I argue that there is methodological space for a functional explanation of the nature of law that does not commit the theorist to a view about the value of that function for society, nor whether law is the best means of accomplishing it. A functional explanation will nonetheless provide a conceptual framework for a better understanding of the nature of law. First I examine the proper role for function in a theory of law and then argue for the possibility of (...) a neutral functional theory, addressing issues raised by Leslie Green, Stephen Perry, Michael Moore and John Finnis. (shrink)

The primary aim of this chapter is to show that several missteps made by others in in their thinking about law as an artefact are due to misconceptions about the role of intentions in understanding law as an artefact. I first briefly recap my own contention that law is a genre of institutionalized abstract artefacts (put forth in The Functions of Law (OUP 2016) and subsequent papers), mostly following Searle’s understanding of institutions and Thomasson’s understanding of public artefacts. I highlight (...) the central place that this theory affords law’s functions, without requiring the theorist to say that possession or performance of the function is either necessary or sufficient for inclusion in the class of law. Some of the most common misunderstandings are exemplified in Brian Leiter’s paper ‘Legal Positivism about the Artifact Law’. He thinks that holding an intentionalist view of artefacts commits the theorist to privileging drafters’ intentions when interpreting law. (It doesn’t.) He also has confusions about the differences between artefact tokens and artefact types leading him to a problematically broad understanding of artefacts. Another problem can be seen in thinking that functional understandings of artefacts are vulnerable to the same problems that arise in functional explanations for biological systems. I go on to consider the work of Luka Burazin and Corrado Roversi, addressing worries that making intentionality central to artefacts implies too much conscious thought is required to make one, noting that several theories of intentionality do not require conscious thought in the execution of intentional action. While those who think a central place for intentionality threatens to leave us unable to explain customary law, this can be dealt with by noting the important distinction between customary rules and customary laws (where the latter requires a decision to enlist public aid in redressing violations). I claim that authors’ intentions are communicated requests for the artefacts’ audiences to see the artefacts as members of their putative kinds. Finally, I address the question of whether or not legal systems are themselves artefacts and institutions, given that they may or may not have been intentionally created. An early lawgiver might have created a legal system by accident in the process of handing down the first laws. I raise the possibility that we might want to impute intentionality to necessary by-products of artefact creation, seeing those by-products as artefacts as well. (shrink)

Wil Waluchow has advanced perhaps the most convincing argument in favour of what he eloquently termed ‘inclusive legal positivism’, the view that a given legal system could make legal validity depend on moral truths. This chapter refocuses the case for the opposing view of exclusive positivism on the metaphysical tension in seeing law as an institutional social fact and yet for its validity to depend on something that is not a social fact, developing an understanding of official mistake as a (...) way of highlighting that tension. If legal validity itself is understood as a socially constructed status (something with which any legal positivist would agree), key officials (as a group) cannot be wrong about the criteria sufficient for institutional membership having been met. While the officials cannot be wrong about the sufficient conditions, they can be wrong about the necessary (gatekeeping) ones and the moral criteria that inclusive positivists say could be included among the criteria of validity are invariably understood to be necessary conditions. That might look like a point in favour of inclusive positivism, but it is only the sufficient conditions that are constitutive of legal validity. Two facets of legal decisions are then marshalled to buttress the case for exclusive positivism: that almost every legal decision is also a determination of validity, and that all such decisions are systemically treated as correct until reviewed by a court of superior jurisdiction (which is itself a sufficient condition for membership). The implication of this is that moral criteria, understood as gatekeepers for legal validity, cannot be constitutive of legal validity. (shrink)

Notions of procedural justice alone are sufficient to support evidentiary exclusions in a wide variety of legal and law-like institutions that focus on conflict resolution, including courts. Special attention is paid to the relevance and need for exclusion of parties’ own assessments of the value of their claims.

I argue that law is not best considered an essentially contested concept. After first explaining the notion of essential contestability and disaggregating the concept of law into several related concepts, I show that the most basic and general concept of law does not fit within the criteria generally offered for essential contestation. I then buttress this claim with the additional explanation that essential contestation is itself a framework for understanding complex concepts and therefore should only be applied when it is (...) useful to gain a greater understanding of uses of the concept to which it is applied (adducing criteria for making such judgments of usefulness). With that in mind, I then show that applying the appellation of essential contestation to the concept of law does not helpfully illuminate the most general concept of law (usually of most interest to legal philosophers) and therefore it should not be used, while allowing that it might be more useful for the related concept of the rule of law. (shrink)

This chapter provides an explanation of precedent as a kind of artefact, in keeping with broader accounts of law that do so, specifically the author’s account of law as a genre of institutionalized abstract artefact. The chapter develops its explanation by responding to an argument by Dan Priel against seeing the common law as an artefact when understood to be a form of custom. The chapter shows that customs can themselves be artefacts but also that the precedential elements of common (...) law are not necessarily quite as customary as sometimes considered, showing that the common law built from precedents fits within a distributed design model of artefacts and that stare decisis has a wider systemic function of upholding certain rule of law principles. It ends with some considerations about the institutional nature of precedents, specifically that judicial decisions are most often both applications and developments of legal norms, but also determinations of legal validity. (shrink)

I examine the impact of the presence of anarchists among key legal officials upon the legal positivist theories of H.L.A. Hart and Joseph Raz. For purposes of this paper, an anarchist is one who believes that the law cannot successfully obligate or create reasons for action beyond prudential reasons, such as avoiding sanction. I show that both versions of positivism require key legal officials to endorse the law in some way, and that if a legal system can continue to exist (...) and function when its key officials reject the reason-giving character of law, then we have a reason to re-examine and amend legal positivism. (shrink)

If medical complicity is understood as compliance with a directive to act against the professional's best medical judgment, the question arises whether it can ever be justified. This paper will trace the contours of what would legitimate a directive to act against a professional's best medical judgment (and in possible contravention of her oath) using Joseph Raz's service conception of authority. The service conception is useful for basing the legitimacy of authoritative directives on the ability of the putative authority to (...) enable subjects to comply better with reasons that already apply to them. Hence, the service conception bases the legitimacy of practical authority on a certain kind of greater knowledge or expertise. This helps to focus the conundrum regarding complicity on the clash of expertise between the medical expert and the governing body tasked with coordinating behaviour and otherwise devising rules for the social good. The ethical dilemma presented by a hypothetically legitimate directive to act against a professional's best medical judgment also serves to highlight the moral dimension of one's duty to obey a legitimate authority. (shrink)

I argue that law is best understood as an institutionalized abstract artifact. Using the ideas of John Searle on institutions and Amie Thomasson on artifacts, I show how the law is capable of generating new reasons for action, arguing against recent work by David Enoch who holds that legal reason-giving is ultimately a form of triggering conditional reasons.

In his 1827 work Rationale of Judicial Evidence, Jeremy Bentham famously argued against exclusionary rules such as hearsay, preferring a policy of “universal admissibility” unless the declarant is easily available. Bentham’s claim that all relevant evidence should be considered with appropriate instructions to fact finders has been particularly influential among judges, culminating in the “principled approach” to hearsay in Canada articulated in R. v. Khelawon. Furthermore, many scholars attack Bentham’s argument only for ignoring the realities of juror bias, admitting universal (...) admissibility would be the best policy for an ideal jury. This article uses the theory of epistemic contextualism to justify the exclusion of otherwise relevant evidence, and even reliable hearsay, on the basis of preventing shifts in the epistemic context. Epistemic contextualism holds that the justification standards of knowledge attributions change according to the contexts in which the attributions are made. Hearsay and other kinds of information the assessment of which rely upon fact finders’ more common epistemic capabilities push the epistemic context of the trial toward one of more relaxed epistemic standards. The exclusion of hearsay helps to maintain a relatively high standards context hitched to the standard of proof for the case and to prevent shifts that threaten to try defendants with inconsistent standards. (shrink)

Scott Shapiro’s theory that law is a social plan is helpful in seeing law essentially as a tool of human creation and as such is sympathetic to understanding law in terms of the social functions it performs, a method I argue for elsewhere. I focus here on two problems with the theory as presented. The planning theory does not adequately explain the persistence of law beyond the utility of those who implement it. Generally, plans can cease to exist as soon (...) as those engaged in them have no more use for them. Laws however, must usually be declared invalid or otherwise nullified for them to have no further effect. Shapiro’s use of self-certification to explain how law is differentiated from other forms of social planning is ad hoc and threatens circularity when he admits it to be a matter of degree. Both of these issues can be better solved by seeing law as an institutionalised abstract artefact, with a greater emphasis upon the nature of institutions doing much of the work done by the idea of planning. (shrink)

Joseph Raz argues that legal authority includes a claim by the law to replace subjects’ contrary reasons. I reply that this cannot be squared with the existence of choice-of-evils defenses to criminal prosecutions, nor with the view that the law has gaps (which Raz shares). If the function of authority is to get individuals to comply better with reason than they would do if left to their own devices, it would not make sense for law to claim both to pre-empt (...) our contrary reasons and to leave open spaces or catch-all exceptions which we must use our own devices to fill. (shrink)

Economic success in competitive systems requires resource redistribution to those who fail. Once we recognize that success in competitive endeavors depends meaningfully on the failure of others, policy implications that involve strong redistributive mechanisms should be drawn. Particular attention is paid to the role of education in fostering a sense of self-esteem necessary to counter the effects of internalized competition.

The Adverse Outcome Pathway (AOP) concept is a knowledge assembly and communication tool to facilitate the transparent translation of mechanistic information into outcomes meaningful to the regulatory assessment of chemicals. The AOP framework and associated knowledgebases (KBs) have received significant attention and use in the regulatory toxicology community. However, it is increasingly apparent that the potential stakeholder community for the AOP concept and AOP KBs is broader than scientists and regulators directly involved in chemical safety assessment. In this paper we (...) identify and describe those stakeholders who currently—or in the future—could benefit from the application of the AOP framework and knowledge to specific problems. We also summarize the challenges faced in implementing pathway-based approaches such as the AOP framework in biological sciences, and provide a series of recommendations to meet critical needs to ensure further progression of the framework as a useful, sustainable and dependable tool supporting assessments of both human health and the environment. Although the AOP concept has the potential to significantly impact the organization and interpretation of biological information in a variety of disciplines/applications, this promise can only be fully realized through the active engagement of, and input from multiple stakeholders, requiring multi-pronged substantive long-term planning and strategies. (shrink)

Since the publication of Kenneth Howard’s 2017 article, “The Religion Singularity: A Demographic Crisis Destabilizing and Transforming Institutional Christianity,” there has been an increasing demand to understand the root causes and historical foundations for why institutional Christianity is in a state of de-institutionalization. In response to Howard’s research, a number of authors have sought to provide a contextual explanation for why the religion singularity is currently happening, including studies in epistemology, church history, psychology, anthropology, and church ministry. The purpose (...) of this article is to offer a brief survey and response to these interactions with Howard’s research, identifying the overall implications of each researcher’s perspective for understanding the religion singularity phenomenon. It explores factors relating to denominational switching in Jeshua Branch’s research, social memory in John Lingelbach’s essay, religious politics in Kevin Seybold’s survey, scientific reductionism in Jack David Eller’s position paper, and institutional moral failure in Brian McLaren’s article. (shrink)

To improve oneself and grow professionally, career development has been found to be crucial, as it serves as a roadmap for the professional growth of employees. However, a barrier, known as the glass ceiling, hinders the progress of employees, especially those in the LGBTQIA+ community. This study explores the impact of the glass ceiling on the career development of selected LGBTQIA+ individuals, shedding light on the barriers faced by this community in the workplace. The researchers used a qualitative multiple-case study (...) and selected ten (10) LGBTQIA+ participants from large enterprises via the judgmental sampling technique. Through thematic analysis, psychological impact, workplace discomfort, lack of recognition, and career progress challenges emerged as the impacts of the glass ceiling on the participants. Strategies for overcoming glass ceiling barriers, such as resilience, self-reflection, and community support, are identified. Thus, the study found that glass ceilings are really evident in the context of businesses. With this, the proposed advocacy plan in the study suggests interventions like workplace inclusion training, mentorship networks, and seminars on employee rights. Furthermore, it emphasizes the call for ongoing research and advocacy efforts to dismantle barriers and cultivate workplaces that not only embrace diversity but also provide equitable opportunities for career growth. (shrink)

This paper explores the logical consequences of the the thesis that all of the essential properties of consciousness can be known introspectively (Completeness, called "Strong Transparency" in the paper, following D.M. Armstrong's older terminology). It is argued that it can be known introspectively that consciousness does not have complete access to its essential properties; and it is show how this undermines conceivability arguments for dualism.

In this essay, we consider the formal and ontological implications of one specific and intensely contested dialectical context from which Deleuze’s thinking about structural ideal genesis visibly arises. This is the formal/ontological dualism between the principles, ἀρχαί, of the One (ἕν) and the Indefinite/Unlimited Dyad (ἀόριστος δυάς), which is arguably the culminating achievement of the later Plato’s development of a mathematical dialectic.3 Following commentators including Lautman, Oskar Becker, and Kenneth M. Sayre, we argue that the duality of the One (...) and the Indefinite Dyad provides, in the later Plato, a unitary theoretical formalism accounting, by means of an iterated mixing without synthesis, for the structural origin and genesis of both supersensible Ideas and the sensible particulars which participate in them. As these commentators also argue, this duality furthermore provides a maximally general answer to the problem of temporal becoming that runs through Plato’s corpus: that of the relationship of the flux of sensory experiences to the fixity and order of what is thinkable in itself. Additionally, it provides a basis for understanding some of the famously puzzling claims about forms, numbers, and the principled genesis of both attributed to Plato by Aristotle in the Metaphysics, and plausibly underlies the late Plato’s deep considerations of the structural paradoxes of temporal change and becoming in the Parmenides, the Sophist, and the Philebus. After extracting this structure of duality and developing some of its formal, ontological, and metalogical features, we consider some of its specific implications for a thinking of time and ideality that follows Deleuze in a formally unitary genetic understanding of structural difference. These implications of Plato’s duality include not only those of the constitution of specific theoretical domains and problematics, but also implicate the reflexive problematic of the ideal determinants of the form of a unitary theory as such. We argue that the consequences of the underlying duality on the level of content are ultimately such as to raise, on the level of form, the broader reflexive problem of the basis for its own formal or meta-theoretical employment. We conclude by arguing for the decisive and substantive presence of a proper “Platonism” of the Idea in Deleuze, and weighing the potential for a substantive recuperation of Plato’s duality in the context of a dialectical affirmation of what Deleuze recognizes as the “only” ontological proposition that has ever been uttered. This is the proposition of the univocity of Being, whereby “being is said in the same sense, everywhere and always,” but is said (both problematically and decisively) of difference itself. (shrink)

This forum contribution addresses two major themes in de Goede’s original essay on ‘Financial security’: (1) the relationship between stable markets and the proverbial ‘security dilemma’; and (2) the development of new decision-technologies to address risk in the post-World War II period. Its argument is that the confluence of these two themes through rational choice theory represents a fundamental re-evaluation of the security dilemma and its relationship to the rule of law governing market relations, ushering in an era of perpetual (...) physical and financial insecurity. (shrink)

This review essay of Economics Rules situates Dani Rodrik’s contribution with respect to the 2007–2008 global economic crisis. This financial meltdown, which the eurozone did not fully recover from before the Covid-19 pandemic, led to soul- searching among economists as well as a call for heterodox economic approaches. Yet, over the past decade, instead the economics profession has maintained its orthodoxy. Rodrik’s Economics Rules offers a critique of the economics profession that is castigating but mild. It calls for economists to (...) use more and diverse models without becoming wedded to any single model or an overarching vision. Yet Rodrik ratifies many of the benchmark models standard to orthodox economics and provides little ground for a fundamental rethinking of the discipline. This essay analyses the conservatism underlying Rodrik’s approach, which upholds general equilibrium theory and rational expectations underlying the efficient market hypothesis. It argues that the economics discipline’s scope-creep to maintain its applicability to all human decision-making, and its acceptance of all-inclusive utility functions, crowds out moral sentiments and civic virtue. Thus. it argues that rather than urging economists simply to be more cautious in their application of models to address particular social concerns, instead economists must recognise their discipline’s inherent limitations. (shrink)

În acest articol încerc să argumentez opinia că, așa cum este definită eugenia, este foarte dificil de făcut o diferențiere clară între știință (medicină, ingineria genetică) și eugenie. Și de stabilit o linie peste care ingineria genetică nu ar trebui să treacă, conform unor norme morale, juridice și religioase. Atâta timp cât acceptăm ajutorul geneticii în găsirea unor modalități de combatere a cancerului, diabetului sau HIV, acceptăm în mod implicit și eugenia pozitivă, conform definiției actuale. Și atâta timp cât acceptăm (...) screening-ul genetic, și intervenții asupra fătului nenăscut, sau avortul, acceptăm în mod implicit și eugenia negativă. În plus, la nivel de guverne, deși oficial eugenia este repudiată, ea a fost legalizată în foarte multe țări până de curând, și încă mai este acceptată și legalizată, chiar dacă în forme mai subtile, și în prezent. În Introducere definesc termenul și modurile de clasificare. Urmează Istoria eugeniei pornind din perioada antică, introducerea eugeniei de Francis Galton, practica eugeniei ca politică de stat în diverse țări, și eugenia actuală (eugenia liberală). Analizez apoi diverse probleme ridicate de Etica eugeniei liberale, și am dezvoltat o secțiune aparte pentru Viitorul eugeniei, cu accent pe proiectul genomului uman. În final, în secțiunea Concluzii expun opiniile personale cu privire la practica actuală a eugeniei. Am folosit ca surse principale de investigație articolele lui Kenneth M. Ludmerer, ”American Geneticists and the Eugenics Movement: 1905-1935”, Kathy J. Cooke, ”Duty or Dream? Edwin G. Conklin's Critique of Eugenics and Support for American Individualism”, Jonathan Anomaly, ”Defending Eugenics”, John R. Harding Jr. ”Beyond Abortion: Human Genetics and the New Eugenics”, Michael Boulter, ”Bloomsbury Scientists”, Chapter Title: The rise of eugenics, 1901–14, Michael Ruse and Edward O. Wilson, ”Moral Philosophy as Applied Science” și Goering, Sara, "Eugenics". (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Journal of the History of Philosophy 41.3 (2003) 417-418 [Access article in PDF] Heidi M. Ravven and Lenn E. Goodman, editors. Jewish Themes in Spinoza's Philosophy. Albany: The State University of New York Press, 2002. Pp. ix + 290. Cloth, $78.50. Paper, $26.95.The current anthology presents an important contribution to the study of Spinoza's relation to Jewish philosophy as well as to contemporary scholarship of Spinoza's metaphysics and political (...) theory.In the opening essay, Lenn Goodman takes upon himself the ambitious task of evaluating Spinoza's positions as to several central disputes throughout the history of philosophy. In this rich and extensive essay Goodman argues that Spinoza's radical rationalism makes him pursue syntheses between traditionally opposed poles. Lee Rice's article, "Love of God in Spinoza," carefully analyzes Spinoza's concept of love and suggests the existence of three kinds of love parallel to the three kinds of knowledge. Warren Montag addresses the unresolved issue of Spinoza's relation to the Kabbalah. Montag sides with Deleuze against the association of Spinozism with the Neo-Platonic theory of emanation, arguing that unlike the Neo-Platonists and Kabbalists, Spinoza's view of God rules out any hierarchy, and does not assume a descent from primal simplicity into complexity. Edwin Curley contributes a beautiful reading of the story of Job and of Maimonides' interpretation of the story. Curley follows Maimonides' discussion of the various positions regarding the question of divine providence and his attempt to identify the speeches of the characters of the book of Job with each of these positions. Following a sensitive consideration of various attempts to [End Page 417] recover Maimonides' own rather concealed view about providence, Curley concludes that "[W]hatever you think Maimonides' final word on Job is, our examination of him certainly supports [Spinoza's] claim that [Maimonides] reads Scripture in terms of Platonic or Aristotelian speculations" (170).Warren Zev Harvey's essay addresses Spinoza's most neglected work, the Compendium of the Grammar of the Hebrew Language. Apart from providing an outline of Spinoza's work as a Hebrew grammarian ("a noun-intoxicated grammarian") and pointing out some of Spinoza's more eccentric views about the nature of the Hebrew language, Harvey makes a compelling case for the importance of the book for the study of Spinoza's metaphysics. He points out a fascinating analogy which Spinoza draws between the parts of speech: (proper) noun, adjectives, and participles, and Spinoza's key metaphysical terms: substance, attributes, and modes. (Think about the weighty implications of this analogy for Curley's interpretation of the substance-mode relation.) According to Harvey, Spinoza's claim that all Hebrew words are derived from nouns is a linguistic parallel to Spinoza's pivotal metaphysical doctrine which makes all things be in the substance (or God). Kenneth Seeskin's article discusses the views of Maimonides and Spinoza on the question of creation and God's relation to the world. Seeskin reconstructs an interesting critical dialogue between these two philosophers. According to Seeskin, both philosophers held that an effect must be similar to its cause. Maimonides' commitment to Negative Theology and to the denial of any common measure between God and finite things forced him to deny causal or explanatory relation between God and the world. What Maimonides can suggest instead is rather to prove that the emergence of the world ex nihilo and according to the divine will, is possible, and even likely given certain astronomical facts of medieval science. Thus, Maimonides would hold that "although we have grounds for believing that creation occurred, we will never be in a position to say how" (120). For Spinoza, such a view constitutes nothing but a "sanctuary of ignorance." Thus, according to Seeskin, Spinoza affirms a clear causal relation between God and the world of finite things insofar as God is said to explain the world. While I tend to agree with most aspects of this analysis, it is important to note that Spinoza also claims that "between the finite and infinite there is no relation" (Letter 54). This... (shrink)

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

contents -/- ONT vol 1 i. short review: Beyond the Black Rainbow ii. as you die, hold one thought iii. short review: LA JETÉE -/- ONT vol 2 i. maya means ii. short review: SANS SOLEIL iii. vocab iv. eros has an underside v. short review: In the Mood for Love -/- ONT vol 3 i. weed weakens / compels me ii. an Ender's Game after-party iii. playroom is a realm of the dead iv. a precise german History v. short (...) review: STATUES ALSO DIE vi. Kenneth Clark, curator for Fascism vii. a protest poem, in industry lit viii. Lawrence and the English Romance -/- ONT vol 4 i. short review: The Eyes of Tammy Faye ii. vR is efficient R iii. all thru Asia, robes for monks iv. same of God, and of the one God sent v. i thought of the Messiah / muse would be vi. conscience is strong vii. a monk's exalted end -/- ONT vol 5 -/- i. for Shakespeare's Richard the Third ii. the truth is i pass over so many words iii. the boori nazar / nadhar iv. i've awe for jihaad v. short review: Hail, Caesar! vi. a minute of Nothing, gone from YouTube vii. we were rivalrous friends, again viii. my bardo pdf ix. within i'm a weak old mandarin -/- ONT vol 6 i. short review: The Intern ii. the confusion of Chinatown iii. we'll remember water, in Theology iv. Respironics versus ResMed v. i'd bet my life for what vi. the Mad Max deity vii. they'd kill my rat, not heal him -/- ONT vol 7 i. Austen would eroticize all life ii. Merchant/Ivory, a name oddly right iii. Ellie Arroway / Agent Starling iv. abattoir / l’abattoir / laboratoire v. von Neumann's brain an anomaly vi. was terrified of death, delighted in the a-bomb vii. the Greatest Brain is variously named -/- ONT vol 8 i. the day they shot the sacrifice ii. Yay or Nay, on Animal Testing iii. an ought is an is / an is is an ought iv. Behaviorism is for zombies v. a finding from the neuro-lab, on empathy vi. i’ve never had discernible abs vii. a cowardice i'm assenting to perpetually -/- ONT vol 9 i. Day of the Locust / Triffids ii. we're wide on a Paramount soundstage iii. HOLLYWOOD, an ecologic history iv. yet one more site of end-time art v. he's "a bookworm with bulging lobes" vi. apartment is my state of being apart vii. enlightenment means a weight's release -/- ONT lates and xtras i. re Gödel's ontological argument ii. deep in pi's numeric noise iii. from Nothing, something iv. endless in the wrong direction, tragic v. they give you all Eternity to answer vi. what of God's mercy? vii. informed consent and prayer viii. i won't live on. a deed i've done may ix. my selective memory x. Janus means: in close-up foam, two faces xi. a liveable world is a readable world xii. what Supervenes from this? xiii. at each extreme our naming is anachronism xiv. Cat is a collapsing of the wave-function xv. diminishing returns in the history of Experiment xvi. all those undershared Nobels xvii. ice preserves the Cold from heat xviii. a desert spreads xix. Pinker's wit, on jokes xx. Rome surrounds St. Paul / Paul is now the center xxi. each is a gathering Ministry xxii. white boy shot execution-style xxiii. the McDonald's Statement of Claim xxiv. first & last: Don Quixote / Ulysses xxv. The Summer of Rave xxvi. this electro is intrinsically anonymous xxvii. all thru Asia, Drake-Rihanna xxviii. WHO IS BETTER: PLATON OR KANT? (shrink)

There is no doubt that custard apple diseases are among the important reasons that destroy the Custard Apple plant and its agricultural crops. This leads to obvious damage to these plants and they become inedible. Discovering these diseases is a good step to provide the appropriate and correct treatment. Determining the treatment with high accuracy depends on the method used to correctly diagnose the disease, expert systems can greatly help in avoiding damage to these plants. The expert system correctly diagnoses (...) Custard Apple disease to make it easier for farmers to find the right treatment based on the appropriate diagnosis. Objectives: A specialized syllable language system was established for the diagnosis of Custard Apple plant disease. (shrink)

The study aimed to identify the relationship between correcting the deviations in the measurement of performance and achieving the objectives of control and the performance of the job at the Islamic University in the Gaza Strip. To achieve the objectives of the research, the researchers used the descriptive analytical approach to collect information. The questionnaire consisted of (20) statements distributed to three categories of employees of the Islamic University (senior management, faculty members, their assistants and members of the administrative board). (...) A random sample of 314 employees was selected and 276 responses were retrieved with a recovery rate of 88.1%. The Statistical Analysis Program (SPSS) was used to enter, process, and analyze the data. The results of the study showed a positive relationship between correcting deviations in performance measurement and achieving the control objectives represented by the functional performance in the Islamic University from the point of view of the members (senior management, faculty and their assistants, and the administrative board), where the relative weight of all the paragraphs was (74.25%). The study recommended the need to ensure that the actual performance of the planned performance is matched and decisions are taken to correct the serious deviations and take the necessary measures in terms of retraining and change in regulations, wages and bonuses and punishment of the culprit, neglect and negligence by mistake. (shrink)

The study aims to identify the efficiency of the university education performance from the perspective of postgraduate and undergraduate students in international and Palestinian universities. The analytical descriptive approach was used for this purpose and the questionnaire was used as a main tool for data collection. The study community consists of: post graduate students, (23850) graduate students and (146355) undergraduate students. The sample of the study was 378 graduate students and 383 undergraduate students. The random stratified sample was used. The (...) Statistical Package of Social Sciences (SPSS) was also used for data analysis. The study reached a number of results, the most important of which are: The level of efficiency of educational performance in Palestinian and international universities from the point of view of postgraduate and undergraduate students was high. And that there are significant differences between the average views of the sample of the study on the efficiency of educational performance in Palestinian and international universities attributed to the University and to the benefit of international universities. The study concluded many recommendations, the most important of which is the necessity of continuing to develop e-learning strategies that affect the efficiency of educational performance and research commensurate with the university's position in the local and international community, which puts it on the best classification between local and international universities through e-learning. (shrink)

Foundational ontologies, central constructs in ontological investigations and engineering alike, are based on ontological categories. Firstly proposed by Aristotle as the very ur- elements from which the whole of reality can be derived, they are not easy to identify, let alone partition and/or hierarchize; in particular, the question of their number poses serious challenges. The late medieval philosopher Dietrich of Freiberg wrote around 1286 a tutorial that can help us today with this exceedingly difficult task. In this paper, I discuss (...) ontological categories and their importance for foundational ontologies from both the contemporary perspective and the original Aristotelian viewpoint, I provide the translation from the Latin into English of Dietrich's De origine II with an introductory elaboration, and I extract a foundational ontology–that is in fact a single-category one–from this text rooted in Dietrich's specification of types of subjecthood and his conception of intentionality as causal operation. (shrink)

Ontologies are some of the most central constructs in today's large plethora of knowledge technologies, namely in the context of the semantic web. As their coinage indicates, they are direct heirs to the ontological investigations in the long Western philosophical tradition, but it is not easy to make bridges between them. Contemporary ontological commitments often take causality as a central aspect for the ur-segregation of entities, especially in scientific upper ontologies; theories of causality and philosophical ontological investigations often go hand-in-hand, (...) and were essentially inseparable in medieval thought. This constitutes the foundation for a bridge, and this article analyzes the causality-based ontology of the late medieval philosopher Dietrich of Freiberg from the viewpoint of today's upper-ontology engineering. In this bridging attempt, it offers a translation into English of the first part of Dietrich's De origine (abbreviated title) that is a compromise between traditional scholarly translations of medieval Latin philosophical texts and contemporary ontology. (shrink)

Artificial intelligence (AI) is an area of computer science that emphasizes the creation of intelligent machines or software that work and react like humans. Some of the activities computers with artificial intelligence are designed for include, Speech, recognition, Learning, Planning and Problem solving. Deep learning is a collection of algorithms used in machine learning, It is part of a broad family of methods used for machine learning that are based on learning representations of data. Deep learning is a technique used (...) to produce Pneumonia detection and classification models using x-ray imaging for rapid and easy detection and identification of pneumonia. In this thesis, we review ways and mechanisms to use deep learning techniques to produce a model for Pneumonia detection. The goal is find a good and effective way to detect pneumonia based on X-rays to help the chest doctor in decision-making easily and accuracy and speed. The model will be designed and implemented, including both Dataset of image and Pneumonia detection through the use of Deep learning algorithms based on neural networks. The test and evaluation will be applied to a range of chest x-ray images and the results will be presented in detail and discussed. This thesis uses deep learning to detect pneumonia and its classification. (shrink)

The van Wijngaarden grammars are two-level grammars that present many interesting properties. In the present article I elaborate on six of these properties, to wit, (i) their being constituted by two grammars, (ii) their ability to generate (possibly infinitely many) strict languages and their own metalanguage, (iii) their context-sensitivity, (iv) their high descriptive power, (v) their productivity, or the ability to generate an infinite number of production rules, and (vi) their equivalence with the unrestricted, or Type-0, Chomsky grammars.

Abstract: Smoke detectors are critical devices for early fire detection and life-saving interventions. This research paper explores the application of Artificial Neural Networks (ANNs) in smoke detection systems. The study aims to develop a robust and accurate smoke detection model using ANNs. Surprisingly, the results indicate a 100% accuracy rate, suggesting promising potential for ANNs in enhancing smoke detection technology. However, this paper acknowledges the need for a comprehensive evaluation beyond accuracy. It discusses potential challenges, such as overfitting, dataset size, (...) and class imbalance, and presents strategies employed to address these issues. Additionally, the paper emphasizes the importance of alternative evaluation metrics, including precision, recall, and F1-score, to assess the model's performance comprehensively. Detailed information regarding the model architecture, data preprocessing, and hyperparameter tuning is provided to enhance the reproducibility of the research. The study also discusses ethical considerations and the implications of false positives and false negatives in smoke detection applications. While achieving 100% accuracy is a notable accomplishment, this paper calls for cautious interpretation and further validation in real-world settings. It concludes by highlighting areas for future research and improvement in smoke detection technology, emphasizing the need for practical deployment and the reduction of false alarms. (shrink)

I argue that an individual has aspects numerically identical with it and each other that nonetheless qualitatively differ from it and each other. This discernibility of identicals does not violate Leibniz's Law, however, which concerns only individuals and is silent about their aspects. They are not in its domain of quantification. To argue that there are aspects I will appeal to the internal conflicts of conscious beings. I do not mean to imply that aspects are confined to such cases, but (...) the best way to start is to recognize them experientially. We can feel the conflicts within ourselves. In doing so we can feel some of our aspects. I will try to enhance our understanding of the concept of aspect by listing and formalizing some principles for its use. After that I will argue that all sorts of individual things have aspects, not just people who are conflicted. (shrink)

For millennia, knowledge has eluded a precise definition. The industrialization of knowledge (IoK) and the associated proliferation of the so-called knowledge communities in the last few decades caused this state of affairs to deteriorate, namely by creating a trio composed of data, knowledge, and information (DIK) that is not unlike the aporia of the trinity in philosophy. This calls for a general theory of knowledge (ToK) that can work as a foundation for a science of knowledge (SoK) and additionally distinguishes (...) knowledge from both data and information. In this paper, I attempt to sketch this generality via the establishing of both knowledge structures and knowledge systems that can then be adopted/adapted by the diverse communities for the respective knowledge technologies and practices. This is achieved by means of a formal–indeed, mathematical–approach to epistemological matters a.k.a. formal epistemology. The corresponding application focus is on knowledge systems implementable as computer programs. (shrink)

There is more than one way to say that composition is identity. Yi has distinguished the Weak Composition thesis from the Strong Composition thesis and attributed the former to David Lewis while noting that Lewis associates something like the latter with me. Weak Composition is the thesis that the relation between the parts collectively and their whole is closely analogous to identity. Strong Composition is the thesis that the relation between the parts collectively and their whole is identity. Yi is (...) right that Strong Composition does not fully reflect my view. We must recognize further what, borrowing Lewis's characterization, could be called the "stronger, and stranger" Composition thesis, or what I'll call the Stronger Composition thesis for short. On Strong Composition, it is only collectively that the parts are identical with the whole. On Stronger Composition, they are individually identical with it as well. I will explain and motivate this thesis. (shrink)

Deep learning may transform health care, but model development has largely been dependent on availability of advanced technical expertise. The aim of this study is to develop a deep learning model to predict the gender from retinal fundus images. The proposed model was based on the Xception pre-trained model. The proposed model was trained on 20,000 retinal fundus images from Kaggle depository. The dataset was preprocessed them split into three datasets (training, validation, Testing). After training and cross-validating the proposed model, (...) it was evaluated using the testing dataset. The result of testing, the area under receiver operating characteristic curve (AUROC) of the model was 0.99, precision, recall, f1-score and accuracy were 99%, precision, recall, f1-score and accuracy were 96.83%, 96.83%, 96.82% and 96.83% respectively.. Clinicians are presently unaware of dissimilar retinal feature variants between females and males, stressing the importance of model explain ability for the prediction of gender from retinal fundus images. The proposed deep learning may enable clinician-driven automated discovery of novel visions and disease biomarkers. (shrink)

Is capitalism inherently predatory? Must there be winners and losers? Is public interest outdated and free-riding rational? Is consumer choice the same as self-determination? Must bargainers abandon the no-harm principle? Prisoners of Reason recalls that classical liberal capitalism exalted the no-harm principle. Although imperfect and exclusionary, modern liberalism recognized individual human dignity alongside individuals' responsibility to respect others. Neoliberalism, by contrast, views life as ceaseless struggle. Agents vie for scarce resources in antagonistic competition in which every individual seeks dominance. This (...) political theory is codified in non-cooperative game theory; the neoliberal citizen and consumer is the strategic rational actor. Rational choice justifies ends irrespective of means. Money becomes the medium of all value. Solidarity and good will are invalidated. Relationships are conducted on a quid pro quo basis. However, agents can freely opt out of this cynical race to the bottom by embracing a more expansive range of coherent action. (shrink)

How is it possible for David Hume to be both withering skeptic and constructive theorist? I recommend an answer like the Pyrrhonian answer to the question how it is possible to suspend all judgment yet engage in active daily life. Sextus Empiricus distinguishes two kinds of assent: one suspended across the board and one involved with daily living. The first is an act of will based on appreciation of reasons; the second is a causal effect of appearances. Hume makes the (...) same distinction, only he extends the sort of assent involved in daily life to theoretical matters as well. He is a skeptic both in finding no reason to grant the first sort of assent and in being subject to the second. (shrink)

Abstract: Artificial Intelligence (AI) is transforming the agricultural sector, enhancing both productivity and sustainability. This paper delves into the impact of AI technologies on agriculture, emphasizing their application in precision farming, predictive analytics, and automation. AI-driven tools facilitate more efficient crop and resource management, leading to higher yields and a reduced environmental footprint. The paper explores key AI technologies, such as machine learning algorithms for crop monitoring, robotics for automated planting and harvesting, and data analytics for optimizing resource use. Additionally, (...) it discusses challenges like data privacy, barriers to technology adoption, and the ethical implications of AI in farming. Integrating AI into agricultural practices holds the promise of greater efficiency and sustainability, paving the way for future innovations. (shrink)

3rd ed, 2021. A circumscription of the classical theory of computation building up from the Chomsky hierarchy. With the usual topics in formal language and automata theory.

ABSTRACT According to David Lewis, alteration is "qualitative difference between temporal parts of something." It follows that moments, since they are simple and lack temporal parts, cannot alter from future to present to past. Here then is another way to put McTaggart's paradox about change in tense. I will appeal to my theory of Aspects to rebut the thought behind this rendition of McTaggart. On my theory, it is possible that qualitatively differing things be numerically identical. I call these differing, (...) numerically identical things "aspects." I will argue that alteration can be a qualitative difference between temporal aspects of something that lacks temporal parts. So a moment can alter in tense. By rejecting Lewis's assumption my theory can solve this version of McTaggart's paradox. (shrink)

Confucius gave counsel that is notoriously hard to follow: "What you do not wish for yourself, do not impose on others" (Huang 1997: 15.24). People tend to be concerned with themselves and to be indifferent to most others. We are distinct from others so our self-concern does not include them, or so it seems. Were we to realize this distinctness is merely apparent--that our true self includes others--Confucius's counsel would be easier to follow. Concern for our true self would extend (...) concern beyond the narrow selves we appear to be. The neo-Confucians held just such a view. They espoused an identity with the universe and everything in it, arguing that this identity explains a natural concern for everyone and everything, not just for our narrow selves. However, many things in the universe differ from each other, that is, some have qualities others lack. If they are all one and the same thing then that one thing differs from itself. I will suggest that the objection can be answered with some metaphysical innovation. I will address the objection by sketching a theory--call it the theory of aspects--that explains how numerically identical things can differ qualitatively. (shrink)

Not focusing on the history of classical logic, this book provides discussions and quotes central passages on its origins and development, namely from a philosophical perspective. Not being a book in mathematical logic, it takes formal logic from an essentially mathematical perspective. Biased towards a computational approach, with SAT and VAL as its backbone, this is an introduction to logic that covers essential aspects of the three branches of logic, to wit, philosophical, mathematical, and computational.

In this article I propose an original view of the nature of shared intention. In contrast to psychological views (Bratman, Searle, Tuomela) and normative views (Gilbert), I argue that both functional roles played by attitudes of individual participants and interpersonal obligations are factors of central and independent significance for explaining what shared intention is. It is widely agreed that shared intention (I) normally motivates participants to act, and (II) normally creates obligations between them. I argue that the view I propose (...) can explain why it is not a mere accident that both (I) and (II) are true of shared intention, while psychological and normative views cannot. The basic idea is that shared intention involves a structure of attitudes of individuals –including, most importantly, attitudes of reliance – which normally plays the relevant motivating roles and creates the relevant obligations. (shrink)

A. Newell and H. A. Simon were two of the most influential scientists in the emerging field of artificial intelligence (AI) in the late 1950s through to the early 1990s. This paper reviews their crucial contribution to this field, namely to symbolic AI. This contribution was constituted mostly by their quest for the implementation of general intelligence and (commonsense) knowledge in artificial thinking or reasoning artifacts, a project they shared with many other scientists but that in their case was theoretically (...) based on the idiosyncratic notions of symbol systems and the representational abilities they give rise to, in particular with respect to knowledge. While focusing on the period 1956-1982, this review cites both earlier and later literature and it attempts to make visible their potential relevance to today's greatest unifying AI challenge, to wit, the design of wholly autonomous artificial agents (a.k.a. robots) that are not only rational and ethical, but also self-conscious. (shrink)

We often appeal to the notion of an agent’s commitment to action to characterize, e.g., an agent’s faithfulness to a promise she has given to another, her robust disposition to pursue a goal she values or cares about, and her determination to stick to that goal. In the philosophy of action, that notion is often associated with the idea of an agent’s intention to act. In ethics, it is associated primarily with the idea of an agent’s commitment to, or endorsement (...) of, a certain norm. This essay argues that both these ideas, of intention and of normative endorsement, are central to the –or, at least, an—ordinary notion of an agent’s (psychological) commitment to action. In so doing, the essay also sheds light on important features of intention. -/- Keywords: commitment – intention – normative endorsement – stability across contexts – coordination. (shrink)

Philosophers of action of different persuasions have suggested that there is a tight connection between the phenomenon of intending and the phenomena of “being settled on” and of “settling” a course of action. For many, this connection supports an important constraint on intention: one may only intend what one takes one’s so intending as settling. Traditionally, this has been understood as a doxastic constraint on intention: what one takes one’s intention as settling is what one believes one’s so intending as (...) settling. This paper proposes an alternative conception of such a constraint. The idea is to conceive of it in terms of the attitude of reliance, rather than of belief. The aim of the paper is three-fold: to clarify the connection between intending to act and the phenomena of being settled on and of settling a course of action, to provide support for the reliance conception of the cited constraint, and to show that this conception drives a wedge in the familiar dispute, between doxastic and conative accounts of intention, as to whether intending to act necessarily involves the belief that one will so act. (shrink)

Genera, typically hand-in-hand with their branching species, are essential elements of vocabulary-based information constructs, in particular scientific taxonomies. Should they also feature in formal ontologies, the highest of such constructs? I argue in this article that the answer is “Yes” and that the question posed in its title also has a Yes-answer: The way medieval ontologists sliced up the world into genera does matter to formal ontology. More specifically, the way Dietrich of Freiberg, a Latin scholastic, conceived and applied strictly (...) generic criteria to slice up the world into its entities can provide some guidelines to the field of formal ontology with respect to not only its contents, but also its scope. In particular, Dietrich's information criterion plays here a central role. (shrink)