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)

Background Several jurisdictions, including Singapore, Australia, New Zealand and most recently Ireland, have a public interest or public good criterion for granting waivers of consent in biomedical research using secondary health data or tissue. However, the concept of the public interest is not well defined in this context, which creates difficulties for institutions, institutional review boards and regulators trying to implement the criterion. Main text This paper clarifies how the public interest criterion can be defensibly deployed. We first explain the (...) ethical basis for requiring waivers to only be granted to studies meeting the public interest criterion, then explore how further criteria may be set to determine the extent to which a given study can legitimately claim to be in the public interest. We propose an approach that does not attempt to measure magnitude of benefit directly, but rather takes into account metrics that are more straightforward to apply. To ensure consistent and justifiable interpretation, research institutions and IRBs should also incorporate procedural features such as transparency and public engagement in determining which studies satisfy the public interest requirement. Conclusion The requirement of public interest for consent waivers in secondary biomedical research should be guided by well-defined criteria for systematic evaluation. Such a criteria and its application need to be periodically subject to intra-committee and intra-institution review, reflection, deliberation and amendment. (shrink)

Some have objected to human enhancement on the grounds that it violates the autonomy of the enhanced. These objections, however, overlook the interesting possibility that autonomy itself could be enhanced. How, exactly, to enhance autonomy is a difficult problem due to the numerous and diverse accounts of autonomy in the literature. Existing accounts of autonomy enhancement rely on narrow and controversial conceptions of autonomy. However, we identify one feature of autonomy common to many mainstream accounts: reasoning ability. Autonomy can then (...) be enhanced by improving people’s reasoning ability, in particular through cognitive enhancement; given how valuable autonomy is usually taken to be, this gives us extra reason to pursue such cognitive enhancements. Moreover, autonomy-based objections will be especially weak against such enhancements. As we will argue, those who are worried that enhancements will inhibit people’s autonomy should actually embrace those enhancements that will improve autonomy. (shrink)

Fichte assigns ‘intellectual intuition’ a new meaning after Kant. But in 1799, his doctrine of intellectual intuition is publicly deemed indefensible by Kant and nihilistic by Jacobi. I propose to defend Fichte’s doctrine against these charges, leaving aside whether it captures what he calls the ‘spirit’ of transcendental idealism. I do so by articulating three problems that motivate Fichte’s redirection of intellectual intuition from being to acting: (1) the regress problem, which states that reflecting on empirical facts of consciousness leads (...) only to further facts and so cannot yield a first principle; (2) the rhapsody problem, which states that the categories form a haphazard set and so lack necessity unless they derive from a first principle; and (3) the nihilism problem, which states that a first principle cannot lie outside our cognition of it, lest it be the cause of our cognition and, being first, the cause of all our actions, reducing us to machines. Crucially, Fichte’s three motivating problems are in fact aspects of a single problem. Leaving any aspect unsolved spoils putative solutions to the other two. Consequently, Fichte requires a single unified solution to all three, which his doctrine of intellectual intuition provides. (shrink)

A rapidly growing body of scholarship embraces virtue jurisprudence, a series of (often ad hoc) attempts to incorporate the philosophical tradition of virtue ethics into legal theory. Broadly understood, virtue ethics describes an approach to moral questions that emphasizes the importance of developing and embodying various virtues, often as manifestations of human flourishing. Scholars typically contrast virtue ethics with deontological and consequentialist moral theories, tracing virtue-centered analysis to ancient Greek philosophers, and in particular to Aristotle. Virtue ethics has experienced a (...) revival over the past 65 years; but, long before that, it proved especially influential in Catholic moral thought, particularly through the work of Aquinas. Perhaps relatedly, scholars have seized on virtue jurisprudence to defend a range of politically conservative positions, such as originalist constitutional interpretation and the propriety of utilizing the law to regulate ostensibly “private” immoralities. This Article reveals the radically underappreciated progressive promise of virtue jurisprudence. Virtue jurisprudence requires no religious commitments whatsoever, but a strong version entails acceptance of the moral significance of developing one’s character—both within and without the law. On a compelling understanding of the virtues, rejecting a state of perpetual disadvantage under the law is a meaningful marker of the virtue of self-respect, and a repudiation of the vice of servility that would otherwise be imposed by the legal system itself. Thus, contrary to the predominant tenor of research on the subject, virtue jurisprudence can ground significant resistance to—and even defiance of—the law. In making this argument, the Article also draws novel connections between virtue jurisprudence and literature on (inter alia) race, feminism, and sexual orientation to reveal the unnoticed potential of virtue jurisprudence to push forward work in those and related areas. At a time when massive and widespread protests across the United States reflect a groundswell of support for overturning certain long-standing, legally-ingrained, systemic disadvantages of people of color, many might be surprised to learn that virtue jurisprudence can serve as a potent theoretical ally. (shrink)

En su libro El libre albedrío: un estudio filosófico Carlos Moya presenta una objeción a los contraejemplos tipo-Frankfurt según la cual lo que hace que una alternativa sea robusta o no es el contexto en el que se encuentra el agente; así, alternativas que, en principio, no se verían como robustas y eximentes, pueden llegar a serlo en circunstancias especiales y los contraejemplos tipo-Frankfurt presentan, justamente, este tipo de circunstancias. En este escrito presento tres objeciones al brillante argumento de Moya. (...) En primer lugar, defiendo que no es claro que la alternativa que él considera robusta esté cumpliendo el papel de soportar, al menos en parte, la atribución de culpa del agente. En segundo lugar, retomo la respuesta que Moya ha dado a una crítica de Pereboom quien lo acusa de presuponer en el seno de su argumento al principio de posibilidades alternativas y, por ende, de caer en una petición de principio. Defiendo que la respuesta que ha dado Moya no le permite eludir la crítica de Pereboom. Finalmente, ofrezco una consideración acerca de cómo podría desarticularse la propuesta de Moya si se logra presentar un contraejemplo tipo-Frankfurt de corte determinista. (shrink)

Kant’s critique/doctrine distinction tracks the difference between a canon for the understanding’s proper use and an organon for its dialectical misuse. The latter reflects the dogmatic use of reason to attain a doctrine of knowledge with no antecedent critique. In the 1790s, Fichte collapses Kant’s distinction and redefines dogmatism. He argues that deriving a canon is essentially dialectical and thus yields an organon: critical idealism is properly a doctrine of science or Wissenschaftslehre. Criticism is furthermore said to refute dogmatism, by (...) which Fichte means Spinozism. Schelling repudiates Fichte’s position in his Philosophical Letters by reviving Kant’s distinction. First, ‘critique’ for Schelling names a canon that is valid for all systems—including Spinozism—and thus favours none—not even the Wissenschaftslehre. Second, Schelling coins ‘dogmaticism’ to refer to what Kant calls ‘dogmatism’: reason’s uncritical claim to doctrine. Hence, he says all systems—even Fichte’s—are susceptible to the ‘enthusiasm’ of mistaking themselves for doctrines or ‘objects of knowledge’, instead of subjectively valid ‘objects of freedom’. I reconstruct Schelling’s argument for reviving Kant’s distinction, while noting two consequences for German idealism. First, if criticism favours no system, a system’s origin cannot be an act of knowledge, e.g., intellectual intuition, but only an act of endorsement. Second, if dogmaticism entails enthusiasm, a system’s goal cannot be absolute knowledge, but only infinite striving. Hence, by retrieving Schelling’s notion of dogmaticism, we can both gain a better understanding of the Letters and register the impact of a core Kantian distinction on the German idealist project. (shrink)

Biological evolution is a complex blend of ever changing structural stability, variability and emergence of new phe- notypes, niches, ecosystems. We wish to argue that the evo- lution of life marks the end of a physics world view of law entailed dynamics. Our considerations depend upon dis- cussing the variability of the very ”contexts of life”: the in- teractions between organisms, biological niches and ecosys- tems. These are ever changing, intrinsically indeterminate and even unprestatable: we do not know ahead of (...) time the ”niches” which constitute the boundary conditions on selec- tion. More generally, by the mathematical unprestatability of the ”phase space”, no laws of mo- tion can be formulated for evolution. We call this radical emergence, from life to life. The purpose of this paper is the integration of variation and diversity in a sound concep- tual frame and situate unpredictability at a novel theoretical level, that of the very phase space. Our argument will be carried on in close comparisons with physics and the mathematical constructions of phase spaces in that discipline. The role of symmetries as invariant preserving transformations will allow us to under- stand the nature of physical phase spaces and to stress the differences required for a sound biological theoretizing. In this frame, we discuss the novel notion of ”enablement”. Life lives in a web of enablement and radical emergence. This will restrict causal analyses to differential cases. Mutations or other causal differ- ences will allow us to stress that ”non conservation princi- ples” are at the core of evolution, in contrast to physical dynamics, largely based on conservation principles as sym- metries. Critical transitions, the main locus of symmetry changes in physics, will be discussed, and lead to ”extended criticality” as a conceptual frame for a better understanding of the living state of matter. (shrink)

The COVID-19 pandemic revealed numerous weaknesses in pandemic preparedness and response, including underfunding, inadequate surveillance, and inequitable distribution of countermeasures. To overcome these weaknesses for future pandemics, WHO released a zero draft of a pandemic treaty in February, 2023, and subsequently a revised bureau's text in May, 2023. COVID-19 made clear that pandemic prevention, preparedness, and response reflect choices and value judgements. These decisions are therefore not a purely scientific or technical exercise, but are fundamentally grounded in ethics. The latest (...) treaty draft reflects these ethical considerations by including a section entitled Guiding Principles and Approaches. Most of these principles are ethical—they establish core values that undergird the treaty. Unfortunately, the treaty draft's set of principles are numerous, overlapping, and show inadequate coherence and consistency. We propose two improvements to this section of the draft pandemic treaty. First, key guiding ethical principles should be clearer and more precise than they currently are. Second, the link between ethical principles and policy implementation should be clearly established and define boundaries on acceptable interpretation, ensuring that signatories abide by these principles. (shrink)

It has recently been argued that reproductive genetic manipulation technologies like mitochondrial replacement and germline CRISPR modifications cannot be said to save anyone’s life because, counterfactually, no one would suffer more or die sooner absent the intervention. The present article argues that, on the contrary, reproductive genetic manipulations may be life-saving (and, from this, have therapeutic value) under an appropriate population health perspective. As such, popular reports of reproductive genetic manipulations potentially saving lives or preventing disease are not necessarily mistaken, (...) though such terminology still requires further empirical validation. (shrink)

Throughout his career, Schelling assigns knowledge of the absolute first principle of philosophy to intellectual intuition. Schelling's doctrine of intellectual intuition raises two important questions for interpreters. First, given that his doctrine undergoes several changes before and after his identity philosophy, to what extent can he be said to “hold onto” the same “sense” of it by the 1830s, as he claims? Second, given that his doctrine of intellectual intuition restricts absolute idealism to what he calls a “science of reason”, (...) which he says cannot prove the absolute’s existence, what other doctrine does he require in order to prove this? I will answer these questions by tracing the shifts in Schelling’s doctrine of intellectual intuition from the 1790s to the 1830s and drawing out its evolving methodological role within his science of intelligibility. (shrink)

In the Vocation of Man, Fichte makes the striking claim that life is eternal, rational, our true being, and the final cause of nature in general and of death in particular. How can we make sense of this claim? I argue that the public lectures that compose the Vocation are a popular expression of Fichte’s pre-existing commitment to what I call immortalism, the view that life is the unconditioned condition of intelligibility. Casting the I as an absolutely self-active or living (...) power enables his philosophical account of both the intelligibility of objects and of what it means to die. This explains his characterization of the Wissenschaftslehre as a system in which ‘all is act, movement, and life’. In Sect. 1, I explain the context of Jacobi’s use of ‘caput mortuum’ as a term for the thing in itself. In Sects. 2 and 3, I reconstruct two immortalist arguments from Fichte’s Jena period. The first is that the I’s self-activity rules out the existence of the thing in itself and thereby vanquishes ‘death’s head’. The second is that, insofar as the I charges us with the moral perfection of nature, it is the final cause of our entire life, including its end. This is to say that the I puts our every moment into question, even our last. In Sect. 4, I use these immortalist arguments to interpret the striking claim from the Vocation. (shrink)

While the idea that philosophy requires self-transformation is historically pervasive, it exerts considerable influence on the post-Kantians who first aim to systematize Kant’s idealism by grounding it on a first principle. In the 1790s, Fichte and Schelling offer competing accounts of the self-transformation that they regard as essential to positing a first principle. Their accounts raise two central questions. First, what makes this kind of self-transformation possible? Second, are there different possible expressions of philosophical self-transformation? In what follows, I will (...) articulate the Fichtean and Schellingian answers to these central questions. For Fichte, the one who summons me to posit a first principle makes possible my philosophical self-transformation, although the latter has an exclusively idealist expression in that I can only genuinely posit the I as first principle, which is to say that philosophical self-transformation depends on mutual recognition and vindicates precisely one philosophical system (Section 1). For Schelling, a brute act of will makes possible my philosophical self-transformation, although the latter has either an idealist or a realist expression in that I can genuinely posit either the I or the not-I as first principle, which is to say that philosophical self-transformation does not depend on mutual recognition and vindicates one of two possible philosophical systems (Section 2). Thus, whereas Fichtean self-transformation is recognitive and non-pluralistic, Schellingian self-transformation is pluralistic and non-recognitive. I conclude with a discussion of how Jacobi poses a challenge to Fichte’s and Schelling’s answers to the two central questions (Section 3). (shrink)

The concept of facticity denotes conditions of experience whose necessity is not logical yet whose contingency is not empirical. Although often associated with Heidegger, Fichte coins ‘facticity’ in his Berlin period to refer to the conclusion of Kant’s metaphysical deduction of the categories, which he argues leaves it a contingent matter that we have the conditions of experience that we do. Such rhapsodic or factical conditions, he argues, must follow necessarily, independent of empirical givenness, from the I through a process (...) of ‘genesis.’ I reconstruct Fichte’s argument by tracing the origin of his neologism, presenting his Jena critique of Kant’s rhapsodic appeal to the forms of judgment, and illustrating the Jena period’s continuity with the Berlin period’s genetic method, while noting a methodological shift whereby Fichte directs his critique against his own doctrine of intellectual intuition in order to eliminate its ‘factical terms.’. (shrink)

This chapter intervenes in recent debates in Kant scholarship about the possibility of a general logical alien. Such an alien is a thinker whose laws of thinking violate ours. She is third-personal as she is radically unlike us. Proponents of the constitutive reading of Kant’s conception of general logic accordingly suggest that Kant rules out the possibility of such an alien as unthinkable. I add to this an often-overlooked element in Kant’s thinking: there is reason to think that he grants—and (...) in fact presupposes—the possibility of a transcendental logical alien. Such an alien is a knower whose laws of experience purport to violate ours. She is first-personal as she is radically like us. In other words, she is us, insofar as we are alienated from ourselves and our experience. I go on to draw an analogy between her, a dogmatist, and another transcendental alien, an evil agent. Just as a dogmatist is alienated from her (our) experiential laws, an evil agent is alienated from her (our) moral law. These forms of theoretical and practical self-conceit require self-knowledge in the form of a critique of speculative or practical reason. In bringing this point out, I aim to shift from the question of whether logical laws constitute our thinking to the question of whether grasping our experiential and moral laws as our laws constitutes our reason. (shrink)

The prospect of consumable meat produced in a laboratory setting without the need to raise and slaughter animals is both realistic and exciting. Not only could such in vitro meat become popular due to potential cost savings, but it also avoids many of the ethical and environmental problems with traditional meat productions. However, as with any new technology, in vitro meat is likely to face some detractors. We examine in detail three potential objections: 1) in vitro meat is disrespectful, either (...) to nature or to animals; 2) it will reduce the number of happy animals in the world; and 3) it will open the door to cannibalism. While each objection has some attraction, we ultimately find that all can be overcome. The upshot is that in vitro meat production is generally permissible and, especially for ethical vegetarians, worth promoting. (shrink)

This paper is a critical examination of Stephen Neale's *The Philosophical Significance of Godel's slingshot*. I am sceptical of the philosophical significance of Godel’s Slingshot (and of Slingshot arguments in general). In particular, I do not believe that Godel’s Slingshot has any interesting and important philosophical consequences for theories of facts or for referential treatments of definite descriptions. More generally, I do not believe that any Slingshot arguments have interesting and important philosophical consequences for theories of facts or for referential (...) treatments of definite descriptions. Friends of facts and referential treatments of definite descriptions can, and should, proceed with the construction of their theories, blithely ignoring the many Slingshots which now litter the landscape. (Of course, there may be other considerations which should give such theorists pause -- but those are other considerations.). (shrink)

The Medical bot project is built using artificial algorithms that analyses user’s queries and understand user’s message. This System is a web application which provides answer to the query of the patients. Patients just have to query through the bot which is used for chatting. Patients can chat using any format there is no specific format the user has to follow. The System uses built in artificial intelligence to answer the query. The answers are appropriate what the user queries. The (...) User can query any Medical related activities through the system. The user does not have to personally go to the Medical for enquiry. The System analyses the question and then answers to the user. The system answers to the query as if it is answered by the person. With the help of artificial intelligence, the system answers the query asked by the patients. The system replies using an effective Graphical user interface which implies that as if a real person is talking to the user. The user just has to register himself to the system and has to login to the system. After login user can access to the various helping pages. Various helping pages has the bot through which the user can chat by asking queries related to Medical activities. The system replies to the user with the help of effective graphical user interface. The user can query about the Medical related activities through online with the help of this web application. The user can query Medical related activities such as date and timing of annual day, sports day, and other cultural activities. This system helps the patients to be updated about the Medical activities. (shrink)

In the Freedom essay, Schelling charges that (1) idealism fails to grasp human freedom’s distinctiveness and that (2) this failure undermines idealism's attempt to refute pantheism, as exemplified by Spinoza. This raises two questions, which I will answer in turn: what, for Schelling, is distinctive of human freedom; and how does the idealists’ failure to grasp it render them unable to refute pantheism? To answer these questions, I will reconstruct Schelling’s argument that freedom has the distinctness of being the unconditioned (...) condition of the world’s intelligibility. My reconstruction will illustrate how Schelling’s notion of freedom as primal will grounds the alleged primacy of practical reason as Kant and Fichte conceive it. I will then consider three objections to Schelling’s argument. Throughout, I will develop the Schellingian idea that freedom is enacted in an unprethinkable decision that cannot be anticipated by any law or principle. (shrink)

Kant’s critique/doctrine distinction tracks the difference between a canon for the understanding’s proper use and an organon for its dialectical misuse. The latter reflects the dogmatic use of reason to attain a doctrine of knowledge with no antecedent critique. In the 1790s, Fichte collapses Kant’s distinction and redefines dogmatism. He argues that deriving a canon is essentially dialectical and thus yields an organon: critical idealism is properly a doctrine of science or Wissenschaftslehre. Criticism is furthermore said to refute dogmatism, by (...) which Fichte means Spinozism. Schelling repudiates Fichte’s position in his Philosophical Letters by reviving Kant’s distinction. First, ‘critique’ for Schelling names a canon that is valid for all systems—including Spinozism—and thus favours none—not even the Wissenschaftslehre. Second, Schelling coins ‘dogmaticism’ to refer to what Kant calls ‘dogmatism’: reason’s uncritical claim to doctrine. Hence, he says all systems—even Fichte’s—are susceptible to the ‘enthusiasm’ of mistaking themselves for doctrines or ‘objects of knowledge’, instead of subjectively valid ‘objects of freedom’. I reconstruct Schelling’s argument for reviving Kant’s distinction, while noting two consequences for German idealism. First, if criticism favours no system, a system’s origin cannot be an act of knowledge, e.g., intellectual intuition, but only an act of endorsement. Second, if dogmaticism entails enthusiasm, a system’s goal cannot be absolute knowledge, but only infinite striving. Hence, by retrieving Schelling’s notion of dogmaticism, we can both gain a better understanding of the Letters and register the impact of a core Kantian distinction on the German idealist project. (shrink)

A precursor to the hard problem of consciousness confronts nihilism. Like physicalism, nihilism collides with the first-personal fact of what perception and action are like. Unless this problem is solved, nature’s inclusion of conscious experience will remain, as Chalmers warns the physicalist, an “unanswered question” and, as Jacobi chides the nihilist, “completely inexplicable". One advantage of Kant’s Copernican turn is to dismiss the question that imposes this hard problem. We need not ask how nature is accompanied by the first-person standpoint (...) because “I think” is an apperceptive form of thinking that must be able to accompany any cognition of nature. Kant’s formal conception of apperception worries Fichte in his Nova Methodo lectures. This conception arguably cannot exhaust the ground of experience, for it does not show why we posit objects “at all". For Fichte, it is our agency that first opens a world of objects, viz., as subjects, means, ends, and obstacles. In what follows, I argue that, for Fichte, the I poses no hard problem because it collides exclusively with nihilistic views like Spinozism, which are refuted by a properly transcendental idealist conception of apperception, according to which the first-person standpoint is the absolute ground of our experience of nature. If transcendental idealism refutes nihilism, nature is no more explicable than that there is something it is like for me to perceive and act. In Section 1, I show why Kantian apperception is necessary for possible experience. In Section 2, I reconstruct Fichte’s argument that a modified conception of apperception refutes guises of nihilism, thereby solving the hard problem of consciousness. In Section 3, I suggest that transcendental idealism undermines Chalmers’ proposed solution to and Dennett’s dismissal of this problem. (shrink)

Aristotle argued that you need some wealth to live well. The Stoics argued that you could live well with or without wealth. But the Cynics argued that wealth is a hinderance. For the Cynics, a good life consists in self-sufficiency, or being able to rule and help yourself. You accomplish this by living simply and naturally, and by subjecting yourself to rigorous philosophical exercises. Cynics confronted people to get them to abandon extraneous possessions and positions of power to live better. (...) And while the Cynics were experts in living in this way, their ascetic lifestyles made their message curious to some audiences. This paper reflects on Cynic ascetic practices and the ways others perceived them. (shrink)

Two attitudes are possible: one, that the world is an absolute jungle and that the exercise of coercive power by rulers is only a manifestation of this; and the other, that it is both necessary and right that there should be this exercise of power, that through it the world is much less of a jungle than it could possibly be without it, so that one should in principle be glad of the existence of such power, and only take exception (...) to its unjust exercise. (shrink)

The current prevailing view is that participation in biomedical research is above and beyond the call of duty. While some commentators have offered reasons against this, we propose a novel public goods argument for an obligation to participate in biomedical research. Biomedical knowledge is a public good, available to any individual even if that individual does not contribute to it. Participation in research is a critical way to support an important public good. Consequently, all have a duty to participate. The (...) current social norm is that individuals participate only if they have a good reason to do so. The public goods argument implies that individuals should participate unless they have a good reason not to. Such a shift would be of great aid to the progress of biomedical research, eventually making society significantly healthier and longer lived. (shrink)

"It is the purpose of this article to attempt to re-examine the account of Thrasymachus' doctrine in Plato's Republic, and to show how it can form a self-consistent whole. [...] In this paper it is maintained that Thrasymachus is holding a form of [natural right]." Note: Volume 40 = new series 9.

Our era is characterized by a significant conflict between populism and anti-populism, both politically and culturally. Populist groups and leaders often portray themselves as the true voices of the common people, gaining electoral support or even taking power by framing society as a battle between the ordinary people and the elite, challenging the political and economic establishment. Conversely, parties within the liberal political spectrum counteract the rise of populism by articulating a strong anti-populist discourse, sometimes successfully dominating the political arena. (...) However, despite the increase in studies on populism, there are not many publications regarding anti-populism. This article seeks to examine the anti-populist discourse in Argentina and Greece, two countries with many similarities in political, economic, and cultural aspects. By analyzing the key ideas of anti-populist discourse, we aim to highlight the common anti-populist logic marked by typical paths of modernization, which not only opposes populism but also frequently disregards or opposes specific social groups, such as minorities. (shrink)

While philosophers are often concerned with the conditions for moral knowledge or justification, in practice something arguably less demanding is just as, if not more, important – reliably making correct moral judgments. Judges and juries should hand down fair sentences, government officials should decide on just laws, members of ethics committees should make sound recommendations, and so on. We want such agents, more often than not and as often as possible, to make the right decisions. The purpose of this paper (...) is to propose a method of enhancing the moral reliability of such agents. In particular, we advocate for a procedural approach; certain internal processes generally contribute to people’s moral reliability. Building on the early work of Rawls, we identify several particular factors related to moral reasoning that are specific enough to be the target of practical intervention: logical competence, conceptual understanding, empirical competence, openness, empathy and bias. Improving on these processes can in turn make people more morally reliable in a variety of contexts and has implications for recent debates over moral enhancement. (shrink)

Moral enhancement is an ostensibly laudable project. Who wouldn’t want people to become more moral? Still, the project’s approach is crucial. We can distinguish between two approaches for moral enhancement: direct and indirect. Direct moral enhancements aim at bringing about particular ideas, motives or behaviors. Indirect moral enhancements, by contrast, aim at making people more reliably produce the morally correct ideas, motives or behaviors without committing to the content of those ideas, motives and/or actions. I will argue, on Millian grounds, (...) that the value of disagreement puts serious pressure on proposals for relatively widespread direct moral enhancement. A more acceptable path would be to focus instead on indirect moral enhancements while staying neutral, for the most part, on a wide range of substantive moral claims. I will outline what such indirect moral enhancement might look like, and why we should expect it to lead to general moral improvement. (shrink)

During his Jena period, Fichte endorses a curious dictum: ‘the kind of philosophy one chooses depends on the kind of person one is’. How can Fichte’s dictum support a vindication of German idealism over Spinozism, which he also calls ‘dogmatism’? I will show that the answer to this seemingly straightforward question reveals a rather complex series of metametaphysical objections that shape the development of the entire German idealist tradition. Ultimately, as I will suggest, the series of metametaphysical questions that shape (...) the German idealist tradition must culminate in the question of how to understand the relation between philosophy and its presuppositions. I will conclude by briefly considering a hermeneutical response to this question. (shrink)

This paper argues that McDowell wrongly assumes that “terror”, Cavell’s reaction to the radical contingency of our shared modes of knowing or our “attunement”, expresses a skepticism that is antinomically bound to an equally unacceptable dogmatism because Cavell rather regards terror as a mood that reveals the “truth of skepticism”, namely, that there is no conclusive evidence for necessary attunement on pain of a category error, and that a precedent for McDowell’s misunderstanding is Hegel’s argument for necessary attunement in a (...) system of knowing, whose refutation Schelling holds it is the “merit of skepticism” to provide. (shrink)

This article is a reply to Michael Gettings' criticisms of a previous paper of mine on Godel's ontological argument. (All relevant bibliographical details may be found in the article.) I provide a patch to my previous -- faulty -- attempt to provide a parody of Godel's ontological argument on the model of Gaunilo's parody of Anselm's Proslogion 2 argument.

The history of philosophy risks a self-opacity whereby we overestimate or underestimate our proximity to prior modes of thinking. This risk is relevant to assessing Hegel’s appropriation by McDowell and Priest. McDowell enlists Hegel for a quietist answer to the problem with assuming that concepts and reality belong to different orders, viz., how concepts are answerable to the world. If we accept Hegel’s absolute idealist view that the conceptual is boundless, this problem allegedly dissolves. Priest enlists Hegel for a dialetheist (...) answer to the problem with assuming that truth and falsity are mutually exclusive, viz., how certain sentences are both true and false. If we accept Hegel’s dialectical view that certain contradictions are necessary, this problem allegedly dissolves. For both McDowell and Priest, we find a true friend in Hegel. I argue that McDowell’s and Priest’s appropriations of Hegel overestimate Hegel’s affinity with quietism and dialetheism. McDowell reads Hegel as a quietist who silences metaphysical claims and the skeptical questions they raise against commonsense, but neglects Hegel’s adaptation of ancient skepticism against commonsense. Priest reads Hegel as a dialetheist who subordinates formal logic to dialectical logic by affirming the truth of certain contradictions, but neglects Hegel’s commitment to resolving contradictions for the sake of truth qua whole. I diagnose their misreadings in terms of what Hegel regards as the three moments of logic and argue that while McDowell jumps to its third moment, Priest stalls at its second moment. According to Hegel’s Encyclopedia Logic, logic has three “moments”: the abstractive moment of the understanding, which “stops short” at fixed categories; the negative moment of dialectic, which discovers the “genuine nature” of the categories, viz., that each “passes over, of itself, into its opposite”; and the positive moment of speculation, which grasps the “unity” of categories through the “dissolution” of their inner opposition. Hegel warns that if these moments are “kept separate from each other […] they are not considered in their truth”. I suggest that quietist and dialetheist readings of Hegel fail to consider truthfully the unified moments of his logic. In his quietist critique of metaphysics, McDowell enlists Hegel to dissolve the problem with assuming the duality of concept and reality. But McDowell helps himself directly to the third moment of logic, where the unity of the categories, and hence the boundlessness of the conceptual, would be fully articulated. Since he arrives at the third moment prematurely, ignoring its prior moments, he obscures its truth (§1). In his dialetheist critique of formal logic, Priest enlists Hegel to dissolve the problem with assuming the duality of truth and falsity. But Priest restricts himself gratuitously to the second moment of logic, where contradictions within the categories are not yet resolved. Since he stalls at the second moment, severed from its final moment, he obscures its truth (§2). I argue we can extricate Hegel from quietist and dialetheist misreadings only if we grasp the truth of the three moments of logic. (shrink)

It is commonly assumed that personalization technologies used by Google for the purpose of tailoring search results for individual users create filter bubbles, which reinforce users’ political views. Surprisingly, empirical evidence for a personalization-induced filter bubble has not been forthcoming. Here, we investigate whether filter bubbles may result instead from a searcher’s choice of search queries. In the first experiment, participants rated the left-right leaning of 48 queries (search strings), 6 for each of 8 topics (abortion, benefits, climate change, sex (...) equality, immigration, nuclear family, Islam, and taxation). An independent sample of participants were then asked to select one of these queries for each of the 8 topics. With the exception of the topic of Islam, participants were significantly more likely to select a query corresponding to their own political leaning, compared to other queries, explaining between 12% and 39% of the variance. A second experiment investigated the effect of the political leaning of the same queries on the overall political leaning of Search Engine Result Pages (SERPs) in Google Search. The top six results of each SERP were rated collectively by a third group of participants, explaining 36.3% of the variance across all 48 search terms (p < .00001). That is, (1) participants in our experiments tended to select own-side search queries, and (2) using those queries tended to yield own-side search results when using the Google search engine. Our results are consistent with the notion of a self-imposed filter bubble in which query selection plays a salient role. (shrink)

As opposed to a ‘one size fits all’ approach, precision medicine uses relevant biological, medical, behavioural and environmental information about a person to further personalize their healthcare. This could mean better prediction of someone’s disease risk and more effective diagnosis and treatment if they have a condition. Big data allows for far more precision and tailoring than was ever before possible by linking together diverse datasets to reveal hitherto-unknown correlations and causal pathways. But it also raises ethical issues relating to (...) the balancing of interests, viability of anonymization, familial and group implications, as well as genetic discrimination. This article analyses these issues in light of the values of public benefit, justice, harm minimization, transparency, engagement and reflexivity and applies the deliberative balancing approach found in theEthical Framework for Big Data in Health and Research to a case study on clinical genomic data sharing. Please refer to that article for an explanation of how this framework is to be used, including a full explanation of the key values involved and the balancing approach used in the case study at the end. Our discussion is meant to be of use to those involved in the practice as well as governance and oversight of precision medicine to address ethical concerns that arise in a coherent and systematic manner. (shrink)

-- 05.04.2024 -- Intervention held at the Italian Philosophical Society’s national congress’ section entitled "Texts, Words and Images: Philosophical Traditions and Translations", at Catholic University of the Sacred Heart, Milan, Italy -- -/- The aim of this intervention is to briefly advance an interpretation of the post- COVID19 digitalisation processes as to be recognised within the philosophical framework of Vorstellung Metaphysik, “metaphysics of representation”. I would maintain that the formula, firstly indicated by Martin Heidegger, can provide us with a tool (...) to interpret contemporary culture as founded on an “iteration” of individual and collective consciousness into non-existent digital realities. Moreover, I will argue that these concepts are philosophically relatable to those of alienation and reification that come from Marxist traditions. Ultimately, the analysis will try to use the above mentioned tools to delve into an interpretation of remote working and education as potential carriers of alienation. (shrink)

En este artículo ofrezco una defensa de la posibilidad de las obligaciones imposibles al ofrecer argumentos en contra de la idea según la cual estas obligaciones son un sinsentido, pues la función esencial de una obligación es la de ser una guía para la acción, y una obligación imposible no puede indicar ninguna acción a realizar. Pretendo mostrar cómo la idea de que las obligaciones han de ser guías de acción, en conjunto con la máxima “deber implica poder”, lleva a (...) consecuencias indeseables, y luego ofrezco argumentos para defender que las obligaciones imposibles están en mejor posición que otras obligaciones para guiar cierto tipo de acciones. (shrink)

Esta es una presentación crítica de la traducción del texto con el que James Beattie critica el ataque a la materia de Goerge Berkeley.

Fichte argues that the conclusion of Kant’s transcendental deduction of the categories is correct yet lacks a crucial premise, given Kant’s admission that the metaphysical deduction locates an arbitrary origin for the categories. Fichte provides the missing premise by employing a new method: a genetic deduction of the categories from a first principle. Since Fichte claims to articulate the same view as Kant in a different, it is crucial to grasp genetic deduction in relation to the sorts of deduction that (...) Kant offers. I propose to interpret genetic deduction as the simultaneous fulfillment of two tasks: answering the question quid facti by deriving the categories from the I and answering the question quid juris by establishing our entitlement to the categories as conditions of experience. While the second task represents Fichte’s agreement with Kant’s transcendental deduction, the first reflects his correction of Kant’s metaphysical deduction. (shrink)

This chapter aims to illuminate ways in which hope was significant in the philosophy of classical Greece. Although ancient Greek philosophies contain few dedicated and systematic expositions on the nature of hope, they nevertheless include important remarks relating hope to the good life, to reason and deliberation, and to psychological phenomena such as memory, imagination, fear, motivation, and pleasure. After an introductory discussion of Hesiod and Heraclitus, the chapter focuses on Plato and Aristotle. Consideration is given both to Plato’s direct (...) comments on hope and to the narrative contexts of his dialogues, with analysis of Plato’s positive and negative representations of hope, hope’s relationship to reason, and Plato’s more psychological approach in the Philebus, where hope finds a place among memory, recollection, pleasure, and pain. The chapter then reviews Aristotle’s discussions of confidence, hope, and courage, observing that although Aristotle does not mention hope as a virtue, he does note its importance to human agency and deliberation and as a foundation for the further development of virtue. The chapter concludes that discussions surrounding hope in ancient Greek philosophy are rich and challenging and can serve as a lively stimulus to further exploration of the concept of hope. (shrink)

It can be hard to see where money fits in the world. Money seems both real and imaginary, since it has obvious causal powers, but is also, just as obviously, something humans have just made up. Recent philosophical accounts of money have declared it to be real, but for very different reasons. John Searle and Francesco Guala disagree over whether money is just whatever acts like money, or just whatever people believe to be money. In developing their accounts of institutions (...) as a part of social reality, each uses money as a paradigm institution, but they disagree on how institutions exist. Searle argues that the institution of money belongs to an ontological level separate from the physical world, held up by the collective intentions of a group, while Guala claims that money is a part of the ordinary physical world and is just whatever performs a “money-like function” in a group, regardless of what that group believes about it. Here, we argue that any purely functional account like Guala’s will be unable to capture the distinctive phenomenon of money, since monetary transactions are defined by the attitudes transactors hold toward them. Money will be obscured or misidentified if defined functionally. As we go on to show by examining recent work by Smit et al., belief in money does not require taking on all of Searle’s ontological commitments, but money and mental contents will stand or fall together. (shrink)

The right to withdraw from participation in research is recognized in virtually all national and international guidelines for research on human subjects. It is therefore surprising that there has been little justification for that right in the literature. We argue that the right to withdraw should protect research participants from information imbalance, inability to hedge, inherent uncertainty, and untoward bodily invasion, and it serves to bolster public trust in the research enterprise. Although this argument is not radical, it provides a (...) useful way to determine how the right should be applied in various cases. (shrink)

Volume 20, Issue 2, February 2020, Page 20-22.

A gas in a box is perhaps the most important model system studied in thermodynamics and statistical mechanics. Usually, studies focus on the gas, whereas the box merely serves as an idealized confinement. The present article focuses on the box as the central object and develops a thermodynamic theory by treating the geometric degrees of freedom of the box as the degrees of freedom of a thermodynamic system. Applying standard mathematical methods to the thermody- namics of an empty box allows (...) equations with the same structure as those of cosmology and classical and quantum mechanics to be derived. The simple model system of an empty box is shown to have interesting connections to classical mechanics, special relativity, and quantum field theory. (shrink)

Materialism in the philosophy of mind — materialismPM — is the view that everything mental is material (or, equivalently, physical). Consciousness — pain, emotional feeling, sensory experience, and so on — certainly exists. So materialismPM is the view that consciousness is wholly material. It has, historically, nothing to do with denial of the existence of consciousness. Its heart is precisely the claim that consciousness — consciousness! — is wholly material. [2] ‘Physicalism’, the view introduced by members of the Vienna Circle (...) in the late 1920s, also has nothing to do with denial of the existence of consciousness. [3] Recently the words ‘materialism’ and ‘physicalism’ have come to be treated as synonymous, and as names for a position in the philosophy of mind that does involve denial of the existence of consciousness. They’ve been used to name a position that (i) directly rejects the heart of materialism (materialismPM) and (ii) is certainly false. This is a pity, because they’re good terms for a view that is very likely true. (shrink)

One of the main challenges faced by Frankfurt-style Cases has been elaborated by Carlos Moya. According to this argument, seemingly insignificant alternatives can become significant and exempting due to the context in which agents find themselves. Given that Frankfurt-style Cases involve extreme situations, seemingly insignificant alternatives become robust, rendering Frankfurt Cases ineffective against the Principle of Alternative Possibilities. This paper provides an overview of the contextual alternatives and Frankfurt Cases debate, presents Moya’s strategy, and ultimately advances an argument to cast (...) doubt on the effectiveness of Moya’s attack on Frankfurt Cases. (shrink)

Jerome Wakefield has argued that a disorder is a harmful dysfunction. This paper develops how Wakefield should construe harmful in his harmful dysfunction analysis. Recently, Neil Feit has argued that classic puzzles involved in analyzing harm render Wakefield’s HDA better off without harm as a necessary condition. Whether or not one conceives of harm as comparative or non-comparative, the concern is that the HDA forces people to classify as mere dysfunction what they know to be a disorder. For instance, one (...) can conceive of cases where simultaneous disorders prevent each other from being, in any traditional sense, actually harmful; in such cases, according to the HDA, neither would be a disorder. I argue that the sense of harm that Wakefield should employ in the HDA is dispositional, similar to the sense of harm used when describing a vile of poison: “Be careful! That’s poison. It’s harmful.” I call this harm in the damage sense. Using this sense of harm enables the HDA to avoid Feit’s arguments, and thus it should be preferred to other senses when analyzing harmful dysfunction. (shrink)