Mark Coeckelbergh is a Belgian philosopher who specializes in the philosophy of technology. His work primarily explores the intersection of technology and society, specifically the philosophical implications of emerging technologies such as AI and robotics. He has written on whether machines can be moral agents and how ethical frameworks should be applied to autonomous machines. He has a broad philosophical perspective drawing on classical sources, Eastern philosophy, Marxism, Foucault, phenomenology, and the postmodernists. In this short text, he brings his (...) remarkable insights and erudition to bear on our attempts at self-improvement in the age of AI. (shrink)

continent. 1.1 : 3-13. / 0/ – Introduction I want to propose, as a trajectory into the philosophically weird, an absurd theoretical claim and pursue it, or perhaps more accurately, construct it as I point to it, collecting the ground work behind me like the Perpetual Train from China Mieville's Iron Council which puts down track as it moves reclaiming it along the way. The strange trajectory is the following: Kant's critical philosophy and much of continental philosophy which has followed, (...) has been a defense against horror and madness. Kant's prohibition on speculative metaphysics such as dogmatic metaphysics and transcendental realism, on thinking beyond the imposition of transcendental and moral constraints, has been challenged by numerous figures proceeding him. One of the more interesting critiques of Kant comes from the mad black Deleuzianism of Nick Land stating, “Kant’s critical philosophy is the most elaborate fit of panic in the history of the Earth.” And while Alain Badiou would certainly be opposed to the libidinal investments of Land's Deleuzo-Guattarian thought, he is likewise critical of Kant's normative thought-bureaucracies: Kant is the one author for whom I cannot feel any kinship. Everything in him exasperates me, above all his legalism—always asking Quid Juris? Or ‘Haven’t you crossed the limit?’—combined, as in today’s United States, with a religiosity that is all the more dismal in that it is both omnipresent and vague. The critical machinery he set up has enduringly poisoned philosophy, while giving great succour to the academy, which loves nothing more than to rap the knuckles of the overambitious [….] That is how I understand the truth of Monique David-Menard’s reflections on the properly psychotic origins of Kantianism. I am persuaded that the whole of the critical enterprise is set up to to shield against the tempting symptom represented by the seer Swedenborg, or against ‘diseases of the head’, as Kant puts it. An entire nexus of the limits of reason and philosophy are set up here, namely that the critical philosophy not only defends thought from madness, philosophy from madness, and philosophy from itself, but that philosophy following the advent of the critical enterprise philosophy becomes auto-vampiric; feeding on itself to support the academy. Following Francois Laruelle's non-philosophical indictment of philosophy, we could go one step further and say that philosophy operates on the material of what is philosophizable and not the material of the external world. [1] Beyond this, the Kantian scheme of nestling human thinking between our limited empirical powers and transcendental guarantees of categorical coherence, forms of thinking which stretch beyond either appear illegitimate, thereby liquefying both pre-critical metaphysics and the ravings of the mad in the same critical acid. In rejecting the Kantian apparatus we are left with two entities – an unsure relation of thought to reality where thought is susceptible to internal and external breakdown and a reality with an uncertain sense of stability. These two strands will be pursued, against the sane-seal of post-Kantian philosophy by engaging the work of weird fiction authors H.P. Lovecraft and Thomas Ligotti. The absolute inhumanism of the formers universe will be used to describe a Shoggothic Materialism while the dream worlds of the latter will articulate the mad speculation of a Ventriloquil Idealism. But first we must address the relation of philosophy to madness as well as philosophy to weird fiction. /1/ – Philosophy and Madness There is nothing that the madness of men invents which is not either nature made manifest or nature restored. Michel Foucault. Madness and Civilization. The moment I doubt whether an event that I recall actually took place, I bring the suspicion of madness upon myself: unless I am uncertain as to whether it was not a mere dream. Arthur Schopenhauer. The World as Will and Idea, Vol. 3. Madness is commonly thought of as moving through several well known cultural-historical shifts from madness as a demonic or otherwise theological force, to rationalization, to medicalization psychiatric and otherwise. Foucault's Madness and Civilization is well known for orientating madness as a form of exclusionary social control which operated by demarcating madness from reason. Yet Foucault points to the possibility of madness as the necessity of nature at least prior to the crushing weight of the church. Kant’s philosophy as a response to madness is grounded by his humanizing of madness itself. As Adrian Johnston points out in the early pages of Time Driven pre-Kantian madness meant humans were seized by demonic or angelic forces whereas Kantian madness became one of being too human. Madness becomes internalized, the external demonic forces become flaws of the individual mind. Foucault argues that, while madness is de-demonized it is also dehumanized during the Renaissance, as madmen become creatures neither diabolic nor totally human reduced to the zero degree of humanity. It is immediately clear why for Kant, speculative metaphysics must be curbed – with the problem of internal madness and without the external safeguards of transcendental conditions, there is nothing to formally separate the speculative capacities for metaphysical diagnosis from the mad ramblings of the insane mind – both equally fall outside the realm of practicality and quotidian experience. David-Menard's work is particularly useful in diagnosing the relation of thought and madness in Kant's texts. David-Menard argues that in Kant's relatively unknown “An Essay on the Maladies of the Mind” as well as his later discussion of the Seer of Swedenborg, that Kant formulates madness primarily in terms of sensory upheaval or other hallucinatory theaters. She writes: “madness is an organization of thought. It is made possible by the ambiguity of the normal relation between the imaginary and the perceived, whether this pertains to the order of sensation or to the relations between our ideas” Kant's fascination with the Seer forces Kant between the pincers of “aesthetic reconciliation” – namely melancholic withdrawal – and “a philosophical invention” – namely the critical project. Deleuze and Guattari's schizoanalysis is a combination and reversal of Kant's split, where an aesthetic over engagement with the world entails prolific conceptual invention. Their embrace of madness, however, is of course itself conceptual despite all their rhizomatic maneuvers. Though they move with the energy of madness, Deleuze and Guattari save the capacity of thought from the fangs of insanity by imbuing materiality itself with the capacity for thought. Or, as Ray Brassier puts it, “Deleuze insists, it is necessary to absolutize the immanence of this world in such a way as to dissolve the transcendent disjunction between things as we know them and as they are in themselves”. That is, whereas Kant relied on the faculty of judgment to divide representation from objectivity Deleuze attempts to flatten the whole economy beneath the juggernaut of ontological univocity. Speculation, as a particularly useful form of madness, might fall close to Deleuze and Guattari’s shaping of philosophy into a concept producing machine but is different in that it is potentially self destructive – less reliant on the stability of its own concepts and more adherent to exposing a particular horrifying swath of reality. Speculative madness is always a potential disaster in that it acknowledges little more than its own speculative power with the hope that the gibbering of at least a handful of hysterical brains will be useful. Pre-critical metaphysics amounts to madness, though this may be because the world itself is mad while new attempts at speculative metaphysics, at post-Kantian pre-critical metaphysics, are well aware of our own madness. Without the sobriety of the principle of sufficient reason we have a world of neon madness: “we would have to conceive what our life would be if all the movements of the earth, all the noises of the earth, all the smells, the tastes, all the light – of the earth and elsewhere, came to us in a moment, in an instant – like an atrocious screaming tumult of things”. Speculative thought may be participatory in the screaming tumult of the world or, worse yet, may produce its spectral double. Against theology or reason or simply commonsense, the speculative becomes heretical. Speculation, as the cognitive extension of the horrorific sublime should be met with melancholic detachment. Whereas Kant's theoretical invention, or productivity of thought, is self -sabotaging, since the advent of the critical project is a productivity of thought which then delimits the engine of thought at large either in dogmatic gestures or non-systematizable empirical wondrousness. The former is celebrated by the fiction of Thomas Ligotti whereas the latter is espoused by the tales of H.P. Lovecraft. /2/ – Weird Fiction and Philosophy. Supernatural horror, in all its eerie constructions, enables a reader to taste treats inconsistent with his personal welfare. Thomas Ligotti Songs of a Dead Dreamer. I choose weird stories because they suit my inclination best—one of my strongest and most persistent wishes being to achieve,momentarily, the illusion of some strange suspension or violation of the galling limitations of time, space, and natural law which forever imprison us and frustrate our curiosity about the infinite cosmic spaces beyond the radius of our sight and analysis H.P. Lovecraft. “Notes on Writing Weird Fiction” Lovecraft states that his creation of a story is to suspend natural law yet, at the same time, he indexes the tenuousness of such laws, suggesting the vast possibilities of the cosmic. The tension that Lovecraft sets up between his own fictions and the universe or nature is reproduced within his fictions in the common theme of the unreliable narrator; unreliable precisely because they are either mad or what they have witnessed questions the bounds of material reality. In “The Call of Cthulhu” Lovecraft writes: The most merciful thing in the world, I think, is the inability of the human mind to correlate all its contents. We live on a placid island of ignorance in the midst of black seas of infinity, and it was not meant that we should voyage far. The sciences, each straining in its own direction, have hitherto harmed us little; but some day the piecing together of dissociated knowledge will open up such terrifying vistas of reality, and of our frightful position therein, that we shall either go mad from the revelation or flee from the deadly light into the peace and safety of a new dark age. Despite Lovecraft's invocations of illusion, he is not claiming that his fantastic creations such as the Old Ones are supernatural but, following Joshi, are only ever supernormal. One can immediately see that instead of nullifying realism Lovecraft in fact opens up the real to an unbearable degree. In various letters and non-fictional statements Lovecraft espoused strictly materialist tenets, ones which he borrowed from Hugh Elliot namely the uniformity of law, the denial of teleology and the denial of non-material existence. Lovecraft seeks to explore the possibilities of such a universe by piling horror upon horror until the fragile brain which attempts to grasp it fractures. This may be why philosophy has largely ignored weird fiction – while Deleuze and Guattari mark the turn towards weird fiction and Lovecraft in particular, with the precursors to speculative realism as well as contemporary related thinkers have begun to view Lovecraft as making philosophical contributions. Lovecraft's own relation to philosophy is largely critical while celebrating Nietzsche and Schopenhauer. This relationship of Lovecraft to philosophy and philosophy to Lovecraft is coupled with Lovecraft's habit of mercilessly destroying the philosopher and the figure of the academic more generally in his work, a destruction which is both an epistemological destruction and an ontological destruction. Thomas Ligotti's weird fiction which he has designated as a kind of “confrontational escapism” might be best described in the following quote from one of his shortstories, “The human phenomenon is but the sum of densely coiled layers of illusion each of which winds itself on the supreme insanity. That there are persons of any kind when all there can be is mindless mirrors laughing and screaming as they parade about in an endless dream”. Whereas Lovecraft's weirdness draws predominantly from the abyssal depths of the uncharted universe, Ligotti's existential horror focuses on the awful proliferation of meaningless surfaces that is, the banal and every day function of representation. In an interview, Ligotti states: We don't even know what the world is like except through our sense organs, which are provably inadequate. It's no less the case with our brains. Our whole lives are motored along by forces we cannot know and perceptions that are faulty. We sometimes hear people say that they're not feeling themselves. Well, who or what do they feel like then? This is not to say that Ligotti sees nothing beneath the surface but that there is only darkness or blackness behind it, whether that surface is on the cosmological level or the personal. By addressing the implicit and explicit philosophical issues in Ligotti's work we will see that his nightmarish take on reality is a form of malevolent idealism, an idealism which is grounded in a real, albeit dark and obscure materiality. If Ligotti's horrors ultimately circle around mad perceptions which degrade the subject, it takes aim at the vast majority of the focus of continental philosophy. While Lovecraft's acidic materialism clearly assaults any romantic concept of being from the outside, Ligotti attacks consciousness from the inside: Just a little doubt slipped into the mind, a little trickle of suspicion in the bloodstream, and all those eyes of ours, one by one, open up to the world and see its horror [...] Not even the solar brilliance of a summer day will harbor you from horror. For horror eats the light and digests it into darkness. Clearly, the weird fiction of Lovecraft and Ligotti amount to a anti-anthrocentric onslaught against the ramparts of correlationist continental philosophy. /3/ – Shoggothic Materialism or the Formless Formless protoplasm able to mock and reflect all forms and organs and processes—viscous agglutinations of bubbling cells—rubbery fifteen-foot spheroids infinitely plastic and ductile—slaves of suggestion, builders of cities—more and more sullen, more and more intelligent, more and more amphibious, more and more imitative—Great God! What madness made even those blasphemous Old Ones willing to use and to carve such things? H.P. Lovecraft. “At the Mountains of Madness” On the other hand, affirming that the universe resembles nothing and is only formless amounts to saying that the universe is something like a spider or spit. Georges Bataille. “Formless”. The Shoggoths feature most prominently in H.P. Lovecraft's shortstory “At the Mountains of Madness” where they are described in the following manner: It was a terrible, indescribable thing vaster than any subway train – a shapeless congeries of protoplasmic bubbles, faintly self -luminous, and with myriads of temporary eyes forming and un-forming as pustules of greenish light all over the tunnel-filling front that bore down upon us, crushing the frantic penguins and slithering over the glistening floor that it and its kind had swept so evilly free of all litter. The term is a litmus test for materialism itself as the Shoggoth is an amorphous creature. The Shoggoths were living digging machines bio engineered by the Elder Things, and their protoplasmic bodies being formed into various tools by their hypnotic powers. The Shoggoths eventually became self aware and rose up against their masters in an ultimately failed rebellion. After the Elder Ones retreated into the oceans leaving the Shoggoths to roam the frozen wastes of the Antarctic. The onto-genesis of the Shoggoths and their gross materiality, index the horrifyingly deep time of the earth a concept near and dear to Lovecraft's formulation of horror as well as the fear of intelligences far beyond, and far before, the ascent of humankind on earth and elsewhere. The sickly amorphous nature of the Shoggoths invade materialism at large, where while materiality is unmistakably real ie not discursive, psychological, or otherwise overly subjectivist, it questions the relation of materialism to life. As Eugene Thacker writes: The Shoggoths or Elder Things do not even share the same reality with the human beings who encounter them—and yet this encounter takes place, though in a strange no-place that is neither quite that of the phenomenal world of the human subject or the noumenal world of an external reality. Amorphous yet definitively material beings are a constant in Lovecraft's tales. In his tale “The Dream-Quest of Unknown Kadatth” Lovecraft describes Azathoth as, “that shocking final peril which gibbers unmentionably outside the ordered universe,” that, “last amorphous blight of nethermost confusion which blashphemes and bubbles at the centre of all infinity,” who, “gnaws hungrily in inconceivable, unlighted chambers beyond time”. Azathoth's name may have multiple origins but the most striking is the alchemy term azoth which is both a cohesive agent and a acidic creation pointing back to the generative and the decayed. The indistinction of generation and degradation materially mirrors the blur between the natural and the unnatural as well as life and non-life. Lovecraft speaks of the tension between the natural and the unnatural is his short story “The Unnameable.” He writes, “if the psychic emanations of human creatures be grotesque distortions, what coherent representation could express or portray so gibbous and infamous a nebulousity as the spectre of a malign, chaotic perversion, itself a morbid blasphemy against Nature?”. Lovecraft explores exactly the tension outlined at the beginning of this chapter, between life and thought. At the end of his short tale Lovecraft compounds the problem as the unnameable is described as “a gelatin—a slime—yet it had shapes, a thousand shapes of horror beyond all memory”. Deleuze suggests that becoming-animal is operative throughout Lovecraft's work, where narrators feel themselves reeling at their becoming non-human or of being the anomalous or of becoming atomized. Following Eugene Thacker however, it may be far more accurate to say that Lovecraft's tales exhibit not a becoming-animal but a becoming-creature. Where the monstrous breaks the purportedly fixed laws of nature, the creature is far more ontologically ambiguous. The nameless thing is an altogether different horizon for thought. The creature is either less than animal or more than animal – its becoming is too strange for animal categories and indexes the slow march of thought towards the bizarre. This strangeness is, as aways, some indefinite swirling in the category of immanence and becoming. Bataille begins “The Labyrinth” with the assertion that being, to continue to be, is becoming. More becoming means more being hence the assertion that Bataille's barking dog is more than the sponge. This would mean that the Shoggotth is altogether too much being, too much material in the materialism. Bataille suggests that there is an immanence between the eater and the eaten, across the species and never within them. That is, despite the chaotic storm of immanence there must remain some capacity to distinguish the gradients of becoming without reliance upon, or at least total dependence upon, the powers of intellection to parse the universe into recognizable bits, properly digestible factoids. That is, if we undo Deleuze's aforementioned valorization of sense which, for his variation of materialism, performed the work of the transcendental, but refuse to reinstate Kant's transcendental disjunction between thing and appearance, then it must be a quality of becoming-as-being itself which can account for the discernible nature of things by sense. In an interview with Peter Gratton, Jane Bennett formulates the problem thusly: What is this strange systematicity proper to a world of Becoming? What, for example, initiates this congealing that will undo itself? Is it possible to identify phases within this formativity, plateaus of differentiation? If so, do the phases/plateaus follow a temporal sequence? Or, does the process of formation inside Becoming require us to theorize a non-chronological kind of time? I think that your student’s question: “How can we account for something like iterable structures in an assemblage theory?” is exactly the right question. Philosophy has erred too far on the side of the subject in the subject-object relation and has furthermore, lost the very weirdness of the non-human. Beyond this, the madness of thought need not override. /4/ - Ventriloquial Idealism or the Externality of Thought My aim is the opposite of Lovecraft's. He had an appreciation for natural scenery on earth and wanted to reach beyond the visible in the universe. I have no appreciation for natural scenery and want the objective universe to be a reflection of a character. Thomas Ligotti. “Devotees of Decay and Desolation.” Unless life is a dream, nothing makes sense. For as a reality, it is a rank failure [….] Horror is more real than we are. Thomas Ligotti. “Professor Nobody's Little Lectures on Supernatural Horror”. Thomas Ligotti's tales are rife with mannequins, puppets, and other brainless entities which of replace the valorized subject of philosophy – that of the free thinking human being. His tales such as “The Dream of the Manikin” aim to destroy the rootedness of consciousness. James Trafford has connected the anti-egoism of Ligotti to Thomas Metzinger – where the self is at best an illusion and we plead desperately for someone else to acknowledge that we are real. Trafford has stated it thus, “Life is played out as an inescapable puppet show, an endless dream in which the puppets are generally unaware that they are trapped within a mesmeric dance of whose mechanisms they know nothing and over which they have no control”. An absolute materialism, for Ligotti, implies an alienation of the idea which leads to a ventriloquil idealism. As Ligotti notes in an interview, “the fiasco and nightmare of existence, the particular fiasco and nightmare of human existence, the sense that people are puppets of powers they cannot comprehend, etc.” And then further elaborates that,“[a]ssuming that anything has to exist, my perfect world would be one in which everyone has experienced the annulment of his or her ego. That is, our consciousness of ourselves as unique individuals would entirely disappear”. The externality of the idea leads to the unfortunate consequence of consciousness eating at itself through horror which, for Ligotti, is more real than reality and goes beyond horror-as-affect. Beyond this, taking together with the unreality of life and the ventriloquizing of subjectivity, Ligotti's thought becomes an idealism in which thought itself is alien and ultimately horrifying. The role of human thought and the relation of non-relation of horror to thought is not completely clear in Ligotti's The Conspiracy Against the Human Race. Ligotti argues in his The Conspiracy Against the Human Race,that the advent of thought is a mistake of nature and that horror is being in the sense that horror results from knowing too much. Yet, at the same time, Ligotti seems to suggest that thought separates us from nature whereas, for Lovecraft, thought is far less privileged – mind is just another manifestation of the vital principal, it is just another materialization of energy. In his brilliant “Prospects for Post-Copernican Dogmatism” Iain Grant rallies against the negative definition of dogmatism and the transcendental, and suggests that negatively defining both over-focuses on conditions of access and subjectivism at the expense of the real or nature. With Schelling, who is Grant's champion against the subjectivist bastions of both Fichte and Kant, Ligotti's idealism could be taken as a transcendental realism following from an ontological realism. Yet the transcendental status of Ligotti's thought move towards a treatment of the transcendental which may threaten to leave beyond its realist ground. Ligotti states: Belief in the supernatural is only superstition. That said, a sense of the supernatural, as Conrad evidenced in Heart of Darkness, must be admitted if one's inclination is to go to the limits of horror. It is the sense of what should not be- the sense of being ravaged by the impossible. Phenomenally speaking, the super-natural may be regarded as the metaphysical counterpart of insanity, a transcendental correlative of a mind that has been driven mad. Again, Ligotti equates madness with thought, qualifying both as supernatural while remaining less emphatic about the metaphysical dimensions of horror. The question becomes one of how exactly the hallucinatory realm of the ideal relates to the black churning matter of Lovecraft's chaos of elementary particles. In his tale “I Have a Special Plan for This World” Ligotti formulates thus: A: There is no grand scheme of things. B: If there were a grand scheme of things, the fact – the fact – that we are not equipped to perceive it, either by natural or supernatural means, is a nightmarish obscenity. C: The very notion of a grand scheme of things is a nightmarish obscenity. Here Ligotti is not discounting metaphysics but implying that if it does exist the fact that we are phenomenologically ill-equipped to perceive that it is nightmarish. For Ligotti, nightmare and horror occur within the circuit of consciousness whereas for Lovecraft the relation between reality and mind is less productive on the side of mind. It is easier to ascertain how the Kantian philosophy is a defense against the diseases of the head as Kant armors his critical enterprise from too much of the world and too much of the mind. The weird fiction of both Lovecraft and Ligotti demonstrates that there is too much of both feeding into one another in a way that corrodes the Kantian schema throughly, breaking it down into a dead but still ontologically potentiated nigredo. The haunting, terrifying fact of Ligotti's idealism is that the transcendental motion which brought thought to matter, while throughly material and naturalized, brings with it the horror that thought cannot be undone without ending the material that bears it either locally or completely. Thought comes from an elsewhere and an elsewhen being-in-thought. The unthinkable outside thought is as maddening as the unthought engine of thought itself within thought which doesn't exist except for the mind, the rotting décor of the brain. /5/ - Hyperstitional Transcendental Paranoia or Self -Expelled Thought Weird fiction has been given some direct treatment in philosophy in the mad black Deleuzianism of Nick Land. Nick Land along with others in the 1990s created the Cyber Culture Research Unit as well as the research group Hyperstition. The now defunct hyperstitional website, an outgrowth of the Cyber Culture Research Unit, defined hyperstition in the following fourfold: 1-Element of effective culture that makes itself real. 2-Fictional quantity functional as a time-traveling device. 3-Coincidence intensifier. 4-Call to the Old Ones. The distinctively Lovecraftian character of hyperstition is hard to miss as is its Deleuzo-Guattarian roots. In the opening pages of A Thousand Plateaus Deleuze and Guattari write, “We have been criticized for over-quoting literary authors. But when one writes, the only question is which other machine the literary machine can be plugged into”. The indisinction of literature and philosophy mirrors the mess of being and knowing as post-correlationist philosophy, where philosophy tries to make itself real where literature, especially the weird, aims itself at the brain-circuit of horror. The texts of both Lovecraft and Ligotti work through horror as epistemological plasticity meeting with proximity as well as the deep time of Lovecraft and the glacially slow time of paranoia in Ligotti. Against Deleuze, and following Brassier, we cannot allow the time of consciousness, the Bergsonian time of the duree, to override natural time, but instead acknowledge that it is an unfortunate fact of existence as a thinking being. Horror-time, the time of consciousness, with all its punctuated moments and drawn out terrors, cannot compare to the deep time of non-existence both in the unreachable past and the unknown future. The crystalline cogs of Kant's account of experience as the leading light for the possibility of metaphysics must be throughly obliterated. His gloss of experience in Prolegomena to any Future Metaphysics could not be more sterile: Experience consists of intuitions, which belong to the sensibility, and of judgments, which are entirely a work of the understanding. But the judgments which the understanding makes entirely out of sensuous intuitions are far from being judgments of experience. For in the one case the judgment connects only the perceptions as they are given in sensuous intuition [....] Experience consists in the synthetic connection of appearances in consciousness, so far as this connection is necessary. Here it is difficult to dismiss the queasiness that Kant's legalism induces upon sight for both Badiou and David-Menard. Kant's thought becomes, as Foucault says when reflecting on Sade's text in relation to nature, “the savage abolition of itself”. For Badiou, Kant's philosophy simply closes off too much of the outside, freezing the world of thought in an all too limited formalism. Critical philosophy is simply the systematized quarantine on future thinking, on thinking which would threaten the formalism which artificially grants thought its own coherency in the face of madness. Even the becoming-mad of Deleuze, while escaping the rumbling ground, makes grounds for itself, mad grounds but grounds which are thinkable in their affect. The field of effects allows for Deleuze's aesthetic and radical empiricism, in which effects and/or occasions make up the material of the world to be thought as a chaosmosis of simulacra. Given a critique of an empiricism of aesthetics, of the image, it may be difficult to justify an attack on Kantian formalism with the madness of literature, which does not aim to make itself real but which we may attempt to make real. That is, how do Lovecraft's and Ligotti's materials, as materials for philosophy to work on, differ from either the operative formalisms of Kant or the implicitly formalized images of Deleuzian empiricism? It is simply that such texts do not aim to make themselves real, and make claims to the real which are more alien to us than familiar, which is why their horror is immediately more trustworthy. This is the madness which Blanchot discusses in The Infinite Conversation through Cervantes and his knight – the madness of book-life, of the perverse unity of literature and life a discussion which culminates in the discussion of one of the weird's masters, that of Kafka. The text is the knowing of madness, since madness, in its moment of becoming-more-mad, cannot be frozen in place but by the solidifications of externalizing production. This is why Foucault ends his famous study with works of art. Furthermore extilligence, the ability to export the products of our maligned brains, is the companion of the attempts to export, or discover the possibility of intelligences outside of our heads, in order for philosophy to survive the solar catastrophe. To borrow again from Deleuze, writing is inseparable from becoming. The mistake is to believe that madness is reabsorbed by extilligence, by great works, or that it could be exorcised by the expelling of thought into the inorganic or differently organic. Going out of our heads does not guarantee we will no longer mean we cannot still go out of our minds. This is simply because of the outside, of matter, or force, or energy, or thing-in-itself, or Schopenhauerian Will. In Lovecraft’s “The Music of Erich Zahn” an “impoverished student of metaphysics” becomes intrigued by strange viol music coming from above his room. After meeting the musician the student discovers that each night he plays frantic music at a window in order to keep some horridness at bay, some “impenetrable darkness with chaos and pandemonium”. The aesthetic defenses provided by the well trained brain can bear the hex of matter for so long, the specter of unalterability within it which too many minds obliterate, collapsing everything before the thought of thought as thinkable or at least noetically mutable on our own terms. Transcendental paranoia is the concurrent nightmare and promise of Paul Humphrey's work, of being literally out of our minds. It is the gothic counterpart of thinking non-conceptually but also of thinking never belonging to any instance of purportedly solid being. As Bataille stated, “At the boundary of that which escapes cohesion, he who reflects within cohesion realizes there is no longer any room for him” Thought is immaterial only to the degree that it is inhuman, it is a power that tries, always with failure, to ascertain its own genesis. Philosophy, if it can truly return to the great outdoors, if it can leave behind the dead loop of the human skull, must recognize not only the non-priority of human thought, but that thought never belongs to the brain that thinks it, thought comes from somewhere else. To return to the train image from the beginning “a locomotive rolling on the surface of the earth is the image of continuous metamorphosis” this is the problem of thought, and of thinking thought, of being no longer able to isolate thought, with only a thought-formed structure. [1] One of the central tenets of Francois Laruelle's non-philosophy is that philosophy has traditionally operated on material already presupposed as thinkable instead of trying to think the real in itself. Philosophy, according to Laruelle, remains fixated on transcendental synthesis which shatters immanence into an empirical datum and an a prori factum which are then fused by a third thing such as the ego. For a critical account of Laruelle's non-philosophy see Ray Brassier's Nihil Unbound. (shrink)

GAMETOGÊNESE -/- Emanuel Isaque Cordeiro da Silva Instituto Agronômico de Pernambuco Departamento de Zootecnia – UFRPE Embrapa Semiárido -/- • _____OBJETIVO -/- Os estudantes bem informados, estão a buscando conhecimento a todo momento. O estudante de Veterinária e Zootecnia, sabe que a Reprodução é uma área de primordial importância para sua carreira. Logo, o conhecimento da mesma torna-se indispensável. No primeiro trabalho da série fisiologia reprodutiva dos animais domésticos, foi abordado de forma clara, didática e objetiva os mecanismos de diferenciação (...) sexual dos embriões em desenvolvimento, quais os genes envolvidos nesse processo e tudo mais. Nesse segundo trabalho, a abordagem será teórica, mas também clara, sobre a formação primordial dos gametas femininos e masculinos, através da ovogênese nas fêmeas e a espermatogênese nos machos. Esse trabalho visa levar a importância do processo de formação dos gametas e a produção hormonal das gônadas, bem como o entendimento sobre as interações com o eixo hipotálamo-hipofisário. -/- •____INTRODUÇÃO -/- A reprodução sexual é um processo mediante a qual dois organismos da mesma espécie unem seu material genético para dar lugar a um organismo fixo com combinação única de genes; para isso, cada organismo produz células que contém a metade do material genético característico da espécie. Essas células haploides (1n) são denominadas gametas; ao combinar-se um gameta masculino com um feminino produz-se uma célula diploide (2n) (zigoto ou ovo) a partir da qual se forma o embrião. A grande maioria das espécies com reprodução sexual são anisogâmicas, o que significa que produzem dois tipos de gametas diferentes: os gametas masculinos são microscópios, móveis e produzem-se em grande quantidade, enquanto que os femininos são grandes, imóveis e produzem-se em menor quantidade. O tipo de gameta que um indivíduo produz é o que define seu sexo; sobre os animais o macho é o indivíduo que produz grandes quantidades de espermatozoides e a fêmea produz uma menor quantidade de óvulos, enquanto que nas plantas as gônadas masculinas são as produtoras pólen e as femininas produzem oosferas. Os gametas são diferentes do resto das células do organismo, as quais se chamam células somáticas; essas últimas são diploides porque contém dois pares de cromossomos, um par herdado do pai do indivíduo e o outro da mãe. As células somáticas, ademais, se dividem por mitose, ao qual os cromossomos se duplicam antes de cada divisão celular e cada uma das células filhas recebe um complemento diploide idêntico dos cromossomos, logo todas as células somáticas de um indivíduo possuem o mesmo material genético, embora cada tipo celular expresse diferentes combinações de genes. Em contraponto, os gametas são células haploides porque possuem somente um par de cromossomos e a metade do material genético característico da espécie. Cada um dos cromossomos em um gameta é resultado da recombinação dos genes contidos nos cromossomos paterno e materno do indivíduo que originam o gameta, e cada um destes possuem uma combinação única de genes. Os gametas se formam a partir das células germinais, que são células que em sua origem são diploides e elas de “comprometem” a manter-se como uma linha celular especial que em determinado momento sofrerá o processo de meiose para dar origem aos gametas haploides, sejam óvulos ou espermatozoides segundo o sexo do animal. Como descrito no trabalho sobre a diferenciação sexual, as células germinativas primordiais originam-se no epiblasto do embrião, e migram desde o saco vitelino até colonizar as cristas gonodais, onde, por sua vez, proliferam-se e se organizam junto com as células somáticas da gônada primitiva para formar o testículo ou o ovário. As células germinais masculinas e femininas tem a mesma origem embrionária. As gônadas indiferenciadas em um embrião possuem três tipos celulares: as células que dão origem aos gametas (ovogonia ou espermatogonia), as precursoras de células que nutrem os gametas em desenvolvimento (células da granulosa no ovário; células de Sertoli no testículo) e as precursoras de células que secretam hormônios sexuais (células da teca no ovário; células de Leydig no testículo). As células germinais são as únicas estruturas do organismo que têm a capacidade de dividir-se por meiose sofrendo uma redução no número de seus cromossomos, sendo responsável pela transmissão da carga genética aos descendentes. Em contraste, as células somáticas somente se dividem por mitose. A formação dos gametas compreende fases sequenciais de mitose, meiose e pós-meiose. Esses processos são altamente organizados e necessitam de um preciso e bem coordenado programa de expressão genética. Uma das características importantes da gametogênese é a redução cromossômica, que através da meiose, reduz pela metade o número de cromossomos e produz células distintas entre si, devido a trocas de material genético entre os pares de cromossomos provenientes do pai e da mãe, o que ocorre no processo de “crossing over” durante a primeira fase da meiose. A gametogênese é o processo mediante o qual as células germinais de cada sexo se multiplicam, dividem e diferenciam até formar os gametas. No caso da formação dos gametas masculinos o processo recebe o nome específico de espermatogênese, e para os gametas femininos é denominado como ovogênese. Embora os dois processos alcancem o objetivo comum de produção das células haploides, por onde compartilham algumas características, existem diferenças marcadas entre eles devido a necessidade de produzir um número muito distinto de gametas, de tamanho diferente, e com características de motilidade também distintas. -/- •___ESPERMATOGÊNESE -/- A espermatogênese é o processo mediante o qual se produz os gametas masculinos denominados espermatozoides. Durante a vida fetal as células germinais e as células somáticas do testículo em formação organizam-se em túbulos seminíferos que se derivam dos cordões sexuais primários e conformam a maior parte da medula do testículo. Na etapa fetal cada tubo seminífero é delimitado por uma membrana basal, recoberta na parte interior pelas células precursoras das células de Sertoli (um tipo de células somáticas). No exterior do túbulo localizam-se as células precursoras das células de Leydig ou intersticiais (figura 1), que também são células somáticas. Entre a membrana basal e as células de Sertoli encontram-se algumas células germinais denominadas espermatogonias de reserva A0 (denominadas gonócitos) que serão o único tipo de células germinais presentes no testículo enquanto o animal não alcançar a puberdade. As células de Sertoli estabelecem na região basal uniões oclusoras entre si, formando parte da barreira hemato-testicular. As espermatogonias A0 localizam-se por dentro da membrana basal do túbulo seminífero, embora fora da barreira hemato-testicular. Figura 1: fase neonatal. Nota-se a grande infiltração de tecido intersticial em quase 50% da seção originando que os túbulos sejam pequenos e redondos em sua maioria. O citoplasma e núcleo das células pré-Leydig são notadas claramente por essa ser uma espécie suína onde o tecido intersticial está claramente diferenciado. Hematoxilina-eosina (X 220.5). Fonte: Embrapa. -/- O número de células de Sertoli no testículo depende da influência do hormônio folículo estimulante (FSH) presente durante a vida fetal e as primeiras etapas de vida pós-natal. A população de células de Sertoli ao chegar a puberdade se manterá fixa durante o resto da vida do animal; existe uma relação positiva entre o tamanho e a população de células de Sertoli e a capacidade de produção de espermatozoides do testículo. As células de Sertoli são as únicas células somáticas que estão no epitélio seminífero, e sua função é a nutrição, sustentação e controle endócrino das células germinais. As células de Sertoli participam ativamente no processo de liberação dos espermatozoides para a luz do túbulo. Nesse momento, as células de Sertoli realizam a fagocitose de parte do citoplasma do espermatozoide dos chamados corpos residuais. As células de Sertoli também fagocitam as células germinais que se degeneram no curso normal da espermatogênese. Essas células ainda sintetizam grande quantidade de proteínas, como por exemplo as proteínas ABP (androgen hinding protein), que transportam andrógenos para todo o aparelho reprodutivo, transferrinas, que transportam ferro para a respiração celular das células germinais e também às inibinas, que regulam a liberação de FSH pela hipófise, através de um sistema de retroalimentação (feedback) negativa (figura 2). Figura 2: epitélio seminífero, células de Sertoli (flecha) (400 X). Fonte: Embrapa. -/- Antes da puberdade dos túbulos seminíferos observam-se ao corte como estruturas de diâmetro pequeno, sem luz, e conformados unicamente pelas células de Sertoli e espermatogonias de reserva e rodeados por abundante tecido intersticial, ao que estão presentes as células precursoras das células de Leydig. Ainda antes da puberdade, a diferenciação celular manifesta-se primeiro pela presença de espermatócitos primários, os quais se degeneram em geral na fase de paquíteno, por falta de estimulação hormonal. A partir de que o animal chega a puberdade inicia-se o processo de espermatogênese, que se manterá durante toda a vida do animal, exceto em espécies de animais silvestres muito estacionais, ao qual pode se suspender durante a época não reprodutiva para voltar e ser retomada na época ou estação reprodutiva. Depois da puberdade, os túbulos seminíferos possuem um diâmetro muito maior; em seu interior observa-se um grande número de células germinais de todos os tipos, diferentes estádios de divisão, e em seu lúmen contém líquido e espermatozoides. Ainda sobre o alcancei da puberdade, as espermatogonias começam a dividir-se aceleradamente por mitose, enquanto que no espaço intersticial as células mesenquimais também começam a se diferenciar e a dar origem as células de Leydig (figura 3). A partir dessa etapa as células de Leydig (totalmente diferenciadas) são também evidentes no exterior do túbulo, junto com as células mioides ou peritubulares que o rodeiam o que ao contrair-se são responsáveis por controlar o avanço dos fluidos e as células presentes no lúmen do túbulo. As células mioides estão situadas ao redor do túbulo, e é creditado a elas a promoção da contração e da integridade estrutural do túbulo. Esse tipo celular apenas se diferencia na puberdade pela ação dos andrógenos (figura 4). As interações entre as células de Sertoli e as mioides parecem ter um papel importante na manutenção das funções do testículo. Durante o processo de espermatogênese, as espermatogonias de reserva dividem-se periodicamente e enquanto algumas células fixas permanecem como espermatogonias de reserva, outras proliferam e sofrem uma seção de divisões mitóticas durante as quais se vão diferenciando até formarem espermatócitos primários (espermatocitogênese ou fase de mitose), logo sofrem divisões especiais mediante as quais reduzem seu número de cromossomos (fase de meiose), e ao final trocam de forma para converter-se em espermatozoides (espermatocitogênese) (figura 5). Cada uma dessas etapas da espermato- gênese será descrito detalhadamente adiante, antes é necessário a explicação de algumas características das células de Sertoli e de Leydig que ajudarão a entender seu papel durante a espermatogênese. Figura 3: células de Leydig no espaço intersticial do testículo bovino adulto PAS (400 X). Fonte: Embrapa. -/- Figura 4: o estabelecimento da puberdade pela presença de espermatozoides no túbulo. Hematoxilina-eosina (400 X). Fonte: Embrapa. Figura 5: fases mitóticas das espermatogonias (A0 e B) para formação de um espermatócito primário e as duas fases de meiose que se sucedem antes da espermatogênese. Fonte: ZARCO, 2018. -/- Ao início da espermatocitogênese as uniões oclusoras entre as células de Sertoli se abrem por etapas (como as comportas de um submarino) para permitir a passagem das espermatogonias em direção ao centro do túbulo seminífero sem que se estabeleça uma continuidade entre o exterior e o interior da barreira hemato-testicular. Uma vez ultrapassada essa barreira, as sucessivas gerações de espermatogonias, espermatócitos, espermátides e espermatozoides irão se localizar em direção ao interior do túbulo seminífero, em estreita associação com as células de Sertoli. Em consequência, as células de Sertoli dividem o túbulo seminífero em dois compartimentos; o compartimento basal (debaixo das uniões oclusoras das células de Sertoli), ao qual residem as espermatogonias de reserva, e o compartimento adluminal (em direção ao centro do túbulo), cujos espaços entre as células de Sertoli desenvolvem o resto do processo de espermatogênese (meiose e espermatocitogênese). Esse feito é importante porque durante a vida fetal as únicas células germinais existentes eram as espermatogonias de reserva, pelo que os antígenos expressados por gerações mais avançadas (espermatogonias intermediárias, secundárias, espermátides e espermatozoides) não são reconhecidos como próprios do corpo pelo sistema imunológico. Logo, o anterior implica que deve existir uma barreira entre eles e o sangue para evitar um ataque imunológico. Em todas as etapas da espermatogênese, as células de Sertoli atuam como células de suporte para as células germinais, que sempre permanecem recoberta pela membrana das células de Sertoli. Também atuam como células nutricionais já que proporcionam o meio em que as células germinais se desenvolvem e maturam, assim como as substâncias que regulam e sincronizam as sucessivas divisões e transformações das células germinais. As células de Sertoli produzem hormônios, como estrógenos e inibina que atuam sobre a hipófise para regular a secreção das gonadotropinas que controlam a espermatogênese. As células de Leydig que residem no exterior do túbulo seminífero também são importantes para a espermatogênese: produzem a testosterona que estimula e mantém a espermatogênese, bem como serve como substrato sobre o qual atua como aromatizador das células de Sertoli para transformá-las em estrógenos. Como supracitado, para seu estudo podemos dividir a espermatogênese em três fase: espermatocitogênese, meiose e espermiogênese (figura 6). Agora, serão descritas cada uma dessas etapas. Em algumas espécies, incluindo no homem, os macrófagos representam o segundo tipo celular intersticial mais numeroso no testículo, depois das células de Leydig. Os macrófagos e vários subtipos de linfócitos são identificados nós testículos de ovinos e ratos. Eles estão intimamente associados com as células de Leydig e atuam juntamente na regulação da esteroidogênese. Figura 6: fluxograma da espermatogênese. -/- Espermatocitogênese -/- A espermatocitogênese, também chamada de etapa proliferativa ou de mitose, consiste numa série de divisões mitóticas sofridas pelas células descendentes de uma espermatogonia de reserva. Uma vez que a célula se divide, abandona o estado de reserva e começa um processo de diferenciação. As espermatogonias de reserva (denominadas espermatogonias A0 na rata ou As nos humanos) são células que existem desde a vida fetal e que permanecem mitoticamente inativas durante a infância. Uma vez que alcançam a puberdade começam a dividir-se em intervalos regulares, e as células filhas podem permanecer como espermatogonias de reserva ou abandonar a reserva e ingressar na dita espermatocitogênese. Uma vez abandonada a reserva, as células filhas que vão se formando em cada divisão permanecem unidas por pontes citoplasmáticas, constituindo um clone que se divide sincronicamente. As células que se formam depois de cada divisão continuam sendo espermatogonias, porém cada geração é ligeiramente diferente da anterior. Na rata, por exemplo, as espermatogonias tipo A0 ao dividir-se originam espermatogonias do tipo A1, que em sucessivas divisões formam espermatogonias dos tipos A2, A3 e A4, as quais, por sua vez, sofrem outra mitose para formar espermatogonias intermediárias e uma mais para formar espermatogonias do tipo B. Essas últimas se diferenciam (sem se dividir) em espermatócitos primários, processo em que termina a fase de espermatocitogênese, que literalmente significa processo de geração de espermatócitos. As espermatogonias tipo A0 são a fonte para a contínua produção de gametas. A metade delas se dividem e formam células iguais (as chamadas células tronco) e a outra metade forma as espermatogonias A1, que sofre novas divisões mitóticas e formam os tipos 2, 3 e 4. O tipo A4 sofre mitose para formar a intermediária (A In), que por mitose, forma a tipo B (figura 6). Esses tipos de espermatogonias podem ser identificadas em evoluções histológicas de acordo com sua organização topográfica na membrana basal dos túbulos seminíferos ou mediante seu conteúdo de heterocromatina. Outra maneira de diferenciação se baseia em marcadores moleculares específicos que distinguem as espermatogonias tronco (A0) das demais, com os fins de isolamento, desenvolvimento in vitro e transplante. As tipo B passam por mitose para formarem os espermatócitos primários; estes iniciam a primeira etapa da meiose formando os espermatócitos secundários; na segunda etapa da divisão meiótica, cada espermatócito secundário se divide e formam as chamadas espermátides. Quando o testículo alcança seu desenvolvimento total, a meiose completa-se e as espermátides originadas se convertem em espermatozoides. Um dos maiores sinais característicos desse fenômeno é o alargamento das espermátides e sua migração em direção ao lúmen do túbulo seminífero (figuras 4, 7 e 8). Figura 7: espermatogonias marcadas por imuno-histoquímica, anticorpo monoclonal TGFa (400 x). Figura 8: fases de divisões meióticas (M), espermatócitos em paquíteno (PA) e espermatócitos secundários (ES). -/- Figura 9: estádio posterior a liberação dos espermatozoides na luz do túbulo. Hematoxilina-eosina (400 x). Mediante as seis divisões mitóticas que ocorrem durante a espermatocitogênese se forma potencialmente um clone de 64 espermatócitos primários a partir de cada espermatogonia A que ingressa sobre o processo. Não obstante, algumas células sofrem apoptose em cada uma das etapas do processo, ao qual o número real formado é menor. Em outras espécies produzem-se um transcurso similar de divisões mitóticas sucessivas durante a espermatocitogênese, embora a nomenclatura utilizada possa ser distinta, por exemplo nos bovinos as duas últimas divisões mitóticas dão origem as espermatogonias de tipo B1 e B2. -/- Meiose -/- Uma vez que as espermatogonias B se diferenciam em espermatócitos primários, esses iniciam a etapa de meiose, com uma nova divisão; desta vez a divisão é do tipo meiótica. Ao completar-se a primeira divisão meiótica (meiose I) se obtém os espermató-citos secundários, que ao sofrer a segunda divisão meiótica (meiose II) dão origem as espermátides. Vale salientar que a meiose é o processo mediante o qual reduz-se a metade do número de cromossomos, pelo que as espermátides que se obtém são células haploides (1n). Os espermatócitos secundários que se formam depois da primeira divisão meiótica contém a metade do número normal de cromossomos, porém a mesma quantidade de DNA já que cada cromossomo é duplo. As espermátides formadas na conclusão da segunda divisão meiótica (figura 7), por sua vez, contém a metade dos cromossomos, e esse já não são duplos, já que se trata de células 1n. Também deve-se enfatizar que durante a meiose é relevante o entrecruzamento dos cromossomos homólogos, pelo que cada espermátide possui uma combinação única e diferente de genes paternos e maternos. Outro ponto que deve ser levado em consideração é que cada espermátide somente possui um cromossomo sexual; a metade das espermátides contém o cromossomo X herdado da mãe do macho que está levando a cabo a espermatogênese e a outra metade contém o cromossomo Y herdado de seu pai. Para cada espermatócito primário que entra no processo de meiose obtém-se cerca de quatro espermátides, pelo qual ao ser completada a meiose potencialmente se poderiam formar até 256 espermátides por cada espermatogonia que abandona a reserva e ingressa na espermatocitogênese. -/- Espermiogênese -/- Durante a espermiogênese, também chamada de fase de diferenciação, as esper-mátides sofrem, sem se dividir, uma metamorfose que as transforma em espermatozoides, os quais finalmente são liberados das células de Sertoli em direção ao lúmen do túbulo seminífero. A espermiogênese é um processo complicado e longo já que a espermátide deve sofrer complexas trocas nucleares, citoplasmáticas e morfológicas que resultam na forma-ção dos espermatozoides. Algumas dessas mudanças incluem a condensação do material nuclear para formação de um núcleo plano e denso, a eliminação do citoplasma para a constituição de uma célula pequena, a formação de uma estrutura especializada denomi-nada acrossomo ou tampa cefálica, e a formação do pescoço e da cauda (flagelo) do esper-matozoide, do que depende a sua motilidade. Durante a maior parte da espermiogênese, as espermátides se mantém com uma estreita associação com as células de Sertoli; logo, chega-se a observar, então, flagelos que se projetam em direção a luz do túbulo que pare-cem sair das células de Sertoli, sendo na realidade os flagelos dos espermatozoides que ainda não tinham sido liberados pelo lúmen. Ao liberar os espermatozoides em direção a luz do túbulo, as células de Sertoli realizam a fagocitose de parte do citoplasma dos espermatozoides (corpos residuais). Também fagocitam os restos de todas as células germinais que sofrem apoptose ou degeneram-se durante a espermatogênese. Credita-se que ao realizar essas funções as células de Sertoli podem fazer uma monitoração eficiente da espermatogênese, o que lhes permitiria emitir sinais para colaborar na regulação desse processo em nível gonodal e a nível sistêmico através da secreção de hormônios como a inibina e o estradiol. Além da inibina e activina, as células de Sertoli sintetizam outras proteínas, como a ABP (proteína ligadora de andrógenos) que serve como uma molécula de transporte de andrógenos dentro dos túbulos seminíferos, ductos deferentes e epidídimo, ou a transfer-rina, que transporta o ferro necessário para a respiração celular. -/- Resultados da espermatogênese -/- O resultado da espermatogênese não significa apenas uma simples multiplicação das células germinais (até 256 espermatozoides a partir de cada espermatogonia A1), senão que através dela são produzidos gametas haploides pequenos, móveis e com grande diversidade genética entre eles, ao mesmo tempo que se mantêm uma reversa de células mãe (espermatogonias A0) a partir das quais se poderiam originar novos ciclos de esper-matogênese durante o resto da vida do animal. -/- Controle hormonal da espermatogênese -/- Como mencionado, o FSH reproduz um importante papel para o estabelecimento das células de Sertoli durante a vida fetal e início da vida pós-natal. O começo da esper-matogênese também é estimulado pelo FSH, que atua sobre as células de Sertoli para estimular sua função e a ativação de sinais dessas células em direção as células germinais, incluindo-as a abandonar a reserva e ingressar na espermatogênese. O FSH, assim mesmo, estimula a mitose durante o resto da espermatogênese e aumenta a eficiência do processo, já que reduz a apoptose e a degeneração de espermatogonias intermediárias e do tipo B. O FSH também estimula as células de Sertoli para produzirem inibina e ABP. Uma vez iniciada a espermatogênese somente requerem níveis baixos de FSH para se mantê-la. As células de Sertoli também devem ser estimuladas pela testosterona para funcio-nar de maneira adequada; se requer também do LH hipofisário: hormônio que estimula as células de Leydig para produzir testosterona. Por sua vez, a secreção de LH e FSH é regulada pelo GnRH hipotalâmico: esse neurohormônio também faz parte do mecanismo de regulação da espermatogênese. A espermatogênese também é modulada em nível local mediante a produção de determinados fatores e interações entre as células. Dentro dos fatores locais podemos mencionar o fator de crescimento parecido com a insulina 1 (IGF-1), o fator de crescimen-to transformante beta (TGF- β), activina, ocitocina e diversas citocinas. Entre as intera-ções celulares existem tanto uniões de comunicação entre as células de Sertoli e as células germinais, como pontes citoplasmáticas entre todas as células germinais que formam o clone de células descendentes de uma espermatogonia A1. Uma vez que as células de Sertoli iniciam sua função na puberdade é possível manter experimentalmente a espermatogênese somente com testosterona, sem ser requeri-dos nenhum outro hormônio. A quantidade de espermatozoides produzidos, no entanto, é maior quando há presença do FSH. Abaixo do estímulo do FSH as células de Sertoli produzem estradiol e inibina, hormônios que geram uma retroalimentação sobre o eixo hipotálamo-hipofisário para a regulação da secreção de gonadotropinas. Em particular, a inibina reduz a secreção de FSH, pelo qual é factível que sirva como um sinal que evite uma excessiva estimulação as células de Sertoli. -/- Ciclo do epitélio seminífero -/- Em cada espécie as espermatogonias de reserva iniciam um novo processo de divi-sões celulares em intervalos fixos: a casa 14 dias no touro; 12 dias no garanhão e a cada 9 dias no cachaço (reprodutor suíno). A nova geração de células que começam a proliferar sobre a base do tubo deslocam-se em direção ao centro do túbulo a geração anterior, que por sua vez deslocam-se as gerações anteriores. Devido as mudanças que vão sofrendo cada geração celular se ajustam a tempos característicos de cada etapa, já que rodas as células em uma determinada seção do túbulo estão sincronizadas entre si pelas células de Sertoli; em cada espécie somente é possível encontrar um certo número de combinações celulares: 14 diferentes combinações no caso da rata, 8 no touro e 6 no ser humano. A sucessão de possíveis combinações até regressar a primeira combinação se conhece como o ciclo do epitélio seminífero. Na maioria das espécies os espermatozoides que são libera-dos em direção a luz do túbulo provém das células que entraram no processo de esperma-togênese quatro gerações antes que a geração que está ingressando nesse momento, pelo que a espermatogênese no touro dura ao redor de 60 dias e um pouco menos em outras espécies domésticas. Significa que os efeitos negativos das alterações na espermatogêne-se podem estar presentes até dois meses depois de que se produziram essas alterações. Como supracitado, geralmente se observa a mesma combinação celular em toda a área de uma determinada secção transversal do túbulo seminífero. No entanto, se fizermos uma série de secções, observa-se que ao longo do túbulo há uma sucessão ordenada de combinações (a primeira em uma determinada secção; a segunda combinação na seguinte secção, e assim sucessivamente em secções subsequentes até regressar a primeira combi-nação. Teremos, então, que ao início da divisão das espermatogonias A1 se produz de forma sincronizada em uma secção do túbulo, e vai-se transmitindo como uma onda peristáltica as secções adjacentes. Esse processo é denominado como onda do epitélio seminífero e graças à esse túbulo seminífero sempre tem secções em todas as etapas da espermatogênese, com o que se alcança uma produção constante de espermatozoides. -/- Alterações da espermatogênese -/- Nas espécies estacionais a espermatogênese, como já mencionado, pode reduzir-se ou inclusive suspender sua atividade fisiológica durante a época não reprodutiva dessas espécimes, porém esse processo fisiológico não pode ser considerado como uma altera-ção. No entanto, a espermatogênese só pode ser alterada pelas enfermidades ou por fatores externos. A principal causa de alterações na espermatogênese é o aumento da temperatura testicular. Por isso, os testículos são localizados na saco escrotal e são “caídos” para fora do corpo como pode-se observar nos bovinos, caprinos, ovinos, caninos e no próprio homem. A temperatura testicular deve estar cerca de 2 a 6 °C abaixo da temperatura corporal normal. As células germinais masculinas são sensíveis ao calor, pelo qual na maioria dos mamíferos os testículos se encontram fora da cavidade abdominal e existe um sofisticado sistema de termorregulação para mantê-los a uma temperatura menor que a corporal. Se a temperatura corporal for elevada ou se os testículos permanecerem na cavidade abdominal, ou ainda se os sistemas termorreguladores do testículo sejam afetados por fatores inflamatórios como edema ou falta de mobilidade testicular dentro do escroto, a temperatura do tecido testicular aumentará e a espermatogênese sofrerá alterações proporcionais ao excesso de temperatura e a duração da elevação. A espermatogênese também pode ser afetada pela exposição a hormônios ou a outras substâncias. É possível que a causa mais comum (sobretudo no homem) seja o uso de esteroides anabólicos, que elevam a concentração de andrógenos na circulação, provo-cando um feedback negativo sobre a secreção de gonadotropinas. Ao deixar de estimular-se o testículo pelas gonadotropinas, este deixará de produzir testosterona, e as concentra-ções de andrógeno exógeno nunca alcançará as altíssimas concentrações de testosterona que normalmente estão presentes a nível do tecido testicular por ser o local onde se produz o hormônio. Também se supõe que diversas substâncias com propriedades estrogênicas derivadas de processos industriais (indústria dos plásticos, hidrocarbonetos etc.) e presentes no ambiente (fatores xenobióticos) podem ser responsáveis pelas alterações na espermatogênese em diversas espécies, entre as quais se inclui o ser humano. -/- • OVOGÊNESE E FOLICULOGÊNESE -/- A ovogênese é o processo seguido pelas células germinais da fêmea para a forma-ção dos óvulos, que são células haploides. Durante a vida fetal as células germinais proliferam-se no ovário por mitose, formando um grande número de ovogonias, algumas das quais se diferenciam em ovócitos primários que iniciam sua primeira divisão meiótica para deter-se na prófase da divisão. Somente alguns desses ovócitos primários retornarão e concluirão a primeira divisão meiótica em algum momento da vida adulta do animal, dando origem a um ovócito secundário e a um corpo polar. O ovócito secundário inicia a sua segunda divisão meiótica, a qual volta a ficar suspensa até receber um estímulo apropriado, já que somente os ovócitos secundários que são ovulados e penetrados por um espermatozoide retornam e concluem a segunda divisão meiótica, dando origem a um óvulo (figura 10). O processo de ovogênese é realizado dentro dos folículos ovarianos, que também tem que sofrer um longo transcurso de desenvolvimento e diferenciação denominado foliculogênese pelo que a ovogênese como tal realiza-se dentro do marco desse último processo. Por essa razão, na seguinte seção descreverei tanto a ovogênese como a folicu-logênese, e a relação que existe entre ambos. Figura 10: representação da ovogênese. Na etapa de proliferação, as células germinais se diferen-ciam por mitose. A meiose I se caracteriza por uma prófase prolongada, ocorrendo a duplicação do DNA. Nas duas divisões, que ocorrem antes da ovulação e depois da fertilização, a quantidade de DNA é reduzida a 1n, com o fim de que a fusão dos pronúcles (singamia) pós-fertilização, seja gerado um zigoto com um número de cromossomos de 2n (diploide). -/- Geração de ovócitos primários e folículos primordiais Tanto a ovogênese como a foliculogênese iniciam-se durante a vida fetal, quando as células germinais primordiais provenientes do saco vitelino colonizam a gônada primitiva e, junto com as células somáticas z organizam-se para a formação dos cordões sexuais secundários, que se desenvolvem principalmente no córtex do ovário. Nesse período, as células germinais que colonizaram o ovário sofrem até 30 divisões mitóticas, proliferando-se até formar milhares ou milhões de ovogonias, que inicialmente formam “ninhos” constituídos cada um deles por um clone de várias ovogonias que descendem da mesma célula precursora e que se mantêm unidas por pontes citoplasmáticas, sincronizan-do suas divisões mitóticas. Nessa etapa alcança-se a máxima população de células germinais no ovário, que antes de nascer se reduzirá drasticamente por apoptose. No ovário do feto humano chegam a haver até sete milhões de células germinais que ao nascimento se reduzem a dois milhões. Os ovários fetais do bovino, de maneira análoga, chegam a ter até 2.100.000 células germinais, que ao nascimento reduzem para 130.000 aproximadamente. A redução no número de ovogonias produz-se ao mesmo tempo que essas células, que vêm dividindo-se por mitose e estão agrupadas em ninhos, iniciam sua primeira divisão meiótica para se transformarem em ovócitos primários: células germinais que se encontram em uma etapa de suspensão (diplóteno) da prófase da primeira divisão meiótica. Nesse período produz-se uma grande proporção de células germinais; as células somáticas dos cordões sexuais, por sua vez, emitem projeções citoplasmáticas que separam a isolam os ovócitos primários sobreviventes, ficando cada um deles rodeados por uma capa de células aplanadas da (pré) granulosa. Ao mesmo tempo em que se forma uma membrana basal entre as células da granulosa e o tecido intersticial do ovário. Ao ovócito primário rodeado de uma capa de células da (pré) granulosa aplanadas e delimita-das por uma membrana basal denomina-se de folículo primordial (figura 11). Nas vacas os folículos primordiais bem formados já estão presentes nos ovários a partir do dia 90 da gestação. A maioria dos folículos primordiais com os que nasce uma fêmea se manterão inativos durante um longo tempo; muitos deles durante toda a vida do animal. Nos folículos primordiais inativos tanto os ovócitos primários como as células da granulosa conservam sua forma original e mantém um metabolismo reduzido estritamente ao mínimo necessário para manter-se viáveis. Por essa razão, ao realizar um corte histológico de qualquer ovário as estruturas mais numerosas que se observam serão os folículos primordiais. No entanto, cada dia da vida de um animal, inclusive desde a vida fetal, um certo número de folículos primordiais reiniciam seu desenvolvimento, e a partir desse momento um folículo exclusivamente pode ter dois destinos: o primeiro, prosseguir seu desenvolvi-mento até chegar a ovular, e o segundo (que é muito mais frequente) encontrar em algum momento condições inadequadas que fazem fronteira com ele para parar seu desenvolvi-mento, levando-o a sofrer atresia e degenerar até desaparecer do ovário. Figura 11: sequência da foliculogênese apresentando as diferentes estruturas que podemos encontrar em cada fase. Fonte: ZARCO, 2018. Culminação da ovogênese A ovogênese somente se completará quando um ovócito primário reinicia a meio-se; completa sua primeira divisão meiótica para formar um ovócito secundário e um primeiro corpo polar e, quando, finalmente sofrer uma segunda divisão meiótica para formar um óvulo e um segundo corpo polar. Os óvulos são as células 1n que constituem os gametas femininos, pouco numerosos, grandes e imóveis. A grande maioria dos ovóci-tos primários, como veremos mais adiante, nunca retomam a meiose e, em consequência, não chegam a formar ovócitos secundários, e muitos dos ovócitos secundários tampouco sofrem uma segunda divisão meiótica, pelo que não chegam a formar os óvulos. Ao longo da vida de uma fêmea, na maioria das espécies, menos de 0,1% dos ovócitos primários (um a cada mil) chega a terminar a ovogênese, dando origem a um óvulo. O supracitado deve-se a que a ovogênese somente pode retomar-se e ser completa-da em ovócitos primários que se encontram dentro dos folículos primordiais que (uma vez ativados) vão alcançando diversas etapas de seu desenvolvimento em momentos precisos aos que encontram as condições ideais de oxigenação, nutrição, vascularização e exposição a fatores parácrinos e a exposição a concentrações de hormônios que se requerem para que o folículo continue em cada etapa de seu desenvolvimento com o processo de foliculogênese até chegar a ovular. Qualquer folículo que não esteja nessas condições ao longo do desenvolvimento sofrerá degeneração e atresia, pelo que o ovócito primário em seu interior nunca chegará ao ponto em que pode retomar a primeira divisão meiótica. No que resta da presente seção revisaremos o processo de foliculogênese em cujo marco se desenvolve a ovogênese; havemos que tomar de conta que essa última se limita ao que ocorre nas células germinais (ovogonia, ovócito primário, secundário e óvulo), pelo qual depende intimamente do desenvolvimento do folículo de que essas células formam parte. Em um princípio a ativação do folículo primordial e o desenvolvimento folicular são independentes das gonadotropinas: não se conhecem os mecanismos precisos median-te os quais um folículo primordial se ativa e reinicia seu desenvolvimento, nem como se decide quais folículos, dentre as dezenas de milhares de ou centenas de milhares presentes em um ovário se reativarão em um dia em particular. A reativação trata-se de uma liberação de influência de fatores inibidores, já que os folículos primordiais se reativam espontaneamente quando cultivados in vitro, isolados do resto do tecido ovariano. Uma vez que um folículo primordial se ativa, inicia-se um longo processo de desenvolvimento que somente depois de vários meses (ao redor de cinco meses no caso dos bovinos) o levará a um estádio em que seu desenvolvimento posterior requer a presença das gonado-tropinas; daí que se diz que as primeiras etapas do desenvolvimento são independentes das gonadotropinas. Durante a fase independente de gonadotropinas, um folículo primordial que tenha sido ativado e tenha começado a crescer; passará primeiro para a etapa de folículo primá-rio, caracterizada por conter um ovócito primário que está rodeado, por sua vez, por uma capa de células da granulosa, que não são planas, e sim cúbicas. Depois, se o folículo continuar crescendo se transformará em um folículo secundário, ao qual as células da granulosa começam a proliferar (aumentando em número) e se organizam em duas ou mais capas que rodeiam o ovócito primário. Entre o ovócito e as células da granulosa que o rodeiam se forma nesta uma zona pelúcida; ainda assim o ovócito mantém contato direto com essas células, mediante o estabelecimento de pontes citoplasmáticas que atravessam a zona pelúcida. Através dessas pontes citoplasmáticas as células da granulosa podem passar nutrientes e informação ao ovócito primário. O volume e o diâmetro do ovócito primário aumentam ao mesmo tempo que as células da granulosa proliferam-se, para incrementar as capas ao redor do ovócito. De maneira gradual o citoplasma do ovócito primário aumenta até 50 vezes seu volume e a proliferação das células continua. Esses folículos que possuem cada vez mais células e portanto mais capas de células da granulosa se denominam folículos secundários. Para evitar confusões, há a necessidade de nomen-clatura ao qual o folículo vá mudando de nome de primordial a primário e logo, de secun-dário, a terciário, por sua vez, o ovócito que encontra-se em seu interior, a todo momento, segue sendo um ovócito primário. Durante a etapa dependente de gonadotropinas, os folículos secundários começam a formar um espaço cheio de líquido, o antro folicular, desse modo se convertem em folí-culos terciários. Com a utilização de outra nomenclatura, a formação do antro marca a transição entre folículos pré-antrais (sem antro) e folículos antrais (com antro). Em algum momento dessa transição entre folículo secundário e terciário, também aparece a depen-dência de folículos em direção as gonadotropinas, pelo qual somente podem seguir crescendo na presença do hormônio luteinizante (LH) e do hormônio folículo estimulante (FSH). Nos bovinos e em outras espécies (para seu estudo), os folículos antrais são dividi-dos em pequenos, médios e grandes. Embora todos eles possuam um antro folicular, dependendo do seu grau de desenvolvimento requerem diferentes concentrações de gona-dotropinas para continuar o crescimento. Os folículos antrais mais pequenos somente re-querem concentrações baixas de LH e FSH, pelo qual podem continuar crescendo em qualquer momento do ciclo estral inclusive em animais que não estão ciclando (fêmeas em anestro pré-puberal, gestacional, lactacional, estacional). Nas etapas posteriores os folículos antrais requerem primeiro concentrações elevadas de FSH, e nas etapas finais somente podem continuar crescendo na presença de pulsos frequentes de LH, pelo qual somente os folículos que encontram-se sob concentrações apropriadas desses hormônios podem seguir crescendo. Por essa razão, nos animais que se encontram em anestro de qualquer tipo somente é possível encontrar folículos antrais pequenos ou médios, segundo a espécie, e nos animais que se encontram ciclando (estro) o maior tamanho folicular encontrado em um determinado dia do ciclo dependerá das concentrações de FSH e LH presentes nesse momento e nos dias anteriores. Um folículo que chega ao estado máximo de desenvolvimento, conhecido como folículo pré-ovulatório, ao final, somente chegará a ovular se for exposto a um pico pré-ovulatório de LH. Como supracitado, cada dia na vida de uma fêmea inicia seu desenvolvimento um certo número de folículos; a grande maioria sofrem atresia, mas depois da puberdade em cada dia do ciclo estral um ou vários folículos vão encontrando ao longo do seu desenvol-vimento concentrações hormonais que lhes permite chegar na etapa de folículo pré-ovula-tório. Somente nestes folículos, e como consequência de um pico pré-ovulatório de LH, se reinicia e completa-se a primeira divisão meiótica do ovócito primário, produzindo duas células distintas. Uma delas é o ovócito secundário, que retém praticamente todo o citoplasma. Contém, assim mesmo, em seu núcleo um par de cromossomos duplos, a outra é o primeiro corpo polar, que é exclusivamente um núcleo com uma quantidade mínima de citoplasma. Na maioria das espécies ovula-se um ovócito secundário que se encontra, então, suspendido na segunda divisão meiótica. Esta segunda divisão meiótica somente reinicia-rá e completarar-se uma vez que o espermatozoide começa a penetrar sob o ovócito secundário. Ao concluir-se a divisão se forma o segundo corpo polar e completa-se a ovogênese com o qual se obtém o óvulo, célula 1n que constitui o gameta feminino. No entanto, o óvulo existe pouco tempo como tal, já que em poucos minutos/horas (depen-dendo da espécie) se produzirá a fusão do núcleo do mesmo (pró-núcleo feminino) com o do espermatozoide (pró-núcleo masculino), com o qual se completa a fertilização e se forma um novo indivíduo (o ovo ou zigoto). -/- Ondas foliculares -/- Como mencionado supra, todos os dias um determinado número de folículos pri-mordiais se ativam e começam a crescer, os quais crescem em um ritmo característico em cada espécie. Isso provoca que em qualquer momento existam nos ovários folículos pri-mordiais (que começam a crescer em alguns dias ou semanas), assim como folículos secundários em diversas etapas do desenvolvimento, os quais iniciaram seu desenvolvi-mento em semanas ou inclusive meses (segundo o grau de desenvolvimento atual). Também em qualquer momento poderá haver folículos antrais nas etapas iniciais de seu desenvolvimento (com antros que já se podem detectar em cortes histológicos mas não são visíveis macroscopicamente). Todos esses folículos chegaram até seu estado de de-senvolvimento atual (primário, secundário ou antral pequeno), independente da etapa do ciclo estral em que sejam observados ou encontrados. Nos bovinos, os folículos que chegam ao início da etapa antral iniciaram seu desenvolvimento cinco meses antes, e todavia requerem ao redor de 42 dias para chegar ao estado pré-ovulatório. Para continuar seu desenvolvimento, os folículos antrais pequenos devem encon-trar concentrações altas de FSH, que os estimulam para prosseguir o crescimento. Cada vez que se produz uma elevação nas concentrações de FSH, esse hormônio estimula o desenvolvimento de um grupo de folículos antrais pequenos, que começaram a crescer muito tempo antes e que o dia da elevação de FSH tenha alcançado o grau de desenvolvi-mento preciso para responder com eficiência a este hormônio, o qual atuará através de seus receptores nas células da granulosa para estimular a produção de estradiol, a secreção de inibina, a produção de líquido folicular e a proliferação das células da granulosa. Um grupo de folículos antrais pequenos é assim recrutado pelo FSH para acelerar seu cresci-mento e aumentar sua produção de estradiol e inibina (figura 12). Mediante um seguimento ultrassonográfico dos ovários é possível identificar pou-cos dias depois um certo número de folículos, que por haver sido recrutados começam um período de crescimento acelerado. Durante alguns dias vários folículos crescem juntos, porém depois um deles é selecionado para continuar crescendo, enquanto que o restante do grupo deixam de fazê-lo e terminam sofrendo atresia. Através da ultrassom é possível identificar o folículo selecionado, agora chamado folículo domi-nante, já que sua trajetória de crescimento sofre um desvio com respeito a seguida pelo restante do grupo. Os folículos que não foram selecionados deixam de crescer e sofrem atresia já que deixam de possuir o suporte gonadotrópico de FSH, uma vez que as concentrações desse hormônio são suprimidos pela inibina e o estradiol produzidos pelo conjunto de folículos que conformam a onda folicular (figura 12), porém o folículo mais desenvolvido do grupo se converterá em dominante. A inibina atua diretamente a nível hipofisário para reduzir a secreção de FSH. Figura 12: onda folicular e relação dos níveis de FSH, estradiol e LH. Fonte: ZARCO, 2018. -/- Figura 13: Recrutamento, seleção e dominação folicular na espécie ovina e influência do FSH e LH nas fases. Fonte: SILVA, E. I. C. da, 2019. -/- A razão pela qual o folículo dominante é capaz de continuar seu desenvolvimento apesar da baixa nas concentrações de FSH é que o folículo é o único que alcançou o grau de progresso necessário para que apareçam os receptores para LH em suas células da granulosa. Esse processo permite ao folículo dominante ser estimulado pela LH, e que requeira baixas concentrações de FSH para manter seu desenvolvimento. A secreção de LH em forma de pulsos de baixa frequência (um pulso a cada quatro a seis horas), característica da fase lútea do ciclo estral; é suficiente para permitir que um folículo dominante continue crescendo por mais dias depois da sua seleção e que mais tarde mantenha-se viável durante alguns dias embora não aumentem de tamanho. Contu-do, se durante o período viável desse folículo não seja finalizada a fase lútea e não diminuam as concentrações de progesterona, o folículo terminará sofrendo atresia devido a exigência de um padrão de secreção acelerada de LH (aproximadamente um pulso por hora) durante o desenvolvimento pré-ovulatório, que somente pode ser produzido com a ausência da progesterona. Uma vez que um folículo dominante sofre atresia deixa de produzir inibina, pelo qual as concentrações de FSH podem elevar-se novamente para iniciar o recrutamento de outro grupo de folículos a partir da qual se origina uma nova onda folicular. Durante o ciclo estral de uma vaca podem gerar-se dois ou três ondas foliculares; somente em raros casos quatro. A etapa de dominância folicular da primeira onda na grande maioria dos casos não coincide com a regressão do corpo lúteo, pelo qual o primei-ro folículo dominante quase invariavelmente termina em atresia. Em algumas vacas o fo-lículo dominante da segunda onda ainda está viável quando se produz a regressão do corpo lúteo e acelera-se a secreção de LH, pelo qual esse segundo folículo dominante se converte em folículo pré-ovulatório e, ao final ovula. Em outros animais o segundo folícu-lo dominante também perde a sua viabilidade antes da regressão do corpo lúteo, por onde nesses animais se inicia uma terceira onda folicular, da qual surge o folículo que finalmen-te ovulará depois de produzir-se a regressão do corpo lúteo. Sem importar a onda em que se origine, uma vez que um folículo dominante é ex-posto a alta frequência de secreção de LH que se produz depois da regressão do corpo lúteo, aumenta ainda mais sua secreção de estradiol até que as altas concentrações desse hormônio comecem a exercer um feedback positivo para a secreção do LH. Isso provoca-rá a aceleração da frequência de secreção do LH até que os pulsos são tão frequentes que começam a ficar por cima e produzir-se o pico pré-ovulatório de LH, que é responsável pela realização da ovulação e a maturação final do ovócito. -/- •___DIFERENÇAS ENTRE ESPERMATOGÊNESE E OVOGÊNESE -/- Enquanto que na fêmea a ovogênese inicia-se durante a vida fetal, no macho a es-permatogênese começa na puberdade. Na fêmea, a partir de um ovócito primário se origi-na um óvulo; no macho, de um espermatócito primário se produzem, teoricamente, quatro espermatozoides. Outra característica interessante é que enquanto a fêmea já conta desde o nasci-mento com todos os ovócitos que necessitará na vida adulta, o macho necessitará chegar a puberdade para iniciar o desenvolvimento das células sexuais, já que ao nascer somente possui gonócitos precursores das células germinais, células de Sertoli e intersticiais. Na vida adulta de uma fêmea, o número de células germinais desaparece paulati-namente. Uma vez iniciada a espermatogênese no macho, a cada ciclo do epitélio seminí-fero as células germinais são renovadas mantendo a provisão para toda a vida reprodutiva. Na fêmea, a meiose sofre duas interrupções em seu transcurso, e no macho é ininterrupta. Figura 14: representação em diagramação comparativa do desenvolvimento da gametogênese. -/- Principais pontos abordados sobre as diferenças entre a gametogênese masculina e feminina: ❙ Na ovogênese a meiose contêm-se em duas ocasiões esperando acontecimentos externos para prosseguir. Já na espermatogênese não existe a suspensão da meiose. ❙ A espermatogênese é um processo contínuo, enquanto que a ovogênese pode completar exclusivamente um óvulo em cada ciclo estral; já que só pode ser completada por mais de um nas espécies que ovulam vários ovócitos no caso das porcas, cadelas, gatas etc. ❙ Na espermatogênese existem células de reserva que permitem a continuação du-rante toda a vida, enquanto que na ovogênese o número de ovócitos primários é limitado. A fêmea somente conta com os que nasceu, e eles não se dividem. ❙ Na espermatogênese obtém-se até 256 espermatozoides para cada espermatogo-nia que inicia o processo, enquanto que na ovogênese somente se obtém um óvulo a partir de cada ovócito primário. ❙ Durante a espermatogênese se produz uma metamorfose que transforma as es-permátides em espermatozoides. Na ovogênese não ocorre um processo análogo. ❙ Na espermatogênese, durante a meiose produzem-se quatro espermátides a partir de cada espermatócito primário. Na ovogênese se produz somente um óvulo a partir de cada ovócito primário; produz, ademais, dois corpos polares. ❙ Todos os óvulos que se produzem durante a ovogênese contém um cromossomo X, enquanto que a metade dos espermatozoides possuem um cromossomo Y e a outra metade um cromossomo X. ❙ Na espermatogênese produzem-se centenas ou dezenas de milhões de esperma-tozoides por dia, enquanto que na ovogênese se produz um ou alguns óvulos a cada ciclo estral. ❙ A espermatogênese produz gametas macroscópicos e com motilidade própria, enquanto que a ovogênese produz gametas grandes e imóveis. -/- REFERÊNCIAS BIBLIOGRÁFICAS -/- ABDEL-RAOUF, Mohammed et al. The postnatal development of the reproductive organs in bullswith special reference to puberty.(Including growth of the hypophysis and the adrenals). Acta endocrinologica, n. Suppl No. 49, 1960. ADONA, Paulo Roberto et al. Ovogênese e foliculogênese em mamíferos. Journal of Health Sciences, v. 15, n. 3, 2013. AERTS, J. M. J.; BOLS, P. E. J. Ovarian follicular dynamics: a review with emphasis on the bovine species. Part I: Folliculogenesis and pre‐antral follicle development. Reproduction in domestic animals, v. 45, n. 1, p. 171-179, 2010. AERTS, J. M. J.; BOLS, P. E. J. Ovarian follicular dynamics. A review with emphasis on the bovine species. Part II: Antral development, exogenous influence and future prospects. Reproduction in domestic animals, v. 45, n. 1, p. 180-187, 2010. ALBERTINI, David F.; CARABATSOS, Mary Jo. Comparative aspects of meiotic cell cycle control in mammals. Journal of molecular medicine, v. 76, n. 12, p. 795-799, 1998. AUSTIN, Colin Russell; SHORT, R. Reproduction in mammals. Cambridge, 1972. BAKER, T. G. Oogenesis and ovulation. In. Reproduction in Mammals I Germ Cells and Fertilization, p. 29-30, 1972. BEARDEN, Henry Joe et al. Reproducción animal aplicada. México: Manual Moderno, 1982. BIGGERS, John D.; SCHUETZ, Allen W. Oogenesis. University Park Press, 1972. BINELLI, Mario; MURPHY, Bruce D. Coordinated regulation of follicle development by germ and somatic cells. Reproduction, Fertility and Development, v. 22, n. 1, p. 1-12, 2009. CHIARINI-GARCIA, Helio; RUSSELL, Lonnie D. High-resolution light microscopic characterization of mouse spermatogonia. Biology of reproduction, v. 65, n. 4, p. 1170-1178, 2001. CHOUDARY, J. B.; GIER, H. T.; MARION, G. B. Cyclic changes in bovine vesicular follicles. Journal of animal science, v. 27, n. 2, p. 468-471, 1968. CLERMONT, Yves; PEREY, Bernard. Quantitative study of the cell population of the seminiferous tubules in immature rats. American Journal of Anatomy, v. 100, n. 2, p. 241-267, 1957. COSTA, DEILER SAMPAIO; PAULA, T. A. R. Espermatogênese em mamíferos. Scientia, v. 4, 2003. CUNNINGHAM, James. Tratado de fisiologia veterinária. Elsevier Health Sciences, 2011. CUPPS, Perry T. (Ed.). Reproduction in domestic animals. Elsevier, 1991. DA SILVA, Emanuel Isaque Cordeiro. Fisiologia Clínica do Ciclo Estral de Vacas Leiteiras: Desenvolvimento Folicular, Corpo Lúteo e Etapas do Estro. 2020. Acervo pessoal. DA SILVA, Emanuel Isaque Cordeiro. Fisiologia da Reprodução Animal: Ovulação, Controle e Sincronização do Cio. 2020. Acervo pessoal. DUKES, Henry Hugh; SWENSON, Melvin J.; REECE, William O. Dukes fisiologia dos animais domésticos. Editora Guanabara Koogan, 1996. EPIFANO, Olga; DEAN, Jurrien. Genetic control of early folliculogenesis in mice. Trends in Endocrinology & Metabolism, v. 13, n. 4, p. 169-173, 2002. ERICKSON, B. H. Development and senescence of the postnatal bovine ovary. Journal of animal science, v. 25, n. 3, p. 800-805, 1966. REFERÊNCIAS BIBLIOGRÁFICAS -/- FELDMAN, Edward C. et al. Canine and feline endocrinology-e-book. Elsevier health sciences, 2014. FUSCO, Giuseppe; MINELLI, Alessandro. The Biology of Reproduction. Cambridge University Press, 2019. GALINA-HIDALGO, Carlos Salvador. A study of the development of testicular function and an evaluation of testicular biopsy in farm animals. 1971. Tese de Doutorado. Royal Veterinary College (University of London). GALLICANO, G. Ian. Composition, regulation, and function of the cytoskeleton in mammalian eggs and embryos. Front Biosci, v. 6, p. D1089-1108, 2001. GILBERT, Scott F. Biología del desarrollo. Ed. Médica Panamericana, 2005. GNESSI, Lucio; FABBRI, Andrea; SPERA, Giovanni. Gonadal peptides as mediators of development and functional control of the testis: an integrated system with hormones and local environment. Endocrine reviews, v. 18, n. 4, p. 541-609, 1997. HAFEZ, Elsayed Saad Eldin; HAFEZ, Bahaa. Reprodução animal. São Paulo: Manole, 2004. HEDGER, Mark P. Testicular leukocytes: what are they doing?. Reviews of reproduction, v. 2, n. 1, p. 38-47, 1997. HUTSON, James C. Testicular macrophages. In: International review of cytology. Academic Press, 1994. p. 99-143. HYTTEL, P. Gametogênese. In. HYTTEL, Poul; SINOWATZ, Fred; VEJLSTED, Morten. Embriologia veterinária. São Paulo: Elsevier Brasil, 2012. JOHNSON, Martin H. Essential reproduction. Nova Jersey: John Wiley & Sons, 2018. JONES, Richard E.; LOPEZ, Kristin H. Human reproductive biology. Academic Press, 2013. KIERSZENBAUM, Abraham L.; TRES, Laura L. Primordial germ cell‐somatic cell partnership: A balancing cell signaling act. Molecular Reproduction and Development: Incorporating Gamete Research, v. 60, n. 3, p. 277-280, 2001. MATZUK, Martin M. et al. Intercellular communication in the mammalian ovary: oocytes carry the conversation. Science, v. 296, n. 5576, p. 2178-2180, 2002. MCLAREN, Anne. Germ and somatic cell lineages in the developing gonad. Molecular and cellular endocrinology, v. 163, n. 1-2, p. 3-9, 2000. MCKINNON, Angus O. et al. (Ed.). Equine reproduction. John Wiley & Sons, 2011. MERCHANT-LARIOS, Horacio; MORENO-MENDOZA, Norma. Onset of sex differentiation: dialog between genes and cells. 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Follicle growth in the immature mouse ovary. European Journal of Endocrinology, v. 62, n. 1, p. 117-132, 1969. PINEDA, Mauricio H. et al. McDonald's veterinary endocrinology and reproduction. Iowa state press, 2003. ROSER, J. F. Endocrine and paracrine control of sperm production in stallions. Animal Reproduction Science, v. 68, n. 3-4, p. 139-151, 2001. RUSSELL, Lonnie D. et al. Histological and histopathological evaluation of the testis. International journal of andrology, v. 16, n. 1, p. 83-83, 1993. RÜSSE, I.; SINOWATZ, F. Gametogenese. Lehrbuch der Embryologie der Haustiere, p. 42-92, 1991. SAITOU, Mitinori; BARTON, Sheila C.; SURANI, M. Azim. A molecular programme for the specification of germ cell fate in mice. Nature, v. 418, n. 6895, p. 293-300, 2002. SALISBURY, Glenn Wade et al. Physiology of reproduction and artificial insemination of cattle. WH Freeman and Company., 1978. SAWYER, Heywood R. et al. Formation of ovarian follicles during fetal development in sheep. Biology of reproduction, v. 66, n. 4, p. 1134-1150, 2002. SCARAMUZZI, R. J.; MARTENSZ, N. D.; VAN LOOK, P. F. A. Ovarian morphology and the concentration of steroids, and of gonadotrophins during the breeding season in ewes actively immunized against oestradiol-17β or oestrone. Reproduction, v. 59, n. 2, p. 303-310, 1980. SEIDEL JR, G. E. et al. Control of folliculogenesis and ovulation in domestic animals: puberal and adult function. In: 9th International Congress on Animal Reproduction and Artificial Insemination, 16th-20th June 1980. II. Round tables. Editorial Garsi., 1980. p. 11-16. SKINNER, Michael K. Cell-cell interactions in the testis. Endocrine Reviews, v. 12, n. 1, p. 45-77, 1991. SMITZ, J. E.; CORTVRINDT, Rita G. The earliest stages of folliculogenesis in vitro. Reproduction, v. 123, n. 2, p. 185-202, 2002. SORENSEN, Anton Marinus. Reproducción animal: principios y prácticas. México, 1982. SUTOVSKY, Peter; MANANDHAR, Gaurishankar. 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Gametogénese. In. PORTA, L. R.; MEDRANO, J. H. H. Fisiología reproductiva de los animales domésticos. Cidade do México: FMVZ-UNAM, 2018. ZIRKIN, Barry R. et al. Endocrine and Paracrine Regulation of Mammalian Spermatogenesis. In: Hormones and Reproduction of Vertebrates. Academic Press, 2011. p. 45-57. -/- REALIZAÇÃO -/- . (shrink)

The world of entrepreneurship has historically been linked with taking risks and the potential for significant rewards. However, there persists a notable gender imbalance in the entrepreneurial landscape, wherein women entrepreneurs remain a minority. Women navigating the entrepreneurial path encounter distinct challenges, setting their experiences apart from their male counterparts. In Balayan, Batangas, despite strides towards gender equality, women entrepreneurs continue to face challenges in the entrepreneurial landscape. This qualitative study delves into the experiences of 10 successful female entrepreneurs who (...) met specific criteria. Accordingly, semi-structured interviews are conducted, exploring various aspects of participants' experiences and revealing their motivations, achievements, challenges, and strategies. Thematic analysis reveals the connection between familial, community-driven, and personal motivations that drive these entrepreneurs forward. Despite facing obstacles such as financial constraints and gender biases, they prioritize financial gains and personal growth. With resilience, innovation, and dedication, these women overcome challenges and achieve success, utilizing support networks and online marketing strategies to their advantage. Recommendations include empowering women in entrepreneurship, strengthening support networks, introducing tailored financial literacy programs, and advocating against gender biases. Implement skill development initiatives and provide specialized education in online marketing. Engage in policy advocacy, celebrate success stories, and continuously research challenges and successes. Foster collaborative partnerships between businesses, educational institutions, and communities, and advocate for increased funding opportunities for sustainable growth. This research emphasizes the strength and capabilities of women entrepreneurs in Balayan, Batangas, affirming that "pink doesn't mean weak.". (shrink)

This article argues that there can be epistemic dilemmas: situations in which one faces conflicting epistemic requirements with the result that whatever one does, one is doomed to do wrong from the epistemic point of view. Accepting this view, I argue, may enable us to solve several epistemological puzzles.

Ormerod and Chronicle reported that optimal solutions to traveling salesperson problems were judged to be aesthetically more pleasing than poorer solutions and that solutions with more convex hull nodes were rated as better figures. To test these conclusions, solution regularity and the number of potential intersections were held constant, whereas solution optimality, the number of internal nodes, and the number of nearest neighbors in each solution were varied factorially. The results did not support the view that the convex hull is (...) an important determinant of figural attractiveness. Also, in contrast to the findings of Ormerod and Chronicle, there were consistent individual differences. Participants appeared to be divided as to whether the most attractive figure enclosed a given area within a perimeter of minimum or maximum length. It is concluded that future research in this area cannot afford to focus exclusively on group performance measures. (shrink)

Whipple disease is a rare, infectious, disease first described from a single case by Whipple in 1907. As well as characterising the clinical and pathological features of the condition, Whipple made two suggestions regarding its aetiology. These were either than the disease was caused by an infectious agent, or that it was of metabolic origin. As the disease is now thought to be caused by infection with the bacterium Tropheryma whipplei, historical reviews of the history of the disease typically mention (...) only the first of these suggestions. In this paper, we therefore revisit Whipple’s other theory. We argue that a diverse and often successful research programme was developed around this mechanism of disease causation which gave rise to many useful findings on the condition. In the later parts of this article, we then turn to discuss the surprising neglect of this period of Whipple disease research in the current literature, and conclude by offering a brief reconstruction of this early history suitable for use in a technical context. (shrink)

Counterspeech is communication that tries to counteract potential harm brought about by other speech. Theoretical interest in counterspeech partly derives from a libertarian ideal – as captured in the claim that the solution to bad speech is more speech – and partly from a recognition that well-meaning attempts to counteract harm through speech can easily misfire or backfire. Here we survey recent work on the question of what makes counterspeech effective at remedying or preventing harm, in those cases where it (...) is effective, as well as work investigating when and why there is a duty to engage in counterspeech. We suggest that the most fruitful area for philosophical inquiry on this topic, currently, relates to the questions about efficacy. Specifically, we argue that there is a need for better frameworks for conceptualizing the efficacy of counterspeech. Philosophers have collaborative work to do, alongside social scientists, in developing these frameworks. (shrink)

A philosopher argues that state-sponsored cyberattacks against central military or civilian targets are always acts of war. What is this philosopher doing? According to conceptual analysts, the philosopher is making a claim about our concept of war. According to philosophical realists, the philosopher is making a claim about war per se. In a quickly developing literature, a third option is being explored: the philosopher is engineering the concept of war. On this view, the philosopher is making a proposal about which (...) concept we should have – even if it deviates from the extant concept, and even if it does not capture ‘what war really is’. The activity or method of proposing such revisionary definitions, as well as the metaphilosophical reflection on it, has become known as conceptual engineering. (shrink)

I discuss what Aquinas’ doctrine of divine simplicity is, and what he takes to be its implications. I also discuss the extent to which Aquinas succeeds in motivating and defending those implications.

Explanation is asymmetric: if A explains B, then B does not explain A. Tradition- ally, the asymmetry of explanation was thought to favor causal accounts of explanation over their rivals, such as those that take explanations to be inferences. In this paper, we develop a new inferential approach to explanation that outperforms causal approaches in accounting for the asymmetry of explanation.

An adequate understanding of the ubiquitous practice of mechanistic explanation requires an account of what Craver termed “constitutive relevance.” Entities or activities are constitutively relevant to a phenomenon when they are parts of the mechanism responsible for that phenomenon. Craver’s mutual manipulability account extended Woodward’s account of manipulationist counterfactuals to analyze how interlevel experiments establish constitutive relevance. Critics of MM argue that applying Woodward’s account to this philosophical problem conflates causation and constitution, thus rendering the account incoherent. These criticisms, we (...) argue, arise from failing to distinguish the semantic, epistemic, and metaphysical aspects of the problem of constitutive relevance. In distinguishing these aspects of the problem and responding to these critics accordingly, we amend MM into a refined epistemic criterion, the “matched interlevel experiments” account. Further, we explain how this epistemological thesis is grounded in the plausible metaphysical thesis that constitutive relevance is causal betweenness. (shrink)

This is an opinionated guide to the literature on epistemic dilemmas. It discusses seven kinds of situations where epistemic dilemmas appear to arise; dilemmic, dilemmish, and non-dilemmic takes on them; and objections to dilemmic views along with dilemmist’s replies to them.

Artificial intelligence (AI) systems have demonstrated impressive performance across a variety of clinical tasks. However, notoriously, sometimes these systems are “black boxes.” The initial response in the literature was a demand for “explainable AI.” However, recently, several authors have suggested that making AI more explainable or “interpretable” is likely to be at the cost of the accuracy of these systems and that prioritizing interpretability in medical AI may constitute a “lethal prejudice.” In this paper, we defend the value of interpretability (...) in the context of the use of AI in medicine. Clinicians may prefer interpretable systems over more accurate black boxes, which in turn is sufficient to give designers of AI reason to prefer more interpretable systems in order to ensure that AI is adopted and its benefits realized. Moreover, clinicians may be justified in this preference. Achieving the downstream benefits from AI is critically dependent on how the outputs of these systems are interpreted by physicians and patients. A preference for the use of highly accurate black box AI systems, over less accurate but more interpretable systems, may itself constitute a form of lethal prejudice that may diminish the benefits of AI to—and perhaps even harm—patients. (shrink)

We discuss recent progress in the development of cognitive ontologies and summarize three challenges in the coordinated development and application of these resources. Challenge 1 is to adopt a standardized definition for cognitive processes. We describe three possibilities and recommend one that is consistent with the standard view in cognitive and biomedical sciences. Challenge 2 is harmonization. Gaps and conflicts in representation must be resolved so that these resources can be combined for mark-up and interpretation of multi-modal data. Finally, (...) Challenge 3 is to test the utility of these resources for large-scale annotation of data, search and query, and knowledge discovery and integration. As term definitions are tested and revised, harmonization should enable coordinated updates across ontologies. However, the true test of these definitions will be in their community-wide adoption which will test whether they support valid inferences about psychological and neuroscientific data. (shrink)

The Repugnant Conclusion served an important purpose in catalyzing and inspiring the pioneering stage of population ethics research. We believe, however, that the Repugnant Conclusion now receives too much focus. Avoiding the Repugnant Conclusion should no longer be the central goal driving population ethics research, despite its importance to the fundamental accomplishments of the existing literature.

Artificial intelligence (AI) systems have demonstrated impressive performance across a variety of clinical tasks. However, notoriously, sometimes these systems are 'black boxes'. The initial response in the literature was a demand for 'explainable AI'. However, recently, several authors have suggested that making AI more explainable or 'interpretable' is likely to be at the cost of the accuracy of these systems and that prioritising interpretability in medical AI may constitute a 'lethal prejudice'. In this paper, we defend the value of interpretability (...) in the context of the use of AI in medicine. Clinicians may prefer interpretable systems over more accurate black boxes, which in turn is sufficient to give designers of AI reason to prefer more interpretable systems in order to ensure that AI is adopted and its benefits realised. Moreover, clinicians may be justified in this preference. Achieving the downstream benefits from AI is critically dependent on how the outputs of these systems are interpreted by physicians and patients. A preference for the use of highly accurate black box AI systems, over less accurate but more interpretable systems , may itself constitute a form of lethal prejudice that may diminish the benefits of AI to - and perhaps even harm - patients. (shrink)

Social epistemologists should be well-equipped to explain and evaluate the growing vulnerabilities associated with filter bubbles, echo chambers, and group polarization in social media. However, almost all social epistemology has been built for social contexts that involve merely a speaker-hearer dyad. Filter bubbles, echo chambers, and group polarization all presuppose much larger and more complex network structures. In this paper, we lay the groundwork for a properly social epistemology that gives the role and structure of networks their due. In particular, (...) we formally define epistemic constructs that quantify the structural epistemic position of each node within an interconnected network. We argue for the epistemic value of a structure that we call the (m,k)-observer. We then present empirical evidence that (m,k)-observers are rare in social media discussions of controversial topics, which suggests that people suffer from serious problems of epistemic vulnerability. We conclude by arguing that social epistemologists and computer scientists should work together to develop minimal interventions that improve the structure of epistemic networks. (shrink)

Background: Current practice frequently fails to provide care consistent with the preferences of decisionally-incapacitated patients. It also imposes significant emotional burden on their surrogates. Algorithmic-based patient preference predictors (PPPs) have been proposed as a possible way to address these two concerns. While previous research found that patients strongly support the use of PPPs, the views of surrogates are unknown. The present study thus assessed the views of experienced surrogates regarding the possible use of PPPs as a means to help make (...) treatment decisions for decisionally-incapacitated patients. -/- Methods: This qualitative study used semi-structured interviews to determine the views of experienced surrogates [n=26] who were identified from two academic medical centers and two community hospitals. The primary outcomes were respondents’ overall level of support for the idea of using PPPs and the themes related to their views on how a PPP should be used, if at all, in practice. -/- Results: Overall, 21 participants supported the idea of using PPPs. The remaining five indicated that they would not use a PPP because they made decisions based on the patient’s best interests, not based on substituted judgment. Major themes which emerged were that surrogates, not the patient’s preferences, should determine how treatment decisions are made, and concern that PPPs might be used to deny expensive care or be biased against minority groups. -/- Conclusions: Surrogates, like patients, strongly support the idea of using PPPs to help make treatment decisions for decisionally-incapacitated patients. These findings provide support for developing a PPP and assessing it in practice. At the same time, patients and surrogates disagree over whose preferences should determine how treatment decisions are made, including whether to use a PPP. These findings reveal a fundamental disagreement regarding the guiding principles for surrogate decision-making. Future research is needed to assess this disagreement and consider ways to address it. (shrink)

This letter addresses the editorial decision to publish the article, “Research on group differences in intelligence: A defense of free inquiry” (Cofnas, 2020). Our letter points out several critical problems with Cofnas's article, which we believe should have either disqualified the manuscript upon submission or been addressed during the review process and resulted in substantial revisions.

In debates over the regulation of communication related to dual-use research, the risks that such communication creates must be weighed against against the value of scientific autonomy. The censorship of such communication seems justifiable in certain cases, given the potentially catastrophic applications of some dual-use research. This conclusion however, gives rise to another kind of danger: that regulators will use overly simplistic cost-benefit analysis to rationalize excessive regulation of scientific research. In response to this, we show how institutional design principles (...) and normative frameworks from free speech theory can be used to help extend the argument for regulating dangerous dual-use research beyond overly simplistic cost-benefit reasoning, but without reverting to an implausibly absolutist view of scientific autonomy. (shrink)

Studies in the psychology of visual expertise have tended to focus on a limited set of expert domains, such as radiology and athletics. Conclusions drawn from these data indicate that experts use parafoveal vision to process images holistically. In this study, we examined a novel, as-of-yet-unstudied class of visual experts—architects—expecting similar results. However, the results indicate that architects, though visual experts, may not employ the holistic processing strategy observed in their previously studied counterparts. Participants (n = 48, 24 architects, 24 (...) naïve) were asked to find targets in chest radiographs and perspective images. All images were presented in both gaze-contingent and normal viewing conditions. Consistent with a holistic processing model, we expected two results: (1) architects would display a greater difference in saccadic amplitude between the gaze- contingent and normal conditions, and (2) architects would spend less time per search than an undergraduate control group. We found that the architects were more accurate in the perspectival task, but they took more time and displayed a lower difference in saccadic amplitude than the controls. Our research indicates a disjunctive conclusion. Either architects are simply different kinds of visual experts than those previously studied, or we have generated a task that employs visual expertise without holistic processing. Our data suggest a healthy skepticism for across-the-board inferences collected from a single domain of expertise to the nature of visual expertise generally. More work is needed to determine whether holism is a feature of all visual expertise. (shrink)

Embedding ethics modules within computer science courses has become a popular response to the growing recognition that CS programs need to better equip their students to navigate the ethical dimensions of computing technologies like AI, machine learning, and big data analytics. However, the popularity of this approach has outpaced the evidence of its positive outcomes. To help close that gap, this empirical study reports positive results from Northeastern’s program that embeds values analysis modules into CS courses. The resulting data suggest (...) that such modules have a positive effect on students’ moral attitudes and that students leave the modules believing they are more prepared to navigate the ethical dimensions they’ll likely face in their eventual careers. Importantly, these gains were accomplished at an institution without a philosophy doctoral program, suggesting this strategy can be effectively employed by a wider range of institutions than many have thought. (shrink)

This essay presents a fully inferentialist-expressivist account of scientific representation. In general, inferentialist approaches to scientific representation argue that the capacity of a model to represent a target system depends on inferences from models to target systems. Inferentialism is attractive because it makes the epistemic function of models central to their representational capacity. Prior inferentialist approaches to scientific representation, however, have depended on some representational element, such as denotation or representational force. Brandom’s Making It Explicit provides a model of how (...) to fully discharge such representational vocabulary, but it cannot be applied directly to scientific representations. Pursuing a strategy parallel to Brandom’s, this essay begins with an account of how surrogative inference is justified. Scientific representation and the denotation of model elements are then explained in terms of surrogative inference by treating scientific representation and denotation as expressive, analogous to Brandom’s account of truth. The result is a thoroughgoing inferentialism: M is a scientific representation of T if and only if M has scientifically justified surrogative consequences that are answers to questions about T. (shrink)

Exploring online criticisms of the ‘take the knee’ protest during ‘Euro 2020’, this article examines how alt- and far-right conspiracies were both constructed and communicated via the social media platform, Twitter. By providing a novel exploration of alt-right conspiracies during an international football tournament, a qualitative thematic analysis of 1,388 original tweets relating to Euro 2020 was undertaken. The findings reveal how, in criticisms levelled at both ‘wokeism’ and the Black Lives Matter movement, antiwhite criticisms of the ‘take the knee’ (...) protest were embroiled in alt-right conspiracies that exposed an assumed Cultural Marxist, ‘woke agenda’ in the tournament’s organization and mainstream media coverage. In conclusion, it is argued that conspiratorial discourses, associated with the alt-right, provided a framework through which the protest could be understood. This emphasises how the significance of conspiracy functions to promote the wider dissemination of alt-right ideology across popular cultural contexts, such as sport. (shrink)

This volume celebrates the various facets of Alan Turing (1912–1954), the British mathematician and computing pioneer, widely considered as the father of computer science. It is aimed at the general reader, with additional notes and references for those who wish to explore the life and work of Turing more deeply. -/- The book is divided into eight parts, covering different aspects of Turing’s life and work. -/- Part I presents various biographical aspects of Turing, some from a personal point of (...) view. -/- Part II presents Turing’s universal machine (now known as a Turing machine), which provides a theoretical framework for reasoning about computation. His 1936 paper on this subject is widely seen as providing the starting point for the field of theoretical computer science. -/- Part III presents Turing’s working on codebreaking during World War II. While the War was a disastrous interlude for many, for Turing it provided a nationally important outlet for his creative genius. It is not an overstatement to say that without Turing, the War would probably have lasted longer, and may even have been lost by the Allies. The sensitive nature of Turning’s wartime work meant that much of this has been revealed only relatively recently. -/- Part IV presents Turing’s post-War work on computing, both at the National Physical Laboratory and at the University of Manchester. He made contributions to both hardware design, through the ACE computer at the NPL, and software, especially at Manchester. Part V covers Turing’s contribution to machine intelligence (now known as Artificial Intelligence or AI). Although Turing did not coin the term, he can be considered a founder of this field which is still active today, authoring a seminal paper in 1950. -/- Part VI covers morphogenesis, Turing’s last major scientific contribution, on the generation of seemingly random patterns in biology and on the mathematics behind such patterns. Interest in this area has increased rapidly in recent times in the field of bioinformatics, with Turing’s 1952 paper on this subject being frequently cited. -/- Part VII presents some of Turing’s mathematical influences and achievements. Turing was remarkably free of external influences, with few co-authors – Max Newman was an exception and acted as a mathematical mentor in both Cambridge and Manchester. -/- Part VIII considers Turing in a wider context, including his influence and legacy to science and in the public consciousness. -/- Reflecting Turing’s wide influence, the book includes contributions by authors from a wide variety of backgrounds. Contemporaries provide reminiscences, while there are perspectives by philosophers, mathematicians, computer scientists, historians of science, and museum curators. Some of the contributors gave presentations at Turing Centenary meetings in 2012 in Bletchley Park, King’s College Cambridge, and Oxford University, and several of the chapters in this volume are based on those presentations – some through transcription of the original talks, especially for Turing’s contemporaries, now aged in their 90s. Sadly, some contributors died before the publication of this book, hence its dedication to them. -/- For those interested in personal recollections, Chapters 2, 3, 11, 12, 16, 17, and 36 will be of interest. For philosophical aspects of Turing’s work, see Chapters 6, 7, 26–31, and 41. Mathematical perspectives can be found in Chapters 35 and 37–39. Historical perspectives can be found in Chapters 4, 8, 9, 10, 13–15, 18, 19, 21–25, 34, and 40. With respect to Turing’s body of work, the treatment in Parts II–VI is broadly chronological. We have attempted to be comprehensive with respect to all the important aspects of Turing’s achievements, and the book can be read cover to cover, or the chapters can be tackled individually if desired. There are cross-references between chapters where appropriate, and some chapters will inevitably overlap. -/- We hope that you enjoy this volume as part of your library and that you will dip into it whenever you wish to enter the multifaceted world of Alan Turing. (shrink)

We address the need for a model by considering two competing theories regarding the origin of life: (i) the Metabolism First theory, and (ii) the RNA World theory. We discuss two interrelated points, namely: (i) Models are valuable tools for understanding both the processes and intricacies of origin-of-life issues, and (ii) Insights from models also help us to evaluate the core objection to origin-of-life theories, called “the inefficiency objection”, which is commonly raised by proponents of both the Metabolism First theory (...) and the RNA World theory against each other. We use Simpson’s Paradox (SP) as a tool for challenging this objection. We will use models in various senses, ranging from taking them as representations of reality to treating them as theories/accounts that provide heuristics for probing reality. In this paper, we will frequently use models and theories interchangeably. Additionally, we investigate Conway’s Game of Life and contrast it with our SP-based approach to emergence-of-life issues. Finally, we discuss some of the consequences of our view. A scientific model is testable in three senses: (i) a logical sense, (ii) a nomological sense, and (iii) a current technological sense. The SP-based model is testable in the first two senses but it is not feasible to test it using current technology. (shrink)

In this review, we present some ethical imperatives observed in this pandemic from a data ethics perspective. Our exposition connects recurrent ethical problems in the discipline, such as, privacy, surveillance, transparency, accountability, and trust, to broader societal concerns about equality, discrimination, and justice. We acknowledge data ethics role as significant to develop technological, inclusive, and pluralist societies. - - - Resumen: En esta revisión, exponemos algunos de los imperativos éticos observados desde la ética de datos en esta pandemia. Nuestra exposición (...) busca conectar problemas éticos típicos dentro de esta disciplina, a saber, privacidad, vigilancia, transparencia, responsabilidad y confianza, con preocupaciones a nivel social relacionadas con la igualdad, discrimi nación y justicia. Consideramos que la ética de datos tiene un rol significativo para desarrollar sociedades tecnificadas, inclusivas y pluralistas. (shrink)

This is the second part of my paper "What is good forestry?" and it completes the argument on how to balance short-term economic interests with the long-term public good.

The National Center for Biomedical Ontology is a consortium that comprises leading informaticians, biologists, clinicians, and ontologists, funded by the National Institutes of Health (NIH) Roadmap, to develop innovative technology and methods that allow scientists to record, manage, and disseminate biomedical information and knowledge in machine-processable form. The goals of the Center are (1) to help unify the divergent and isolated efforts in ontology development by promoting high quality open-source, standards-based tools to create, manage, and use ontologies, (2) to create (...) new software tools so that scientists can use ontologies to annotate and analyze biomedical data, (3) to provide a national resource for the ongoing evaluation, integration, and evolution of biomedical ontologies and associated tools and theories in the context of driving biomedical projects (DBPs), and (4) to disseminate the tools and resources of the Center and to identify, evaluate, and communicate best practices of ontology development to the biomedical community. Through the research activities within the Center, collaborations with the DBPs, and interactions with the biomedical community, our goal is to help scientists to work more effectively in the e-science paradigm, enhancing experiment design, experiment execution, data analysis, information synthesis, hypothesis generation and testing, and understand human disease. (shrink)

We report the results of a vignette experiment with a quota sample of the German population in which we analyze the interplay between need, equity, and accountability in third-party distributive decisions. We asked subjects to divide firewood between two hypothetical persons who either differ in their need for heat or in their productivity in terms of their ability to chop wood. The experiment systematically varies the persons’ accountability for their neediness as well as for their productivity. We find that subjects (...) distribute significantly fewer logs of wood to persons who are held accountable for their disadvantage. Independently of being held accountable or not, the needier person is always compensated with a share of logs that exceeds her contribution, while the person who contributes less is punished in terms of receiving a share of logs smaller than her need share. Moreover, there is a domain effect in terms of subjects being more sensitive to lower contributions than to greater need. (shrink)

We take up the challenge of developing an international network with capacity to survey the world's scientists on an ongoing basis, providing rich datasets regarding the opinions of scientists and scientific sub-communities, both at a time and also over time. The novel methodology employed sees local coordinators, at each institution in the network, sending survey invitation emails internally to scientists at their home institution. The emails link to a ‘10 second survey’, where the participant is presented with a single statement (...) to consider, and a standard five point Likert scale. In June 2023, a group of 30 philosophers and social scientists invited 20,085 scientists across 30 institutions in 12 countries to participate, gathering 6,807 responses to the statement 'Science has put it beyond reasonable doubt that COVID-19 is caused by a virus'. The study demonstrates that it is possible to establish a global network to quickly ascertain scientific opinion on a large international scale, with high response rate, low opt-out rate, and in a way that allows for significant (perhaps indefinite) repeatability. Measuring scientific opinion in this new way would be a valuable complement to currently available approaches, potentially informing policy decisions and public understanding across diverse fields. (shrink)

Some of the most significant policy responses to cases of fraudulent and questionable conduct by scientists have been to strengthen professionalism among scientists, whether by codes of conduct, integrity boards, or mandatory research integrity training programs. Yet there has been little systematic discussion about what professionalism in scientific research should mean. In this paper I draw on the sociology of the professions and on data comparing codes of conduct in science to those in the professions, in order to examine what (...) precisely the model of professionalism implies for scientific research. I argue that professionalism, more than any other single organizational logic, is appropriate for scientific research, and that codes of conduct for scientists should strengthen statements concerning scientific autonomy and competence, as well as the scientific service ideal. (shrink)

Distrust in scientific experts can be surprisingly stubborn, persisting despite evidence supporting the experts’ views, demonstrations of their competence, or displays of good will. This stubborn distrust is often viewed as a manifestation of irrationality. By contrast, this article proposes a logic of “status distrust”: low-status individuals are objectively vulnerable to collective decision-making, and can justifiably distrust high-status scientific experts if they are not confident that the experts do not have their best interests at heart. In phenomena of status distrust, (...) social status is thus an indicator of distrust, and this has wider implications for the literatures on trust in science and on expert communication. (shrink)

Darwin hypothesized that some animals, when selecting sexual partners, possess a genuine “sense of beauty” that cannot be accounted for by the logic of natural selection. This hypothesis has been notoriously controversial. In this chapter I propose that the concept of agency can be useful to operationalize the “sense of beauty”, and can help identify the conditions under which one can infer that animals are acting as (aesthetic) agents. Focusing on a case study of the behavior of the Pavo cristatus, (...) I identify the types of evidence that would allow for the inference of agency through aesthetic choice. (shrink)

The dominant view today on evolutionary progress is that it has been thoroughly debunked. Even value-neutral progress concepts are seen to lack important theoretical underpinnings: natural selection provides no rationale for progress, and natural selection need not even be invoked to explain large-scale evolutionary trends. In this paper I challenge this view by analysing how natural selection acts in heterogeneous environments. This not only undermines key debunking arguments, but also provides a selectionist rationale for a pattern of “evolutionary unfolding”, where (...) life radiates across an increased range of exploitation of environmental heterogeneity. (shrink)

When a loved one dies, it is common for the bereaved to feel profoundly lonely, disconnected from the world with the sense that they no longer belong. In philosophy, this experience of ‘loss and loneliness’ has been interpreted according to both a loss of possibilities and a loss of the past. But it is unclear how these interpretations apply to the distinctive way in which loss and loneliness manifest in old age. Drawing on the phenomenological analyses of old age given (...) by de Beauvoir and Améry, I consider how the diminishment of the capacity for projection and recollection complicate recent interpretations of loss and loneliness, whilst nevertheless reinforcing the conclusion that in old age subjectivity is necessarily impoverished. Developing a critical stance on de Beauvoir and Améry’s underlying conception of subjectivity, I turn to Levinas in considering whether or not there is a way to reimagine subjectivity such that the estrangement and alienation of older adults might be ameliorated rather than exacerbated. Grounded in the passive body-in-itself rather than the self-transcending capacity of the body-for-itself, I suggest it becomes possible to reconceptualise the experience of loss and loneliness in old age; both in terms of what is lost and what needs to be restored if older adults are to be helped to find themselves at home in the world in the midst of, and indeed because of, manifold loss. (shrink)

The ability to solve problems is a prerequisite in preparing mathematics preservice teachers. This study assessed preservice teachers’ problem-solving difficulties and performance, particularly in worded problems on number sense, measurement, geometry, algebra, and probability. Also, academic profile differences in the preservice teacher’s problem-solving performance and common errors were determined. A descriptive-comparative research design was employed with 158 random respondents. Data were gathered face-to-face during the first semester of the school year 2022-2023, and data were analyzed with the aid of jamovi (...) software, ensuring ethical measures. Overall findings revealed that the preservice teachers experienced average difficulty in solving problems. The low performance of the preservice teachers on the given problems was also demonstrated. Further analysis revealed a significant difference between the preservice teachers’ problem-solving performance based on their subject preference and program. Moreover, the error analysis revealed that the preservice teachers incurred comprehension errors in misrepresentation, misinterpretation, and miscalculation. These results will serve as a measure for policymakers and curriculum developers of the teacher education institution concerned to make relevant enhancements to the math courses offered in the elementary and secondary education programs. (shrink)

BioPortal is a Web portal that provides access to a library of biomedical ontologies and terminologies developed in OWL, RDF(S), OBO format, Protégé frames, and Rich Release Format. BioPortal functionality, driven by a service-oriented architecture, includes the ability to browse, search and visualize ontologies (Figure 1). The Web interface also facilitates community-based participation in the evaluation and evolution of ontology content.

In the past decade, policy-makers in science have been concerned with harmonizing research integrity standards across Europe. These standards are encapsulated in the European Code of Conduct for Research Integrity. Yet, almost every European country today has its own national-level code of conduct for research integrity. In this study we document in detail how national-level codes diverge on almost all aspects concerning research integrity – except for what constitutes egregious misconduct. Besides allowing for potentially unfair responses to joint misconduct by (...) international collaborations, we argue that the divergences raise questions about the envisaged self-regulatory function of the codes of conduct. (shrink)

Recent work by Kahan et al. (2017) on the psychology of motivated numeracy in the context of intracultural disagreement suggests that people are less likely to employ their capabilities when the evidence runs contrary to their political ideology. This research has so far been carried out primarily in the USA regarding the liberal–conservative divide over gun control regulation. In this paper, we present the results of a modified replication that included an active reasoning intervention with Western European participants regarding both (...) the hierarchy–egalitarianism and individualism–collectivism divides over immigration policy (n = 746; considerably less than the preregistration sample size). We reproduce the motivated numeracy effect, though we do not find evidence of increased polarization of high-numeracy participants. (shrink)

Enlightenment values are built around the presumption of an independent rational self, citizen, consumer and pursuer of self-interest. Even the authoritarian and communitarian variants of the Enlightenment presumed the existence of autonomous individuals, simply arguing for greater weight to be given to their collective interests. Since Hume, however, radical Enlightenment empiricists have called into question the existence of a discrete, persistent self. Today neuroscientific reductionism has contributed to the rejection of an essentialist model of personal identity. Contemporary transhumanism has yet (...) to grapple with the radical consequences of the erosion of liberal individualism on their projects of individually chosen enhancement and longevity. Most transhumanists still reflect an essentialist idea of personal identity, even as they embrace projects of radical cognitive enhancement that would change every constituent element of consciousness. Transhumanists need to grapple with how their projects and ethics would change if personal identity is an arbitrary, malleable fiction. (shrink)

We advance the understanding of the philosophy and psychology of curiosity by operationalizing and constructing an empirical measure of Nietzsche’s conception of inquisitive curiosity, expressed by the German term Wissbegier, (“thirst for knowledge” or “need/impetus to know”) and Neugier (“curiosity” or “inquisitiveness”). First, we show that existing empirical measures of curiosity do not tap the construct of inquisitive curiosity, though they may tap related constructs such as idle curiosity and phenomenological curiosity. Next, we map the concept of inquisitive curiosity and (...) connect it to related concepts, such as open-mindedness and intellectual humility. The bulk of the paper reports four studies: an Anglophone exploratory factor analysis, an Anglophone confirmatory factor analysis, an informant study, and a Germanophone exploratory and confirmatory factor analysis. (shrink)

A growing body of work in free speech theory is interested in the nature of counterspeech, i.e. speech that aims to counteract the effects of harmful speech. Counterspeech is usually defined in opposition to legal responses to harmful speech, which try to prevent such speech from occurring in the first place. In this paper we challenge this way of carving up the conceptual terrain. Instead, we argue that our main classificatory division, in theorising responses to harmful speech, should be between (...) pro-discursive and anti-discursive responses. Some legal responses to harmful speech, so we argue, make a positive discursive contribution in their own right. That is, legal restrictions on harmful speech can have a function that is importantly similar to speech that aims at countering the effects of harmful speech. (shrink)

It has recently been argued that a person’s moral judgments (about both their own and others’ actions) are constrained by the nature and extent of their relevant ignorance and, thus, that such judgments are determined in the first instance by the person’s epistemic circumstances. It has been argued, in other words, that the epistemic is logically prior to other normative (e.g., ethical, prudential, pecuniary) considerations in human decision-making, that these other normative considerations figure in decision-making only after (logically and temporally) (...) relevant ignorance has constrained the decision-maker’s menu of options. If this is right, then a person’s moral judgments in some set of circumstances should vary with their knowledge and ignorance of these circumstances. In this study, we test the hypothesis of the logical priority of the epistemic. We describe two experiments in which subjects’ knowledge and ignorance of relevant consequences were manipulated. In the second experiment, we also compared the effect of ignorance on moral judgments with that of personal force, a factor previously shown to influence moral judgments. We found broad empirical support for the armchair arguments that epistemic considerations are logically prior to normative considerations. (shrink)

The translational research community, in general, and the Clinical and Translational Science Awards (CTSA) community, in particular, share the vision of repurposing EHRs for research that will improve the quality of clinical practice. Many members of these communities are also aware that electronic health records (EHRs) suffer limitations of data becoming poorly structured, biased, and unusable out of original context. This creates obstacles to the continuity of care, utility, quality improvement, and translational research. Analogous limitations to sharing objective data in (...) other areas of the natural sciences have been successfully overcome by developing and using common ontologies. This White Paper presents the authors’ rationale for the use of ontologies with computable semantics for the improvement of clinical data quality and EHR usability formulated for researchers with a stake in clinical and translational science and who are advocates for the use of information technology in medicine but at the same time are concerned by current major shortfalls. This White Paper outlines pitfalls, opportunities, and solutions and recommends increased investment in research and development of ontologies with computable semantics for a new generation of EHRs. (shrink)

I develop a broadly reliabilist theory of non-ideal epistemic rationality and argue that if it is correct we should reject the recently popular idea that the standards of non-ideal epistemic rationality are mere social conventions.

Getting a graduate education is one of the most important parts of a professional in a field. It allows them to climb higher in the professional rankings or even get higher pay for their academic work. All graduate students are adults and self-directed due to their past experiences in work or practice. However, when the pandemic hit the world, these self-directed learners were not spared from shutting of schools. In the Philippines, most graduate schools deliver their lessons through the traditional (...) mode or face-to-face until the pandemic that they shifted in the emerging online learning modality. Using the mixed method of quantitative and qualitative type of study the researchers were able to gather 419 graduate students from various regions of the archipelago to take part in the study. The researchers found out that upon experiencing the benefits of online learning, graduate students want to continue this modality even in the future. More than a third of the respondents also claimed that they want the blended or hybrid type of graduate studies as opposed to going back to the more traditional face-to-face classes. The reasons for these can vary on each learner’s situation. (shrink)

We propose that measures of information integration can be more straightforwardly interpreted as measures of agency rather than of consciousness. This may be useful to the goals of consciousness research, given how agency and consciousness are “duals” in many (although not all) respects.