Intentional action is often accompanied by knowledge of what one is doing—knowledge which appears non-observational and non-inferential. G.E.M. Anscombe defends the stronger claim that intentional action always comes with such knowledge. Among those who follow Anscombe, some have altered the features, content, or species of the knowledge claimed to necessarily accompany intentional action. In this paper, I argue that there is no knowledge condition on intentional action, no matter the assumed features, content, or species of the knowledge. Further, rather than (...) follow the usual methodology in this debate of arguing by counterexample, I present an argument that explains why we continue to find counterexamples: intentional action and knowledge are regulated by thresholds under distinct pressures; in particular, the threshold of control regulating intentional action is disparately influenced by the role of intentional action in practical normativity. (shrink)

I argue for an account of creativity that unifies creative achievements in the arts, sciences, and other domains and identifies its characteristic value. This account draws upon case studies of creative work in both the arts and sciences to identify creativity as a kind of successful exploration. I argue that if creativity is properly understood in this way, then it is fundamentally a property of processes, something only agents can achieve, something that comes in degrees, subjectively novel, and non-formulaic. As (...) I develop the account, I show how it avoids challenges faced by other accounts of creativity, especially concerning creativity’s value. Hills and Bird (2018, 2019) have together argued that creativity is not necessarily valuable. My account challenges this view. If I am right that creativity is a kind of successful exploration, then creativity does have a characteristic value, specifically epistemic value. (shrink)

This paper seeks to answer the question: Can contemporary forms of artificial intelligence be creative? To answer this question, I consider three conditions that are commonly taken to be necessary for creativity. These are novelty, value, and agency. I argue that while contemporary AI models may have a claim to novelty and value, they cannot satisfy the kind of agency condition required for creativity. From this discussion, a new condition for creativity emerges. Creativity requires curiosity, a motivation to pursue epistemic (...) goods. I argue that contemporary AI models do not satisfy this new condition. Because they lack both agency and curiosity, it is a mistake to attribute the same sort of creativity to AI that we prize in humans. Finally, I consider the question of whether these AI models stand to make human creativity in the arts and sciences obsolete, despite not being creative themselves. I argue, optimistically, that this is unlikely. (shrink)

Both proponents and critics of the desire theory of welfare have narrowly focused on the positive side of the theory while virtually ignoring its negative side. On the positive side, the desire theorist says that getting what you want is good for you. But what should the desire theorist say is bad for you? A common and plausible-sounding answer is that if getting what you want is good for you, then surely not getting what you want is bad for you. (...) I argue that this answer is a mistake that would commit desire theorists to a claim that is implausible by their own lights, namely that a state of affairs could be bad for you even if you were not at all bothered by it. The desire theorist should instead say that getting what you are averse to is bad for you. If desire satisfaction is good for you, then aversion satisfaction, not desire frustration, is bad for you. (shrink)

In this paper I articulate a view of doxastic control that helps defend the legitimacy of our practice of blaming people for their beliefs. I distinguish between three types of doxastic control: intention-based, reason-based, and influence-based. First I argue that, although we lack direct intention-based control over our beliefs, such control is not necessary for legitimate doxastic blame. Second, I suggest that we distinguish two types of reason-responsiveness: sensitivity to reasons and appreciation of reasons. I argue that while both capacities (...) are necessary for satisfying the control condition, neither is sufficient. Finally, I defend an influence-based view of doxastic control according to which we have the capacity to execute intentions to engage in reflection that causally influences our beliefs in positive epistemic ways. This capacity is both necessary and sufficient for satisfying the control condition for legitimate doxastic blame. I end by defending the view from two objections: that reflection is not necessary for meeting the control condition, and that it is not sufficient. (shrink)

According to internalism about prudential value, the token states of affairs that are basically good for you must be suitably connected, under the proper conditions, to your positive attitudes. It is commonly thought that any theory of welfare that implies internalism is guaranteed to respect the alienation constraint, the doctrine that you cannot be alienated from that which is basically good for you. The assumption is that because internalism requires a necessary connection between a subject’s positive attitudes and each state (...) of basic benefit to that subject, theories that imply internalism will only postulate goods that resonate with the subject. In this paper, I show that extant formulations of internalism do not have this desirable feature. The central defect of traditional formulations is that they do not respect an important but overlooked truth about alienation: namely, that even if a state of affairs is suitably connected to your positive attitudes, your negative attitudes can nonetheless render you alienated from it. By taking into account the relevance of the negative attitudes, I propose the new internalism—the view that x is basically good for you only if you have a net positive attitude towards it—as a way to advance our thinking about what is required to avoid alienating theories of welfare. (shrink)

In this paper, I solve a puzzle generated by three conflicting claims about the relationship between faith, belief, and control: according to the Identity Thesis, faith is a type of belief, and according to Fideistic Voluntarism, we sometimes have control over whether or not we have faith, but according to Doxastic Involuntarism, we never have control over what we believe. To solve the puzzle, I argue that the Identity Thesis is true, but that either Fideistic Voluntarism or Doxastic Voluntarism is (...) false, depending on how we understand "control." I distinguish two notions of control: direct intention-based control and indirect reflective control. I argue that though we have direct intention-based control over neither belief nor faith, we have indirect reflective control over each of them. Moreover, indirect reflective control helps explain how we can be held accountable for each. (shrink)

In this chapter, we explore whether agents have an epistemic duty to eradicate implicit bias. Recent research shows that implicit biases are widespread and they have a wide variety of epistemic effects on our doxastic attitudes. First, we offer some examples and features of implicit biases. Second, we clarify what it means to have an epistemic duty, and discuss the kind of epistemic duties we might have regarding implicit bias. Third, we argue that we have an epistemic duty to eradicate (...) implicit biases that have negative epistemic impact. Finally, we defend this view against the objection that we lack the relevant control over implicit bias that’s required for such a duty. We argue that we have a kind of reflective control over the implicit biases that we are duty-bound to eradicate. And since, as we show, we have this control over a wide variety of implicit biases, there are a lot of implicit biases that we have epistemic duties to eradicate. (shrink)

Technological developments have resulted in tremendous increases in the volume and diversity of the data and information that must be processed in the course of biomedical and clinical research and practice. Researchers are at the same time under ever greater pressure to share data and to take steps to ensure that data resources are interoperable. The use of ontologies to annotate data has proven successful in supporting these goals and in providing new possibilities for the automated processing of data and (...) information. In this chapter, we describe different types of vocabulary resources and emphasize those features of formal ontologies that make them most useful for computational applications. We describe current uses of ontologies and discuss future goals for ontology-based computing, focusing on its use in the field of infectious diseases. We review the largest and most widely used vocabulary resources relevant to the study of infectious diseases and conclude with a description of the Infectious Disease Ontology (IDO) suite of interoperable ontology modules that together cover the entire infectious disease domain. (shrink)

As part of the development of the Symbolic and Sub-symbolic Robotics Intelligence Control System, we have implemented a memory store to allow a robot to retain knowledge from previous exp...

There is a well-known equivalence between avoiding accuracy dominance and having probabilistically coherent credences (see, e.g., de Finetti 1974, Joyce 2009, Predd et al. 2009, Pettigrew 2016). However, this equivalence has been established only when the set of propositions on which credence functions are defined is finite. In this paper, I establish connections between accuracy dominance and coherence when credence functions are defined on an infinite set of propositions. In particular, I establish the necessary results to extend the classic accuracy (...) argument for probabilism to certain classes of infinite sets of propositions including countably infinite partitions. (shrink)

Some actions we perform “just like that” without taking a means, e.g., raising your arm or wiggling your finger. Other actions—the nonbasic actions—we perform by taking a means, e.g., voting by raising your arm or illuminating a room by flipping a switch. A nearly ubiquitous view about nonbasic action is that one's means to a nonbasic action constitutes the nonbasic action, as raising your arm constitutes voting or flipping a switch constitutes illuminating a room. In this paper, I challenge this (...) view. I argue that one's means to a nonbasic action can cause rather than constitute it. In the process, we gain a clearer understanding of the scope of our agency—one that includes mental actions such as judgment and decision—and the pluralistic nature of basic features of action including control, purposefulness, and agent participation. (shrink)

Eleonore Stump insightfully develops Aquinas’s theodicy to account for a significant source of human suffering, namely the undermining of desires of the heart. Stump argues that what justifies God in allowing such suffering are benefits made available to the sufferer through her suffering that can defeat the suffering by contributing to the fulfillment of her heart’s desires. We summarize Stump’s arguments for why such suffering requires defeat and how it is defeated. We identify three problems with Stump’s account of how (...) such suffering is defeated and offer solutions to each. We defend and strengthen Stump’s response to the hardest cases for her view, and explain what her view demands of God. (shrink)

Santiago Ramón y Cajal practice what became neuroscience in the remote town of Ayerbe, Aragón Spain. He struggled to travel to conferences in northern Europe to share his remarkable discovery.

James Prosek paints flora and fauna, but first became known for his paintings of trout. This essay situates Prosek's paintings, especially those at the Lowe Museum exhibit, within the long tradition of the depiction of nature. The essay comments on the relationship between the representation of nature and the nature of representation.

The most recent versions of official psychiatric diagnostic guidelines include a new addition: Prolonged Grief Disorder (PGD). PGD is controversial due to concerns about harmful looping effects. Some opponents of PGD’s inclusion in the DSM worry that the diagnosis may pathologize normal human experiences and alienate grievers from their grief. This paper argues that these concerns are less troubling than they initially appear (in part because they assume an unhelpful, and conceptually optional, background understanding of health conditions as pathologies) and (...) calls attention to overlooked beneficial looping effects that might be achieved by medicalizing (some) experiences of grief. (shrink)

One of the central problems in the philosophy of action is to spell out the distinction between action and what merely happens, e.g., a wink versus an eye twitch. This essay proposes a theory of action offering an account of this distinction. The central claim of the theory is that action is movement that is controlled by the mover, where movement is understood capaciously and control is characterized by a trio of conditions consisting of an aim condition, a modal condition, (...) and an explanatory condition. Importantly, being controlled is shown to be a determinable property of movements, and its determination dimensions are isolated. Paired with the claim that action is movement that is controlled by the mover, this account of control as a determinable illuminates the diversity within the category of action. (shrink)

Robust metanormative realists think that there are irreducibly normative, metaphysically heavy normative facts. One might wonder how we could be epistemically justified in believing that such facts exist. In this paper, I offer an answer to this question: one’s belief in the existence of robustly real normative facts is epistemically justified because so believing is indispensable to being a successful inquirer for creatures like us. The argument builds on Enoch's (2007, 2011) deliberative indispensability argument for Robust Realism but avoids relying (...) on an overly pragmatic account of the sources of basic epistemic justification. Instead, I suggest that the sources of basic epistemic justification are those belief-forming methods which are indispensable for zetetically indispensable projects, that is, projects which are constitutive of being a successful inquirer for embodied, agential creatures like ourselves. (shrink)

In this paper, I introduce the notion of ‘philosophy moves’: prominent tropes featured in contemporary academic philosophy. Moves are more than patterns—they are tools for advancing and enriching philosophical debates. By recognizing these patterns in the philosophical literature, we collect an ensemble of moves for deployment in novel contexts, each with the potential to forge new paths of philosophical investigation through a given topic. The moves featured in this paper are constructive and progressive, with the potential to push past stalemates (...) and open a wider conceptual landscape. Following a presentation of five exemplars taken from the philosophy of biology literature, I show how different moves could be made within a current interdisciplinary debate. Overall, I aim to demonstrate that recognizing these patterns is insightful pedagogically and potentially useful when used as part of one’s philosophical methodology. (shrink)

Numerous studies of the beliefs of people with anorexia nervosa (AN) suggest that a subset of such individuals may experience delusions. We first describe what makes a belief delusional and conclude that such characteristics can be appropriately applied to some beliefs of people with AN. Next, we outline how delusional beliefs may relate to the broader psychopathological process in AN, including: (1) they may be epiphenomenal; (2) they may be an initial partial cause of AN; (3) they may be caused (...) by aspects of AN; or (4) they may be sustaining causes, possibly involved in reciprocal causal relations with aspects of AN. We argue that there is good reason to believe that delusional beliefs of people with AN are not merely epiphenomenal, but rather that they’re causally connected to AN. Because of this, empirical studies can be designed to test for the presence of causal relations. We describe how these studies should be designed. The results of such studies have important implications for understanding the experience of individuals with AN and for the treatment of AN. We outline these implications. (shrink)

Judgment subjectivism is the view that x is good for S if and only if, because, and to the extent that S believes, under the proper conditions, that x is good for S. In this paper, I offer three related arguments against the theory. The arguments are about what judgment subjectivism implies about the well-being of welfare nihilists, people who believe there are no welfare properties, or at least that none are instantiated. I maintain that welfare nihilists can be benefited (...) and harmed. Judgment subjectivism is implausible because it implies otherwise. (shrink)

The Infectious Disease Ontology (IDO) is a suite of interoperable ontology modules that aims to provide coverage of all aspects of the infectious disease domain, including biomedical research, clinical care, and public health. IDO Core is designed to be a disease and pathogen neutral ontology, covering just those types of entities and relations that are relevant to infectious diseases generally. IDO Core is then extended by a collection of ontology modules focusing on specific diseases and pathogens. In this paper we (...) present applications of IDO Core within various areas of infectious disease research, together with an overview of all IDO extension ontologies and the methodology on the basis of which they are built. We also survey recent developments involving IDO, including the creation of IDO Virus; the Coronaviruses Infectious Disease Ontology (CIDO); and an extension of CIDO focused on COVID-19 (IDO-CovID-19).We also discuss how these ontologies might assist in information-driven efforts to deal with the ongoing COVID-19 pandemic, to accelerate data discovery in the early stages of future pandemics, and to promote reproducibility of infectious disease research. (shrink)

According to subjectivism about ill-being, the token states of affairs that are basically bad for you must be suitably connected, under the proper conditions, to your negative attitudes. This article explores the prospects for this family of theories and addresses some of its challenges. This article (i) shows that subjectivism about ill-being can be derived from a more general doctrine that requires a negatively valenced relationship between any welfare subject and the token states that are of basic harm to that (...) subject and (ii) responds to some objections, including the objection that subjectivists about ill-being cannot plausibly explain the badness of pain. (shrink)

A repository of clinically associated Staphylococcus aureus (Sa) isolates is used to semi‐automatically generate a set of application ontologies for specific subfamilies of Sa‐related disease. Each such application ontology is compatible with the Infectious Disease Ontology (IDO) and uses resources from the Open Biomedical Ontology (OBO) Foundry. The set of application ontologies forms a lattice structure beneath the IDO‐Core and IDO‐extension reference ontologies. We show how this lattice can be used to define a strategy for the construction of a new (...) taxonomy of infectious disease incorporating genetic, molecular, and clinical data. We also outline how faceted browsing and query of annotated data is supported using a lattice application ontology. (shrink)

An accurate classification of bacteria is essential for the proper identification of patient infections and subsequent treatment decisions. Multi-Locus Sequence Typing (MLST) is a genetic technique for bacterial classification. MLST classifications are used to cluster bacteria into clonal complexes. Importantly, clonal complexes can serve as a biological species concept for bacteria, facilitating an otherwise difficult taxonomic classification. In this paper, we argue for the inclusion of terms relating to clonal complexes in biomedical ontologies.

Vaccine research, as well as the development, testing, clinical trials, and commercial uses of vaccines involve complex processes with various biological data that include gene and protein expression, analysis of molecular and cellular interactions, study of tissue and whole body responses, and extensive epidemiological modeling. Although many data resources are available to meet different aspects of vaccine needs, it remains a challenge how we are to standardize vaccine annotation, integrate data about varied vaccine types and resources, and support advanced vaccine (...) data analysis and inference. To address these problems, the community-based Vaccine Ontology (VO) has been developed through collaboration with vaccine researchers and many national and international centers and programs, including the National Center for Biomedical Ontology (NCBO), the Infectious Disease Ontology (IDO) Initiative, and the Ontology for Biomedical Investigations (OBI). VO utilizes the Basic Formal Ontology (BFO) as the top ontology and the Relation Ontology (RO) for definition of term relationships. VO is represented in the Web Ontology Language (OWL) and edited using the Protégé-OWL. Currently VO contains more than 2000 terms and relationships. VO emphasizes on classification of vaccines and vaccine components, vaccine quality and phenotypes, and host immune response to vaccines. These reflect different aspects of vaccine composition and biology and can thus be used to model individual vaccines. More than 200 licensed vaccines and many vaccine candidates in research or clinical trials have been modeled in VO. VO is being used for vaccine literature mining through collaboration with the National Center for Integrative Biomedical Informatics (NCIBI). Multiple VO applications will be presented. (shrink)

I argue that Goethe’s scientific writings carry in them the seeds of the theory of evolution. Goethe’s works on plant morphology reflects the conflicting ideas of his era on the discreteness and on the stability of species. Goethe’s theory of plant morphology provides a link between the discontinuous view of nature, as exemplified in works of the Swedish botanist Carl Linnaeus (1707-1778), and the continuous view of nature, as exemplified in the work of the English naturalist Charles Darwin (1809-1882).

In a recent study, we found a negative association between psychopathy and violence against genetic relatives. We interpreted this result as a form of nepotism and argued that it failed to support the hypothesis that psychopathy is a mental disorder, suggesting instead that it supports the hypothesis that psychopathy is an evolved life history strategy. This interpretation and subsequent arguments have been challenged in a number of ways. Here, we identify several misunderstandings regarding the harmful dysfunction definition of mental disorder (...) as it applies to psychopathy and regarding the meaning of nepotism. Furthermore, we examine the evidence provided by our critics that psychopathy is associated with other disorders, and we offer a comment on their alternative model of psychopathy. We conclude that there remains little evidence that psychopathy is the product of dysfunctional mechanisms. (shrink)

As the digitization of information accelerates, the push to encode our surrounding numerically instead of linguistically increases. The role that language has traditionally played in the nomenclature of an integrative taxonomy is being replaced by the numeric identification of one or few quantitative characteristics. Nineteenth-century scientific systems of color identification divided, grouped, and named colors according to multiple characteristics. Now color identification relies on numeric values applied to spectrographic readings. This means of identification of color lacks the taxonomic rigor of (...) nineteenth century systems. Identifying color by numeric value instead of by grouping and naming them, strips color taxonomy of all but one quantitative aspect of a color. I use the case of color taxonomy to argue against a similar trend of numeric identification in the biological sciences. Unlike historically more integrative approaches to taxonomy in biology, genomic sequencing identifies one or few quantitative characteristics to encode an organism. If genomic sequencing becomes the primary means of identification in the biological sciences, just as in numeric systems of color identification, scientific taxonomy would suffer. Basing my analysis on theories of perception of division and on theories of language, I use the cases of color and species to argue for the advantages of an integrative taxonomic system of naming and categorizing over a method of identification, which encodes limited characteristics numerically. I hold that language is the most sophisticated tool for systematic taxonomy and that taxonomic nomenclature should be retained. (shrink)

Harold Brown has written an ambitious work, which traces the formation of concepts in individuals and cultures, examines case studies of concepts in calculus, mathematics, biology and related fields, summarises important philosophical works on the theory of concepts, and seeks to reconcile scientific realism with conceptual change. Brown considers himself a scientific realist but concedes that this very label is one that depends on a long history of concepts that came before, and may indeed be superseded as conceptual change continues. (...) Yet, concepts are not strictly relative to their contexts. ‘‘The usual claim is that truth is relative – period; and this claim assumes a non-relativized truth-concept’’ (p. 309). Crucial to his goal of developing a theory of concepts is how Brown reconciles conceptual change with objectivity. (shrink)

This article is about a very important metaphysical concept, macrocosm/microcosm and its appearance in Doric thought which in turn influenced Socrates and Plato. But since this concept has been gainsaid and negated in recent articles and distorted by some ancient thinkers it will be necessary to conduct reconstructive surgery to restore it to its pristine condition. Hopefully, this paper will illustrate how metaphysics is done with the use of the Mind's eye, in the reading of reality that was part and (...) parcel of the Greek mind but also in understanding the ancient Greeks themselves and their culture especially in the creation of the classical republican form of government. This account will discuss what macrocosm/microcosm is, its part in the Cosmos and hence its centrality in the Natural Law and in philosophy (wisdom). Second, it will prove the concept thru another natural law principle, righteousness. Third, point out it's provenance in Doric thought. In a corollary, it points to what the impact macrocosm/microcosm has on the true meaning "to be a lover of wisdom" and its importance in the concept of theosis. More than a research/academic article, this paper is also an exposition in which it will attempt to demonstrate the use and the mechanics of this principle by using a saying of Homer and the tripartite paradigm of the family. (shrink)

This paper addresses a family of issues surrounding the biological phenomenon of resistance and its representation in realist ontologies. The treatments of resistance terms in various existing ontologies are examined and found to be either overly narrow, internally inconsistent, or otherwise problematic. We propose a more coherent characterization of resistance in terms of what we shall call blocking dispositions, which are collections of mutually coordinated dispositions which are of such a sort that they cannot undergo simultaneous realization within a single (...) bearer. A definition of ‘protective resistance’ is proposed for use in the Infectious Disease Ontology (IDO) and we show how this definition can be used to characterize the antibiotic resistance in Methicillin-Resistant Staphylococcus aureus (MRSA). The ontological relations between entities in our MRSA case study are used alongside a series of logical inference rules to illustrate logical reasoning about resistance. A description logic representation of blocking dispositions is also provided. We demonstrate that our characterization of resistance is sufficiently general to cover two other cases of resistance in the infectious disease domain involving HIV and malaria. (shrink)

The COVID-19 pandemic prompted immense work on the investigation of the SARS-CoV-2 virus. Rapid, accurate, and consistent interpretation of generated data is thereby of fundamental concern. Ontologies––structured, controlled, vocabularies––are designed to support consistency of interpretation, and thereby to prevent the development of data silos. This paper describes how ontologies are serving this purpose in the COVID-19 research domain, by following principles of the Open Biological and Biomedical Ontology (OBO) Foundry and by reusing existing ontologies such as the Infectious Disease Ontology (...) (IDO) Core, which provides terminological content common to investigations of all infectious diseases. We report here on the development of an IDO extension, the Virus Infectious Disease Ontology (VIDO), a reference ontology covering viral infectious diseases. We motivate term and definition choices, showcase reuse of terms from existing OBO ontologies, illustrate how ontological decisions were motivated by relevant life science research, and connect VIDO to the Coronavirus Infectious Disease Ontology (CIDO). We next use terms from these ontologies to annotate selections from life science research on SARS-CoV-2, highlighting how ontologies employing a common upper-level vocabulary may be seamlessly interwoven. Finally, we outline future work, including bacteria and fungus infectious disease reference ontologies currently under development, then cite uses of VIDO and CIDO in host-pathogen data analytics, electronic health record annotation, and ontology conflict-resolution projects. (shrink)

This paper addresses the use of dispositions in the Infectious Disease Ontology (IDO). IDO is an ontology constructed according to the principles of the Open Biomedical Ontology (OBO) Foundry and uses the Basic Formal Ontology (BFO) as an upper ontology. After providing a brief introduction to disposition types in BFO and IDO, we discuss three general techniques for representing combinations of dispositions under the headings blocking dispositions, complementary dispositions, and collective dispositions. Motivating examples for each combination of dispositions is given (...) along with a specific use case in IDO. Description logic restrictions are used to formalize statements relating to these combinations. (shrink)

Stillbirths are largely excluded from international measures of mortality and morbidity. Zeshan Qureshi and colleagues argue that stillbirth should be higher on the global health agenda.

The COVID-19 pandemic prompted immense work on the investigation of the SARS-CoV-2 virus. Ontologies – structured, controlled, vocabularies – are designed to support consistency of interpretation, and thereby to prevent the development of data silos. This paper describes how ontologies are serving this purpose in the virus research domain, following the principles of the Open Biological and Biomedical Ontology (OBO) Foundry and drawing on the resources of the Infectious Disease Ontology (IDO) Core. We report the development of the Virus Infectious (...) Disease Ontology (VIDO), a reference ontology extending IDO Core covering viral infectious diseases. We examine newly minted terms, showcase ontology term reuse, and illustrate the use of VIDO by annotating selections from recent life science research on SAR-CoV-2, in the interest of supporting machine learning projects. (shrink)

The Center for Disease Control and Prevention’s Active Bacterial Core Surveillance (CDC ABCs) Program is a collaborative effort betweeen the CDC, state health departments, laboratories, and universities to track invasive bacterial pathogens of particular importance to public health [1]. The year-end surveillance reports produced by this program help to shape public policy and coordinate responses to emerging infectious diseases over time. The ABCs case report form (CRF) data represents an excellent opportunity for data reuse beyond the original surveillance purposes.

The Cell Ontology (CL) is designed to provide a standardized representation of cell types for data annotation. Currently, the CL employs multiple is_a relations, defining cell types in terms of histological, functional, and lineage properties, and the majority of definitions are written with sufficient generality to hold across multiple species. This approach limits the CL’s utility for cross-species data integration. To address this problem, we developed a method for the ontological representation of cells and applied this method to develop a (...) dendritic cell ontology (DC-CL). DC-CL subtypes are delineated on the basis of surface protein expression, systematically including both species-general and species-specific types and optimizing DC-CL for the analysis of flow cytometry data. This approach brings benefits in the form of increased accuracy, support for reasoning, and interoperability with other ontology resources. 104. Barry Smith, “Toward a Realistic Science of Environments”, Ecological Psychology, 2009, 21 (2), April-June, 121-130. Abstract: The perceptual psychologist J. J. Gibson embraces a radically externalistic view of mind and action. We have, for Gibson, not a Cartesian mind or soul, with its interior theater of contents and the consequent problem of explaining how this mind or soul and its psychological environment can succeed in grasping physical objects external to itself. Rather, we have a perceiving, acting organism, whose perceptions and actions are always already tuned to the parts and moments, the things and surfaces, of its external environment. We describe how on this basis Gibson sought to develop a realist science of environments which will be ‘consistent with physics, mechanics, optics, acoustics, and chemistry’. (shrink)

A response to critical commentaries. Crookston begins her commentary by noting that my book would have been better with answers to “the following three questions: (1) Why is the harm principle the right principle upon which to base a theory of toleration? (2) How is Cohen thinking of the concept of volenti? (p. x ) Is interference (i.e., the abandonment of toleration) ever morally required by the harm principle?” (p. x ). She is right, and I address these questions below (...) in Sections 2, 3, and 4. That is the bulk of this essay. I then turn to Kelley's issues in Sections 6, 7, and 8; these have to do with “the link between toleration and relativism,” the way I distinguish “the concepts of toleration and endurance,” and a “question about moral toleration” (p. x ). Despite much agreement, there are points of contention and I try to make my position clearer in response . (shrink)

This is the review of a book by Paula Byrne on Lord Mansfield's great-niece, Dido, whom he raised as his own daughter. Lord Mansfield was the Lord Chief Justice of England in the Eighteenth Century. The child was brought to him as an infant and grew up to become what we would today term his paralegal clerk in his Library at Kenwood House. His great-niece was the child of a black slave and his sister's son, Sir John Lindsay. This (...) is also a narrative of the British Slave trade including some of Lord Mansfield's judgements at the King's Bench Division, Royal Courts of Justice. (shrink)

Is the being in an irreversible persistent vegetative state as the result of a horrible accident numerically identical to the human person, Lindsay, who existed before the accident? Many proponents of Thomistic metaphysics have argued that Aquinas’s answer to this question must be “yes.” In particular, it seems that Aquinas’s commitment to both Aristotelian hylomorphism and the unity of substantial form (viz., that each body/soul composite possesses one and only one substantial form) entails the position that the human person (...) remains alive as long as biological life persists. I argue, however, that although Aquinas does possess a deeply integrated account of human nature and is indeed committed to the claim that the person, Lindsay, exists as long as Lindsay’s body lives, there is good reason to suppose that he also holds that the body in the PVS is not Lindsay’s body in anything more than an equivocal sense. (shrink)

The incompleteness of set theory ZF C leads one to look for natural nonconservative extensions of ZF C in which one can prove statements independent of ZF C which appear to be “true”. One approach has been to add large cardinal axioms.Or, one can investigate second-order expansions like Kelley-Morse class theory, KM or Tarski-Grothendieck set theory T G or It is a nonconservative extension of ZF C and is obtained from other axiomatic set theories by the inclusion of Tarski’s (...) axiom which implies the existence of inaccessible cardinals. See also related set theory with a filter quantifier ZF (aa). In this paper we look at a set theory NC# ∞# , based on bivalent gyper infinitary logic with restricted Modus Ponens Rule In this paper we deal with set theory NC# ∞# based on bivalent gyper infinitary logic with Restricted Modus Ponens Rule. Nonconservative extensions of the canonical internal set theories IST and HST are proposed. (shrink)

The incompleteness of set theory ZFC leads one to look for natural extensions of ZFC in which one can prove statements independent of ZFC which appear to be "true". One approach has been to add large cardinal axioms. Or, one can investigate second-order expansions like Kelley-Morse class theory, KM or Tarski- Grothendieck set theory TG [1]-[3] It is a non-conservative extension of ZFC and is obtaineed from other axiomatic set theories by the inclusion of Tarski's axiom which implies the (...) existence of inaccessible cardinals [1].Non-conservative extension of ZFC based on an generalized quantifiers considered in [4]. In this paper we look at a set theory NC_{∞^{#}}^{#},based on bivalent gyper infinitary logic with restricted Modus Ponens Rule [5]-[8]. In this paper we deal with set theory NC_{∞^{#}}^{#} based on gyper infinitary logic with Restricted Modus Ponens Rule. Set theory NC_{∞^{}}^{} contains Aczel's anti-foundation axiom [9]. We present a new approach to the invariant subspace problem for Hilbert spaces. Our main result will be that: if T is a bounded linear operator on an infinite-dimensional complex separable Hilbert space H,it follow that T has a non-trivial closed invariant subspace. Non-conservative extension based on set theory NC_{∞}^{#} of the model theoretical nonstandard analysis [10]-[12] also is considered. (shrink)

In 1966 Gene Roddenberry, then a relatively unknown TV writer, created what was to become a cultural sensation. From cell phones and tablets, to MRI machines and medical jet injectors, Star Trek has undoubtedly anticipated much of the technology that we take for granted today. Moreover, the disagreements, fights and jokes between Captain Kirk (William Shatner), Dr Leonard ‘Bones’ McCoy (DeForest Kelley) and Mr Spock (Leonard Nimoy) were expertly crafted for dramatic impact. But I’m not writing this to confess (...) to you my obsessive infatuation with the Star Trek universe. Instead I want to discuss how the beliefs and practices of Vulcans like Spock are similar to those of the Stoic school of philosophy. (shrink)

According to Cantor (Mathematische Annalen 21:545–586, 1883 ; Cantor’s letter to Dedekind, 1899 ) a set is any multitude which can be thought of as one (“jedes Viele, welches sich als Eines denken läßt”) without contradiction—a consistent multitude. Other multitudes are inconsistent or paradoxical. Set theoretical paradoxes have common root—lack of understanding why some multitudes are not sets. Why some multitudes of objects of thought cannot themselves be objects of thought? Moreover, it is a logical truth that such multitudes do (...) exist. However we do not understand this logical truth so well as we understand, for example, the logical truth $${\forall x \, x = x}$$ . In this paper we formulate a logical truth which we call the productivity principle. Rusell (Proc Lond Math Soc 4(2):29–53, 1906 ) was the first one to formulate this principle, but in a restricted form and with a different purpose. The principle explicates a logical mechanism that lies behind paradoxical multitudes, and is understandable as well as any simple logical truth. However, it does not explain the concept of set. It only sets logical bounds of the concept within the framework of the classical two valued $${\in}$$ -language. The principle behaves as a logical regulator of any theory we formulate to explain and describe sets. It provides tools to identify paradoxical classes inside the theory. We show how the known paradoxical classes follow from the productivity principle and how the principle gives us a uniform way to generate new paradoxical classes. In the case of ZFC set theory the productivity principle shows that the limitation of size principles are of a restrictive nature and that they do not explain which classes are sets. The productivity principle, as a logical regulator, can have a definite heuristic role in the development of a consistent set theory. We sketch such a theory—the cumulative cardinal theory of sets. The theory is based on the idea of cardinality of collecting objects into sets. Its development is guided by means of the productivity principle in such a way that its consistency seems plausible. Moreover, the theory inherits good properties from cardinal conception and from cumulative conception of sets. Because of the cardinality principle it can easily justify the replacement axiom, and because of the cumulative property it can easily justify the power set axiom and the union axiom. It would be possible to prove that the cumulative cardinal theory of sets is equivalent to the Morse–Kelley set theory. In this way we provide a natural and plausibly consistent axiomatization for the Morse–Kelley set theory. (shrink)

Este artigo procura analisar algumas das principais ideias abordadas no encontro anual promovido pela “American Association for the Advancement of Sciencie” em Boston (EUA) em 1953. Parte do encontro foi para abordar sobre o estado atual da concepção operacional de significado desenvolvida por Percy W. Bridgman a partir de 1927. As principais ideias tratadas no encontro foram posteriormente publicadas pela revista “The Scientific Montly” em 1954-1955 e republicadas no capítulo 2 do livro “The validation of scientific theories” (1961), editado por (...) Philipp Frank. A obra de 1961 será utilizada aqui como referência para as citações. Os autores dos capítulos são Henry Margenau, Gustav Bergmann, Carl G. Hempel, R. B. Lindsay, Raymond J. Sieger, Adolf Gründbaun, além do artigo do próprio Percy Bridgman. Este debate surgiu a mais de 20 anos depois da publicação da primeira obra de Bridgman, a saber, “The Logic of Modern Physics” (1927), onde ele apresenta pela primeira vez sua concepção de significado dos conceitos científicos baseada em procedimentos operacionais. A obra de 1927 trouxe os debates sobre a importância da linguagem científica e da correspondência empírica, uma questão pertinente na filosofia da ciência da época inflacionada pela filosofia da ciência do empirismo lógico. Os debates do encontro tiveram como objetivo apresentar questionamentos e fazer exposições gerais sobre a forma como a concepção operacional pode ser interpretada por cientistas e filósofos da época, seja em seus elementos favoráveis na ciência, enquanto resolvendo questões pertinentes para cientistas e filósofos da ciência, seja por mostrar também as limitações da concepção operacional através dos questionamentos dirigidos a ela. Ressaltamos a importância deste debate na época e nos dias atuais. Temos aqui um material que pode servir de direcionamento histórico e de debate filosófico para algumas das questões pertinentes dos filósofos da ciência da época. (shrink)

Dido Belle was the illegitimate daughter of Captain Lindsay, the aristocratic nephew of William Murray, Scottish by birth and Lord Chief Justice of England for many decades. The book tells the story of Dido's life in Lord Mansfield homes, from the time her father begged Lord and Lady Mansfield to be wards of the child Dido to the death at age 88 of Lord Mansfield, mainly cared for by Dido and to Dido's young death at age 43. It also (...) raises issues of financial queries, Wills, Probate, and the place of a woman in society in those days, not quite chattel but not equal to men. (shrink)

REPRODUÇÃO ANIMAL: O CICLO ESTRAL DE BOVINOS LEITEIROS – Desenvolvimento Folicular, Corpo Lúteo e Etapas do Estro ANIMAL REPRODUCTION: THE OESTROUS CYCLE OF DAIRY BOVINES -Follicular Development, Corpus Luteum and Stages of Estrus Apoio: Emanuel Isaque Cordeiro da Silva Departamento de Zootecnia da UFRPE E-mail: [email protected] WhatsApp: (82)98143-8399 FISIOLOGIA CLÍNICA DO CICLO ESTRAL DE BOVINOS LEITEIROS 1. RESUMO A fêmea bovina apresenta ciclos estrais em intervalos de 19 a 23 dias e estes só são interrompidos durante a gestação ou devido (...) a alguma patologia. O estro é o período de aceitação da cópula e tem uma duração de 8 a 18 horas. Durante o metaestro ocorre a ovulação e se desenvolve o corpo lúteo. O diestro é o estágio mais longo do ciclo e é caracterizado pela presença de um corpo lúteo. Se a gestação não for estabelecida, o endométrio segrega prostaglandina F2α(PGF2α) o que induz a luteólise, reiniciando assim um novo ciclo. 2. EIXO HIPOTÁLAMO-HIPÓFISE-OVÁRIO As hormonas são substâncias produzidas por diferentes células do organismo que exercem funções específicas em outras células (células brancas). Algumas hormonas atuam na mesma célula que a secreta (atividade autocrina), outras nas células vizinhas (atividade parácrina) e outras são transportadas pelo sangue e exercem a sua função em células de outros órgãos (atividade endócrina). Existem outros tipos de hormônios que comunicam a diferentes indivíduos e são conhecidos como feromônios. Os feromônios regulam diferentes funções, entre as quais se destacam as reprodutivas. O hipotálamo encontra-se na base do cérebro, é formado por núcleos pares de neurônios e comunica-se com a hipófise através de um sistema circulatório especializado conhecido como sistema porta-hipotálamo-hipofisário. Os neurônios da área ventromedial e da área pré-óptica do hipotálamo secretam a hormona libertadora das gonadotropinas (GnRH), que por sua vez chega à hipófise através do sistema porta-hipotálamo-hipofisário e estimula a secreção da hormona luteinizante (LH) e da hormona folículo estimulante (FSH). A LH mantém um padrão de secreção paralelo à secreção da GnRH; ou seja, uma parcela de GnRH corresponde a uma parcela de LH, ao contrário da FSH que tem uma produção basal elevada inibida pelo estradiol e inibina, por este motivo, a sua secreção não apresenta um padrão pulsante semelhante à LH. A GnRH tem duas formas de secreção: a primeira é pulsante ou tônica, regulada por estímulos externos (fotoperíodo, bioestimulação, amamentação) e por estímulos internos (metabolitos, hormonas metabólicas, hormonas sexuais); a segunda forma é pré-ovulatória ou cíclica e é estimulada pelos estrogênios durante o estro e inibida pela progesterona. A secreção de alguns hormônios, bem como diversos processos fisiológicos, são sincronizados com a duração do dia e da noite (ritmos endógenos). A luz é percebida pelos fotorreceptores da retina e o sinal luminoso chega à glândula pineal através de conexões neuronais (trato retino-hipotalâmico). Na glândula pineal, o estímulo produzido pela luz inibe a síntese da melatonina. Desta forma, a duração do dia e da noite (fotoperíodo) é registada pelas variações nas concentrações da melatonina. Na vaca, sabe-se que o fotoperíodo influencia alguns processos reprodutivos, embora não seja, em sentido estrito, uma espécie com um padrão reprodutivo sazonal. Os feromônios sexuais são excretados através da urina, fezes e fluidos corporais; eles são percebidos pelo epitélio olfatório e órgão vomeronasal. Posteriormente, algumas vias nervosas, estimulam no hipotálamo a frequência dos pulsos de secreção da GnRH. A exposição a feromonas femininas provoca no macho um aumento na frequência de secreção do LH e isto por sua vez aumenta as concentrações de testosterona. Os feromônios masculinos induzem na fêmea um aumento da frequência de secreção do LH, estimulando o crescimento folicular e a secreção de estradiol. A estimulação sexual provocada pelo macho ou pela fêmea é denominada bioestimulação. As alterações na condição corporal estão positivamente correlacionadas com as concentrações séricas de insulina, fator de crescimento semelhante à insulina tipo I (IGF- I) e leptina. Assim, quanto maior a classificação da condição corporal, maior é a concentração sérica destas hormonas, que atuam como sinais que chegam ao hipotálamo e modificam a frequência de secreção da GnRH. Por exemplo, a transição do anestro para a ciclicidade coincide com um aumento da condição corporal e das concentrações de insulina, IGF- I e leptina (figura 1). Figura 1. A transição do anestro para a ciclicidade coincide com um aumento da condição corporal e das concentrações de insulina, IGF- I e leptina. Estas hormonas atuam como sinais que chegam ao hipotálamo e aumentam a frequência de secreção da GnRH. Fonte: GALINA, et al. 2008. Os estrogênios podem ter um feedback positivo ou negativo sobre a secreção da GnRH, o que depende da fase do ciclo reprodutivo. Em animais pré-púberes e em anestro pós-parto, os estrogênios inibem a secreção de GnRH, mas durante o período de proestro e estro há uma estimulação para a secreção de GnRH. A progesterona reduz a secreção da GnRH, bem como a resposta da hipófise à GnRH, inibindo assim a maturação folicular e a ovulação. Por esta razão, a progesterona foi utilizada com sucesso como contraceptivo em humanos e para o controle artificial da reprodução em animais domésticos (figura 2). Figura 2. Retroalimentação entre o hipotálamo, hipófise e o ovário. A GnRH estimula na hipófise a síntese e secreção de LH e FSH. Na fase pré-púbere e no anestro pós-parto, os estrogênios inibem a secreção de GnRH, enquanto no proestro e estro, estimulam-na. A progesterona inibe a secreção da GnRH e diminui a resposta da hipófise à GnRH. Os estrogênios e a inibina suprimem a secreção de FSH diretamente na hipófise. Fonte: GALINA, et al. 2008. Os neurônios secretores da GnRH não têm receptores para estrogênios nem progesterona, pelo que estas hormonas não têm forma de regular diretamente a secreção da GnRH. Existe um grupo de neurônios hipotalâmicos que exprimem o gene Kiss-1 que codifica o peptídeo kisspeptina. Os neurônios secretores da GnRH têm receptores para este peptídeo, de modo que a kisspeptina fornece a informação aos neurônios secretores da GnRH em relação às concentrações de hormônios sexuais. A kisspeptina é um potente estimulador (secretagogo) da secreção da GnRH e é muito provável que nos próximos anos venha a fazer parte dos recursos hormonais para o controle artificial da reprodução, não só nos bovinos, mas em todas as espécies domésticas. 3. DESENVOLVIMENTO FOLICULAR O ovário é responsável pela produção de ovócitos e pela síntese de hormônios sexuais, estrogênios e progesterona, que promovem e regulam a fertilização do ovócito e a manutenção da gestação. O ovócito encontra-se no interior do folículo ovárico rodeado por células granulosas que participam de forma ativa no seu crescimento e maturação. As experiências in vitro demonstram a dependência dos ovócitos das células da granulosa, assim, quando os ovócitos são induzidos a amadurecer devem estar rodeados por várias camadas de células da granulosa para que este processo seja bem sucedido, caso contrário, não adquirem o potencial para desenvolver um embrião. Embora as células da teca interna não estejam em contato direto com o ovócito, seu papel na maturação deste o exercem mediante a produção de andrógenos, mesmos que são convertidos em estrogênios pelas células da granulosa. Além disso, as células da teca favorecem o estabelecimento da rede capilar que apoia o desenvolvimento folicular. Por outro lado, os novos conhecimentos indicam que o ovócito não é um elemento passivo no desenvolvimento folicular, mas regula a função das células foliculares; o que significa que ele próprio participa na criação de um microambiente ideal para a sua maturação. Além disso, é possível que o ovócito tenha um papel na ativação do desenvolvimento dos folículos primordiais. A fêmea bovina nasce com aproximadamente 200 mil folículos, dos quais muito poucos se ativam e iniciam seu crescimento, e a maior parte deles sofre atresia em diferentes etapas de desenvolvimento. Ao nascimento, os folículos estão na fase mais elementar e são conhecidos como folículos primordiais. Posteriormente estes folículos se ativam e se transformam em folículos primários e secundários; até este momento os folículos não têm antro (etapa pré-antral) e seu desenvolvimento é independente das gonadotropinas. Quando os folículos formam o antro são conhecidos como folículos terciários e seu desenvolvimento é dependente das gonadotropinas (etapa antral). O crescimento folicular no estágio antral ocorre em forma de ondas e cada onda começa com um aumento nos níveis de FSH, o qual promove o crescimento de um grupo de cinco a seis folículos (~4 mm de diâmetro); este processo é conhecido como recrutamento. Subsequentemente, um único folículo continua a crescer (folículo dominante), o que provoca um aumento das concentrações de estrogênios e inibina, uma diminuição das concentrações de FSH e atresia dos folículos subordinados, pois eles dependem totalmente desta hormona, enquanto o folículo dominante continua o seu desenvolvimento estimulado pela LH. O folículo dominante perdura de quatro a seis dias e se não chega a ovular, sofre atresia. Após a atresia do folículo dominante, diminuem-se os níveis de estrogênio e inibina, observa-se um aumento das concentrações de FSH e inicia-se uma nova onda folicular. O folículo dominante que está presente quando o corpo lúteo sofre regressão, continua seu desenvolvimento e ovula, em resposta ao pico pré-ovulatório de LH. Além de promover a liberação do ovócito, a secreção pré-ovulatória de LH regula a formação do corpo lúteo a partir das células foliculares, processo conhecido como luteinização. Durante o ciclo estral são apresentadas de duas a três ondas foliculares. As vacas com três ondas foliculares têm uma fase lútea mais longa e, consequentemente, um ciclo estral mais longo, de 22 a 23 dias; enquanto as vacas com duas ondas apresentam um ciclo estral de 18 a 21 dias. Nas vacas leiteiras, cerca de 70% apresentam duas ondas foliculares, enquanto 30% exibem três ondas (figura 3 e 4). Nas vacas com duas ondas foliculares, o período de dominação folicular é maior do que nas de três ondas. O tempo de dominação influencia o potencial dos ovócitos para desenvolver um embrião viável; assim, a porcentagem de concepção é menor quando ovulam folículos que tiveram mais dias de dominação dos que quando ovulam folículos com menor tempo de dominação (figura 5). Figura 5. O crescimento folicular no estágio antral ocorre na forma de ondas. Cada onda começa com um aumento nas concentrações de FSH, o que promove o recrutamento de cinco a seis folículos (~4 mm de diâmetro). Posteriormente um único folículo continua crescendo (folículo dominante), enquanto seus companheiros (subordinados) sofrem atresia. O folículo dominante perdura de quatro a seis dias e se não chega a ovular, sofre atresia. Após a atresia do folículo dominante observa-se um aumento das concentrações de FSH, iniciando-se uma nova onda folicular. 3.1 Ovulação múltipla Nos últimos anos tem-se observado um aumento na proporção de vacas com ovulação múltipla (20% x 1% em novilhas), o que tem provocado um aumento da proporção de partos gêmeos (8% x 1% em novilhas). A frequência de vacas com ovulação múltipla está associada com a alta produção de leite; de modo que, as vacas que produzem menos de 40 kg mostram 6% de ovulações múltiplas e aquelas que produzem mais de 50 kg alcançam até 50%. A causa deste fenômeno ainda é obscura, contudo, observaram-se diferenças nas concentrações de FSH, de tal forma que as vacas que desenvolvem de dois a três folículos dominantes numa onda folicular, apresentam níveis de FSH mais elevados que as vacas que têm apenas um folículo dominante. Em vacas em lactação, a concentração de progesterona é baixa devido ao aumento do metabolismo hepático, o que aumenta a sua taxa de eliminação. Foi observado que as vacas que tiveram uma fase lútea com níveis de progesterona mais elevados, no ciclo anterior à inseminação, apresentam menos ovulações múltiplas em comparação com as vacas que tiveram níveis de progesterona mais baixos. Propõe-se que as baixas concentrações de progesterona permitam um aumento da frequência de secreção da GnRH e, consequentemente, da LH e da FSH, favorecendo a predominância múltipla e, eventualmente, a ovulação de mais de um folículo. Nos rebanhos leiteiros, as gestações gêmeas não são desejáveis porque aumenta o risco de perda da gestação e, se esta chegar ao término, haverá o risco de perda da gestação e, se esta for concluída, o risco de distorcia é consideravelmente mais elevado (figuras 6, 7, 8 e 9). Figura 6. As baixas concentrações de progesterona sérica nas vacas em lactação permitem um aumento da frequência de secreção da GnRH, bem como o aumento da LH e da FSH. Isto favorece a dominação múltipla e eventualmente a ovulação de mais de um folículo. Esta figura mostra a dominância de dois folículos em cada onda folicular (codominância). Figura 7. Ovários de uma vaca leiteira em diestro com três folículos dominantes. Figura 8. Ovários de uma vaca leiteira com três corpos lúteos. Figura 9. Ovários de uma vaca leiteira com dois corpos hemorrágicos. Fonte: Acervo pessoal do autor. IFPE, 2017-18. 4. DESENVOLVIMENTO E CONTROLE DA FUNÇÃO DO CORPO LÚTEO Quando o folículo dominante completa sua maturação, ele produz níveis de estrogênio suficientes para provocar a liberação máxima da GnRH, o que desencadeia o pico pré-ovulatório da LH. Esta secreção de LH provoca a ovulação e inicia as mudanças para que o folículo se transforme em um corpo lúteo, processo conhecido como luteinização. A luteinização compreende todas as mudanças morfológicas, endócrinas e enzimáticas que ocorrem no folículo ovulatório até que este se transforme num corpo lúteo. O processo de luteinização começa a partir da elevação pré-ovulatória de LH; mesmo antes da ovulação. A luteinização do folículo dominante (≥8 mm de diâmetro) pode ser induzida hormonalmente pela injeção de GnRH ou gonadotropina coriónica humana (hCG). A ovulação ocorre em média 30 horas após o pico pré-ovulatório de LH. A secreção pré-ovulatória de LH desencadeia a liberação de enzimas proteolíticas e de mediadores da inflamação na parede folicular, as quais degradam o tecido conjuntivo e ocasionam morte celular. Posteriormente, a PGF2α induz contrações da teca externa, levando à ruptura folicular e à expulsão do ovócito. Após a ovulação, as células da teca interna e da granulosa migram e distribuem-se nas paredes do folículo. As células da teca interna se diferenciam e se multiplicam em células lúteas pequenas, enquanto que as células da granulosa se hipertrofiam e dão origem às células lúteas grandes. Estas alterações são facilitadas pela ruptura da membrana basal que separa a camada celular da granulosa da teca interna. Em forma paralela começa a formação de uma ampla rede de capilares que se distribuem em todo o corpo lúteo em formação, e chegam a constituir até 20% do volume desta estrutura (figuras 10 e 11). A progesterona é o principal produto de secreção do corpo lúteo. No quinto dia do ciclo estral, as concentrações séricas desta hormona são superiores a 1 ng/ ml, indicando que o corpo lúteo adquiriu a sua plena funcionalidade. A progesterona atua basicamente sobre os órgãos genitais da fêmea, sendo responsável pela preparação do útero para o estabelecimento e manutenção da gestação. Na mucosa do oviduto e do útero, estimula a secreção de substâncias que promovem o desenvolvimento do embrião, até que este comece a nutrir-se através da placenta. A progesterona suprime a resposta imunitária do útero, o que é necessário para tolerar o embrião, já que este é um tecido estranho para a vaca. Além disso, a progesterona evita as contrações do útero, fecha o colo do útero e modifica as características do muco cervical, tornando-o mais viscoso, impedindo a passagem de agentes estranhos para o interior do útero. Na glândula mamária estimula o desenvolvimento do sistema alveolar, preparando-a para a síntese e a secreção de leite. 5. REGRESSÃO DO CORPO LÚTEO A regressão lútea é um processo ativo ocasionado pela secreção uterina da PGF2α. O mecanismo pelo qual se inicia a síntese e secreção da PGF2α depende de uma interação entre o corpo lúteo, os folículos e o útero. Os estrogênios produzidos no folículo dominante desempenham um papel importante no início da secreção de PGF2α, uma vez que promovem a síntese de receptores para oxitocina. Além disso, os estrogénios estimulam no endométrio a produção da fosfolipase A e da ciclooxigenase; enzimas indispensáveis para a síntese da PGF2α. Durante o ciclo estral, a progesterona inibe a síntese da PGF2α através da supressão da formação de receptores para o estradiol. Após um período de 12 a 14 dias de exposição à progesterona, as células endometriais tornam-se insensíveis à progesterona. Quando isso ocorre, as células endometriais sintetizam receptores para estradiol, permitindo que o estradiol produzido no folículo dominante estimule a síntese de receptores para oxitocina. Neste momento, o endométrio está pronto para sintetizar e secretar PGF2α, em resposta ao estímulo da oxitocina. A primeira secreção de oxitocina é de origem hipotalâmica, o que desencadeia o primeiro pulso de PGF2α. Os seguintes episódios de PGF2α são induzidos pela oxitocina produzida no corpo lúteo. A PGF2α é secretada em episódios (pulsos) com intervalos de seis a oito horas, sendo necessários cinco a seis episódios para a luteólise ocorrer. Se a PGF2α não seguir este padrão de secreção, a regressão do corpo lúteo falhará. Além da PGF2α de origem uterina, o corpo lúteo também produz PGF2α, que aumenta o efeito luteolítico. A falta de sensibilidade à PGF2α observada nos corpos lúteos imaturos (primeiros cinco dias após a ovulação) deve-se ao fato de, neste período, o corpo lúteo ainda não produzir PGF2α (figura 12, 13 e 14). 6. ETAPAS DO CICLO ESTRAL O ciclo estral é dividido em quatro etapas bem definidas. 6.1 Estro Neste estágio a fêmea aceita a cópula ou a monta de outra vaca. O estro é provocado pelo aumento significativo das concentrações de estradiol produzido pelo folículo pré-ovulatório e pela ausência de um corpo lúteo. A duração desta etapa é de 8 a 18 horas. 6.2 Metaestro O metaestro é a etapa posterior ao estro, tem uma duração de quatro a cinco dias. Durante esta etapa ocorre a ovulação e se desenvolve o corpo de lúteo. Após a ovulação, observa-se uma depressão no lugar ocupado pelo folículo ovulatório (depressão ovulatória) e, posteriormente, se desenvolve o corpo hemorrágico (corpo lúteo em processo de formação). Durante o metaestro, as concentrações de progesterona começam a aumentar até atingirem níveis superiores a 1 ng/ml, momento a partir da qual considera-se que o corpo lúteo atingiu a maturidade. O momento em que as concentrações de progesterona são superiores a 1 ng/ml toma-se como critério fisiológico a determinação do fim do metaestro e o início do diestro. Um evento hormonal que se destaca neste período consiste na apresentação do pico pós-ovulatório de FSH, o qual desencadeia a primeira onda de desenvolvimento folicular. Algumas vacas apresentam sangramento conhecido como sangramento metaestral (figura 15). 6.3 Diestro O diestro é o estágio de maior duração do ciclo estral, de 12 a 14 dias. Durante este estágio o corpo lúteo mantém sua plena funcionalidade, o que se reflete em concentrações sanguíneas de progesterona, maiores que 1 ng/ml. Além disso, nesta fase, pode-se encontrar folículos de tamanho diferente devido às ondas foliculares. Após 12-14 dias de exposição à progesterona, o endométrio começa a secretar PGF2α em um padrão pulsátil, ao qual termina com a vida do corpo lúteo e com o diestro. Em termos endócrinos, quando o corpo lúteo perde a sua funcionalidade, ou seja, quando as concentrações de progesterona diminuem abaixo de 1 ng/ml, finaliza-se o diestro e começa o proestro. Convém mencionar que durante esta fase, a LH é secretada com uma frequência muito baixa e a FSH tem incrementos responsáveis pelas ondas foliculares. 6.4 Proestro O proestro caracteriza-se pela ausência de um corpo lúteo funcional e pelo desenvolvimento e maturação do folículo ovulatório. O proestro na vaca dura de dois a três dias. Um evento hormonal característico desta etapa é o aumento da frequência dos pulsos de secreção de LH que levam à maturação final do folículo ovulatório e ao aumento do estradiol sérico, que desencadeia o estro. Para além da classificação do ciclo estral acima descrita, existe outra que divide o ciclo em duas fases: progestacional (lútea) e estrogênica (folicular). A fase progestacional inclui o metaestro e o diestro, e a fase estrogênica ao proestro e estro (figura 16). Figura 16. Etapas do ciclo estral. Adaptado e elaborado a partir de FERREIRA, 2010. 7. CONCLUSÕES PRÉVIAS  O ciclo estral dura de 19 a 23 dias.  A vaca é receptiva durante 8 a 18 horas (estro).  Ao nascimento uma bezerra tem cerca de 200 mil folículos primordiais.  Durante o ciclo estral se apresentam de duas a três ondas foliculares.  De cinco a seis folículos são recrutados em cada onda folicular.  Cerca de 70% das vacas têm duas ondas foliculares e 30% apresentam três ondas.  Entre 10 e 20% das vacas têm ovulações múltiplas (dois a três folículos) e 8% têm partos gêmeos.  A ovulação ocorre 30 horas após o pico pré-ovulatório de LH.  A secreção pré-ovulatória de LH é de 15 a 30 ng/ml.  12 a 14 dias são necessários para que o endométrio se torne insensível à progesterona e comece a secretar PGF2α. - São necessários cinco a seis pulsos de PGF2α com um intervalo de oito horas para ocasionar a luteólise.  O corpo lúteo não é sensível à PGF2α nos primeiros cinco dias do ciclo estral. 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