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. Londres: Cambridge University Press, 1972. BRONSON, Franklin H. Mammalian reproductive biology. Chicago: University of Chicago Press, 1989. BUEHR, Mia. The primordial germ cells of mammals: some current perspectives. Experimental cell research, v. 232, n. 2, p. 194-207, 1997. BYSKOV, Anne G. Differentiation of mammalian embryonic gonad. Physiological reviews, v. 66, n. 1, p. 71-117, 1986. CAPEL, Blanche et al. Migration of mesonephric cells into the mammalian gonad depends on Sry. Mechanisms of development, v. 84, n. 1-2, p. 127-131, 1999. CAPEL, Blanche. The battle of the sexes. Mechanisms of development, v. 92, n. 1, p. 89-103, 2000. DERIVAUX, Jules; BARNABÉ, Renato Campanarut. Reprodução dos animais domésticos. Zaragoza: Acribia, 1980. DOMENICE, Sorahia et al. Aspectos moleculares da determinação e diferenciação sexual. Arquivos Brasileiros de Endocrinologia & Metabologia, v. 46, n. 4, p. 433-443, 2002. DONAHOE, Patricia K. et al. Mullerian inhibiting substance activity in bovine fetal, newborn and prepubertal testes. Biology of reproduction, v. 16, n. 2, p. 238-243, 1977. HAFEZ, Elsayed Saad Eldin; HAFEZ, B. Reprodução animal. São Paulo: Manole, 2004. HANLEY, Neil A. et al. Steroidogenic factor 1 (SF-1) is essential for ovarian development and function. Molecular and cellular endocrinology, v. 163, n. 1-2, p. 27-32, 2000. HIORT, Olaf; PAUL-MARTIN, H. The molecular basis of male sexual differentiation. European journal of endocrinology, v. 142, n. 2, p. 101-110, 2000. HOLY, Lubos; MARTÍNEZ JÚSTIZ, G. Colab. Biología de la reproducción bovina. Havana: Revolucionária, 1975. JOSSO, Nathalie et al. The role of anti-Müllerian hormone in gonadal development. Molecular and cellular endocrinology, v. 145, n. 1-2, p. 3-7, 1998. JOST, Alfred et al. Studies on sex differentiation in mammals. In: Proceedings of the 1972 Laurentian Hormone Conference. Londres: Academic Press, 1973. p. 1-41. KNOBIL, Ernst. Knobil and Neill's physiology of reproduction. EUA: Gulf Professional Publishing, 2006. KOFMAN ALFARO, S.; MERCHANT LARIOS, H.; PEREZ PALACIOS, G. Diferenciacion sexual. I. Bases biologicas del dimorfismo sexual. Rev. invest. clín, p. 349-59, 1982. KOOPMAN, Peter. Sry and Sox9: mammalian testis-determining genes. Cellular and Molecular Life Sciences CMLS, v. 55, n. 6-7, p. 839-856, 1999. MCDONALD, L. E. Veterinary endocrinology. Lea & Febiger, Philadelphia, Pa, 1969. MEIZEL, S.; JOHNSON, M. H. Development in mammals. MH Johnson, Ed, v. 3, p. 1-64, 1978. MELLO, Maricilda Palandi de; ASSUMPÇÃO, Juliana de G.; HACKEL, Christine. Genes envolvidos na determinação e diferenciação do sexo. Arquivos Brasileiros de Endocrinologia & Metabologia, v. 49, n. 1, p. 14-25, 2005. -/- REFERÊNCIAS BIBLIOGRÁFICAS MERCHANT-LARIOS, H. Ovarian differentiation. The Vertebrate Ovary, p. 47-81, 1978. MIES FILHO, Antonio. Reprodução dos animais. Porto Alegre: Sulina, 1987. NEF, Serge; PARADA, Luis F. Hormones in male sexual development. Genes & Development, v. 14, n. 24, p. 3075-3086, 2000. PARKER, Keith L.; SCHEDL, Andreas; SCHIMMER, Bernard P. Gene interactions in gonadal development. Annual review of physiology, v. 61, n. 1, p. 417-433, 1999. SWAIN, Amanda; LOVELL-BADGE, Robin. Mammalian sex determination: a molecular drama. Genes & development, v. 13, n. 7, p. 755-767, 1999. WILHELM, Dagmar; PALMER, Stephen; KOOPMAN, Peter. Sex determination and gonadal development in mammals. Physiological reviews, v. 87, n. 1, p. 1-28, 2007. WILSON, Jean D.; GRIFFIN, James E.; GEORGE, Fredrick W. Sexual differentiation: early hormone synthesis and action. Biology of reproduction, v. 22, n. 1, p. 9-17, 1980. -/- Emanuel Isaque Cordeiro da Silva Belo Jardim, 07 de Maio de 2020. (shrink)

Using path-breaking discoveries of cognitive science, Mark Johnson argues that humans are fundamentally imaginative moral animals, challenging the view that morality is simply a system of universal laws dictated by reason. According to the Western moral tradition, we make ethical decisions by applying universal laws to concrete situations. But Johnson shows how research in cognitive science undermines this view and reveals that imagination has an essential role in ethical deliberation. Expanding his innovative studies of human reason in Metaphors (...) We Live By and The Body in the Mind, Johnson provides the tools for more practical, realistic, and constructive moral reflection. (shrink)

Anydomainofscientificresearchhasitssustainingorthodoxy. Thatis, research on a problem, whether in astronomy, physics, or biology, is con- ducted against a backdrop of broadly shared assumptions. It is these as- sumptionsthatguideinquiryandprovidethecanonofwhatisreasonable-- of what "makes sense." And it is these shared assumptions that constitute a framework for the interpretation of research results. Research on the problem of how we see is likewise sustained by broadly shared assump- tions, where the current orthodoxy embraces the very general idea that the business of the visual system is to (...) create a detailed replica of the visual world, and that it accomplishes its business via hierarchical organization and by operatingessentiallyindependently of other sensorymodalitiesas well as independently of previous learning, goals, motor planning, and motor execution. (shrink)

Why is it that some instances of disagreement appear to be so intractable? And what is the appropriate way to handle such disagreements, especially concerning matters about which there are important practical and political needs for us to come to a consensus? In this paper, I consider an explanation of the apparent intractability of deep disagreement offered by hinge epistemology. According to this explanation, at least some deep disagreements are rationally unresolvable because they concern ‘hinge’ commitments that are unresponsive to (...) rational considerations. This explanation, if correct, seems to have troubling implications for how we should respond to deep disagreement. If my position on a topic is not responsive to rational considerations, then what choice have I but to dogmatically hold to that position, and simply dismiss the views of those with whom I disagree? I address this problem by identifying an attitude of intellectual humility that is appropriate to have towards one's hinge commitments, and suggest that this attitude provides the basis for a non-rational, constructive way to resolve deep disagreement. (shrink)

As inductive decision-making procedures, the inferences made by machine learning programs are subject to underdetermination by evidence and bear inductive risk. One strategy for overcoming these challenges is guided by a presumption in philosophy of science that inductive inferences can and should be value-free. Applied to machine learning programs, the strategy assumes that the influence of values is restricted to data and decision outcomes, thereby omitting internal value-laden design choice points. In this paper, I apply arguments from feminist philosophy of (...) science to machine learning programs to make the case that the resources required to respond to these inductive challenges render critical aspects of their design constitutively value-laden. I demonstrate these points specifically in the case of recidivism algorithms, arguing that contemporary debates concerning fairness in criminal justice risk-assessment programs are best understood as iterations of traditional arguments from inductive risk and demarcation, and thereby establish the value-laden nature of automated decision-making programs. Finally, in light of these points, I address opportunities for relocating the value-free ideal in machine learning and the limitations that accompany them. (shrink)

Despite considerable growth in understanding of various aspects of sporting and exercise embodiment over the last decade, in-depth investigations of embodied affectual experiences in running remain limited. Furthermore, within the corpus of literature investigating pleasure and the hedonic dimension in running, much of this research has focused on experiences of pleasure in relation to performance and achievement, or on specific affective states, such as enjoyment, derived after completing a run. We directly address this gap in the qualitative literature on sporting (...) and exercise embodiment by contributing novel insights on the mind-body pleasures of running via focusing analytic attention towards the pleasures recalled by runners as experienced during positive, rewarding running experiences. Applying conceptual insights drawn from sociological phenomenology, we analyse data from an in-depth, event-focused interview study with distance runners who reported positive, rewarding experiences in recent recreational runs. Through reflexive thematic analysis, we present findings in relation to three themes: (1) ‘running feels like it should’; (2) sensory engagements; and (3) time out. The study contributes fresh perspectives, both conceptually and in relation to data-collection approach, to a small literature on the lived experience of pleasure in sport, exercise and physical cultures. (shrink)

The genetic modification of pigs as a source of transplantable organs is one of several possible solutions to the chronic organ shortage. This paper describes existing ethical tensions in xenotransplantation (XTx) that argue against pursuing it. Recommendations for lifelong infectious disease surveillance and notification of close contacts of recipients are in tension with the rights of human research subjects. Parental/guardian consent for pediatric xenograft recipients is in tension with a child’s right to an open future. Individual consent to transplant is (...) in tension with public health threats that include zoonotic diseases. XTx amplifies concerns about justice in organ transplantation and could exacerbate existing inequities. The prevention of infectious disease in source animals is in tension with the best practices of animal care and animal welfare, requiring isolation, ethologically inappropriate housing, and invasive reproductive procedures that would severely impact the well-being of intelligent social creatures like pigs. (shrink)

The possibilities of unconscious perception and unconscious bias prompt parallel debates about unconscious mental content. This chapter argues that claims within these debates alleging the existence of unconscious content are made fraught by ambiguity and confusion with respect to the two central concepts they involve: consciousness and content. Borrowing conceptual resources from the debate about unconscious perception, the chapter distills the two conceptual puzzles concerning each of these notions and establishes philosophical strategies for their resolution. It then argues that empirical (...) evidence for unconscious bias falls victim to these same puzzles, but that progress can be made by adopting similar philosophical strategies. Throughout, the chapter highlights paths forward in both debates, illustrates how they serve as fruitful domains in which to study the relationship between philosophy and empirical science, and uses their combined study to further understanding of a general theory of unconscious content. (shrink)

ABSTRACT: Hobbes belonged to philosophical and scientific circles grappling with the big question at the dawn of modern physics: materialism and its consequences for morality. ‘Matter in motion’ may be a core principle of this materialism but it is certainly inadequate to capture the whole project. In wave after wave of this debate the Epicurean view of a fully determined universe governed by natural laws, that nevertheless allows to humans a sphere of libertas, but does not require a creator god (...) or teleology to explain it, comes up against monotheism and its insistence on the incoherence of an ordered world in the absence of a God and his purposes. The following questions were central to this debate: Can we understand the universe as law-governed in the absence of a god? If so, what room is there in a fully determined mechanical universe for human freedom? If humans do enjoy freedom, does the same hold for other animals? Is this freedom compatible with standard views of morality? (shrink)

A new translation and edition of Aristotle's Protrepticus (with critical comments on the fragments) -/- Welcome -/- The Protrepticus was an early work of Aristotle, written while he was still a member of Plato's Academy, but it soon became one of the most famous works in the whole history of philosophy. Unfortunately it was not directly copied in the middle ages and so did not survive in its own manuscript tradition. But substantial fragments of it have been preserved in several (...) works by Iamblichus of Chalcis, a third century A.D. neo-Pythagorean philosopher and educator. On the basis of a close study of Iamblichus' extensive use and excerption of Aristotle's Protrepticus, it is possible to reconstruct the backbone of the lost work, and then to flesh it out with the other surviving reports about the work from antiquity (for example in Alexander of Aphrodisias and other ancient commentators on Aristotle). It is also possible to identify several papyrus fragments of the work, and many references and literary allusions in later authors, especially Cicero, whose own lost dialogue Hortensius was a defense of philosophy modeleld on Aristotle's. (shrink)

An interruption. Rethinking the first three chapters of this book, I have come to suspect that, not unlike Iris Murdoch and Emmanuel Levinas, the way I imagine ‘ethics’ floats on an idea that any ethical substantive position or ethical theory is always shaped through our existential condition and our embodied encounter with others. To Murdoch, existence is the disposition for our responses to the ways in which we perceive reality, and yet, although these responses are always part of who we (...) are, they are not always part of what we do, and so, we set ourselves ethical tasks when we desire to act ethically. As scholar Bridget Clarke argues, “to attend to something [for Murdoch] is to approach it with a just and loving eye, and therewith to perceive it in its unbounded particularity and complexity, and so, as it truly is.” Or as I argue, to attend to the other ‘justly and lovingly’, Murdoch would instruct, is not merely to accurately collect details about the other and then arrive at an approximation of its being, but also to apprehend the other as ‘distinctly singular’ and ‘distinctly foreign’ from oneself–which at once forgoes any assimilation of the other into oneself, incidentally. The recognition of the other as ‘one who embodies human otherness and dignity’ becomes the condition for and coherent way of imagining and accessing moral reality. Moreover, for Diane Davis, this “being-for-the-other names a pre-originary obligation to respond to the other [and] it is in this response that both the self and the other emerge as existents” whose ethical projects are each challenged by the markedly different and infinitely other being. This obligation, Levinas might also say, is an ‘authority’ that is experienced like the effect of the other upon me, so that I am subsequently motivated to enact ethical task-making. I am not, therefore, “pulling everything other into the same, the known, the comprehended,” nor am I looking to any normative theories as authoritative templates from which I act ethically. And so, unlike Husserl, I am not “joining the philosophical tradition in its fundamental disrespect for all things other,” but instead, by dispositioning myself between these theories in responsible Levinasian fashion, I will be tracking them in response to their confronting me, and not as normative theories that are applicable to real and lived experiences. (shrink)

To Aaron Pacitti and Michael Cauvel–whose journal article, “Rent-Seeking Behavior and Economic Justice: A Classroom Exercise” broadly argues that “understanding the [complexities] of rent-seeking behavior helps fill the gap between economics and politics”–the varieties of rent are wide and, therefore, can only be described in their category-specific positions. I will discuss three of these categories in more detail below, but for now, I propose that a useful working grasp of economic rent involves “the amount paid to the owner of a (...) factor of production over the cost that is to be necessarily incurred on utilizing such elements in the production process.” In math terms, ‘economic rent’ equals the agreed-upon-amount paid by the consumer (when that amount far exceeds the market value of the product) minus the cost spent by the producer to make the product (when that cost is far below the typical amount to produce the product). Originally, the concept of economic rent concerned land ownership and the production of natural goods. Two major economists, Adam Smith and David Ricardo, offered insights into the general makeup and logic of what they called, the rent of land and simply rent, respectively. (shrink)

An overview of the influence of Lucretius poem On the Nature of Things (De Rerum Natura) on the renaissance and scientific revolution of the seventeenth century, and an examination of its continuing influence over physical atomism in the nineteenth and twentieth centuries.

In this opinion piece we propose the investigation of psychedelic-assisted psychotherapy for the treatment of body dysmorphic disorder (BDD). BDD is a psychiatric disorder characterised by appearance-based preoccupations and accompanying compulsions. While safe and effective treatments for BDD exist, non-response and relapse rates remain high. Therefore, there is a need to investigate promising new treatment options for this highly debilitating condition. Preliminary evidence suggests safety, feasibility, and potential efficacy of psychedelic treatments in disorders that share similar psychopathological mechanisms with BDD. (...) Drawing on this evidence, as well as on relevant qualitative reports and theoretical proposals, we argue that it would be worthwhile to conduct a phase 2a study aimed at assessing the safety and feasibility of psychedelic-assisted psychotherapy in BDD. We also offer some suggestions for how future research ought to proceed. (shrink)

This paper brings new work to bear on the perennial question about Hobbes's atheism to show that as a debate about scepticism it is falsely framed. Hobbes, like fellow members of the Mersenne circle, Descartes and Gassendi, was no sceptic, but rather concerned to rescue physics and metaphysics from radical scepticism by exploring corporealism. In his early letter of November 1640, Hobbes had issued a provocative challenge to Descartes to abandon metaphysical dualism and subscribe to a ?corporeal God?; a provocation (...) to which the Frenchman angrily responded, but was perhaps importantly influenced. Hobbes's minimal realism was consonant with atheism, to which Descartes felt he was being forced. Moreover, Hobbes was unrelenting in his battle against Cartesian dualism, for which he saw Robert Boyle's experimental science as a surrogate. (shrink)

In a recent book and article, James Sterba has argued that there is no free will defense. It is the purpose of this article to show that, in the most technical sense, he is wrong. There is a version of the free will defense that can solve what Sterba (rightly) takes to be the most interesting and severe version of the logical problem of moral evil. However, I will also argue that, in effect (or, we might say, in practice), Sterba (...) is correct. The only working version of the free will defense requires embracing a view that entails consequences theists traditionally have not and cannot accept. Consequently, the one and only free will solution is not viable. Unless some other solution can be found (Sterba argues there is none), the logical problem of evil, as Sterba understands it, either commits one to atheism, or a version of theism that practically all theists would regard as a heresy. (shrink)

This is part 1 of 6 of the dossier What Do We Talk about when We Talk about Queer Death?, edited by M. Petricola. The contributions collected in this article sit at the crossroads between thanatology and queer theory and tackle questions such as: how can we define queer death studies as a research field? How can queer death studies problematize and rethink the life-death binary? Which notions and hermeneutic tools could be borrowed from other disciplines in order to better (...) define queer death studies? The present article includes the following contributions: – MacCormack P., What does queer death studies mean?; – Radomska M., On queering death studies; – Lykke N., Death as vibrancy; – Hillerup Hansen I., What concreteness will do to resolve the uncertain; – Olson P., Queer objectivity as a response to denials of death; – Manganas N., The queer lack of a chthonic instinct. (shrink)

The COVID-19 pandemic put immense pressure on healthcare systems globally, including those of highly developed countries like the United States and United Kingdom. During the pandemic, professional nursing organizations were the first to call attention to the disproportionate pandemic-related deaths among Filipino nurses. These organizations played a central role in addressing the various crises Filipino nurses faced due to their vulnerabilities as frontliners, ethnic minorities, and migrants in their host countries. Using the Volatile, Uncertain, Complexity, and Ambiguous (VUCA) framework, this (...) monograph assesses the pandemic-response actions and strategies of PNAA and PNAUK, two Filipino nursing associations in the US and UK. The major themes suggest that the two organizations are multifunctional entities with the capacity to act as lobbyists, research organizations, and decision-makers when adapting, strategizing, and coping with VUCA conditions. These findings corroborate previous findings on the potentiality of diasporic nursing organizations in addressing the gaps in government support for migrant workers in the healthcare industry. (shrink)

Buddhist philosophy asserts that human suffering is caused by ignorance regarding the true nature of reality. According to this, perceptions and thoughts are largely fabrications of our own minds, based on conditioned tendencies which often involve problematic fears, aversions, compulsions, etc. In Buddhist psychology, these tendencies reside in a portion of mind known as Store consciousness. Here, I suggest a correspondence between this Buddhist Store consciousness and the neuroscientific idea of stored synaptic weights. These weights are strong synaptic connections built (...) in through experience. Buddhist philosophy claims that humans can find relief from suffering through a process in which the Store consciousness is transformed. Here, I argue that this Buddhist 'transformation at the base' corresponds to a loosening of the learned synaptic connections. I will argue that Buddhist meditation practices create conditions in the brain which are optimal for diminishing the strength of our conditioned perceptual and behavioural tendencies. (shrink)

Hegel's interpretation of Sophocles' play Antigone is central to an understanding of woman's role in the Hegelian system. Hegel is fascinated by this play and uses it in both the Phenomenology and the Philosophy of Right to demonstrate that familial ethical life is woman's unique responsibility. Antigone is revealed as the paradigmatic figure of womanhood and family life in both the ancient and modern worlds, although there are fundamental differences between these two worlds for Hegel. Through an immanent critique of (...) both the Phenomenology and the Philosophy of Right which focuses on the role of woman as presented by Hegel in the figure of Antigone, my analysis reveals the limitations of Hegel’s dialectical theory. (shrink)

Christian apologists, like Willian Lane Craig and Stephen T. Davis, argue that belief in Jesus’ resurrection is reasonable because it provides the best explanation of the available evidence. In this article, I refute that thesis. To do so, I lay out how the logic of inference to the best explanation (IBE) operates, including what good explanations must be and do by definition, and then apply IBE to the issue at hand. Multiple explanations—including (what I will call) The Resurrection Hypothesis, The (...) Lie Hypothesis, The Coma Hypothesis, The Imposter Hypothesis, and The Legend Hypothesis—will be considered. While I will not attempt to rank them all from worst to best, what I will reveal is how and why The Legend Hypothesis is unquestionably the best explanation, and The Resurrection Hypothesis is undeniably the worst. Consequently, not only is Craig and Davis’ conclusion mistaken, but belief in the literal resurrection of Jesus is irrational. In presenting this argument, I do not take myself to be breaking new ground; Robert Cavin and Carlos Colombetti have already presented a Bayesian refutation of Craig and Davis’ arguments. But I do take myself to be presenting an argument that the average person (and philosopher) can follow. It is my goal for the average person (and philosopher) to be able to clearly understand how and why the hypothesis “God supernaturally raised Jesus from the dead” fails utterly as an explanation of the evidence that Christian apologist cite for Jesus’ resurrection. (shrink)

Disagreements about abortion are often assumed to reduce to disagreements about fetal personhood (and mindedness). If one believes a fetus is a person (or has a mind), then they are “pro-life.” If one believes a fetus is not a person (or is not minded), they are “pro-choice.” The issue, however, is much more complicated. Not only is it not dichotomous—most everyone believes that abortion is permissible in some circumstances (e.g. to save the mother’s life) and not others (e.g. at nine (...) months of a planned pregnancy)—but scholars on both sides of the issue (e.g. Don Marquis and Judith Thomson) have convincingly argued that fetal personhood (and mindedness) are irrelevant to the debate. To determine the extent to which they are right, this article will define “personhood,” its relationship to mindedness, and explore what science has revealed about the mind before exploring the relevance of both to questions of abortion’s morality and legality. In general, this article does not endorse a particular answer to these questions, but the article should enhance the reader’s ability to develop their own answers in a much more informed way. (shrink)

Reformation commentators were well aware of the allegorical referents for Leviathan and Behemoth in the book of Job, representing the powerful states of Ancient Egypt and Assyria, but played them down. Hobbes did not.

Two problems are considered here. One relates to who has moral status, and the other relates to who has moral responsibility. The criteria for mattering morally have long been disputed, and many humans and nonhuman animals have been considered “marginal cases,” on the contested edges of moral considerability and concern. The marginalization of humans and other species is frequently the pretext for denying their rights, including the rights to health care, to reproductive freedom, and to bodily autonomy. There is broad (...) agreement across cultural and philosophical traditions about the capacities and responsibilities of moral agents. I propose an inclusive and expansive way of thinking about moral status, situating it not in the characteristics or capacities of individuals, but in the responsibilities and obligations of moral agents. Moral agents, under this view, are not privileged or entitled to special treatment but rather have responsibilities. I approach this by considering some African communitarian conceptions of moral status and moral agency. I propose that moral agency can also be more expansive and include not just individual moral agents but collective entities that have some of the traits of moral agents: power, freedom, and the capacity to recognize and act on the demands of morality and acknowledge and respect the rights of others. Expanding who and what is a moral agent correspondingly extends moral responsibility for respecting rights and fostering the conditions for the health and well-being of humans and animals onto the collective entities who uniquely have the capacity to attend to global-scale health threats such as pandemics and human-caused climate change. (shrink)

Social integration was theorized to be a ‘secularizing’ process for immigrants in Western Europe. Assuming that immigrants adapt to new social environments by complying with the mainstream culture of their receiving countries, immigrant religiosity is expected to decline as they assimilate in societies where secular norms prevail. Alternatively, religion could be a coping mechanism for immigrants who struggle to assimilate in their receiving countries. ‘Buffer’ theories of religion suggest that religious identity could be interchangeable with ethnicity and nationality to mitigate (...) the identity conflicts immigrants experience. This paper addresses the following research question: What role does religion play in the identity conflict experienced by immigrants who are both an ethnic minority and a national of a Western European country? Particularly, I explore the pertinence of religious identity for first-generation Sub-Saharan African Christian immigrants (SSACI) in Germany and France, where the models of immigrant assimilation diverge. Statistical tests were conducted on data derived from two surveys to compare religious, national, and ethnic self-identities at the group and individual levels. The group comparisons suggest that Christianity was indeed more salient for SSACI than native-born Christians. SSACIs without citizenship were also more likely to experience identity conflict, to which they may cope by associating less with their ethnicity or more with their religious identity. Perceived discrimination was associated with identity conflict only in Germany where immigrant assimilation is traditionally based on a common ancestry, in contrast to the values-based model in France. These are consistent with the predictions derived from ‘buffer’ theories of immigrant religiosity but longitudinal studies are needed for a more robust understanding of these trends. (shrink)

We offer a sceptical examination of a thesis recently advanced in a monograph published by Princeton University Press, entitled Greek Buddha: Pyrrho’s Encounter with Early Buddhism in Central Asia. In this dense and probing work, Christopher I. Beckwith, a professor of Central Eurasian studies at Indiana University, Bloomington, argues that Pyrrho of Elis adopted a form of early Buddhism during his years in Bactria and Gandhāra, and that early Pyrrhonism must be understood as a sect of early Buddhism. In making (...) his case Beckwith claims that virtually all scholars of Greek, Indian, and Chinese philosophy have been operating under flawed assumptions and with flawed methodologies, and so have failed to notice obvious and undeniable correspondences between the philosophical views of the Buddha and of Pyrrho. In this study we take Beckwith’s proposal and challenge seriously, and we examine his textual basis and techniques of translation, his methods of examining passages, his construal of problems and his reconstruction of arguments. We find that his presuppositions are contentious and doubtful, his own methods are extremely flawed, and that he draws unreasonable conclusions. Although the result of our study is almost entirely negative, we think it illustrates some important general points about the methodology of comparative philosophy. (shrink)

As a representative of the papacy Bellarmine was an extremely moderate one. In fact Sixtus V in 1590 had the first volume of his Disputations placed on the Index because it contained so cautious a theory of papal power, denying the Pope temporal hegemony. Bellarmine did not represent all that Hobbes required of him either. On the contrary, he proved the argument of those who championed the temporal powers of the Pope faulty. As a Jesuit he tended to maintain the (...) relative autonomy of the state, denying the temporal powers ascribed by radical papalists and Augustinians. Their argument was generally framed as a syllogism: Christ, who possessed direct temporal power as both God and man, exercised it on earth; the Pope is the vicar of Christ; therefore the Pope possesses and may exercise direct temporal jurisdiction. Bellarmine simply denied that Christ had exercised the temporal power, which as God, it is true, he possessed. Moreover, he drew up and circulated a list of patristic passages collected under the title De Regno Christi quale sit, to prove to the Pope the orthodoxy of his position. (shrink)

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

The ongoing war on drugs in the Philippines has become the epicenter of discourse and concern regarding human rights, populism, and illiberal democracy. While most studies focus on President Duterte's controversial 'strongman' persona and mass appeal, very few have sought to analyze the locals' attitudes towards him as cognitive-affective phenomena. To address this gap, this paper provides an in-depth qualitative analysis of pre-selected subjects in Davao and Manila, two regions in the Philippines with arguably the most salient pro-and anti-Duterte populations, (...) respectively, in 2019. Using a mapping software modeled after Paul Thagard's emotional coherence theory, this study maps the possible cognitive-affective processes underpinning the political ideologies of an influential leftist organization in the Philippines. Cognitive dissonance theory was used to consolidate the qualitative analyses of data derived from the surveys and interviews. The findings suggest that the two populations' political ideologies were relatively similar, as expected of subjects who belong to the same organization. However, the significant differences in the subjects' stances towards the Duterte administration suggest that the socio-political contexts of Manila and Davao could affect political opinions and views despite their similar core political ideologies. (shrink)

In some influential histories of ancient philosophy, teleological explanation and mechanistic explanation are assumed to be directly opposed and mutually exclusive alternatives. I contend that this assumption is deeply flawed, and distorts our understanding both of teleological and mechanistic explanation, and of the history of mechanistic philosophy. To prove this point, I shall provide an overview of the first systematic treatise on mechanics, the short and neglected work Mechanical Problems, written either by Aristotle or by a very early member of (...) his school. I will argue that the work is thoroughly Aristotelian in methodology, and that taking it seriously can deepen our understanding of Aristotle’s discussion of animal and human self-motion in the Physics and On the Movement of Animals. (shrink)

I develop a positive interpretation of Democritus' theory of agency and responsibility, building on previous studies that have already gone far in demonstrating his innovativeness and importance to the history and philosophy of these concepts. The interpretation will be defended by a synthesis of several familiar ethical fragments and maxims presented in the framework of an ancient problem that, unlike the problem of free will and determinism, Democritus almost certainly did confront: the problem of the causes of human goodness and (...) success. I will argue that Democritus' account of the virtues and success is naturally interpreted as an intellectualist one. His focus on our intellectual powers as the source of our own agency and cause of our success led him to remarkable breakthroughs in moral psychology, including the development of a kind of cognitive-behavioral therapy for stress and anxiety, and the proposal of an autonomous source of moral sanction. (shrink)

The concept of bias is pervasive in both popular discourse and empirical theorizing within philosophy, cognitive science, and artificial intelligence. This widespread application threatens to render the concept too heterogeneous and unwieldy for systematic investigation. This article explores recent philosophical literature attempting to identify a single theoretical category—termed ‘bias’—that could be unified across different contexts. To achieve this aim, the article provides a comprehensive review of theories of bias that are significant in the fields of philosophy of mind, cognitive science, (...) machine learning, and epistemology. It focuses on key examples such as perceptual bias, implicit bias, explicit bias, and algorithmic bias, scrutinizing their similarities and differences. Although these explorations may not conclusively establish the existence of a natural theoretical kind, pursuing the possibility offers valuable insights into how bias is conceptualized and deployed across diverse domains, thus deepening our understanding of its complexities across a wide range of cognitive and computational processes. (shrink)

The concept of kosmos did not play the leading role in Aristotle’s physics that it did in Pythagorean, Atomistic, Platonic, or Stoic physics. Although Aristotle greatly influenced the history of cosmology, he does not himself recognize a science of cosmology, a science taking the kosmos itself as the object of study with its own phenomena to be explained and its own principles that explain them. The term kosmos played an important role in two aspects of his predecessor’s accounts that Aristotle (...) rejected: first, cosmogeny and kosmopoiia, generation or creation of the kosmos; second, diakosmêsis, arranging of a plurality of kosmoi. Aristotle was extremely critical of accounts involving kosmopoiia and diakosmêsis and he developed general dialectical strategies against them. In emphatically distinguishing his view from all his predecessors (including Plato), he uses the terms ho ouranos (the heaven), to holon (the whole), and to pan (the totality) in preference to ho kosmos (the kosmos or world). There is usually no harm in speaking loosely of ‘Aristotle’s cosmology’ when referring to his concept of the order of nature and the ouranos. Nevertheless, Aristotle’s theoretical philosophy offers something very different from those of his predecessors for whom kosmos was a keyword. (shrink)

A semantics is presented for Storrs McCall's separate axiomatizations of Aristotle's accepted and rejected polysyllogisms. The polysyllogisms under discussion are made up of either assertoric or apodeictic propositions. The semantics is given by associating a property with a pair of sets: one set consists of things having the property essentially and the other of things having it accidentally. A completeness proof and a semantic decision procedure are given.

As artforms, film and street art seem incompatible. Contra this incompatibility, I investigate their combination: cinematic street art. Two promising cases are the artworks MUTO and Repopulate, but I argue neither is suitable. MUTO only counts if I accept the transparency thesis, the claim that photographs allow us to literally see their depicta. Repopulate only counts if we reject Noel Carroll’s requirement that a cinematic performance token isn’t itself an artwork. However, these imperfect cases demonstrate what is required in order (...) to have cinematic street art: the artwork is a 1) aconsensual artwork that 2) does not merely use street art as imagery or 3) merely use the street as a performance space. I introduce two hypothetical artworks inspired by this approach and discuss their merits, as well as their pitfalls relevant to my own desiderata. As such, this article serves as the foment for broader discussion within the philosophy of street art. (shrink)

Quentin Skinner’s dedication to investigating Hobbes’s concept of liberty in a number of essays and books has born some unusual fruit. Not only do we see the enormous problems that Hobbes set himself by proceeding as he did, but Skinner’s careful analysis allows us to chart Hobbes’ ingenuity as he tried to steer a path between the Charybdis of determinism and the Scylla of voluntarism – not very successfully, as we shall see. The upshot is a theory of individual freedom (...) and civil liberty to challenge the classical republican traditionThis Article does not have an abstract. (shrink)

On 4 December 2006, during discussions on the Corporate Manslaughter and Corporate Homicide Bill, Andrew Dismore, Member of Parliament and then Chair of the Joint Committee on Human Rights, said, ‘Organisations can kill people … but it is the actions and omissions of people in organisations that cumulatively cause death’. However, the corporate entity is a vehicle for the communal actions of those who guide the business activities. Attempting to seek out persons or people that are solely responsible for deaths (...) and violations of human rights caused by companies is fruitless. The entity is a vehicle for those actions, it possesses its own, often deep, pockets of finance and resources, and it has a public image. It is more useful to punish the corporate entity, in instances where the corporate behaviour has led to death and human rights abuses, as it is in seeking out individual defendants. Soft law options have not brought about a sufficient reduction in instances of deaths caused by corporate behaviour across jurisdictional borders. This article will argue that the time has now come to establish an international hard law on corporate killing, and for states to ensure that there is a viable path towards a redress for victims and their families along with adopting a duty to assist the victim or their family to pursue redress to ensure a fair balance of power against transnational companies. (shrink)

What is it that we are doing when we make ethical claims and judgments, such as the claim that we morally ought to assist refugees? This dissertation introduces and defends a novel theory of ethical thought and discourse. I begin by identifying the surface features of ethical thought and discourse to be explained, including the realist and cognitivist (i.e. belief-like) appearance of ethical judgments, and the apparent close connection between making a sincere ethical judgment and being motivated to act on (...) it. I examine prominent attempts to explain these features, with a focus on recent ‘hybrid’ theories combining elements of expressivism and cognitivism. Despite their initial promise, I argue that extant hybrid theories are nevertheless committed to problematic semantic, metasemantic, or pragmatic assumptions. I then discuss what I take to be the strongest existing option, ethical neo-expressivism (Bar-On and Chrisman, 2009; Bar-On, Chrisman, and Sias, 2014), and develop it into an explicitly hybrid theory proposing that ethical judgments incorporate both motivationally-charged affective states and moral beliefs. I then supplement this account with a theory of the proper function (following Millikan, 1984) of ethical claims and judgments, arguing that they function simultaneously to track the morally salient features of social situations, and to coordinate our behavior around these features. Finally, I defend one of the cognitivist commitments of the theory – namely, that objective moral knowledge is possible – by applying recent work on the epistemology of fundamental or ‘core’ intellectual commitments (Lynch, 2012; Pritchard, 2016) to the moral realm. (shrink)

We hope to show that the overall protreptic plan of Aristotle's ethical writings is based on the plan he used in his published work Protrepticus (Exhortation to Philosophy), by highlighting those passages that primarily offer hortatory or protreptic motivation rather than dialectical argumentation and analysis, and by illustrating several ways that Aristotle adapts certain arguments and examples from his Protrepticus. In this essay we confine our attention to the books definitely attributable to the Nicomachean Ethics (thus excluding the common books).

This essay, published in Political Theory in 1975, was one of the first to address the subject of the last two long books of Hobbes's Leviathan on religion. It addresses the purpose of these books and the relation between Hobbes's philosophy, ecclesiology and theology and the problems they raise.

Attention has turned from Hobbes the systematic thinker to his inconsistencies, as the essays in the Hobbes symposium published in the recent volume of Political Theory suggest. Deborah Baumgold, in “The Difficulties of Hobbes Interpretation,” shifted the focus to “the history of the book,” and Hobbes’s method of serial composition and peripatetic insertion, as a major source of his inconsistency. Accepting Baumgold’s method, the author argues that the manner of composition does not necessarily determine content and that fundamental paradoxes in (...) Hobbes’s work have a different provenance, for which there are also contextual answers. Hobbes was a courtier’s client, but one committed early to a materialist ontology and epistemology, and these commitments shackled him in treating the immediate political questions with which he was required to deal, leading to systemic paradoxes in his treatment of natural law, liberty, authorization, and consent. (shrink)

Clinical Legal Education programmes now take place in most law schools in England and Wales. However, legal education continues to be predominantly focused on the analysis and application of rules, doctrines, and theories to hypothetical scenarios or essay questions. This form of pedagogy either minimises or ignores the role of the client in terms of supplying lawyers with knowledge pertinent to their case. In other words, it overlooks the fact that the lawyer’s acquisition of knowledge is not confined to technical (...) rationality. This article seeks to achieve three broad aims. First, to contribute to the debate concerning the epistemology of reflective practice. Second, to develop a theoretical reflective cycle, informed by Kant’s transcendental idealism, which seeks to maximise knowledge acquisition in legal education, namely knowledge supplied by the client. Third, to address implicit bias using the proposed reflective cycle. An optimal pedagogy for using this cycle is Clinical Legal Education, namely live client clinics. (shrink)

Critics have alleged that Democritus’ ethical prescriptions (“gnomai”) are incompatible with his physics, since his atomism seems committed to necessity or chance (or an awkward combination of both) as a universal cause of everything, leaving no room for personal responsibility. I argue that Democritus’ critics, both ancient and contemporary, have misunderstood a fundamental concept of his causality: a cause called “spontaneity”, which Democritus evidently considered a necessary (not chance) cause, compatible with human freedom, of both atomic motion and human actions. (...) Some influential contemporary compatibilists have argued that freedom and responsibility are compatible with causal determinism, but not intentional constraint where some other agent is intentionally manipulating or coercing one’s actions. In line with this, Democritus holds that humans should not blame their actions on other agents like the gods, or agent-like external forces like fate or chance, but should assume ultimate intentional control over their own choices and actions. The famous remark of his associate Leucippus that “everything happens for a reason and out of necessity” is a fitting slogan of their atomistic philosophy, for Democritus pursued what can without anachronism be recognized as a causal theory of freedom. (shrink)

This paper focuses on the interpretation of the Italian approximative adverb quasi 'almost' by primarily looking at cases in which it modifies temporal connectives, a domain which, to our knowledge, has been largely unexplored thus far. Consideration of this domain supports the need for a scalar account of the semantics of quasi (close in spirit to Hitzeman's semantic analysis of almost, in: Canakis et al. (eds) Papers from the 28th regional meeting of the Chicago Linguistic Society, 1992). When paired with (...) suitable analyses of temporal connectives, such an account can provide a simple explanation of the patterns of implication that are observed when quasi modifies locational (e. g. quando 'when'), directional (e. g. fino 'until' and da 'since'), and event-sequencing temporal connectives (e. g. prima 'before' and dopo ' after'). A challenging empirical phenomenon that is observed is a contrast between the modification of fino and da by quasi, on the one hand, and the modification of prima and dopo by the same adverb, on the other. While quasi fino and quasi da behave symmetrically, a puzzling asymmetry is observed between quasi prima and quasi dopo. To explain the asymmetry, we propose an analysis of prima and dopo on which the former has the meaning of the temporal comparative più presto 'earlier', while the latter is seen as an atomic predicate denoting temporal succession between events (Del Prete, Nat Lang Semantics 16: 157-203, 2008). We show that the same pattern of implication observed for quasi prima is attested when quasi modifies overt comparatives, and propose a pragmatic analysis of this pattern that uniformly applies to both cases, thus providing new evidence for the claim that prima is underlyingly a comparative. A major point of this paper is a discussion of the notion of scale which is relevant for the semantics of quasi', in particular, we show that the notion of Horn (entailment-based) scale is not well-suited for handling modification of temporal connectives, and that a more general notion of scale is required in order to provide a uniform analysis of quasi as a cross-categorial modifier. (shrink)

I discuss how Aristotle’s formulation of the problem of moral luck relates to his natural philosophy. I review well-known passages from Nicomachean Ethics I/X and Eudemian Ethics I/VII and Physics II, but in the main focus on EE VII 14 (= VIII 2). I argue that Aristotle’s position there (rejecting the elimination of luck, but reducing luck so far as possible to incidental natural and intelligent causes) is not only consistent with his treatment of luck in Physics II, but is (...) to be expected, given that the dialectical path of EE VII 14 runs exactly parallel to that of Physics II 4-6. Although Aristotle resolves some issues that he raises, he cannot avoid the problem of constitutive moral luck that, as Thomas Nagel puts it, pertains to ‘the kind of person you are, where this is not just a question of what you deliberately do, but of your inclinations, capacities, and temperament’. The problem for Aristotle follows not only from his ethical positions, but also directly from his more general physical and political principles and assumptions. Furthermore, the problem touches the very essence of Aristotle’s moral theory. (shrink)

We propose a semantic analysis of the particles afinal (European Portuguese) and alla fine (Italian) in terms of the notion of truth unpersistence, which combines both epistemic modality and constraints on discourse structure. We argue that the felicitous use of these modal particles requires that the truth of a proposition p* fail to persist through a temporal succession of epistemic states, where p* is incompatible with the proposition modified by afinal/alla fine, and that the interlocutors share knowledge of a previous (...) epistemic attitude toward p*. We analyze two main cases, that of plan-related propositions and that of propositions without plans. We also discuss the connections between truth unpersistence and evidentiality. (shrink)