moderator for affective outcomes in response to school-based mindfulness training. Sixth grade students (N = 100) were randomly assigned to either the six weeks of mindfulness meditation or the active control group as part of a history class curriculum. Participants in the (...) mindfulness meditation group completed short mindfulness meditation sessions four to five times per week, in addition to didactic instruction (Asian history). The control group received matched experiential activity in addition to didactic instruction (African history) from the same teacher with no meditation component. Self-reported measures of emotional wellbeing/affect, mindfulness, and self-compassion were obtained at pre and post intervention. Meditators reported greater improvement in emotional wellbeing compared to those in the control group. Importantly, gender differences were detected, such that female meditators reported greater increases in positive affect compared to females in the control group, whereas male meditators and control males displayed equivalent gains. Uniquely among females but not males, increases in self-reported self-compassion were associated with improvements in affect. These findings support the efficacy of school-based mindfulness interventions, and interventions tailored to accommodate distinct developmental needs of female and male adolescents. (shrink)

This volume of articles, literature and case studies illustrates the central importance of human values throughout healthcare. The readings are structured around the main stages of the clinical encounter from the patient's perspective.

Throughout the biological and biomedical sciences there is a growing need for, prescriptive ‘minimum information’ (MI) checklists specifying the key information to include when reporting experimental results are beginning to find favor with experimentalists, analysts, publishers and funders alike. Such checklists aim to ensure that methods, data, analyses and results are described to a level sufficient to support the unambiguous interpretation, sophisticated search, reanalysis and experimental corroboration and reuse of data sets, facilitating the extraction of maximum value from data sets (...) them. However, such ‘minimum information’ MI checklists are usually developed independently by groups working within representatives of particular biologically- or technologically-delineated domains. Consequently, an overview of the full range of checklists can be difficult to establish without intensive searching, and even tracking thetheir individual evolution of single checklists may be a non-trivial exercise. Checklists are also inevitably partially redundant when measured one against another, and where they overlap is far from straightforward. Furthermore, conflicts in scope and arbitrary decisions on wording and sub-structuring make integration difficult. This presents inhibit their use in combination. Overall, these issues present significant difficulties for the users of checklists, especially those in areas such as systems biology, who routinely combine information from multiple biological domains and technology platforms. To address all of the above, we present MIBBI (Minimum Information for Biological and Biomedical Investigations); a web-based communal resource for such checklists, designed to act as a ‘one-stop shop’ for those exploring the range of extant checklist projects, and to foster collaborative, integrative development and ultimately promote gradual integration of checklists. (shrink)

Locke clearly intends what I call his 'linguistic thesis,' the claim that words signify nothing but ideas, to tell against Aristotelian essentialism. I argue that current interpretations of Locke's anti-essentialist arguments have not accorded the linguistic thesis its proper role. This is largely due to the prevalent misreadings of that thesis. Locke's view is that words reliably indicate ideas in the mind of the speaker. It is only once we see this that we can understand how the (...) thesis functions in Locke's anti-Aristotelian project. (shrink)

In this review, we describe some of the central philosophical issues facing origins-of-life research and provide a targeted history of the developments that have led to the multidisciplinary field of origins-of-life studies. We outline these issues and developments to guide researchers and students from all fields. With respect to philosophy, we provide brief summaries of debates with respect to (1) definitions (or theories) of life, what life is and how research should be conducted in the absence of an accepted theory (...) of life, (2) the distinctions between synthetic, historical, and universal projects in origins-of-life studies, issues with strategies for inferring the origins of life, such as (3) the nature of the first living entities (the “bottom up” approach) and (4) how to infer the nature of the last universal common ancestor (the “top down” approach), and (5) the status of origins of life as a science. Each of these debates influences the others. Although there are clusters of researchers that agree on some answers to these issues, each of these debates is still open. With respect to history, we outline several independent paths that have led to some of the approaches now prevalent in origins-of-life studies. These include one path from early views of life through the scientific revolutions brought about by Linnaeus (von Linn.), Wöhler, Miller, and others. In this approach, new theories, tools, and evidence guide new thoughts about the nature of life and its origin.We also describe another family of paths motivated by a” circularity” approach to life, which is guided by such thinkers as Maturana & Varela, Gánti, Rosen, and others. These views echo ideas developed by Kant and Aristotle, though they do so using modern science in ways that produce exciting avenues of investigation. By exploring the history of these ideas, we can see how many of the issues that currently interest us have been guided by the contexts in which the ideas were developed. The disciplinary backgrounds of each of these scholars has influenced the questions they sought to answer, the experiments they envisioned, and the kinds of data they collected. We conclude by encouraging scientists and scholars in the humanities and social sciences to explore ways in which they can interact to provide a deeper understanding of the conceptual assumptions, structure, and history of origins-of-life research. This may be useful to help frame future research agendas and bring awareness to the multifaceted issues facing this challenging scientific question. (shrink)

The Planteome project provides a suite of reference and species-specific ontologies for plants and annotations to genes and phenotypes. Ontologies serve as common standards for semantic integration of a large and growing corpus of plant genomics, phenomics and genetics data. The reference ontologies include the Plant Ontology, Plant Trait Ontology, and the Plant Experimental Conditions Ontology developed by the Planteome project, along with the Gene Ontology, Chemical Entities of Biological Interest, Phenotype and Attribute Ontology, and others. The project also provides (...) access to species-specific Crop Ontologies developed by various plant breeding and research communities from around the world. We provide integrated data on plant traits, phenotypes, and gene function and expression from 95 plant taxa, annotated with reference ontology terms. (shrink)

REMARKS ON EVOLUTION AND TIME-SCALES, Graham Cairns-Smith; HODGSON'S BLACK BOX, Thomas Clark; DO HODGSON'S PROPOSITIONS UNIQUELY CHARACTERIZE FREE WILL?, Ravi Gomatam; WHAT SHOULD WE RETAIN FROM A PLAIN PERSON'S CONCEPT OF FREE WILL?, Gilberto Gomes; ISOLATING DISPARATE CHALLENGES TO HODGSON'S ACCOUNT OF FREE WILL, Liberty Jaswal; FREE AGENCY AND LAWS OF NATURE, Robert Kane; SCIENCE VERSUS REALIZATION OF VALUE, NOT DETERMINISM VERSUS CHOICE, Nicholas Maxwell; COMMENTS ON HODGSON, J.J.C. Smart; THE VIEW FROM WITHIN, Sean Spence; COMMENTARY ON HODGSON, Henry Stapp.

The aim of this paper is to provide a conceptual framework that will help in understanding and evaluating, along social and ethical lines, the issue of killing day-old male chicks and two alternative directions of responsible innovations to solve this issue. The following research questions are addressed: Why is the killing of day-old chicks morally problematic? Are the proposed alternatives morally sound? To what extent do the alternatives lead to responsible innovation? The conceptual framework demonstrates clearly that there is a (...) moral “lock-in”, and why the killing of day-old chicks is indeed an issue. Furthermore, it is shown that both alternative directions address some important objections with regard to the killing of day-old chicks, but that they also raise new dilemmas. It also becomes clear that the framework enables and secures anticipation, reflection, deliberation with and responsiveness to stakeholders, the four dimensions of responsible innovation, in a structured way. (shrink)

Objective: To examine the current ethical review process of ethics committees in a non-pharmacological trial from the perspective of a clinical investigator.Design: Prospective collection of data at the Study Centre of the German Surgical Society on the duration, costs and administrative effort of the ERP of a randomised controlled multicentre surgical INSECT Trial between November 2003 and May 2005.Setting: Germany.Participants: 18 ethics committees, including the ethics committee handling the primary approval, responsible overall for 32 clinical sites throughout Germany. 8 ethics (...) committees were located at university medical schools and 10 at medical chambers. Duration was measured as days between submission and receipt of final approval, costs in euros and administrative effort by calculation of the product of the total number of different types of documents and the mean number of copies required .Results: The duration of the ERP ranged from 1 to 176 days. The median duration was 26 days at MSUs compared with 34 days at medical chambers. The total cost was €2947. 1 of 8 ethics committees at universities and 8 of 10 at medical chambers charged a median fee of €162 . The administrative effort for primary approval was 30. Four ethics committees required a higher administrative effort for secondary approval .Conclusion: The ERP for non-pharmacological multicentre trials in Germany needs improvement. The administrative process has to be standardised: the application forms and the number and content of the documents required should be identical or at least similar. The fees charged vary considerably and are obviously too high for committees located at medical chambers. However, the duration of the ERP was, with some exceptions, excellent. A centralised ethics committee in Germany for multicentre trials such as the INSECT Trial can simplify the ERP for clinical investigators in and outside the country. (shrink)

There are a bewildering variety of claims connecting Darwin to nineteenth-century philosophy of science—including to Herschel, Whewell, Lyell, German Romanticism, Comte, and others. I argue here that Herschel’s influence on Darwin is undeniable. The form of this influence, however, is often misunderstood. Darwin was not merely taking the concept of “analogy” from Herschel, nor was he combining such an analogy with a consilience as argued for by Whewell. On the contrary, Darwin’s Origin is written in precisely the manner that one (...) would expect were Darwin attempting to model his work on the precepts found in Herschel’s Preliminary Discourse on Natural Science. While Hodge has worked out a careful interpretation of both Darwin and Herschel, drawing similar conclusions, his interpretation misreads Herschel’s use of the vera causa principle and the verification of hypotheses. The new reading that I present here resolves this trouble, combining Hodge’s careful treatment of the structure of the Origin with a more cautious understanding of Herschel’s philosophy of science. This interpretation lets us understand why Darwin laid out the Origin in the way that he did and also why Herschel so strongly disagreed, including in Herschel’s heretofore unanalyzed marginalia in his copy of Darwin’s book. (shrink)

There are two motivations commonly ascribed to historical actors for taking up statistics: to reduce complicated data to a mean value (e.g., Quetelet), and to take account of diversity (e.g., Galton). Different motivations will, it is assumed, lead to different methodological decisions in the practice of the statistical sciences. Karl Pearson and W. F. R. Weldon are generally seen as following directly in Galton’s footsteps. I argue for two related theses in light of this standard interpretation, based on a reading (...) of several sources in which Weldon, independently of Pearson, reflects on his own motivations. First, while Pearson does approach statistics from this "Galtonian" perspective, he is, consistent with his positivist philosophy of science, utilizing statistics to simplify the highly variable data of biology. Weldon, on the other hand, is brought to statistics by a rich empiricism and a desire to preserve the diversity of biological data. Secondly, we have here a counterexample to the claim that divergence in motivation will lead to a corresponding separation in methodology. Pearson and Weldon, despite embracing biometry for different reasons, settled on precisely the same set of statistical tools for the investigation of evolution. (shrink)

That the world is awash with resentment poses a genuine question for educators. Here, we will suggest that resentment can be better harnessed for good if we stop focusing on people and tribes and, instead, focus on systems: those invisible norms that often produce locked-in structures of social interaction. A “systems lens” is vast, so fixes will have to be an iterative process of reflection, and revision toward a more just system. Nonetheless, resentment toward the status quo may be an (...) important element in keeping that otherwise tedious process going, with the caveat that resentment is only productive when it is combined with reason, and that, therefore, educators, rather than privileging participant reactive attitudes, ought, instead, to promote participant reactive reasoning, as the latter can be a genuine force for both personal and interpersonal growth, while the former might very well do the reverse. (shrink)

Wat betreft economische groei en ontwikkeling van de werkloosheid heeft de Nederlandse economie het sinds 1973 slechter gedaan dan andere OECD-landen. Op de vraag naar de oorzaken van die slechte prestatie zijn in het verleden uiteenlopende antwoorden gegeven door o.m. Bomhoff en Clavaux. Ook zijn er diverse wegen aangegeven om op te rukken naar een betere positie. In dit artikel presenteren de auteurs de resultaten van een internationale doorsnee-analyse om de verschillen in economisch succes tussen landen met behulp van een (...) eenvoudig neo-klassiek macro-economisch model te verklaren. Dit biedt de mogelijkheid om te traceren wat de rol van de exportgroei, de groei van de bevolking, de wisselkoers, de verhouding tussen de binnenlandse en de buitenlandse prijsontwikkeling en de investeringsquote voor verschillen in economische ontwikkeling is geweest. Vooral de uitvoer gecorrigeerd voor de omvang van de bevolking, de investeringsquote en de nominale wisselkoers komen als belangrijke verklarende variabelen naar voren. Op grond van hun analyse komen de auteurs tot de conclusie dat een beleid gericht op het verbeteren van de Nederlandse economische prestatie op lange termijn zich vooral zou moeten concentreren op het benutten van exportkansen en op een hoog investeringsniveau ter bevordering van technologische vernieuwing en daarmee verbetering van de concurrentiepositie. Daarbij moet worden voorkomen dat revaluatie van de gulden het exporteffect teniet doet. (shrink)

The fructose 6-phosphate (Fru-6P) saturation curve for phosphofructokinase (PFK) from E. coli is sigmoidal in the presence of saturating MgATP levels, while the corresponding curve for B. stearothermophilus PFK is essentially hyperbolic. Sigmoidality can be due to apparent cooperativity arising from the kinetic mechanism of an enzyme. We have determined the kinetic mechanism of B. stearothermophilus PFK (BsPFK). BsPFK was found to obey a non rapid-equilibrium random mechanism similar to the one E. coli PFK (EcPFK) follows. Substrate inhibition by MgATP (...) was observed. We propose that substrates bind to BsPFK through two alternative pathways, one of which is slower. The substrate inhibition arises in part from reaction flux through the slower pathway. Although EcPFK and BsPFK obey similar kinetic mechanisms, they are inhibited differently by MgATP: EcPFK is profoundly inhibited, BsPFK only weakly. The structural basis for this difference could be closure of the active site via a conformational transition that occurs in EcPFK, but not BsPFK. To investigate the importance of this transition for MgATP inhibition of EcPFK, we have constructed a chimeric enzyme (ChiPFK) that contains the "rigid" ATP-binding domain of BsPFK grafted onto the remainder of the EcPFK subunit. Our results indicate that ChiPFK is locked in an "open" structure resembling the activated form of EcPFK. It is insensitive to heterotropic regulation. Nevertheless, ChiPFK exhibits residual cooperativity. Possible explanations for the cooperativity are discussed. The 6F loop is proposed to be important in PFK allosteric behavior. Residues along the loop are largely conserved between BsPFK and EcPFK, except for 161, which is a glutamate in BsPFK, and a glutamine in EcPFK. Using site-directed mutagenesis, Glu 161 of BsPFK has been changed to glutamine and alanine. Similarly, Gin 161 of EcPFK has been changed to glutamate, arginine and alanine. Of the five mutants, one, QA161, was particularly interesting. Though activated normally by GDP, it was completely insensitive to PEP inhibition. This indicates that the hydrogen-bonding ability of residue 161 is critical for PEP inhibition of EcPFK, and that GDP activation and PEP inhibition follow different structural pathways. (shrink)

On the History of Political Philosophy: Great Political Thinkers from Thucydides to Locke is a lively and lucid account of the major political theorists and philosophers of the ancient Greek, Roman, medieval, renaissance, and early modern periods. The author demonstrates the continuing significance of some political debates and problems that originated in the history of political philosophy. Topics include discussions concerning human nature, different views of justice, the origin of government and law, the rise and development of different forms (...) of government, idealism and realism in international relations, the distinction between just and unjust war, and the sources of public authority and the nature of legitimate sovereignty. The organizing principle of the book is the idea that the great political thinkers were searching for the best political order and a criterion for human conduct in both domestic and international politics. The book presupposes no previous knowledge of political philosophy. It will therefore be a valuable introductory book for students of philosophy, politics, and international relations. As it opens eyes to the perceptions that historical knowledge may convey, it will also be an illuminating and engaging reading for a general reader. (shrink)

Quine's aim in this slim book is to "update, sum up and clarify variously intersecting views on cognitive meaning, objective referencce, and the grounds of knowledge." Only nine pages had previously appeared as the book came to print. It is based largely on unpublished lectures and informal discussions of the past ten years back to the Immanuel Kant Lectures given at Stanford in 1980. It does not, then duplicate Leonelli's Italian translation of the Kant lectures, La Scienza E I Datti (...) di Senso, which appeared in 1987. (shrink)

This is a description and analysis of the intellectual culture of the eighteenth-century Church of England. Challenging conventional perceptions of the Church as an intellectually moribund institution, the study traces the influence of thinkers such as Locke, Newton, Burke, and Gibbon on theological debate in England during this period.

This book collects and focuses recent writings of Arthur Schlesinger on the themes of its title. In its short Foreword and seven concise essays, the book aims to explore, in some contrast with the genre of “instant history,” the relationship between President George W. Bush’s Iraq adventure and the national past. This aim and the present work are deserving of wide attention, both because of the contemporary need to deal with the extended war in Iraq and because Americans, in particular, (...) need to attend to their own history, if we are to avoid past mistakes and make the best use of our ongoing political traditions and institutions. In order to know better where we might go in the future, we need an adequate picture of where we have been in the past. Schlesinger invites us to debate the war, the Presidency, and their relation to the American past. (shrink)

This book focuses on issues in epistemology, semantics and logic with Quine’s views always setting the themes, even if Quine does not always remain quite at center stage. Gochet, Professor at Liège and Secretary to the Editorial Board of Logique et Analyse is a prominent of Quine’s views in Europe. The author does not aim to take up the whole of Quine’s philosophy here. Rather, the aim is to “focus on a few central themes...and to treat them thoroughly.” Continental Europe (...) not only recognizes Quine’s importance, then, but it is prepared to talk back: a point which has become increasingly evident in the wake of several recent works on Quine by W.K. Essler (1975), J. Largeault (1980) and Henri Lauener (1982). Gochet has made an earlier contribution to this in the form of his Quine en Perspective (1978) and its German translation (1984). But the present volume is not a further translation of the earlier work. Rather, the author “tried to avoid overlap.”. (shrink)

For Berkeley, minds are not Cartesian spiritual substances because they cannot be said to exist (even if only conceptually) abstracted from their activities. Similarly, Berkeley's notion of mind differs from Locke's in that, for Berkeley, minds are not abstract substrata in which ideas inhere. Instead, Berkeley redefines what it means for the mind to be a substance in a way consistent with the Stoic logic of 17th century Ramists on which Leibniz and Jonathan Edwards draw. This view of mind, (...) I conclude, is definitely not the bundle theory that some critics have portrayed it as being. (shrink)

In this paper we briefly examine and evaluate Quine’s physicalism. On the supposition, in accordance with Quine’s views, that there can be no change of any sort without a physical change, we argue that this point leaves plenty of room to understand and accept a limited autonomy of the special sciences and of other domains of disciplinary and common-sense inquiry and discourse. The argument depends on distinguishing specific, detailed programs of reduction from the general Quinean strategy of reduction by explication. (...) We argue that the details of the relations of particular sciences, disciplines and domains of discourse depend on empirical evidence and empirical-theoretical developments and that the generalized approach of reduction by explication is also subject to related empirical-theoretical constraints. So understood, physicalism lacks much of the controversial force and many of the implications sometimes associated with it. (shrink)

This is the Introduction to my translation of Quine's Kant Lectures. Part of my interpretation is that an "esoteric doctrine" in involved in Quine's distinctive semantic claims: his skepticism of the credulity of non-expert evaluation of discourse and theory.

This paper is the expository and evaluative introduction to my new edition of Emerson's Society and Solitude, Twelve Chapters.

One claim found in the received historiography of the biometrical school (comprised primarily of Francis Galton, Karl Pearson, and W. F. R. Weldon) is that one of the biometricians' great flaws was their inability to look past their population-focused, statistical, gradualist understanding of evolutionary change – which led, in part, to their ignoring developments in cellular biology around 1900. I will argue, on the contrary, that the work of the biometricians was, from its earliest days, fundamentally concerned with connections between (...) statistical patterns of inheritance and the underlying cellular features that gave rise to them. Such work remained current with contemporary knowledge of chromosomes, cytology, and development; in this article, I explore the first case. The biometricians were thus well positioned to understand the relationship between the patterns of Mendelian inheritance and the statistical distributions with which they primarily occupied themselves. Ignorance of this connection, then, is not the reason why they rejected Mendelism. Further, both Galton and Weldon – though each in their own unique way – decided to turn to biological detail as a way to better justify the generality of their statistical approaches to heredity. Perhaps paradoxically, then, for these biometricians, detail offered an approach to theoretical generality. (shrink)

Berkeley's doctrine of archetypes explains how God perceives and can have the same ideas as finite minds. His appeal of Christian neo-Platonism opens up a way to understand how the relation of mind, ideas, and their union is modeled on the Cappadocian church fathers' account of the persons of the trinity. This way of understanding Berkeley indicates why he, in contrast to Descartes or Locke, thinks that mind (spiritual substance) and ideas (the object of mind) cannot exist or be (...) thought of apart from one another. It also hints at why Gregory of Nyssa's immaterialism sounds so much like Berkeley's. (shrink)

Providing the most thorough coverage available in one volume, this comprehensive, broadly based collection offers a wide variety of selections in four major genres, and also includes a section on film. Each of the five sections contains a detailed critical introduction to each form, brief biographies of the authors, and a clear, concise editorial apparatus. Updated and revised throughout, the new Fourth Edition adds essays by Margaret Mead, Russell Baker, Joan Didion, Annie Dillard, and Alice Walker; fiction by Nathaniel Hawthorne, (...) Ursula K. LeGuin, Anton Chekov, James Joyce, Katherine Mansfield, F. Scott Fitzgerald, William Faulkner, Alice Walker, Louise Erdrich, Donald Barthelme, and James McPherson; poems by John Donne, Robert Browning, Walt Whitman, Edwin Arlington Robinson, e.e. cummings, Langston Hughes, W.H. Auden, Philip Levine, and Louise Gluck; and plays by August Wilson, Marsha Norman, Wendy Wasserstein, and Vaclav Havel. The chapter devoted to film examines the relation of film to literature and gives the complete screenplay for Citizen Kane plus close analysis of a scene from the film. With its innovative structure, comprehensive coverage, and insightful and stimulating presentation of all kinds of literature, this is an anthology readers will turn to again and again. (shrink)

Both G.F.W. Hegel and Carl Schmitt took seriously the problem of political sovereignty entailed by liberal political theories. In Dictatorship (1919) and Political Theology (1922), Schmitt rejects liberal political theories that argue for the immediate unity of democracy and legality i.e., popular sovereignty, because he thinks they cannot secure political sovereignty. In the Philosophy of Right, Hegel denounces popular sovereignty for similar reasons. Yet given Schmitt’s negative assessment of Hegel their positions are seldom related to one another. I argue in (...) this paper that Schmitt’s analysis of liberal political theories is similar to Hegel’s analysis of Rousseau’s liberal ideas. I contend, however, that Schmitt’s solution, which collapses the distinction between the executive and the legislative power in favor of the former, fails to secure political sovereignty. Contrary to Schmitt, Hegel conceives of the liberal predicament as a basic determination of any political state that rests on the division of the legislative and executive power. Hegel argues that the constitutional monarchy is a genuine instantiation of political sovereignty that can maintain not only the division of these powers, but also their unity. In this regard, I argue that Hegel’s conception of the division of powers provides a more convincing theory of the problem afflicting modern states than Schmitt’s and at least deserves to be taken more seriously by critics of Schmitt’s solution such as Hannah Arendt, Leo Strauss, Jurgen Habermas, Andreas Kalyvas and Chantal Mouffe. (shrink)

State of nature theories have a long history and play a lively role in contemporary work. Theories of this kind share certain nontrivial commitments. Among these are commitments to inclusion of a Lockean proviso among the principles of justice and to an assumption of invariance of political principles across changes of circumstances. In this article I want to look at those two commitments and bring to light what I believe are some important difficulties they engender. For nonpattern state of nature (...) theories, the justness of a society is marked by the conformance of the society to procedural principles. Distributions of resources and the like have no particular import for questions of justice. Whatever may later result, so long as it came about in accordance with the rules determined by the principles of justice, is itself just. The Lockean proviso is one of the principles of justice governing property and other rights of nonpattern theories of justice. The proviso hangs as a "shadow" over the results of the operation of the other (usual) principles of justice. It is intended to remedy a complaint which arises when the positions of those no longer at liberty to use some resource are worsened (1) by no longer being able to use freely what they previously were free to use and (2) in such a way that they fall below a "baseline." Following Locke, a traditional formulation of the proviso is to allow acquisition just so long as there is "enough and as good" left over for others. Section I concerns the relation of the Lockean proviso to pattern and nonpattern principles of justice, demonstrating that a Lockean proviso turns a nonpattern into a pattern theory of justice. Section II is about the relation of the Lockean proviso to the ideas revealed by an examination of a state of nature, suggesting reasons to reject ideal theories of justice. (shrink)

This article is the SIXTH of several excerpts from my book The Nondual Mind: Vedānta, Kashmiri Pratyabhijñā Shaivism, and Spinoza (the full book is posted on this site). “I liked James H. Cumming’s The Nondual Mind a lot. It is beautifully written, thoughtful, and very clear.” (Prof. Yitzhak Y. Melamed, Charlotte Bloomberg Professor of Philosophy, Johns Hopkins University) “James H. Cumming’s scholarly interpretation of Spinoza’s works, persuasively showing how 17th century European ideas that ushered in the Enlightenment find a precursor (...) in 10th century Kashmir, is a masterpiece of reason and philosophy that will leave the reader with profound thoughts on the meaning of history, God, and life itself. As a senior staff attorney in my chambers for many years at the California Supreme Court and a top scholar of ethics and philosophy of law, Mr. Cumming never ceased to amaze me with his outstanding research and intellect. This scholarly book is a must read for all who want to know why Spinoza continues to influence contemporary philosophy and how his work is still relevant in today’s challenging, interconnected world.” (Hon. Ming W. Chin, Associate Justice (Retired), Supreme Court of California, 1996–2020). (shrink)

This article is the SECOND of several excerpts from my book The Nondual Mind: Vedānta, Kashmiri Pratyabhijñā Shaivism, and Spinoza (the full book is posted on this site). “I liked James H. Cumming’s The Nondual Mind a lot. It is beautifully written, thoughtful, and very clear.” (Prof. Yitzhak Y. Melamed, Charlotte Bloomberg Professor of Philosophy, Johns Hopkins University) “James H. Cumming’s scholarly interpretation of Spinoza’s works, persuasively showing how 17th century European ideas that ushered in the Enlightenment find a precursor (...) in 10th century Kashmir, is a masterpiece of reason and philosophy that will leave the reader with profound thoughts on the meaning of history, God, and life itself. As a senior staff attorney in my chambers for many years at the California Supreme Court and a top scholar of ethics and philosophy of law, Mr. Cumming never ceased to amaze me with his outstanding research and intellect. This scholarly book is a must read for all who want to know why Spinoza continues to influence contemporary philosophy and how his work is still relevant in today’s challenging, interconnected world.” (Hon. Ming W. Chin, Associate Justice (Retired), Supreme Court of California, 1996–2020). (shrink)

This article is part of a For-Discussion-Section of Methods of Information in Medicine about the paper "Biomedical Informatics: We Are What We Publish", written by Peter L. Elkin, Steven H. Brown, and Graham Wright. It is introduced by an editorial. This article contains the combined commentaries invited to independently comment on the Elkin et al. paper. In subsequent issues the discussion can continue through letters to the editor.

Berkeley's immaterialism has more in common with views developed by Henry More, the mathematician Joseph Raphson, John Toland, and Jonathan Edwards than those of thinkers with whom he is commonly associated (e.g., Malebranche and Locke). The key for recognizing their similarities lies in appreciating how they understand St. Paul's remark that in God "we live and move and have our being" as an invitation to think to God as the space of discourse in which minds and ideas are identified. (...) This way of speaking about God, adapted by Karl Barth and Paul Tillich, opens up new ways to think about the relation between God and finite minds. (shrink)

will give an overview of the fascinating communication between G. W. Leibniz and Pierre Bayle on pre-established harmony and sudden change in the soul which started from Bayle’s footnote H to the article “Rorarius” in his Dictionnaire historique et critique (1697) and ended in 1706 with Bayle’s death. I will compare the views presented in the communication to Leibniz’s reflections on the soul in his partly concurrent Nouveaux essais sur l’entendement humain (1704) and argue that many topics in the communication (...) with Bayle are discussed with more details in Nouveaux essais. I also argue that the communication helped Leibniz to respond to Locke’s views concerning uneasiness in An Essay Concerning Human Understanding, II, xxi. Bayle himself, however, was not able to completely understand Leibniz’s views on spontaneity as he was unaware of the contents of the Nouveaux essais, especially the systematic role of petites perceptions in Leibniz’s philosophy of mind. I will also reflect on whether the controversy could have ended in agreement if it would have continued longer. (shrink)

This book focuses on issues in epistemology, semantics and logic with Quine’s views always setting the themes, even if Quine does not always remain quite at center stage. Gochet, Professor at Liège and Secretary to the Editorial Board of Logique et Analyse is a prominent of Quine’s views in Europe. The author does not aim to take up the whole of Quine’s philosophy here. Rather, the aim is to “focus on a few central themes...and to treat them thoroughly.” Continental Europe (...) not only recognizes Quine’s importance, then, but it is prepared to talk back: a point which has become increasingly evident in the wake of several recent works on Quine by W.K. Essler (1975), J. Largeault (1980) and Henri Lauener (1982). Gochet has made an earlier contribution to this in the form of his Quine en Perspective (1978) and its German translation (1984). But the present volume is not a further translation of the earlier work. Rather, the author “tried to avoid overlap.”. (shrink)

For Berkeley, a thing's existence 'esse' is nothing more than its being perceived 'as that thing'. It makes no sense to ask (with Samuel Johnson) about the 'esse' of the mind or the specific act of perception, for that would be like asking what it means for existence to exist. Berkeley's "existere is percipi or percipere" (NB 429) thus carefully adopts the scholastic distinction between 'esse' and 'existere' ignored by Locke and others committed to a substantialist notion of mind. (...) Following the Stoics, Berkeley proposes that, 'as' the existence of ideas, minds "subsist" rather than "exist" and, accordingly, cannot be identified as independently existing things. (shrink)

Tarihte herhalde çok az soru Tanrı’nın varlığı sorusu kadar sık sorulmuş, çok yanıtlanmış ve verilen birbirinden farklı onca yanıta rağmen kesin bir sonuca ulaştırılamayıp tartışılmaya devam etmiştir. Yine de geçmişe dönüp baktığımızda bu soruya verilen farklı yanıtların farklı uygarlıkların inşa edilmesine, bazılarının yıkılmasına, acımasız çatışmalara ve her şeye rağmen kucaklaşmalara da vesile olduğunu görüyoruz. Tanrı var mı? Varsa onu nasıl bilebiliriz? Tanrı yoksa her şey mubah mı? İnsan aklı ilahi olanı kavrayabilir mi? Tanrı’nın varlığı ahlaklı olmanın şartı mı? Evren akıllı (...) bir tasarımcının imzasını taşıyor mu? Bu kitapta felsefeci William David Beck, bu sorulara tarihte verilen yanıtları ve bu konudaki tartışmaları ele alarak meselenin genel ve tarihsel bir tablosunu bize sunuyor. Platon, Aristoteles, Marcus Aurelius gibi Eski Yunan ve Roma düşünürlerinden Anselmus, Thomas Aquinas, Augustinus ve Yahudi-Hıristiyan geleneğine, Doğu’nun bilgelerine, İbni Rüşd, Fârâbî ve Gazzâlî gibi İslam düşünürlerinden Alvin Plantinga, Graham Oppy, Sam Harris, Richard Dawkins, Max Tegmark gibi Batılı modern ilahiyatçılara, bilim insanlarına ve Yeni Ateizm hareketine kadar uzanan bir çizgide “Tanrı var mı?” sorusuna verilen çeşitli yanıtları ve bu yanıtlara sunulan akılcı gerekçeleri ortaya koyarak soruya felsefece bir yanıt vermenin nasıl bir iş olduğunu da gösteriyor. (shrink)

This review shows how Auden was a philosopher of religion and therefore, this review calls for reassessing the poet Auden as a philosopher concerned with prayer and the necessity of the transcendent in life.

DESENVOLVIMENTO EMBRIONÁRIO E DIFERENCIAÇÃO SEXUAL -/- E. I. C. da Silva Departamento de Agropecuária – IFPE Campus Belo Jardim Departamento de Zootecnia – UFRPE sede -/- 1.1 INTRODUÇÃO O sexo foi definido como a soma das diferenças morfológicas, fisiológicas e psicológicas que distinguem o macho da fêmea permitindo a reprodução sexual e assegurando a continuidade das espécies. Os processos de diferenciação sexual são realizados durante o desenvolvimento embrionário, onde ocorre a proliferação, diferenciação e maturação das células germinativas e primordiais, precursoras (...) de ovócitos e espermatozoides em fêmeas e machos, respectivamente. Assim, os embriões machos e fêmeas iniciam o seu desenvolvimento de forma semelhante, de modo que em ambos os sexos se estabelecem em estruturas idênticas a partir das quais se formarão os órgãos reprodutores correspondentes a cada sexo. O conhecimento da origem e do desenvolvimento do aparelho genital é indispensável para entender sua função e as alterações que produzem infertilidade ou esterilidade. 1.2 DETERMINAÇÃO DO SEXO CROMOSSÔMICO Nos mamíferos, o sexo cromossômico é determinado no momento da fertilização, quando um óvulo, que contém um cromossomo X, é fecundado por um espermatozoide portador de um cromossomo X ou um cromossomo Y. No primeiro caso, o complemento cromossômico seria XX, o que originaria uma fêmea (sexo homogamético), e no segundo daria como resultado um macho com a fórmula cromossômica XY (sexo heterogâmico). 1.3 A GÔNADA INDIFERENCIADA A primeira manifestação das gônadas se aprecia no embrião em forma de um par de eminências longitudinais chamadas cristas ou dobras gonodais, situadas em ambos os lados da linha média entre os mesonefros (rins em desenvolvimento) e do mesentério dorsal. Nos embriões dos mamíferos, as células germinativas primordiais (CGP) manifestam-se em estágios precoces do desenvolvimento, podendo ser detectadas pela primeira vez na metade da gastrulação. As CGP são células grandes, de citoplasma claro e núcleo grande e redondo, localizadas na parede do saco vitelino, perto do alantoide. Essas células possuem grande capacidade de proliferação e vão migrar desde o endoderma do intestino e o epitélio do saco vitelino, através do mesentério, até as cristas gonodais. Isso ocorre por volta do 26° dia da gestação no bovino. Sua migração realiza-se graças aos movimentos de translocação passiva e deslocamento ameboide ativo. Desconhece-se o mecanismo pelo qual estas células são dirigidas para as cristas gonodais, porém foram estudadas algumas moléculas que se expressam durante sua migração e que poderiam desempenhar um papel importante na diferenciação deste tipo celular. A fosfatase alcalina é uma enzima que tem sido usada como marcador de CGP para determinar a sua origem e migração. Num estudo recente, foi inserido um marcador fluorescente que se exprime unicamente nas células germinativas primordiais de embriões transgênicos, e utilizando este marcador e a fosfatase alcalina determinou-se a origem e o padrão de migração destas células. O primeiro sinal de diferenciação das células germinativas primordiais é a expressão de fosfatase alcalina, e esta apareceu pela primeira vez na parte mais posterior da linha primitiva. No sétimo dia de desenvolvimento no embrião do camundongo, o endoderma visceral (AF+) é substituído pelo endoderma definitivo (AF-) originado na parte anterior da linha primitiva. O fator de transcrição Oct-4 é expresso nas CGP de ambos os sexos, pelo que acredita-se estar envolvido na mantença a totipotêncialidade das células. O receptor tirosina quinase, cujo ligante é o fator de Steel, é outra das moléculas que expressam as CGP. Tem sido demonstrado que este receptor possui um papel muito importante na sobrevivência deste tipo celular. Existem outros fatores que promovem a sobrevivência e/ou proliferação de CGP in vitro. Em experiências realizadas com o fator de transformação beta I (TGFβ-I), observou-se que este tem um efeito negativo sobre a proliferação das CGP. Outra atividade que tem sido postulada a este fator é o de um agente quimioatraente que possivelmente possa direcionar a migração destas células para a gônada. a) Um formado pelas células germinativas primordiais (precursoras dos gametas masculinos ou femininos), rodeadas de células somáticas das quais posteriormente se derivarão as células de Sertoli no macho e as células da granulosa na fêmea. b) O tecido que formará o estroma da gônada: tecido conjuntivo, vasos sanguíneos e as células intersticiais com atividade esteroidogênica (células de Leydig no testículo e a teca interna do ovário). As células somáticas do primórdio gonodal originam-se do mesoderma. Inicialmente são de três tipos: mesenquimáticas, mesoteliais e endoteliais. As células mesenquimáticas e mesoteliais iniciam grande atividade proliferativa ao chegar as CGP. Observa-se então uma condensação de células de origem mesotelial e mesenquimatoso que forma um agregado compacto denominado "blastema gonodal". A partir deste primórdio embrionário, diferenciam-se dois tecidos gonodais: os cordões sexuais e o estroma. Os cordões sexuais são arranjos epiteliais que se encontram delimitados por uma folha basal, e dentro deles encontramos as CGP. Por sua vez, no estroma encontram-se células do tipo mesenquimático e vasos sanguíneos. Neste momento, as gônadas são indiferenciadas e bipotencialmente sexuais, sendo impossível diferenciar, morfologicamente, uma gônada masculina de uma feminina, mas no caso dos machos genéticos já existe uma diferenciação da gônada a nível molecular. Nesta fase já se encontram presentes as estruturas das quais se desenvolvem os dutos mesonéfricos ou de Wolff precursores do aparelho genital masculino e os dutos paramesonéfricos ou de Müller que darão origem ao aparelho reprodutor feminino. Há uma série de fatores envolvidos no desenvolvimento precoce da gônada, entre os quais o fator esteroidogênico I (SFI: Steroidogenic fator l), que é um membro da subfamília de receptores nucleares, receptores órfãos. Este fator de transcrição tem um local de ligação ao DNA composto por dois dedos-de-Zinc. O SFI foi identificado como um ativador de genes envolvidos na biossíntese de esteroides em diferentes células. O SFI está presente durante o desenvolvimento embrionário em regiões associadas com funções endócrinas como gônadas, adrenais, pituitárias e hipotálamos. Os animais homozigotos para o gene SFI defeituoso, necessitam de gônadas e adrenais e têm a função gonadotrófica alterada. Os ratos sem SFI carecem de gonadotrofos e têm um desenvolvimento anormal do núcleo ventro-medial do hipotálamo; em particular as gônadas deixam de se desenvolver entre os dias 11 a 15 e degeneram-se por apoptose. No entanto, a crista genital forma-se e é colonizada pelas células germinativas, o que indica que estas continuam a receber o sinal adequado para a sua migração. Portanto, o SFI não está envolvido no desenvolvimento precoce da gônada e do sistema urogenital, mas parece estar envolvido na manutenção do crescimento das células somáticas presentes na gônada indiferenciada. O gene associado ao tumor de Wilms (WTI: Wilm's tumor Associated) está envolvido no desenvolvimento da gônada e do rim. Durante o desenvolvimento embrionário, WTI se expressa em todo o mesoderma intermediário e posteriormente na gônada indiferenciada, bem como no rim em formação. WTI regula o sinal indutivo do mesênquima para o epitélio celômico dos mesonefros. Se este for o caso, então WTI é responsável pelo crescimento da crista genital ao dirigir a entrada do epitélio celômico. Dado que estas células darão origem às células de Sertoli, a carência de WTI pode causar o desenvolvimento de embriões XY como fêmeas simplesmente porque não se formam as células de Sertoli. Em geral, todos os genes importantes na diferenciação do mesoderma intermediário e do sistema urogenital intervêm no desenvolvimento da gônada precoce. 1.4 DIFERENCIAÇÃO GONODAL O desenvolvimento das gônadas e ductos genitais descritos até o momento, é o mesmo para ambos os sexos. Igualmente, os genes descritos, que estão envolvidos no desenvolvimento das gônadas, ductos genitais e migração das células germinativas, afetam igualmente os embriões com genótipo XX ou XY. A gônada primitiva consiste anatomicamente de uma medula (interna) e uma crosta (externa), e de acordo com o local onde ocorre a colonização das células germinativas, diferenciara em testículo ou um ovário, respectivamente. Nos mamíferos, a primeira manifestação estrutural de diferenciação sexual é detectada na gônada dos machos, onde as células germinativas estão localizadas na medula. A diferenciação do testículo inicia-se quando os cordões sexuais se separam do epitélio celômico como consequência dos arranjos produzidos por uma invasão do mesênquima e vasos sanguíneos que provoca a compactação dos cordões, agora denominados cordões testiculares. As células que rodeiam os cordões se achatam e formam as células mioides, que são responsáveis pela formação das membranas basais. As células do epitélio interno, ou seja, as células de Sertoli, têm duas funções principais: o suporte das CGP e a síntese da hormona antimulleriana, responsável pela regressão dos ductos de Müller e secretada durante o período de diferenciação sexual. As células do estroma que rodeiam os cordões testiculares diferenciam-se para formar vários tipos de células: células mioides, fibroblastos, endotélio e células de Leydig, que são as mais importantes pela sua atividade endócrina. Posteriormente, os cordões testiculares dão origem aos túbulos seminíferos, que contêm o epitélio que produzirá os espermatozoides ao chegar à puberdade. Na fêmea, durante os estágios iniciais de diferenciação gonodal, não se observam mudanças em relação à gônada indiferenciada, só pode-se observar um certo crescimento devido à proliferação de células somáticas e germinativas. As células germinativas iniciam um período de proliferação, que termina com o início da meiose. Iniciada a meiose, dá-se o processo de foliculogênese; neste momento os cordões epiteliais se fragmentam, de tal maneira que cada ovócito fica rodeado de células epiteliais cobertas por uma folha basal fina (figura 1). Para que a gônada primitiva se desenvolva em testículo é indispensável a presença do cromossoma Y, independentemente do número de cromossomas X que contenha o genoma de um indivíduo. O gene determinante do testículo encontra-se localizado no cromossoma Y, denominado sry em ratos e SRY em humanos. O gene sry se expressa durante o desenvolvimento embrionário na crista genital de embriões de camundongos. A expressão é detectável no dia 10,5, pouco depois do aparecimento das cristas genitais, atinge o seu máximo durante o dia 11,5 e mantém-se até pouco depois de ocorrerem os primeiros sinais morfológicos de diferenciação testicular no dia 12,5. Este padrão de expressão é compatível com a teoria de que sry atua induzindo a ativação dos genes (figura 2) que conduzem ao desenvolvimento testicular, sem que exista a necessidade da expressão contínua de sry para manter a diferenciação do testículo após o dia 12,5. Como mencionado anteriormente, a gônada primitiva é composta por vários tipos de células. No entanto, as células germinativas primordiais não são o local de expressão do sry, já que os embriões que necessitam de células germinativas mantêm a expressão de sry e desenvolvem o sexo gonodal normalmente. As células somáticas na gônada em desenvolvimento incluem também as células de suporte. Sabe-se que é nestas células que o sry é expresso para que se diferenciem em células de Sertoli, e a expressão transitória de sry indica que deve ativar a outros genes para a manutenção das células de Sertoli. Uma vez diferenciadas as células de Sertoli, elas se encarregarão da diferenciação do resto das células na gônada. -/- Figura 1: Representação da diferenciação dos órgãos genitais internos. Adaptado de BRONSON, 1989. Figura 2: Cascada de genes envolvidos na diferenciação sexual, adaptado de KOOPMAN, 1999. O fator sry é necessário para a diferenciação do testículo. Embora não se conheçam os genes que provavelmente regulam esse gene, estudos realizados em camundongos demonstram que este gene parece coordenar-se com certos genes autossômicos. Entre estes genes autossômicos, o sox9, que é produzido pelas células de Sertoli uma vez que são estimuladas por sry, de modo que sox9 é um dos genes relacionados estruturalmente com sry. O Sox9 funciona como um fator de transcrição, mas não se sabe se a proteína tem qualquer outra função estrutural; este gene exprime-se abundantemente nos condrócitos e está relacionado com defeitos do aparelho ósseo chamados displasia campomélica. Curiosamente, os pacientes XY com esta condição sofrem frequentemente de reversão do sexo. O Sox9 é um dos poucos genes, além do SRY, do qual as mutações demonstraram interferir com a determinação sexual masculina. No entanto, apenas 75% dos pacientes com anomalias esqueléticas de tipo displasia campomélica têm reversão sexual e não foram encontrados casos de reversão sexual devido a um defeito de Sox9 que não seja acompanhado de defeitos esqueléticos. Isso indica que o Sox9 é apenas um membro da rede de genes que são ativados para determinar a diferenciação sexual, enquanto a rota que rege a condrogênese é mais sensível a perturbações deste. O momento em que se detecta a expressão do gene Sox9 (11dpc em ratos) coincide com a máxima expressão de sry, o que poderia indicar a possibilidade de que sry regule positivamente a Sox9. De fato, na região do promotor de Sox9 há um local de união ao que potencialmente se pode unir o sry. A expressão de Sox9 durante a diferenciação sexual sugere um papel abaixo de sry na diferenciação das células de Sertoli. O cromossoma X também é importante na diferenciação gonodal. O gene DAX-I foi isolado do lócus DSS (Dosage sensitive sex reversal) do cromossoma X. DAX-I é parte da cascata de determinação sexual, mas não é necessário para a formação do testículo. DAX-I é um membro dos receptores nucleares conhecidos como receptores órfãos. Este gene demonstrou ser um poderoso repressor da transcrição de SFI e de vários genes. Os padrões de expressão de DAX-I são complementares daqueles de SFI, ambos expressos nas cristas genitais. Em resumo, dada a evidência exposta, desenvolveu-se a hipótese de que DAX-I é um antagonista de sry; esse antagonismo é dependente dos níveis relativos de DAX-I e sry e de um limiar que varia de espécie para espécie. A DAX-I foi classificada como o gene antitestículo. Na fêmea (cariótipo XX) é importante que ocorra a inativação de um dos cromossomas sexuais X para que se mantenha o equilíbrio genético ao igualar o conteúdo de DNA dos cromossomas. Esse cromossoma inativado constitui o chamado corpúsculo de Barr. No entanto, para que a meiose se realize, é necessário dos dois cromossomas X ativos nos ovócitos para assegurar a diferenciação ovárica e a fertilidade. 1.5 DIFERENCIAÇÃO DOS DUCTOS SEXUAIS O embrião possui, além das gônadas indiferenciadas, dois sistemas de ductos: os de potencialidade masculina denominam-se ductos de Wolff ou mesonéfricos, e os de potencialidade feminina se chamam ductos de Müller ou paramesonéfricos (figura 1). Se a diferenciação gonodal levou à formação de um testículo, a partir do ducto mesonéfrico ou de Wolff se desenvolverão os ductos eferentes, o epidídimo, os ductos deferentes e as vesículas seminais. As hormonas importantes no desenvolvimento do aparelho genital masculino são a testosterona, produzida pelas células de Leydig, e sua forma 5α reduzida, a 5α di-hidrotestosterona. Acredita-se que a testosterona é responsável pela virilização dos ductos de Wolff, e a di-hidrotestosterona dos órgãos genitais externos. No macho, os canais de Müller atrofiam-se devido à ação de uma hormona fetal de origem testicular denominada hormona inibidora das estruturas de Müller (HIM) ou hormona antimulleriana. Este processo começa assim que os cordões espermáticos se formam e se diferenciam as células de Sertoli. A existência de HIM foi proposta baseada em estudos realizados em bezerras freemartin, devido à existência de uma hormona responsável pela atresia dos ductos de Müller que na fêmea dá origem ao útero e aos ovidutos. Essa hormona provoca a involução do aparelho genital do bovino nas gestações gemelares nas quais os produtos de diferente sexo têm comunicação sanguínea por ter ocorrido a anastomose dos vasos de ambas as placentas (figura 3). A HIM é uma glicoproteína pertencente à subfamília de TGFβ, é expressa pelas células que darão origem às células de Sertoli e é um dos primeiros marcadores de diferenciação nestas células. A HIM é secretada na vida adulta pelas células de Sertoli no testículo e por células da granulosa no ovário. No rato a HIM é expressa-se no 12° dia em um teste padrão que segue muito de perto o aumento na expressão de sry. No macho, esta secreção de HIM continua durante a vida fetal e adulta, contudo os níveis de HIM declinam na puberdade devido a um aumento na secreção de testosterona. Vários fatores intervêm na regulação do gene de HIM, incluindo os acima descritos SFI e Sox9. O gene HIM contém segmentos de DNA que são conservados em várias espécies de vertebrados. Existe um nexo de ligação para SFI, que ativa a transcrição de HIM. A mutação no local de ligação de SFI resulta em reversão do sexo em indivíduos XY incluindo genitais femininos normais, presença de um útero formado enfatizando a importância de SFI na determinação sexual e na expressão de HIM. Embora SFI seja um bom candidato como regulador de HIM, é expresso em outras células, como as de Leydig e adrenais, que não expressam HIM. Em contrapartida, Sox9 é expresso unicamente nas células de Sertoli que são as produtoras de HIM. O gene HIM também tem um nexo de ligação para Sox9. Além disso, Sox9 pode atuar sinergicamente com SFI para promover a secreção de HIM. Ao contrário destes dois fatores de transcrição, DAX-I antagoniza a ação de Sox9 e provavelmente SFI sobre o promotor de HIM. Assim, para que as células de Sertoli secretem HIM, a transcrição de DAX-I deve diminuir. Figura 3: Representação da diferenciação dos órgãos genitais externos. Adaptado de BRONSON, 1989. Os ductos de Wolff tornam-se o sistema de ejaculação do macho. A porção mais próxima dos testículos dá origem ao epidídimo, a parte central ao ducto deferente e a porção mais distal às vesículas seminais. A próstata e a parte membranosa da uretra do macho desenvolvem-se a partir da porção pélvica do seio urogenital. A virilização e diferenciação dos ductos de Wolff dependem da produção de testosterona pelo testículo. Quanto aos órgãos genitais externos do macho, o tubérculo genital é ampliado e as dobras uretrais se fundem para formar a uretra peniana. A fusão das dobras uretrais aproxima os tubérculos genitais para formar o escroto (figura 4). Figura 4: Diferenciação do aparelho genital da fêmea e do macho. Adaptado de KOOPMAN, 1989. A diferenciação dos órgãos genitais da fêmea ocorre de forma passiva, já que a ausência de testículos e por isso da hormona inibidora dos ductos de Müller (HIM), assim como dos andrógenos virilizantes, favorece o desenvolvimento dos ductos de Müller, enquanto os de Wolff sofrem atrofia. A porção cefálica dos ductos de Müller dá origem aos ovidutos, que na sua terminação caudal se fundem com o útero. O contato dos ductos de Müller com o seio urogenital induz uma intensa proliferação celular que resulta na formação da área uterovaginal localizado entre o seio urogenital e os ductos de Müller. As células do prato uterovaginal proliferam e aumentam a distância entre as duas estruturas criando o espaço que formará a vagina quando o prato é canalizado e forma um lúmen. Em contraste com o que ocorre no macho, na fêmea a maior parte do seio urogenital se mantém exposta na superfície da abertura onde desembocam a vagina e a uretra. O tubérculo urogenital da fêmea tem um crescimento limitado e forma o clitóris. A sequência de passos da diferenciação sexual do aparelho genital é resumida na tabela 1. Tabela 1: Destino em desenvolvimento dos rudimentos sexuais dos fetos macho e fêmea dos mamíferos -/- Rudimento sexual Macho Fêmea Gônada Testículo Ovário Ductos de Müller (Paramesonéfricos) Vestígios Útero, parte da vagina, ovidutos Ductos de Wolff (Mesonéfricos) Ductos eferentes deferentes, epidídimo, vesículas seminais Vestígios Seio urogenital Uretra, próstata, glândulas bulbouretrais Parte da vagina, uretra, vestíbulo, glândulas vestibulares Tubérculo genital Pênis Clitóris Pregas vestibulares Escroto Lábios vulvares Fonte: HAFEZ, 2004. 1.6 DIFERENCIAÇÃO SEXUAL DO HIPOTÁLAMO Os processos de diferenciação sexual não se limitam apenas às células somáticas do organismo do feto, mas incluem também os centros nervosos superiores do cérebro. Assim, da mesma maneira que a gônada e os ductos sexuais se desenvolvem para o tipo feminino ou masculino, propôs-se que o cérebro pode ser "masculinizado" ou permanecer "Feminizado". A diferenciação do hipotálamo vai depender do ambiente esteroidal do neonato e ocorre na fase perinatal. Estes eventos serão de grande transcendência na vida reprodutiva do indivíduo. Tanto a fêmea como o macho nascem com a capacidade de secreção de gonadotropinas de acordo com um padrão cíclico; contudo, no macho, a exposição do hipotálamo à ação dos andrógenos testiculares durante os primeiros dias da vida extrauterina provoca a masculinização, com o qual o hipotálamo do macho é programado para que a secreção de gonadotropinas se realize a um ritmo relativamente constante por parte da hipófise (secreção tônica). Na fêmea, tanto a secreção tônica como a cíclica se conservam. No entanto, observou-se que a injeção de testosterona ou o transplante de testículo na rata fêmea durante os primeiros dias de vida, suprime a sua futura atividade estral (secreção cíclica). Por outro lado, se os ovários forem transplantados para o rato macho normal castrado na idade adulta, o animal não desenvolve qualquer atividade cíclica, mas se os machos transplantados forem castrados ao nascer, o ovário é capaz de efetuar mudanças cíclicas e ovulações. Isto foi demonstrado em roedores, mas não em animais domésticos ou na espécie humana. Portanto, o padrão de secreção de gonadotropinas, seja cíclico ou tônico, não depende da hipófise, mas do hipotálamo e sua correta diferenciação. 1.7 CONCLUSÕES A maioria dos conhecimentos no campo da biologia do desenvolvimento e, muito especificamente, dos processos de diferenciação sexual têm sido originados de estudos relacionados com desordens congênitas, que na sua maioria devem-se a defeitos de genes específicos. A análise detalhada destas desordens permitiu entender alguns mecanismos endócrinos, moleculares e genéticos envolvidos na diferenciação sexual. A identificação do gene sry como determinante do testículo foi uma contribuição crucial e abriu as portas à compreensão dos mecanismos moleculares e celulares relacionados com o desenvolvimento do testículo. Se este gene não estiver presente, é criado um programa genético alternativo para levar a cabo a diferenciação gonodal para o ovário. Finalmente, devemos ter presente que é necessária uma correlação entre mudanças morfológicas e expressão de genes durante o desenvolvimento para entender os mecanismos relacionados com a diferenciação. -/- Apoio -/- Realização -/- REFERÊNCIAS BIBLIOGRÁFICAS ANDERSON, Robert et al. The onset of germ cell migration in the mouse embryo. Mechanisms of development, v. 91, n. 1-2, p. 61-68, 2000. AUSTIN, Colin Russell; SHORT, R. V. Reproduction in Mammals: Volume 1, Germ Cells and Fertilization. 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Mullerian inhibiting substance activity in bovine fetal, newborn and prepubertal testes. Biology of reproduction, v. 16, n. 2, p. 238-243, 1977. HAFEZ, Elsayed Saad Eldin; HAFEZ, B. Reprodução animal. São Paulo: Manole, 2004. HANLEY, Neil A. et al. Steroidogenic factor 1 (SF-1) is essential for ovarian development and function. Molecular and cellular endocrinology, v. 163, n. 1-2, p. 27-32, 2000. HIORT, Olaf; PAUL-MARTIN, H. The molecular basis of male sexual differentiation. European journal of endocrinology, v. 142, n. 2, p. 101-110, 2000. HOLY, Lubos; MARTÍNEZ JÚSTIZ, G. Colab. Biología de la reproducción bovina. Havana: Revolucionária, 1975. JOSSO, Nathalie et al. The role of anti-Müllerian hormone in gonadal development. Molecular and cellular endocrinology, v. 145, n. 1-2, p. 3-7, 1998. JOST, Alfred et al. Studies on sex differentiation in mammals. In: Proceedings of the 1972 Laurentian Hormone Conference. Londres: Academic Press, 1973. p. 1-41. KNOBIL, Ernst. Knobil and Neill's physiology of reproduction. EUA: Gulf Professional Publishing, 2006. KOFMAN ALFARO, S.; MERCHANT LARIOS, H.; PEREZ PALACIOS, G. Diferenciacion sexual. I. Bases biologicas del dimorfismo sexual. Rev. invest. clín, p. 349-59, 1982. KOOPMAN, Peter. Sry and Sox9: mammalian testis-determining genes. Cellular and Molecular Life Sciences CMLS, v. 55, n. 6-7, p. 839-856, 1999. MCDONALD, L. E. Veterinary endocrinology. Lea & Febiger, Philadelphia, Pa, 1969. MEIZEL, S.; JOHNSON, M. H. Development in mammals. MH Johnson, Ed, v. 3, p. 1-64, 1978. MELLO, Maricilda Palandi de; ASSUMPÇÃO, Juliana de G.; HACKEL, Christine. Genes envolvidos na determinação e diferenciação do sexo. Arquivos Brasileiros de Endocrinologia & Metabologia, v. 49, n. 1, p. 14-25, 2005. -/- REFERÊNCIAS BIBLIOGRÁFICAS MERCHANT-LARIOS, H. Ovarian differentiation. The Vertebrate Ovary, p. 47-81, 1978. MIES FILHO, Antonio. Reprodução dos animais. Porto Alegre: Sulina, 1987. NEF, Serge; PARADA, Luis F. Hormones in male sexual development. Genes & Development, v. 14, n. 24, p. 3075-3086, 2000. PARKER, Keith L.; SCHEDL, Andreas; SCHIMMER, Bernard P. Gene interactions in gonadal development. Annual review of physiology, v. 61, n. 1, p. 417-433, 1999. SWAIN, Amanda; LOVELL-BADGE, Robin. Mammalian sex determination: a molecular drama. Genes & development, v. 13, n. 7, p. 755-767, 1999. WILHELM, Dagmar; PALMER, Stephen; KOOPMAN, Peter. Sex determination and gonadal development in mammals. Physiological reviews, v. 87, n. 1, p. 1-28, 2007. WILSON, Jean D.; GRIFFIN, James E.; GEORGE, Fredrick W. Sexual differentiation: early hormone synthesis and action. Biology of reproduction, v. 22, n. 1, p. 9-17, 1980. -/- Emanuel Isaque Cordeiro da Silva Belo Jardim, 07 de Maio de 2020. (shrink)

This article is the FIFTH of several excerpts from my book The Nondual Mind: Vedānta, Kashmiri Pratyabhijñā Shaivism, and Spinoza (the full book is posted on this site). “I liked James H. Cumming’s The Nondual Mind a lot. It is beautifully written, thoughtful, and very clear.” (Prof. Yitzhak Y. Melamed, Charlotte Bloomberg Professor of Philosophy, Johns Hopkins University) “James H. Cumming’s scholarly interpretation of Spinoza’s works, persuasively showing how 17th century European ideas that ushered in the Enlightenment find a precursor (...) in 10th century Kashmir, is a masterpiece of reason and philosophy that will leave the reader with profound thoughts on the meaning of history, God, and life itself. As a senior staff attorney in my chambers for many years at the California Supreme Court and a top scholar of ethics and philosophy of law, Mr. Cumming never ceased to amaze me with his outstanding research and intellect. This scholarly book is a must read for all who want to know why Spinoza continues to influence contemporary philosophy and how his work is still relevant in today’s challenging, interconnected world.” (Hon. Ming W. Chin, Associate Justice (Retired), Supreme Court of California, 1996–2020). (shrink)

This is a expository and critical review of Arthur Schlesinger, Jr. 's last book, War and the American Presidency. The book collects and focuses recent writings of Arthur Schlesinger on the themes of its title. In its short Foreword and seven concise essays, the book aims to explore, in some contrast with the genre of “instant history,” the relationship between President George W. Bush’s Iraq adventure and the national past. This aim and the present work are deserving of wide attention, (...) both because of the contemporary need to deal with the extended war in Iraq and because Americans, in particular, need to attend to their own history, if we are to avoid past mistakes and make the best use of our ongoing political traditions and institutions. In order to know better where we might go in the future, we need an adequate picture of where we have been in the past. Schlesinger invites us to debate the war, the Presidency, and their relation to the American past. (shrink)