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

We aim to establish the following claim: other factors held constant, the relative weights of the epistemic burdens of competing treatment options serve to determine the options that patient surrogates pursue. Simply put, surrogates confront an incentive, ceteris paribus, to pursue treatment options with respect to which their knowledge is most adequate to the requirements of the case. Regardless of what the patient would choose, options that require more knowledge than the surrogate possesses (or is likely to learn) will either (...) be neglected altogether or deeply discounted in the surrogate’s incentive structure. We establish this claim by arguing that the relation between epistemic burdens and incentives in decision-making is a general feature of surrogate decision-making. After establishing the claim, we draw out some of the implications for surrogate decision-making in medicine and offer philosophical and psychological explanations of the phenomenon. (shrink)

The practice of medicine frequently involves the unconsented restriction of liberty. The reasons for unilateral liberty restrictions are typically that being confined, strapped down, or sedated are necessary to prevent the person from harming themselves or others. In this paper, we target the ethics of chemical restraints, which are medications that are used to intentionally restrict the mental states associated with the unwanted behaviors, and are typically not specifically indicated for the condition for which the patient is being treated. Specifically, (...) we aim to identify the conditions under which chemical restraints are ethically permissible. It is wrong to assume that what is morally true of physical restraints is also true of chemical restraints. Our aim is thus to identify the conditions under which chemical restraints are permissible while distinguishing these conditions from those of the application of physical restraints. (shrink)

Slow codes—insincere attempts at resuscitation—are widely regarded in medicine and medical ethics as morally impermissible. My goal here is to enrich this special issue on the slow code with an argument for the permissibility of slow codes that is rooted in moral psychology. Specifically, if we take seriously the results from moral psychology, the slow code is not only permissible, it is often the best option. The context of the decision about whether to perform a slow code is analogous to (...) thoroughly investigated moral dilemmas such as the trolley problem. In particular, when the trolley problem is framed as a trilemma, it becomes clear that the decisional context of the slow code is analogous to the famous moral dilemma. Since in the trolley problem the choice analogous to the slow code is the best choice, the slow code may be the best choice when facing patient or family requests for futile CPR. In establishing this claim, I address a range of objections to the slow code. I conclude with an empirically supported explanation of the conventional wisdom. Resistance to the slow code doesn’t sprout from the act’s moral properties, but from moral judgments influenced by factors such as emotion, physical distance, and personal force. (shrink)

Augustine’s privation theory of evil maintains that something is evil in virtue of a privation, a lack of something which ought to be present in a particular nature. While it is not evil for a human to lack wings, it is indeed evil for a human to lack rationality according to the end of a rational nature. Much of the literature on the privation theory focuses on whether it can successfully defend against counterexamples of positive evils, such as pain. This (...) focus of the discussion is not surprising, given that the privation theory is a theory about the nature of evil. But it is also a theory that protects venerable theological concerns, namely, that God is the good creator of everything, and that everything is good. It is the purpose of this article to further this discussion on both fronts. I argue that the counterexample of pain still defeats the privation theory despite the most recent defense. What is more, I suggest, this is not theologically disastrous. The individual who rejects the privation theory is not obligated to reject the theological theses which motivate it. To show how a rejection of the privation theory is a live option, I offer an alternative view of evil that also maintains these theological theses and encompasses both privative and positive evils. (shrink)

Description In this paper, we propose an advanced mathematical framework centered around the Energy Number Field (E), which fundamentally avoids the conventional concept of zero by introducing a neutral ele- ment, νE. Through this approach, we redefine core mathematical constructs, including limits, continuity, differentiation, integration, and series summation, ensuring they operate seamlessly within a zero-less paradigm. We address and redefine matrix operations, topology, metric spaces, and complex analysis, aligning them with the principles of E. Additionally, we explore non-mappable properties of (...) energy numbers in the context of symmetry groups, non-standard fields, fractional calculus, and non-Euclidean geometries. By employing νE as the central element, our framework resolves conventional zero-related sin- gularities and computational anomalies, offering a novel perspective that bridges advanced mathematical theories with practical applications in physics, computational algorithms, and topological transforma- tions. This work paves the way for future research to experimentally validate these formulations and explore potential applications in advanced physics, quantum mechanics, and beyond. (shrink)

There is recent empirical evidence that personal identity is constituted by one’s moral traits. If true, this poses a problem for those who advocate for moral enhancement, or the manipulation of a person’s moral traits through pharmaceutical or other biological means. Specifically, if moral enhancement manipulates a person’s moral traits, and those moral traits constitute personal identity, then it is possible that moral enhancement could alter a person’s identity. I go a step further and argue that under the right conditions, (...) moral enhancement can constitute murder. I then argue that these conditions are not remote. (shrink)

This article seeks to constructively retrieve Anselm’s theology of the Holy Spirit by responding to a recent criticism of his doctrine of atonement. This criticism is called the question of efficacy and focuses particularly on how Anselm holds humanity to participate in and receive the divine gift of atonement. In short, this paper argues that the Spirit’s prevenient and subsequent grace allow for an individual to respond freely and in faith to Christ’s work, resulting in three individually necessary and jointly (...) sufficient conditions for union to be restored with God and human flourishing to obtain in Anselm’s thinking. In order to argue this, the paper proceeds in four sections. First, it discusses the question of efficacy. Second, it discusses the Spirit’s work in relation to an individual initially accepting Christ’s Gift. The paper then proceeds by discussing the subsequent work of the Spirit and redemptive role of faith that are inherently tied to the initial work. The paper then concludes by analyzing alternative approaches to this question of efficacy. (shrink)

Contemporary scholarship is divided over whether Anselm maintains a version of Eudaemonism. The debate centers on the question of whether the will for justice only moderates the will for happiness or, instead, provides a distinct end for which to act. Because of two key passages, various scholars hold that Anselm maintained elements of medieval Eudaemonism. In this article, I argue that Anselm separates morality from happiness, and I provide a sketch of his alternative view. First, I argue against some recent (...) perspectives that Anselm maintained Eudaemonism. To do so, I provide a non-Eudaemonist reading of the two key passages and show how Eudaemonist readings are lacking in different respects. Second, I examine what this argument means for Anselm’s understanding of happiness and moral obligation. While there are some Eudaemonist themes in Anselm’s thinking, he flatly denies and revises aspects of the system. (shrink)

Humans are morally deficient in a variety of ways. Some of these deficiencies threaten the continued existence of our species. For example, we appear to be incapable of responding to climate change in ways that are likely to prevent the consequent suffering. Some people are morally better than others, but we could all be better. The price of not becoming morally better is that when those events that threaten us occur, we will suffer from them. If we can prevent this (...) suffering from occurring, then we ought to do so. That we ought to make ourselves morally better in order to prevent very bad things from happening justifies, according to some, the development and administration of moral enhancement. I address in this paper the idea that moral enhancement could give rise to moral transhumans, or moral post-persons. Contrary to recent arguments that we shouldn’t engender moral post-persons, I argue that we should. Roughly, the reasons for this conclusion are that we can expect moral post-persons to resemble the morally best of us, our moral exemplars. Since moral exemplars promote their interests by promoting the interests of others (or they promote others’ interests at the expense of their own) we can expect moral post-persons to pursue our interests. Since we should also pursue our own interests, we should bring about moral post-persons. (shrink)

Some theorists argue that moral bioenhancement ought to be compulsory. I take this argument one step further, arguing that if moral bioenhancement ought to be compulsory, then its administration ought to be covert rather than overt. This is to say that it is morally preferable for compulsory moral bioenhancement to be administered without the recipients knowing that they are receiving the enhancement. My argument for this is that if moral bioenhancement ought to be compulsory, then its administration is a matter (...) of public health, and for this reason should be governed by public health ethics. I argue that the covert administration of a compulsory moral bioenhancement program better conforms to public health ethics than does an overt compulsory program. In particular, a covert compulsory program promotes values such as liberty, utility, equality, and autonomy better than an overt program does. Thus, a covert compulsory moral bioenhancement program is morally preferable to an overt moral bioenhancement program. (shrink)

Evaluative concepts and emotions appear closely connected. According to a prominent account, this relation can be expressed by propositions of the form ‘something is admirable if and only if feeling admiration is appropriate in response to it’. The first section discusses various interpretations of such ‘Value-Emotion Equivalences’, for example the Fitting Attitude Analysis, and it offers a plausible way to read them. The main virtue of the proposed way to read them is that it is well-supported by a promising account (...) of emotions, namely the Perceptual Theory of Emotions, which emphasises the analogies between emotions and sensory perceptual experiences. The second section considers a worry about whether concepts such as admirable are really evaluative. It is maintained that even though the arguments used to show that thick terms and concepts are not inherently evaluative can be transposed to affective concepts, these arguments can be resisted. So there is no need to abandon the intuitive claim that affective concepts are inherently evaluative. (shrink)

Epistemic burdens – the nature and extent of our ignorance (that and how) with respect to various courses of action – serve to determine our incentive structures. Courses of action that seem to bear impossibly heavy epistemic burdens are typically not counted as options in an actor’s menu, while courses of action that seem to bear comparatively heavy epistemic burdens are systematically discounted in an actor’s menu relative to options that appear less epistemically burdensome. That ignorance serves to determine what (...) counts as an option means that epistemic considerations are logically prior to moral, prudential, and economic considerations: in order to have moral, prudential, or economic obligations, one must have options, and epistemic burdens serve to determine our options. One cannot have obligations without doing some epistemic work. We defend this claim on introspective grounds. We also consider how epistemic burdens distort surrogate decision-making. The unique epistemology of surrogate cases makes the priority of the epistemic readily apparent. We then argue that anyone who accepts a principle similar to ought implies can is committed to the logical priority of the epistemic. We also consider and reject several possible counterarguments. -/- . (shrink)

Moral bioenhancement is the potential practice of manipulating individuals’ moral behaviors by biological means in order to help resolve pressing moral issues such as climate change and terrorism. This practice has obvious ethical implications, and these implications have been and continue to be discussed in the bioethics literature. What have not been discussed are the epistemological implications of moral bioenhancement. This article details some of these implications of engaging in moral bioenhancement. The argument begins by making the distinction between moral (...) bioenhancement that manipulates the contents of mental states and that which manipulates other, non-representational states. Either way, I argue, the enhanced moral psychology will fail to conform to epistemic norms, and the only way to resolve this failure and allow the moral bioenhancement to be effective in addressing the targeted moral issues is to make the moral bioenhancement covert. (shrink)

The literature acknowledges a distinction between immoral, amoral and moral management. This paper makes a case for the employee (at any level) as a moral agent, even though the paper begins by highlighting a body of evidence which suggests that individual moral agency is sacrificed at work and is compromised in deference to other pressures. This leads to a discussion about the notion of discretion and an examination of a separate, contrary body of literature which indicates that some individuals in (...) corporations may use their discretion to behave in a socially entrepreneurial manner. My underlying assumption is that CSR isn’t solely driven by economics and that it may also be championed as a result of a personal morality, inspired by employees’ own socially oriented personal values. A conceptual framework is put forward and it is suggested that individuals may be categorized as Active or Frustrated Corporate Social Entrepreneurs; Conformists or Apathetics, distinguished by their individualistic or collectivist personal values. In a discussion of the nature of values, this paper highlights how values may act as drivers of our behavior and pays particular attention to the values of the entrepreneur, thereby linking the existing debate on moral agency with the field of corporate social responsibility. (shrink)

Various thinkers are concerned that the Orthodox view of Ancestral Sin does not avoid the age-old Augustinian concern of Pelagianism. After all, the doctrine of Ancestral Sin maintains that fallen human beings do not necessarily or inevitably commit actual sins. In contemporary literature, this claim could be articulated as a denial of the ‘inevitability thesis.’ A denial of the inevitability thesis, so contemporary thinkers maintain, seems to imply both that human beings can place themselves in right relation to God as (...) well as the Pelagian denial that all require Christ's work to attain this right relation to God. This article demonstrates that the Ancestral Sin, along with a denial of the inevitability thesis, is neither Pelagian nor Semi-Pelagian. I show that the doctrine of Ancestral Sin denies (Semi-) Pelagianism in various ways. I show that, for Ancestral Sin to entail (Semi-) Pelagianism, one must commit to several assumptions, each of which is plausibly deniable and none of which Orthodox thinkers affirm. (shrink)

Despite the lack of evidence for their effectiveness, the use of physical restraints for patients is widespread. The best ethical justification for restraining patients is that it prevents them from harming themselves. We argue that even if the empirical evidence supported their effectiveness in achieving this aim, their use would nevertheless be unethical, so long as well known exceptions to informed consent fail to apply. Specifically, we argue that ethically justifiable restraint use demands certain necessary and sufficient conditions. These conditions (...) are that the physician obtain informed consent for their application, that their application be medically appropriate, and that restraints be the least liberty-restricting way of achieving the intended benefit. It is a further question whether their application is ever medically appropriate, given the dearth of evidence for their effectiveness. (shrink)

Default positions, predetermined starting points that aid in complex decision-making, are common in clinical medicine. In this article, we identify and critically examine common default positions in clinical ethics practice. Whether default positions ought to be held is an important normative question, but here we are primarily interested in the descriptive, rather than normative, properties of default positions. We argue that default positions in clinical ethics function to protect and promote important values in medicine—respect for persons, utility, and justice. Further, (...) default positions in clinical ethics may also guard against harm. Where default positions exist, there are epistemic burdens to overturn them. The person wishing to reject the default position, rather than the person endorsing it, bears this burden. The person who bears the burden of meeting the epistemic requirements must provide evidence proportional to the degree of harm the default position protects against. Default positions that protect against significant harm impose significant epistemic requirements to overturn. This asymmetry not only makes medical decision-making more economical but also serves to promote and protect certain values. The identification and analysis of common and recognizable default positions can help to identify other default positions and the conditions under which their associated epistemic requirements are met. The article concludes with considerations of potential problems with the use of default positions in clinical ethics. (shrink)

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

In this paper, we consider the question of whether there exists an essential relation between emotions and wellbeing. We distinguish three ways in which emotions and wellbeing might be essentially related: constitutive, causal, and epistemic. We argue that, while there is some room for holding that emotions are constitutive ingredients of an individual’s wellbeing, all the attempts to characterise the causal and epistemic relations in an essentialist way are vulnerable to some important objections. We conclude that the causal and epistemic (...) relation between emotions and wellbeing is much less strong than is commonly thought. (shrink)

As the science and technology of the brain and mind develop, so do the ways in which brains and minds may be surveilled and manipulated. Some cognitive libertarians worry that these developments undermine cognitive liberty, or “freedom of thought.” I argue that protecting an individual’s cognitive liberty undermines others’ ability to use their own cognitive liberty. Given that the threatening devices and processes are not relevantly different from ordinary and frequent intrusions upon one’s brain and mind, strong protections of cognitive (...) liberty may proscribe neurotechnological intrusions, but also ordinary intrusions. Thus, the cognitive libertarian position “hog-ties” others’ use of their own liberties. This problem for the cognitive libertarian is the same problem that ordinary libertarianism faces in protecting individual rights to property and person. But the libertarian strategies for resolving the problem don’t work for the cognitive libertarian. I conclude that the right to mental privacy is weaker than what cognitive libertarians want it to be. (shrink)

Brummett and Salter propose a useful and timely taxonomy of clinical ethics expertise (2019). As the field becomes further “professionalized” this taxonomy is important, and the core of it is right. It needs some refinement around the edges, however. In their conclusion, Brummett and Salter rightly point out that there is a significant difference between the ethicist whose recommendations are procedure- and process-heavy, consensus-driven, and dialogical and the authoritarian ethicist whose recommendations flow from “private moral views” (Brummett and Salter, 2019). (...) This admission doesn’t go far enough. Brummett and Salter’s taxonomy fails to capture the notion that offering recommendations whose normative force is moral is different in kind from recommendations whose normative force is non-moral, such as those recommendations that are free of moral content or justified by convention. The difference is in kind, not scale. I argue further that clinical ethics expertise, if possible, consists at least in offering recommendations whose normative force is moral. These two claims imply that the taxonomy fails to cut clinical ethics expertise at the joints: the ethicist who offers justified non-moral normative recommendations is a different kind of ethicist from the one who offers justified moral normative recommendations, yet both are categorized as clinical ethics experts. I finish by offering a refinement of the taxonomy that more precisely categorizes clinical ethicists. (shrink)

We critically engage two traditional views of scientific data and outline a novel philosophical view that we call the pragmatic-representational view of data. On the PR view, data are representations that are the product of a process of inquiry, and they should be evaluated in terms of their adequacy or fitness for particular purposes. Some important implications of the PR view for data assessment, related to misrepresentation, context-sensitivity, and complementary use, are highlighted. The PR view provides insight into the common (...) but little-discussed practices of iteratively reusing and repurposing data, which result in many datasets’ having a phylogeny—an origin and complex evolutionary history—that is relevant to their evaluation and future use. We relate these insights to the open-data and data-rescue movements, and highlight several future avenues of research that build on the PR view of data. (shrink)

In a recent issue of Bioethics, I argued that compulsory moral bioenhancement should be administered covertly. Alexander Zambrano has criticized this argument on two fronts. First, contrary to my claim, Zambrano claims that the prevention of ultimate harm by covert moral bioenhancement fails to meet conditions for permissible liberty‐restricting public health interventions. Second, contrary to my claim, Zambrano claims that covert moral bioenhancement undermines autonomy to a greater degree than does overt moral bioenhancement. In this paper, I rebut both of (...) these arguments, then finish by noting important avenues of research that Zambrano’s arguments motivate. (shrink)

Emotions often misfire. We sometimes fear innocuous things, such as spiders or mice, and we do so even if we firmly believe that they are innocuous. This is true of all of us, and not only of phobics, who can be considered to suffer from extreme manifestations of a common tendency. We also feel too little or even sometimes no fear at all with respect to very fearsome things, and we do so even if we believe that they are fearsome. (...) Indeed, instead of shunning fearsome things, we might be attracted to them. Emotions that seem more thought-involving, such as shame, guilt or jealousy, can also misfire. You can be ashamed of your big ears even though we can agree that there is nothing shameful in having big ears, and even though you judge that having big ears does not warrant shame. And of course, it is also possible to experience too little or even no shame at all with respect to something that is really shameful. Many of these cases involve a conflict between one’s emotion and one’s evaluative judgement. Emotions that are thus conflicting with judgement can be called ‘recalcitrant emotions’. The question I am interested in is whether or not recalcitrant emotions amount to emotional illusions, that is, whether or not these cases are sufficiently similar to perceptual illusions to justify the claim that they fall under the same general heading. The answer to this depends on what emotions are. For instance, the view that emotions are evaluative judgments makes it difficult to make room for the claim that emotional errors are perceptual illusions. Fearing an innocuous spider would simply amount to making the error of judging that the spider is fearsome while it is in fact innocuous. This might involve an illusion of some sort, but it certainly does not amount to anything like a perceptual illusion. In this chapter, I argue that recalcitrant emotions are a kind of perceptual illusion.. (shrink)

The movement of people across borders is one of the most pressing issues of our time. Yet it is still unclear how migration should be regulated to be fair to the sending societies, the host societies and the individual migrant. What is at issue? Are we discussing migration from an ethical or from a political philosophical perspective, or both? Are we discussing migration from a global justice perspective or social justice perspective? Do we consider political legitimacy and democratic self-determination as (...) part of our analysis? How should we balance demands of justice in immigration compared to those of emigration? (shrink)

In biomedical ethics, there is widespread acceptance of moral realism, the view that moral claims express a proposition and that at least some of these propositions are true. Biomedical ethics is also in the business of attributing moral obligations, such as “S should do X.” The problem, as we argue, is that against the background of moral realism, most of these attributions are erroneous or inaccurate. The typical obligation attribution issued by a biomedical ethicist fails to truly capture the person's (...) actual obligations. We offer a novel argument for rife error in obligation attribution. The argument starts with the idea of an epistemic burden. Epistemic burdens are all of those epistemic obstacles one must surmount in order to achieve some aim. Epistemic burdens shape decision-making such that given two otherwise equal options, a person will choose the option that has the lesser of epistemic burdens. Epistemic burdens determine one's potential obligations and, conversely, their non-obligations. The problem for biomedical ethics is that ethicists have little to no access to others' epistemic burdens. Given this lack of access and the fact that epistemic burdens determine potential obligations, biomedical ethicists often can only attribute accurate obligations out of luck. This suggests that the practice of attributing obligations in biomedical ethics is rife with error. To resolve this widespread error, we argue that this practice should be abolished from the discourse of biomedical ethics. (shrink)

Recently a number of scientists have proposed substantial changes to the practice of climate modeling, though they disagree over what those changes should be. We provide an overview and critical examination of three leading proposals: the unified approach, the hierarchy approach and the pluralist approach. The unified approach calls for an accelerated development of high-resolution models within a seamless prediction framework. The hierarchy approach calls for more attention to the development and systematic study of hierarchies of related models, with the (...) aim of advancing understanding. The pluralist approach calls for greater diversity in modeling efforts, including, on some of its variants, more attention to empirical modeling. After identifying some of the scientific and institutional challenges faced by these proposals, we consider their expected gains and costs, relative to a business-as-usual modeling scenario.We find the proposals to be complementary, having valuable synergies. But since resource limitations make it unlikely that all three will be pursued, we offer some reflections on more limited changes in climate modeling that seem well within reach and that can be expected to yield substantial benefits. (shrink)

We thank all the thoughtful authors for their insightful comments. In this response, we try to address some of themes that emerged from the commentaries. We leave aside some of those comments that...

The moral error theory generally does not receive good press in metaethics. This paper adds to the bad news. In contrast to other critics, though, I do not attack error theorists’ characteristic thesis that no moral assertion is ever true. Instead, I develop a new counter-argument which questions error theorists’ ability to defend their claim that moral utterances are meaningful assertions. More precisely: Moral error theorists lack a convincing account of the meaning of deontic moral assertions, or so I will (...) argue. (shrink)

This paper explores the mathematical details behind the geometric transformation of folding a circle into a cone. It includes detailed theo- rems, proofs, and Python implementations for visualization, providing a thorough analysis of the transformation process.

Most current dental ethics curricula use a deontological approach to biomedical and dental ethics that emphasizes adherence to duties and principles as properties that determine whether an act is ethical. But the actual ethical orientation of students is typically unknown. The purpose of the current study was to determine the ethical orientation of dental students in resolving clinical ethical dilemmas. First-year students from one school were invited to participate in an electronic survey that included eight vignettes featuring ethical conflicts common (...) to the health care setting. The Multidimensional Ethics Scale was used to evaluate the students’ ethical judgments of these conflicts. Students rated each vignette along 13 ethically relevant items using a 7-point scale. Nine of the thirteen items were analyzed because they represent the dominant ethical theories, including deontology. One hundred sixteen dental students successfully completed the survey. Of the analyzed items, those associated with deontology had comparatively weak associations with whether students judged the action to be ethical and whether students judged themselves likely to perform the action. Whether an action was judged to be caring had the strongest association with whether the action was judged to be ethical and whether students judged themselves likely to perform the action. These results suggest that adherence to duties or principles has weaker association with students’ ethical judgments and behavior compared to caring, which was found to be more influential in their ethical judgments and behavior. Current dental school curricula with a primary focus on deontology may no. (shrink)

This paper provides suggestions for educators who have a desire to learn about, or are already committed to, challenging ableism and disablism. As philosophy teachers, we have the opportunity to facilitate student reflection regarding disability, which puts students in a position to make decisions about whether to retain their habitual ways of comporting themselves toward disabled people or to begin the process of forming new perceptual practices. I contend that existential phenomenology, as formulated by Maurice Merleau-Ponty and Linda Martín Alcoff, (...) provides insights regarding the habitual formation of perceptual practices that are useful for thinking about ways that perception may be informed by ableism and disablism. Jessica Cadwallader demonstrates how their insights can be usefully applied to thinking about perceptions of disability. Through analysis of past encounters with people with disabilities, Cadwallader suggests that students change their habitual ways of responding to people with disabilities. While such reflections may be valuable for making habitual perceptual practices explicit, I would suggest that this is only a condition for the possibility of changing ablist perceptual practices rather than the change itself. Students are likely to enter the classroom lacking the insight that they are even engaging in perceptual practices informed by cultural narratives rather than simply perceiving people with impairments as they are. I argue that an approach to teaching on disability that thematizes perceptual practices regarding disability, and takes experiences of disabled people into account, would be more effective than the one Cadwallader describes. Understanding the ways that people with disabilities experience being constructed as a problem through ableist perceptual practices could help students recognize their own potential to impact others in positive and negative ways. (shrink)

This paper argues for a conception of the natural rights of non-human animals grounded in Kant’s explanation of the foundation of human rights. The rights in question are rights that are in the first instance held against humanity collectively speaking—against our species conceived as an organized body capable of collective action. The argument proceeds by first developing a similar case for the right of every human individual who is in need of aid to get it, and then showing why the (...) situation of animals is similar. I first review some of the reasons why people are resistant to the idea that animals might have rights. I then explain Kant’s conception of natural rights. I challenge the idea that duties of aid and duties of kindness to animals fit the traditional category of “imperfect duties” and argue that they are instead cases of “imperfect right.” I explain how you can hold a right against a group, and why it is legitimate to conceive of humanity as such a group. I then argue that Kant’s account of the foundation of property rights is grounded in a conception of the common possession of the Earth that grounds a right to aid and the rights of animals to be treated in ways that are consistent with their good. Finally, I return to the objections to the idea that animals have rights and offer some responses to them. (shrink)

As the federal government distributed remdesivir to some of the states COVID-19 hit hardest, policymakers scrambled to develop criteria to allocate the drug to their hospitals. Our state, Michigan, was among those states to receive an initial quantity of the drug from the U.S. government. The disparities in burden of disease in Michigan are striking. Detroit has a death rate more than three times the state average. Our recommendation to the state was that it should prioritize the communities that bear (...) a disproportionate burden of suffering in the allocation of the new potential treatment. This recommendation is justified not only for new drugs with uncertain effects, but also for drugs of certain benefit or vaccines. For states with significant health disparities, such as Michigan, this allocation priority may help to repair them. In fact, any other allocation strategy may make them worse. (shrink)

Berger (forthcoming) states that moral intimacy is important in applying the best interests standard. But what he calls moral intimacy requires that someone has overcome epistemic burdens needed to represent the patient. We argue elsewhere that good surrogate decision-making is first and foremost a matter of overcoming epistemic burdens, or those obstacles that stand in the way of a surrogate decision-maker knowing what a patient wants and how to satisfy those preferences. Berger’s notion of moral intimacy depends on epistemic intimacy: (...) the fact that a surrogate's epistemic burdens with respect to the best interests of the incapacitated patient have been adequately surmounted, plus some other feature. Thus, where a particular patient-surrogate relationship fails to be morally intimate, what is lacking is either epistemic intimacy or this second feature. Furthermore, Berger uses the notion of moral intimacy as an explanans for the application of the best interests standard. We argue that the notions of epistemic intimacy and epistemic burdens not only help to explain the notion of moral intimacy, but also better explain the application of the best interests standard. Given the role of epistemic burdens and the epistemic intimacy that overcoming them enables, bioethicists and physicians should consider a surrogate’s epistemic standing relative to the patient’s best interests before pronouncing on the former’s ethical probity. (shrink)

Among psychiatric conditions, delusions have received significant attention in the philosophical literature. This is partly due to the fact that many delusions are bizarre, and their contents interesting in and of themselves. But the disproportionate attention is also due to the notion that by studying what happens when perception, cognition, and belief go wrong, we can better understand what happens when these go right. In this paper, I attend to delusions for the second reason—by evaluating the epistemology of delusions, we (...) can better understand the epistemology of ordinary belief. More specifically, given recent advancements in our understanding of how delusions are formed, the epistemology of delusions motivates a proper functionalist account of the justification of belief. Proper functionalist accounts of the justification of belief hold that whether a belief is justified is partly determined by whether the system that produces the belief is functioning properly. Whatever pathology is responsible for delusion formation, restoring it to its proper function resolves the epistemic condition, an effect which motivates proper functionalism. (shrink)

One difficulty in understanding recent debates is that not only have many terms been used to refer to weakness of will – “akrasia” and “incontinence” have often been used as synonyms of “weakness of will” – but quite different phenomena have been discussed in the literature. This is why the present entry starts with taxonomic considerations. The second section turns to the question of whether it is possible to freely and intentionally act against one’s better judgment.

According to recent suggestions within the global pragmatism discussion, metaethical debate must be fundamentally re-framed. Instead of carving out metaethical differences in representational terms, it has been argued that metaethics should be given an inferentialist footing. In this paper, I put inferentialist metaethics to the test by subjecting it to the following two criteria for success: Inferentialist metaethicists must be able to save the metaethical differences between moral realism and expressivism, and do so in a way that employs understandings of (...) these metaethical accounts which would be acceptable to moral realists or expressivists who endorse an inferentialist theory of meaning. Two results follow from my discussion. The first concerns inferentialist metaethics more narrowly, casting doubts on inferentialists’ ability to fulfil the two criteria for success by showing that proposed metaethical demarcation attempts either meet the first criterion but violate the second, or pass the second criterion but fail the first. The second upshot pertains to the global pragmatism debate more widely, pressing the point that inferentialists have not as yet provided a convincing account of ontological commitment. (shrink)

Recent work has defended “Euclidean” theories of set size, in which Cantor’s Principle (two sets have equally many elements if and only if there is a one-to-one correspondence between them) is abandoned in favor of the Part-Whole Principle (if A is a proper subset of B then A is smaller than B). It has also been suggested that Gödel’s argument for the unique correctness of Cantor’s Principle is inadequate. Here we see from simple examples, not that Euclidean theories of set (...) size are wrong, but that they must be either very weak and narrow or largely arbitrary and misleading. (shrink)

In this paper, I develop a metasemantics for relaxed moral realism. More precisely, I argue that relaxed realists should be inferentialists about meaning and explain that the role of evaluative moral vocabulary is to organise and structure language exit transitions, much as the role of theoretical vocabulary is to organise and structure language entry transitions.

Interventions aiming to slow, stop, or reverse the aging process are starting to enter clinical trials. Though this line of research is nascent, it has the potential to not only prevent prolonged human suffering, but also to extend human well-being. As this line of research develops, it is important to understand the ethical constraints of conducting such research. This paper discusses some of these constraints. In particular, it discusses the ethical difficulties of conducting this research in a way that would (...) produce reliable data regarding the effectiveness of an anti-aging intervention. Clinical trials of such interventions, I argue, will be faced with a dilemma between two confounding variables. Eliminating the variables requires introducing ethically problematic research practices. Thus, researchers must either perform research in ethically problematic ways, or forego the conduct of high-impact clinical research on anti-aging interventions. (shrink)

After discussing de Sousa's view of emotion in akrasia, I suggest that emotions be viewed as nonconceptual perceptions of value (see Tappolet 2000). It follows that they can render intelligible actions which are contrary to one's better judgment. An emotion can make one's action intelligible even when that action is opposed by one's all-things-considered judgment. Moreover, an akratic action prompted by an emotion may be more rational than following one's better judgement, for it may be the judgement and not the (...) perception which is in error. By contrast, "cool" akrasia is genuinely puzzling; it is not clear whether it exists. (shrink)

There is no uniquely standard concept of an effectively decidable set of real numbers or real n-tuples. Here we consider three notions: decidability up to measure zero [M.W. Parker, Undecidability in Rn: Riddled basins, the KAM tori, and the stability of the solar system, Phil. Sci. 70(2) (2003) 359–382], which we abbreviate d.m.z.; recursive approximability [or r.a.; K.-I. Ko, Complexity Theory of Real Functions, Birkhäuser, Boston, 1991]; and decidability ignoring boundaries [d.i.b.; W.C. Myrvold, The decision problem for entanglement, in: (...) R.S. Cohen et al. (Eds.), Potentiality, Entanglement, and Passion-at-a-Distance: Quantum Mechanical Studies fo Abner Shimony, Vol. 2, Kluwer Academic Publishers, Great Britain, 1997, pp. 177–190]. Unlike some others in the literature, these notions apply not only to certain nice sets, but to general sets in Rn and other appropriate spaces. We consider some motivations for these concepts and the logical relations between them. It has been argued that d.m.z. is especially appropriate for physical applications, and on Rn with the standard measure, it is strictly stronger than r.a. [M.W. Parker, Undecidability in Rn: Riddled basins, the KAM tori, and the stability of the solar system, Phil. Sci. 70(2) (2003) 359–382]. Here we show that this is the only implication that holds among our three decidabilities in that setting. Under arbitrary measures, even this implication fails. Yet for intervals of non-zero length, and more generally, convex sets of non-zero measure, the three concepts are equivalent. (shrink)

The theoretical foundations of climate science have received little attention from philosophers thus far, despite a number of outstanding issues. We provide a brief, non-technical overview of several of these issues – related to theorizing about climates, climate change, internal variability and more – and attempt to make preliminary progress in addressing some of them. In doing so, we hope to open a new thread of discussion in the emerging area of philosophy of climate science, focused on theoretical foundations.

A probability distribution is regular if no possible event is assigned probability zero. While some hold that probabilities should always be regular, three counter-arguments have been posed based on examples where, if regularity holds, then perfectly similar events must have different probabilities. Howson (2017) and Benci et al. (2016) have raised technical objections to these symmetry arguments, but we see here that their objections fail. Howson says that Williamson’s (2007) “isomorphic” events are not in fact isomorphic, but Howson is speaking (...) of set-theoretic representations of events in a probability model. While those sets are not isomorphic, Williamson’s physical events are, in the relevant sense. Benci et al. claim that all three arguments rest on a conflation of different models, but they do not. They are founded on the premise that similar events should have the same probability in the same model, or in one case, on the assumption that a single rotation-invariant distribution is possible. Having failed to refute the symmetry arguments on such technical grounds, one could deny their implicit premises, which is a heavy cost, or adopt varying degrees of instrumentalism or pluralism about regularity, but that would not serve the project of accurately modelling chances. (shrink)

Newton published his deduction of universal gravity in Principia (first ed., 1687). To establish the universality (the particle-to-particle nature) of gravity, Newton must establish the additivity of mass. I call ‘additivity’ the property a body's quantity of matter has just in case, if gravitational force is proportional to that quantity, the force can be taken to be the sum of forces proportional to each particle's quantity of matter. Newton's argument for additivity is obscure. I analyze and assess manuscript versions of (...) Newton's initial argument within his initial deduction, dating from early 1685. Newton's strategy depends on distinguishing two quantities of matter, which I call ‘active’ and ‘passive’, by how they are measured. These measurement procedures frame conditions on the additivity of each quantity so measured. While Newton has direct evidence for the additivity of passive quantity of matter, he does not for that of the active quantity. Instead, he tries to infer the latter from the former via conceptual analyses of the third law of motion grounded largely on analogies to magnetic attractions. The conditions needed to establish passive additivity frustrate Newton's attempted inference to active additivity. (shrink)

This article constructively retrieves St. Anselm of Canterbury’s theory of retributive justice and provides a defense of what can be called the retributive model of hell. In the first part of this article, we develop the place of retributive punishment in Anselm’s thinking and discuss how and when retributive punishment is a good thing. In the second part, we apply Anselm’s thinking on retributive justice to the problem of hell and provide a defense of how hell, defined as a state (...) of receiving retributive, damnatory, and irreversible punishment, is good. We then address a series of objections. Despite some criticism that both Anselm and the retributive model of hell receive in the contemporary literature, Anselm’s account of retributive justice can make unique and constructive contributions to the contemporary discussion of hell; by retrieving and applying Anselm’s thought to the problem of hell, we intend to kill two birds with one stone. (shrink)

Much thought has been devoted to how metaethical disagreement between moral realism and expressivism can be saved once minimalism starts creeping. Very little thought has been given to how creeping minimalism affects error-theories’ disagreement with their metaethical competitors. The reason for this omission, I suspect, is found in the belief that whilst locating distinctive moral realist and expressivist positions within a minimalist landscape poses a severe challenge, no such difficulties are encountered when differentiating error-theories from moral realism and expressivism. In (...) the first part of this paper, I show that this belief is mistaken: Insofar as moral realists and error-theorists are still taken to disagree, creeping minimalism renders their disagreement moral, but makes these positions metaethically indistinguishable. In the second part of the paper, I present a modified inferentialist solution to the problem of creeping minimalism which seeks to put error-theories back on the metaethical map. Yet, this too comes at a cost, in that it significantly modifies our interpretation of error-theories. Whichever way we turn, then, creeping minimalism not only forces us to re-phrase metaethical positions in a way that is compatible with minimalism, but also requires us to change our very understanding of these positions. (shrink)