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)

This paper explores connections between theories of morality and theories of properties. It argues that (1) moral realism is in tension with predicate, class and mereological nominalism; (2) moral non-naturalism is incompatible with standard versions of resemblance nominalism, immanent realism and trope theory; and (3) the standard semantic arguments for property realism do not support moral realism. I also raise doubts about trope-theoretic explanations of moral supervenience and argue against one version of the principle that we should accept theories that (...) maintain neutrality. (shrink)

Awarding rights to rivers, forests, and other environmental entities (EEs) is a new and increasingly popular approach to environmental protection. The distinctive feature of such rights of nature (RoN) legislation is that direct duties are owed to the EEs. This paper presents a novel rebuttal of the strongest argument against RoN: the no interest argument. The crux of this argument is that because EEs are not sentient, they cannot possess the kinds of interests necessary to ground direct duties. Therefore, they (...) cannot be legitimate rights-bearers. After considering and rejecting standard responses to this argument, the paper challenges its fundamental assumption: that rights-correlative duties must be grounded in the interests of the rights-bearer. The paper then presents the RoN critic with a dilemma. The critic must either accept that EEs are legitimate rights-bearers, or delegitimise many well-established rights-bearers along with EEs. Either way, the no interest argument loses its force. (shrink)

The following is a transcript of the interview I (Yasuko Kitano) conducted with Neil Levy (The Centre for Applied Philosophy and Public Ethics, CAPPE) on the 23rd in July 2009, while he was in Tokyo to give a series of lectures on neuroethics at The University of Tokyo Center for Philosophy. I edited his words for publication with his approval.

The moral belief problem is that of reconciling expressivism in ethics with both minimalism in the philosophy of language and the syntactic discipline of moral sentences. It is argued that the problem can be solved by distinguishing minimal and robust senses of belief, where a minimal belief is any state of mind expressed by sincere assertoric use of a syntactically disciplined sentence and a robust belief is a minimal belief with some additional property R. Two attempts to specify R are (...) discussed, both based on the thought that beliefs are states that aim at truth. According to the first, robust beliefs are criticisable to the extent that their content fails to match the state of the world. This sense fails to distinguish robust beliefs from minimal beliefs. According to the second, robust beliefs function to have their content match the state of the world. This sense succeeds in distinguishing robust beliefs from minimal beliefs. The conclusion is that the debate concerning the cognitive status of moral convictions needs to address the issue of the function of moral convictions. Evolutionary theorising may be relevant, but will not be decisive, in answering this question. (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)

In this paper we argue that political envy is central to unraveling the racial dynamics in Spike Lee's Do The Right Thing. Building upon Sara Protasi’s taxonomy of envy and, in particular, from her analysis of some DTRT scenes, we conduct a more thorough interrogation of how political emotions, most notably envy, shape race relations in the film. We start by summarizing Protasi’s account of envy and then review two alternative accounts of political emotions. After elucidating what envy is and (...) how it becomes politically valenced, we analyze three key scenes that are the most emblematic of political envy: 1) a discussion between three Black characters on the street corner, 2) an exchange between the film’s main character, Mookie, and his racist co-worker, Pino; and 3) the film’s climactic riot sequence. Our analysis of these three scenes, in addition to complementing previous readings of Do The Right Thing, highlight envy’s potential to either impede or promote political action. (shrink)

The rightness and wrongness of actions fits on a continuous scale. This fits the way we evaluate actions chosen among a diverse range of options, even though English speakers don’t use the words “righter” and “wronger”. I outline and defend a version of scalar consequentialism, according to which rightness is a matter of degree, determined by how good the consequences are. Linguistic resources are available to let us truly describe actions simply as right. Some deontological theories face problems in accounting (...) for degrees of rightness, as they don't invoke continuous parameters among the right-making features of action. (shrink)

This paper elaborates and defends an expressivist account of the claims of mind-independence embedded in ordinary moral thought. In response to objections from Zangwill and Jenkins it is argued that the expressivist 'internal reading' of such claims is compatible with their conceptual status and that the only 'external reading' available doesn't commit expressivisists to any sort of subjectivism. In the process a 'commitment-theoretic' account of the semantics of conditionals and negations is defended.

Recent work in neuroimaging suggests that some patients diagnosed as being in the persistent vegetative state are actually conscious. In this paper, we critically examine this new evidence. We argue that though it remains open to alternative interpretations, it strongly suggests the presence of consciousness in some patients. However, we argue that its ethical significance is less than many people seem to think. There are several different kinds of consciousness, and though all kinds of consciousness have some ethical significance, different (...) kinds underwrite different kinds of moral value. Demonstrating that patients have phenomenal consciousness — conscious states with some kind of qualitative feel to them — shows that they are moral patients, whose welfare must be taken into consideration. But only if they are subjects of a sophisticated kind of access consciousness — where access consciousness entails global availability of information to cognitive systems — are they persons, in the technical sense of the word employed by philosophers. In this sense, being a person is having the full moral status of ordinary human beings. We call for further research which might settle whether patients who manifest signs of consciousness possess the sophisticated kind of access consciousness required for personhood. (shrink)

This paper argues that qualia share their physical correlates' locations. The first premise comes from the theory of relativity: If something shares a time with a physical event in all reference frames, it shares that physical event’s location. The second premise is that qualia share times with their correlates in all reference frames. Having qualia and correlates share locations makes relations between them easier to explain, improving both physicalist and dualist theories.

A number of concerns have been raised about the possible future use of pharmaceuticals designed to enhance cognitive, affective, and motivational processes, particularly where the aim is to produce morally better decisions or behavior. In this article, we draw attention to what is arguably a more worrying possibility: that pharmaceuticals currently in widespread therapeutic use are already having unintended effects on these processes, and thus on moral decision making and morally significant behavior. We review current evidence on the moral effects (...) of three widely used drugs or drug types: propranolol, selective serotonin reuptake inhibitors, and drugs that effect oxytocin physiology. This evidence suggests that the alterations to moral decision making and behavior caused by these agents may have important and difficult-to-evaluate consequences, at least at the population level. We argue that the moral effects of these and other widely used pharmaceuticals warrant further empirical research and ethical analysis. (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)

Actions performed in a state of automatism are not subject to moral evaluation, while automatic actions often are. Is the asymmetry between automatistic and automatic agency justified? In order to answer this question we need a model or moral accountability that does justice to our intuitions about a range of modes of agency, both pathological and non-pathological. Our aim in this paper is to lay the foundations for such an account.

In this paper we sketch a new version of aesthetic expressivism. We argue that one advantage of this view is that it explains various putative norms on the formation and revision of aesthetic judgement. We begin by setting out our proposed explananda and a sense in which they can be understood as governing the correct response to putative higher-order evidence in aesthetics. We then summarise some existing discussions of expressivist attempts to explain these norms, and objections raised to them. This (...) will allow us to identify the pitfalls that a good expressivist explanation needs to avoid. Finally, we sketch our preferred version of aesthetic expressivism which includes as a crucial part a hypothesis concerning the distinctive expressive function of aesthetic practice. We then consider how this theory can explain the putative aesthetic norms whilst avoiding the previous objections. (shrink)

What are the conditions on a successful naturalistic account of moral properties? In this paper I discuss one such condition: the possibility of moral concepts playing a role in good empirical theories on a par with those of the natural and social sciences. I argue that Peter Railton’s influential account of moral rightness fails to meet this condition, and thus is only viable in the hands of a naturalist who doesn’t insist on it. This conclusion generalises to all versions of (...) naturalism that give a significant role to a dispositional characterisation of moral properties. I also argue, however, that the epistemological and semantic motivations behind naturalism are consistent with a version of naturalism that doesn’t insist on the explanatory condition. The conclusion is that those naturalists who are attracted to accounts of moral properties such as Railton’s would do better not to insist on this\break condition. (shrink)

Propositionalism is the view that the contents of intentional attitudes have a propositional structure. Objectualism opposes propositionalism in allowing the contents of these attitudes to be ordinary objects or properties. Philosophers including Talbot Brewer, Paul Thagard, Michelle Montague, and Alex Grzankowski attack propositionalism about such attitudes as desire, liking, and fearing. This article defends propositionalism, mainly on grounds that it better supports psychological explanations.

I argue that one intends that ϕ if one has a desire that ϕ and an appropriately related means-end belief. Opponents, including Setiya and Bratman, charge that this view can't explain three things. First, intentional action is accompanied by knowledge of what we are doing. Second, we can choose our reasons for action. Third, forming an intention settles a deliberative question about what to do, disposing us to cease deliberating about it. I show how the desire- belief view can explain (...) why these phenomena occur when they occur, and why they don't when they don't. (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)

This paper presents the Universality Argument that pleasure is goodness. The first premise defines goodness as what should please all. The second premise reduces 'should' to perceptual accuracy. The third premise invokes a universal standard of accuracy: qualitative identity. Since the pleasure of all is accurate solely about pleasure, pleasure is goodness, or universal moral value. The argument proceeds from a moral sense theory that analyzes moral concepts as concerned with what all should hope for, feel guilty about, and admire. (...) This requires rejecting practical anti-empiricism, the view that moral judgment concerns empirically inaccessible norms governing action. (shrink)

This essay presents an ideal for modern Western romantic love.The basic ideas are the following: people want to form a distinctive sort of plural subject with another, what Nozick has called a "We", they want to be loved for properties of certain kinds, and they want this love to establish and sustain a special sort of commitment to them over time.

This essay defends a strong version of the Humean theory of motivation on which desire is necessary both for motivation and for reasoning that changes our desires. Those who hold that moral judgments are beliefs with intrinsic motivational force need to oppose this view, and many of them have proposed counterexamples to it. Using a novel account of desire, this essay handles the proposed counterexamples in a way that shows the superiority of the Humean theory. The essay addresses the classic (...) objection that the Humean theory cannot explain the feeling of obligation, Stephen Darwall's example of motivationally potent reasoning that is not based on preexisting desires, Thomas Scanlon's criticism that the Humean theory fails to account for the structure and phenomenology of deliberation, and the phenomenon of akrasia as discussed by John Searle. In each case a Humean account explains the data at least as thoroughly as opposing views can, while fitting within a simpler total account of how we deliberate and act. (shrink)

The identity theory, advocated as a solution to the mind-body problem by materialists such as Feigl and Smart, has been criticized for implying the existence of irreducible properties. After summarizing the relevant theses of materialism, I consider several versions of the irreducible properties objection, and argue that they are all unsuccessful.

Heidegger’s ontological views, his observations about liberalism and fascism, and his evaluative commitments are three premises of an argument for fascism. The ontological premise is that integrated wholes and objects of a creator or user’s will are ontologically superior, as Being and Time suggests in discussing Being-a-whole, creating art, and using equipment. The social premise is that fascist societies are wholes integrated by dictatorial will, while liberal societies are looser aggregates of free individuals, as Heidegger describes in his 1930s seminars. (...) The evaluative premise, shared with the medieval tradition and expressed in his notebook remarks about war, is that ontological superiority makes things better. The conclusion that fascism is better than liberalism should be rejected along with the evaluative premise. (shrink)

This paper outlines a new metasemantic theory of moral reason statements, focused on explaining how the reasons thus stated can be inescapable. The motivation for the theory is in part that it can explain this and other phenomena concerning moral reasons. The account also suggests a general recipe for explanations of conceptual features of moral reason statements. (Published with Open Access.).

In this paper I argue that the explanationist argument in favour of moral realism fails. According to this argument, the ability of putative moral properties to feature in good explanations provides strong evidence for, or entails, the metaphysical claims of moral realism. Some have rejected this argument by denying that moral explanations are ever good explanations. My criticism is different. I argue that even if we accept that moral explanations are (sometimes) good explanations the metaphysical claims of realism do not (...) follow. (shrink)

Causal exclusion arguments are taken to threaten the autonomy of the special sciences, and the causal efficacy of mental properties. A recent line of response to these arguments has appealed to “independently plausible” and “well grounded” theories of causation to rebut key premises. In this paper I consider two papers which proceed in this vein and show that they share a common feature: they both require causes to be proportional to their effects. I argue that this feature is a bug, (...) and one that generalises: any attempt to rescue the autonomy of the special sciences, or the efficacy of the mental, from exclusion worries had better not look to proportionality for help. (shrink)

Consider two deeply appealing thoughts: first, that we experience external particulars, and second, that what it’s like to have an experience – the phenomenal character of an experience – is somehow independent of external particulars. The first thought is readily captured by phenomenal particularism, the view that external particulars are sometimes part of the phenomenal character of experience. The second thought is readily captured by phenomenal generalism, the view that external particulars are never part of phenomenal character. -/- Here I (...) show that a novel version of phenomenal generalism can capture both thoughts in a satisfying fashion. Along the way, I reveal severe problems facing phenomenal particularism and also shed light on the mental kinds under which experiences fall. (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)

A central area of current philosophical debate in the foundations of mathematics concerns whether or not there is a single, maximal, universe of set theory. Universists maintain that there is such a universe, while Multiversists argue that there are many universes, no one of which is ontologically privileged. Often forcing constructions that add subsets to models are cited as evidence in favour of the latter. This paper informs this debate by analysing ways the Universist might interpret this discourse that seems (...) to necessitate the addition of subsets to V. We argue that despite the prima facie incoherence of such talk for the Universist, she nonetheless has reason to try and provide interpretation of this discourse. We analyse extant interpretations of such talk, and analyse various tradeoffs in naturality that might be made. We conclude that the Universist has promising options for interpreting different forcing constructions. (shrink)

In this chapter, we argue for three theses: (1) we lack the power to form beliefs at will (i.e., directly); at very least, we lack the power to form at will beliefs of the kind that proponents of doxastic voluntarism have in mind; but (2) we possess a propensity to form beliefs for non-epistemic reasons; and (3) these propensities—once we come to know we have them—entail that we have obligations similar to those we would have were doxastic voluntarism true. Specifically, (...) we will argue that we have obligations to avoid triggering these propensities to form beliefs that are unwarranted or even immoral. (shrink)

We can infer moral conclusions from nonmoral evidence using a three-step procedure. First, we distinguish the processes generating belief so that their reliability in generating true belief is statistically predictable. Second, we assess the processes’ reliability, perhaps by observing how frequently they generate true nonmoral belief or logically inconsistent beliefs. Third, we adjust our credence in moral propositions in light of the truth ratios of the processes generating beliefs in them. This inferential route involves empirically discovering truths of the form (...) “Process P, which generates belief in moral proposition M, has truth ratio T", and using them to discover probabilities for moral propositions. The inferential route is noncircular, and progress along it is driven fundamentally by induction. (shrink)

In “The Evolutionary Debunking of Quasi-Realism,” Neil Sinclair and James Chamberlain present a novel answer that quasi-realists can pro-vide to a version of the reliability challenge in ethics—which asks for an explanation of why our moral beliefs are generally true—and in so doing, they examine whether evolutionary arguments can debunk quasi-realism. Although reliability challenges differ from EDAs in several respects, there may well be a connection between them. For the explanatory premise of an EDA may state that a particular (...) theory of beliefs of a certain kind does not, or cannot, provide a plausible account of why those beliefs might be generally true, and its epistemic premise may state that, if that is the case, then the beliefs in question have a negative epistemic status or the theory is false inasmuch as, if it were true, it would lead to those beliefs having such a negative epistemic status. The quasi-realist can answer the reli-ability challenge by claiming that, when we form our moral beliefs through a process of well-informed impartial reflection, we form them in response to the non-moral features of things on which depend the moral features they have. Hence, when we form beliefs by means of such a process, we are most likely forming true moral beliefs. (shrink)

Some philosophers (including Urmson, Humberstone, Shah, and Velleman) hold that believing that p distinctively involves applying a norm according to which the truth of p is a criterion for the success or correctness of the attitude. On this view, imagining and assuming differ from believing in that no such norm is applied. I argue against this view with counterexamples showing that applying the norm of truth is neither necessary nor sufficient for distinguishing believing from imagining and assuming. Then I argue (...) that the different functional properties of these mental states are enough to distinguish them, and that norm-application doesn't help us draw the functional distinctions. (shrink)

We explain and explore class-theoretic potentialism—the view that one can always individuate more classes over a set-theoretic universe. We examine some motivations for class-theoretic potentialism, before proving some results concerning the relevant potentialist systems (in particular exhibiting failures of the $\mathsf {.2}$ and $\mathsf {.3}$ axioms). We then discuss the significance of these results for the different kinds of class-theoretic potentialists.

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)

This paper applies the theory of teleosemantics to the issue of moral content. Two versions of teleosemantics are distinguished: input-based and output-based. It is argued that applying either to the case of moral judgements generates the conclusion that such judgements have both descriptive (belief-like) and directive (desire-like) content, intimately entwined. This conclusion directly validates neither descriptivism nor expressivism, but the application of teleosemantics to moral content does leave the descriptivist with explanatory challenges which the expressivist does not face. Since teleosemantics (...) ties content to function, the paper also offers an account of the evolutionary function of moral judgements. (shrink)

Ethical reductionism is the best version of naturalistic moral realism. Reductionists regard moral properties as identical to properties appearing in successful scientific theories. Nonreductionists, including many of the Cornell Realists, argue that moral properties instead supervene on scientific properties without identity. I respond to two arguments for nonreductionism. First, nonreductionists argue that the multiple realizability of moral properties defeats reductionism. Multiple realizability can be addressed in ethics by identifying moral properties uniquely or disjunctively with properties of the special sciences. Second, (...) nonreductionists argue that irreducible moral properties explain empirical phenomena, just as irreducible special-science properties do. But since irreducible moral properties don't successfully explain additional regularities, they run the risk of being pseudoscientific properties. Reductionism has all the benefits of nonreductionism, while also being more secure against anti-realist objections because of its ontological simplicity. (shrink)

I argue that if David Lewis’ modal realism is true, modal realists from different possible worlds can fall in love with each other. I offer a method for uniquely picking out possible people who are in love with us and not with our counterparts. Impossible lovers and trans-world love letters are considered. Anticipating objections, I argue that we can stand in the right kinds of relations to merely possible people to be in love with them and that ending a trans-world (...) relationship to start a relationship with an actual person isn't cruel to one's otherworldly lover. (shrink)

This chapter considers the nature of imagination and belief, exploring how deeply these two states of mind differ. It first addresses a range of cognitive and motivational differences between imagination and belief which suggest that they're fundamentally different states of mind. Then it addresses imaginative immersion, delusions, and the different norms we apply to the two mental states, which some theorists regard as providing support for a more unified picture of imagination and belief.

Many philosophers argue that the face-value of moral practice provides presumptive support to moral realism. This paper analyses such arguments into three steps. (1) Moral practice has a certain face-value, (2) only realism can vindicate this face value, and (3) the face-value needs vindicating. Two potential problems with such arguments are discussed. The first is taking the relevant face-value to involve explicitly realist commitments; the second is underestimating the power of non-realist strategies to vindicate that face-value. Case studies of each (...) of these errors are presented, drawn from the writings of Shafer-Landau, Brink and McNaughton, and from recent work in experimental metaethics. The paper then considers weak presumptive arguments, according to which both realist and non-realist vindications of moral practice are possible, but the realist vindications are more natural. It is argued that there is no sense of ‘natural’ available that can make these arguments work. The conclusion is that all extant presumptive arguments for moral realism fail. (shrink)

Bayesian models of legal arguments generally aim to produce a single integrated model, combining each of the legal arguments under consideration. This combined approach implicitly assumes that variables and their relationships can be represented without any contradiction or misalignment, and in a way that makes sense with respect to the competing argument narratives. This paper describes a novel approach to compare and ‘average’ Bayesian models of legal arguments that have been built independently and with no attempt to make them consistent (...) in terms of variables, causal assumptions or parameterization. The approach involves assessing whether competing models of legal arguments are explained or predict facts uncovered before or during the trial process. Those models that are more heavily disconfirmed by the facts are given lower weight, as model plausibility measures, in the Bayesian model comparison and averaging framework adopted. In this way a plurality of arguments is allowed yet a single judgement based on all arguments is possible and rational. (shrink)

Let's suppose you think that there are no uncountable sets. Have you adopted a restrictive position? It is certainly tempting to say yes---you've prohibited the existence of certain kinds of large set. This paper argues that this intuition can be challenged. Instead, I argue that there are some considerations based on a formal notion of restrictiveness which suggest that it is restrictive to hold that there are uncountable sets.

This paper advances three necessary conditions on a successful account of sentential negation. First, the ability to explain the constancy of sentential meaning across negated and unnegated contexts (the Fregean Condition). Second, the ability to explain why sentences and their negations are inconsistent, and inconsistent in virtue of the meaning of negation (the Semantic Condition). Third, the ability of the account to generalize regardless of the topic of the negated sentence (the Generality Condition). The paper discusses three accounts of negation (...) available to moral expressivists. The first—the dominant commitment account—fails to meet the Fregean Condition. The two remaining accounts—commitment semantics and the expression account—satisfy all three conditions. A recent argument that the dominant commitment account is the only option available to expressivists is considered and rejected. (shrink)

In the contemporary philosophy of set theory, discussion of new axioms that purport to resolve independence necessitates an explanation of how they come to be justified. Ordinarily, justification is divided into two broad kinds: intrinsic justification relates to how `intuitively plausible' an axiom is, whereas extrinsic justification supports an axiom by identifying certain `desirable' consequences. This paper puts pressure on how this distinction is formulated and construed. In particular, we argue that the distinction as often presented is neither well-demarcated nor (...) sufficiently precise. Instead, we suggest that the process of justification in set theory should not be thought of as neatly divisible in this way, but should rather be understood as a conceptually indivisible notion linked to the goal of explanation. (shrink)

This paper is a concise survey of recent expressivist theories of discourse, focusing on the ethical case. For each topic discussed recent trends are summarised and suggestions for further reading provided. Issues covered include: the nature of the moral attitude; ‘hybrid’ views according to which moral judgements express both beliefs and attitudes; the quasi-realist programmes of Simon Blackburn and Allan Gibbard; the problem of creeping minimalism; the nature of the ‘expression’ relation; the Frege-Geach problem; the problem of wishful thinking; the (...) role of moral intuitions; expressivism in aesthetics. (shrink)

This paper argues that a counterpart-theoretic treatment of events, combined with a counterfactual theory of causation, can help resolve three puzzles from the causation literature. First, CCT traces the apparent contextual shifts in our causal attributions to shifts in the counterpart relation which obtains in those contexts. Second, being sensitive to shifts in the counterpart relation can help diagnose what goes wrong in certain prominent examples where the transitivity of causation appears to fail. Third, CCT can help us resurrect the (...) much-maligned fragility response to the problems of late pre-emption by understanding fragility in counterpart-theoretic terms. Some reasons to prefer this CCT approach to rivals are discussed. (shrink)