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)

The Genetic Algorithm (GA) and Simulated Annealing (SA), two techniques for global optimization, were applied to a reduced (simplified) form of the phase problem (RPP) in computational crystallography. Results were compared with those of "enhanced pair flipping" (EPF), a more elaborate problem-specific algorithm incorporating local and global searches. Not surprisingly, EPF did better than the GA or SA approaches, but the existence of GA and SA techniques more advanced than those used in this study suggest that these techniques still hold (...) promise for phase problem applications. The RPP is, furthermore, an excellent test problem for such global optimization methods. (shrink)

In my opinion it cannot be denied but that your discourse carries with it much of probability, arguing, as we say, ex suppositione, namely, granting that the Earth moves with the two motions assigned it by Copernicus; but, if one excludes those motions, all that you have said is vain and invalid; and for the exclusion of that hypothesis, it is very manifestly hinted by your discourse itself.

Both Philip and Andrew are philosophy students whose interests converge around the philosophy of technology broadly understood. Philip's interest is specifically aimed toward the ethics of Transhumanism and depictions of Transhumanism in works of fiction. On the other hand, Andrew finds himself more focused on religious behavior in the technological world. While the two perspectives might not seem that close, there is certain to be an overlap in Andrew and Philip's shared understanding of how technological phenomena play a crucial role (...) concerning religion and society. (shrink)

ABSTRACT Offsetting is a very ineffective way to do good. Offsetting your lifetime emissions may increase aggregated life expectancy by at most seven years, while giving the amount it costs to offset your lifetime emissions to a malaria charity saves in expectation the life of at least one child. Is there any moral reason to offset rather than giving to some charity that does good so much more effectively? There might be such a reason if your offsetting compensated or somehow (...) benefitted the victims of your emission, since that could mean that you would satisfy the duty not to harm others by emitting and offsetting. But that is typically not true. If your emission harms some person and your offsetting benefits some person, then these are most likely different people. Hence, I conclude, we have a stronger reason to give to effective charities than we have to offset our emissions. (shrink)

Signing Ceremony of MOU on Professional Legal Diploma, Government of Dubai 2020.

Jordan agreed to extensive liberalization undertakings under the General Agreement on Trade in Services (“GATS”) that would open some sectors that were previously closed or restricted to foreign suppliers and investors. It undertook horizontal commitments in cross-border movement of individuals and commercial presence covering all types of services.

Many philosophers think that we should use a lottery to decide who gets a good to which two persons have an equal claim but which only one person can get. Some philosophers think that we should save identified persons from harm even at the expense of saving a somewhat greater number of statistical persons from the same harm. I defend a principled way of justifying both judgements, namely, by appealing to the decreasing marginal moral value of survival chances. I identify (...) four desiderata that, I contend, any such justification should satisfy, and explain how my account meets these desiderata, unlike some previous accounts. (shrink)

This paper examines the metaphysically modest view that attributionsof normative reasons can be made true in the absence of a responseindependent normative reality. The paper despairs in finding asatisfactory account of normative reasons in metaphysically modestterms.

This book is a translation of W.V. Quine's Kant Lectures, given as a series at Stanford University in 1980. It provide a short and useful summary of Quine's philosophy. There are four lectures altogether: I. Prolegomena: Mind and its Place in Nature; II. Endolegomena: From Ostension to Quantification; III. Endolegomena loipa: The forked animal; and IV. Epilegomena: What's It all About? The Kant Lectures have been published to date only in Italian and German translation. The present book is filled out (...) with the translator's critical Introduction, "The esoteric Quine?" a bibliography based on Quine's sources, and an Index for the volume. (shrink)

The veil of ignorance argument was used by John C. Harsanyi to defend Utilitarianism and by John Rawls to defend the absolute priority of the worst off. In a recent paper, Lara Buchak revives the veil of ignorance argument, and uses it to defend an intermediate position between Harsanyi's and Rawls' that she calls Relative Prioritarianism. None of these authors explore the implications of allowing that agent's behind the veil are averse to ambiguity. Allowing for aversion to ambiguity---which is both (...) the most commonly observed and a seemingly reasonable attitude to ambiguity---however supports a version of Egalitarianism, whose logical form is quite different from the theories defended by the aforementioned authors. Moreover, it turns out that the veil of ignorance argument neither supports standard Utilitarianism nor Prioritarianism unless we assume that rational people are insensitive to ambiguity. (shrink)

Neoclassical economists use expected utility theory to explain, predict, and prescribe choices under risk, that is, choices where the decision-maker knows---or at least deems suitable to act as if she knew---the relevant probabilities. Expected utility theory has been subject to both empirical and conceptual criticism. This chapter reviews expected utility theory and the main criticism it has faced. It ends with a brief discussion of subjective expected utility theory, which is the theory neoclassical economists use to explain, predict, and prescribe (...) choices under uncertainty, that is, choices where the decision-maker cannot act on the basis of objective probabilities but must instead consult her own subjective probabilities. (shrink)

With the coronavirus pandemic and the Omicron variant once again forcing countries into lockdown, this essay seeks to outline a Foucauldian critique of various legal measures taken by the Danish government to cope with COVID-19 during the first year and a half of the pandemic. The essay takes a critical look at the extra-legal measures employed by the Danish government, as the Danish politicians attempted to halt the spread of the, now almost forgotten, Cluster 5 COVID-19 variant. This situation will (...) serve as a critical point from where to start using Foucault’s writings on life and biopolitics in order to expose various legally problematic governmental decisions that became visible during the handling of COVID-19 in general and the Cluster 5 mutation in particular. Reframing the pandemic within Foucault’s concept of biopolitics, this essay concludes that the state of exception has led to an increase in biopolitical logic, where some lives have come to matter more than others. As a critical counterpoint to this logic, the conclusion suggests that the notion of biocommunism could provide a suitable reconfiguration of communism. A reconfiguration that could mitigate some of the issues related to biopolitics is uncovered earlier in the essay. (shrink)

The relationship between “Towards a Critique of Violence” (1921) and the work of Franz Kafka has been well established by several critical studies devoted to Walter Benjamin. However, it is striking that Benjamin himself, already well acquainted with the work of the Czech writer in 1921, never made any comment to Kafka’s work in this essay, and, more broadly, in any of the related texts that make up the project on the ‘Critique of Violence’. In this article, we analyze a (...) set of notions (Entstellung, Entsühnung, Zurechstellen) that allow us to establish a mediated relationship between this essay and the articles and letters that Benjamin devoted to Kafka in the 1930s. This relationship takes us back to the only piece in which Benjamin carries out an autonomous treatment of the “category of justice” (1916) in which he identifies -as it will happen eighteen years later, in the essay on Kafka (1934)- the locus of justice in the “non-violence”, thus untying the knot that binds in a perhaps indiscernible way in the Jewish tradition the notions of “messianism” and “violence”. (shrink)

This classic collection of essays, first published in 1968, represents H.L.A. Hart's landmark contribution to the philosophy of criminal responsibility and punishment. Unavailable for ten years, this new edition reproduces the original text, adding a new critical introduction by John Gardner, a leading contemporary criminal law theorist.

We present an epistemological schema of natural sciences inspired by Peirce's pragmaticist view, stressing the role of the \emph{phenomenological map}, that connects reality and our ideas about it. The schema has a recognisable mathematical/logical structure which allows to explore some of its consequences. We show that seemingly independent principles as the requirement of reproducibility of experiments and the Principle of Sufficient Reason are both implied by the schema, as well as Popper's concept of falsifiability. We show that the schema has (...) some power in demarcating science by first comparing with an alternative schema advanced during the first part of the 20th century which has its roots in Hertz and has been developed by Einstein and Popper. Further, the identified differences allow us to focus in the construction of Special Relativity, showing that it uses an intuited concept of velocity that does not satisfy the requirements of reality in Peirce. While the main mathematical observation connected with this issue has been known for more than a century, it has not been investigated from an epistemological point of view. A probable reason could be that the socially dominating epistemology in physics does not encourage such line of work. We briefly discuss the relation of the abduction process presented in this work with discussions regarding ``abduction'' in the literature and its relation with ``analogy''. (shrink)

In this field questions arise which are certainly difficult; but as I listened last time to members of the group, I felt that the main difficulty perhaps lay in determining precisely what questions we are trying to answer. I have the conviction that if we could only say clearly what the questions are, the answers to them might not appear so elusive. So I have begun with a simple list of questions about discretion which in one form or another were, (...) as it seemed to me, expressed by the group last time. I may indeed have omitted something and inserted something useless: if so, no doubt I shall be informed of this later. The central questions then seem to me to be the following: 1. What is discretion, or what is the exercise of discretion? 2. Under what conditions and why do we in fact accept or tolerate discretion in a legal system? 3. Must we accept discretion or tolerate discretion, and if so, why? 4. What values does the use of discretion menace, and what values does it maintain or promote? 5. What can be done to maximize the beneficial operation of the use of discretion and to minimize any harm that it does? (shrink)

SummaryThis paper argues that the influence of language on science, philosophy and other field is mediated by communicative practices. Where communications is more restrictive, established linguistic structures exercise a tighter control over innovations and scientifically motivated reforms of language. The viewpoint here centers on the thesis that argumentation is crucial in the understanding and evaluation of proposed reforms and that social practices which limit argumentation serve to erode scientific objectivity. Thus, a plea is made for a sociology of scientific belief (...) designed to understand and insure social‐institutional conditions of the possibility of knowledge and its growth. A chief argument draws on work of Axelrod concerning the evolution of cooperation. (shrink)

This essay delves into the multifaceted concept of determin-ism within the domain of physics, scrutinizing prevalent definitions and classifications. Navigating through the nuances of deterministic behavior, we distinguish it from colloquial interpretations of "non-deterministic." By examining determin-ism through the lenses of natural laws, weak determinism, and strong determinism, we unravel the intricate relationship between predictability and the underlying mathematical structures of the universe. Classical mechanics serves as an exemplar of deterministic principles, while statistical mechanics introduces complexities that challenge simplistic classifications. (...) The interplay between ignorance and non-determinism emerges as a pivotal consideration, urging a nuanced understanding of deter-ministic frameworks amidst intricate systems. In essence, this exploration seeks to reconcile the richness of deterministic behavior with the complexities inherent in the natural world. (shrink)

Catastrophic risk raises questions that are not only of practical importance, but also of great philosophical interest, such as how to define catastrophe and what distinguishes catastrophic outcomes from non-catastrophic ones. Catastrophic risk also raises questions about how to rationally respond to such risks. How to rationally respond arguably partly depends on the severity of the uncertainty, for instance, whether quantitative probabilistic information is available, or whether only comparative likelihood information is available, or neither type of information. Finally, catastrophic risk (...) raises important ethical questions about what to do when catastrophe avoidance conflicts with equity promotion. (shrink)

It has recently been argued that indeterminacy and indeterminism make most ordinary counterfactuals false. I argue that a plausible way to avoid such counterfactual skepticism is to postulate the existence of primitive modal facts that serve as truth-makers for counterfactual claims. Moreover, I defend a new theory of ‘might’ counterfactuals, and develop assertability and knowledge criteria to suit such unobservable ‘counterfacts’.

English title: "The early literary education of the young José Gaos in Valencia (1915-1919)"Resumen: Nuestra intención en este texto es investigar acerca de los primeros años de formación del pensamiento de José Gaos (1900-1969); así pues, no parece ser demasiado erróneo pensar que aquél, hacia 1915 no era, aún, puramente “filosófico”: la Filosofía representaba parte de su formación, cumpliendo el mismo papel —eso sí: básico y fundamental— que desempeñó la Literatura. El primer auténtico encuentro con la Filosofía se daría antes (...) de su llegada a Valencia, en ese mismo año de 1915; pero ese también es el año en que Gaos recibirá una sólida formación estético-literaria a través de prensa y revistas filosóficas, especialmente en el grupo que conformó junto con Max Aub, José Medina Echeverría y su hermano Carlos Gaos. Abstract: This paper investigates in detail about the early years of José Gaos (1900-1969) and his education in philosophy and literature. Therefore, we know that their studies (academic or not) were not purely “philosophical” in 1915. Literature and philosophy played in Gaos an equally important role. The first real encounter with philosophy happens before he comes to Valencia in 1915; but in this year Gaos also receives a strong education, in aesthetic and literary, through press and philosophical journals, and especially within the group formed with Max Aub, José Medina Echeverría and his brother Carlos Gaos. Palabras clave: José Gaos, literatura, juventud, formación, Valencia. Keywords: José Gaos, literature, youth, education, Valencia. (shrink)

Culling seems to be a cruel method of human interference in the lives of elephants. The method of culling is generally used to control population numbers of highly developed mammals to protect vegetation and habitat for other less important species. Many people are against human interference in the lives of elephants. In this article aspects of this highly controversial issue are explored. Three fascinating characteristics of this ethical dilemma are discussed in the introductory part, and then the major arguments raised (...) against human interference in the lives of elephants are evaluated. These arguments are the following: First, that nature should be allowed to run its course and establish its own balance; nature will thus solve the problem of elephant overpopulation. The second argument raised by animal-rights activists as well as by animal-welfare groups either claim that animals have rights that humans must respect at all times, or that all sentient beings have interests that humans ought to respect, as those beings can experience pleasure or pain. The third argument often associates culling elephants as method for population control with the commercial use and exploitation of wilderness areas. Many people argue that it is unethical to use wildlife as a sustainable resource for fighting poverty. In conclusion it is stated that despite these arguments human intervention in the lives of elephants are ethically justified. (shrink)

In this paper we briefly examine and evaluate Quine’s physicalism. On the supposition, in accordance with Quine’s views, that there can be no change of any sort without a physical change, we argue that this point leaves plenty of room to understand and accept a limited autonomy of the special sciences and of other domains of disciplinary and common-sense inquiry and discourse. The argument depends on distinguishing specific, detailed programs of reduction from the general Quinean strategy of reduction by explication. (...) We argue that the details of the relations of particular sciences, disciplines and domains of discourse depend on empirical evidence and empirical-theoretical developments and that the generalized approach of reduction by explication is also subject to related empirical-theoretical constraints. So understood, physicalism lacks much of the controversial force and many of the implications sometimes associated with it. (shrink)

This is the Introduction to my translation of Quine's Kant Lectures. Part of my interpretation is that an "esoteric doctrine" in involved in Quine's distinctive semantic claims: his skepticism of the credulity of non-expert evaluation of discourse and theory.

This paper is the expository and evaluative introduction to my new edition of Emerson's Society and Solitude, Twelve Chapters.

Recent studies show that the current punitive approach to bullying, in the form of zero-tolerance policies, is ineffective in reducing bullying and school violence. Despite this significant finding, anti-bullying legislation is increasing. The authors argue that these policies are not only ineffective but that they are also unjust, harmful, and stigmatizing. They advocate a broader integrative approach to bullying programs that includes both victims and bullies.

This volume offers a collection of in-depth explorations of pragmatism as a framework for discussions in philosophy of science and metaphysics. Each chapter involves explicit reflection on what it means to be pragmatist, and how to use pragmatism as a guiding framework in addressing topics such as realism, unification, fundamentality, truth, laws, reduction, and more. -/- .

The Precautionary Principle (PP) is an influential principle of risk management. It has been widely introduced into environmental legislation, and it plays an important role in most international environmental agreements. Yet, there is little consensus on precisely how to understand and formulate the principle. In this paper I prove some impossibility results for two plausible formulations of the PP as a decision-rule. These results illustrate the difficulty in making the PP consistent with the acceptance of any trade-offs between catastrophic risks (...) and more ordinary goods. (shrink)

Dr Peter Sjöstedt-H reviews Dr Andrew R. Gallimore's book, Alien Information Theory. -/- This was published on PsyPressUK on 13 June 2019.

A moderately risk averse person may turn down a 50/50 gamble that either results in her winning $200 or losing $100. Such behaviour seems rational if, for instance, the pain of losing $100 is felt more strongly than the joy of winning $200. The aim of this paper is to examine an influential argument that some have interpreted as showing that such moderate risk aversion is irrational. After presenting an axiomatic argument that I take to be the strongest case for (...) the claim that moderate risk aversion is irrational, I show that it essentially depends on an assumption that those who think that risk aversion can be rational should be skeptical of. Hence, I conclude that risk aversion need not be irrational. (shrink)

Walter Reese-Schäfer, Karl-Otto Apel, Zur Einführung (with an Afterword by Jürgen Habermas), Junis Verlag GmbH, Hamburg 1990, 176pp. DM 17.80 -/- The author, presently a freelance writer published in the newspaper “Die Zeit” and the magazine “Stern,” pro­vides in this small book a clear and concise introduction to sources, themes and conclusions in the philosophy of Karl-Otto Apel. Apel, Emeritus Pro­fessor at Frank­furt, and close colleague of Habermas, characterizes his viewpoint as a “transcen­dental pragmatism” in which a Kantian concern for (...) question regarding “the conditions for the possi­bility of some­thing,” (p.10) mixes with deontological discourse-ethics, semeiotic themes from Peirce, an ap­proach to fallibilism, the demand for “final justifica­tions” (Letzt­begründung) and German her­meneutics. In view of the “den­sity and concentration” of Apel’s texts, which often have a “deterrent effect” upon those not already at home with “the phil­osophical language game,” it is the announced aim of this book to provide a work of translation and clarification of Apel’s special­ized efforts --in effect an orientation to Apel’s work. The book divides into an Introduction, 8 chapters and a summary conclusion --with Habermas’ appreciation, “A Master Builder with Hermeneutic Feeling --The Way of Philosopher Karl-Otto Apel,” bringing up the rear. There is also a bibliography of primary and secondary sources and a short table outlining highlights of Apel’s career. The “Introduction” provides a good overview of the aims of the book and gets one started on central themes. (shrink)

Suppose that a decision-maker's aim, under certainty, is to maximise some continuous value, such as lifetime income or continuous social welfare. Can such a decision-maker rationally satisfy what has been called "continuity for easy cases" while at the same time satisfying what seems to be a widespread intuition against the full-blown continuity axiom of expected utility theory? In this note I argue that the answer is "no": given transitivity and a weak trade-off principle, continuity for easy cases violates the anti-continuity (...) intuition. I end the note by exploring an even weaker continuity condition that is consistent with the aforementioned intuition. (shrink)

Those who are risk averse with respect to money, and thus turn down some gambles with positive monetary expectations, are nevertheless often willing to accept bundles involving multiple such gambles. Therefore, it might seem that such people should become more willing to accept a risky but favourable gamble if they put it in context with the collection of gambles that they predict they will be faced with in the future. However, it turns out that when a risk averse person adopts (...) the long-term perspective, she faces a decision-problem that can be analysed as a noncooperative game between different “time-slices” of herself, where it is in the interest of each time-slice (given its prediction about other slices) to turn down the gamble with which it is faced. Hence, even if a risk averse but rational person manages to take the long-term perspective, she will, in the absence of what Hardin called “mutual coercion”, end up in a situation analogous to the “tragedy of the commons”. (shrink)

Can a man be a feminist? If so, what would it mean? I want to participate in a dialogue between women and men on how to accommodate women’s moral concerns. I propose that the fundamental values of justice embodied in the South African constitutional democracy require men to be feminist. These values provide the best safeguard of the important interests and values of both women and men. Men who accept these values can support the main concerns of feminism. The implications (...) of the argument in this article range from public issues to the most private aspects of marriage. (shrink)

This paper briefly describes the life of Otte Gross and his thoughts on sexuality, society, and repression. This provides the basis to interpret the #MeToo movement as functioning in the same way as a repressed memory that breaks through to consciousness. Gross' suggestion that society "rapes" individuals and his assertion of a primordial matriarchal society are useful insights in understanding the #Metoo movement.

Lately, there has been a lot of talk about the Ghettos, about wayward youths and Instagram rappers that glorify violence. In this piece, a Warsaw-based philosopher contributes to this discussion by examining the music of the ghetto and the culture of riots. Not in opposition to how bourgeois society usually frames such acts of discontent but rather as a reasonable democratic right that minorities are entitled to.

This book provides a concise overview, with excellent historical and systematic coverage, of the problems of the philosophy of language in the analytic tradition. Howard Callaway explains and explores the relation of language to the philosophy of mind and culture, to the theory of knowledge, and to ontology. He places the question of linguistic meaning at the center of his investigations. The teachings of authors who have become classics in the field, including Frege, Russell, Carnap, Quine, Davidson, and Putnam are (...) critically analyzed. I share completely his conviction that contemporary Anglo-American philosophy follows the spirit of the enlightenment in insisting on intellectual sincerity, clarity, and the willingness to meet scientific doubts or objections openly. --Professor Henri Lauener, Editor of Dialectica. (shrink)

This book presents the author’s many and varied contributions to the revival and re-evaluation of American pragmatism. The assembled critical perspective on contemporary pragmatism in philosophy emphasizes the American tradition of cultural pluralism and the requirements of American democracy. Based partly on a survey of the literature on interest-group pluralism and critical perspectives on the politics of globalization, the monograph argues for reasoned caution concerning the practical effects of the revival. Undercurrents of “vulgar pragmatism” including both moral and epistemic relativism (...) threaten the intellectual and moral integrity of American thought – and have contributed to the present sense of political crisis. -/- The text chiefly contributes to the evaluation of the contemporary influence of the philosophy of John Dewey (1859–1952) and his late development of the classical pragmatist tradition. In comparison to Ralph Waldo Emerson (1803–1882), William James (1842–1910), and earlier currents of American thought, Dewey’s philosophy, dominated by its overall emphasis on unification, is weaker in its support for the pluralism of cultural and religious contributions which have lent moral self-restraint to American policy and politics, both foreign and domestic. With all due homage to Dewey’s conception of philosophy, centered on human problems and the need for our ameliorative efforts, the argument is that in the contemporary revival, Dewey’s thought has been too often captured by “post-modernist” bandwagons of self-promotion and institutional control. -/- This work defends democratic individualism against more collectivist and corporatist tendencies in contemporary neo-pragmatism, and it draws upon up-to-date political analysis in defense of America’s long republican tradition. Pragmatism will not and cannot be removed from, or ignored, in American intellectual and moral history; and its influence on disciplines from law to politics, sociology and literary criticism has been immense. However, pragmatism has often been weak in commitment to cultural pluralism and in its accounts of truth. (shrink)

This new critical edition is an examination of William James’s Essays in Radical Empiricism in light of the scientific naturalism prominent in James’s Principles of Psychology and the subsequent development of Darwinian, functional psychology and functionalism in psychology, the philosophy psychology and the philosophy of mind. This is sure to be a controversial look at James's late philosophy of "radical empiricism" and "pure experience." The critical perspective of the edition evokes realism of cognitive relations, contemporary empiricism and recent developments in (...) cognitive science and contemporary philosophy of mind. (shrink)

This paper presents a new kind of problem in the ethics of distribution. The problem takes the form of several “calibration dilemmas,” in which intuitively reasonable aversion to small-stakes inequalities requires leading theories of distribution to recommend intuitively unreasonable aversion to large-stakes inequalities. We first lay out a series of such dilemmas for prioritarian theories. We then consider a widely endorsed family of egalitarian views and show that they are subject to even more forceful calibration dilemmas than prioritarian theories. Finally, (...) we show that our results challenge common utilitarian accounts of the badness of inequalities in resources. (shrink)

In various writings Michel Foucault has shown how, in the beginning of the 19th century, in settings such as army barracks, psychiatric hospitals and penitentiary institutions, the modern human sciences were ‹born› as an ensemble of disciplines (medical biology, psychiatry, psychology, criminology, and the like) From the beginning, the nature-nurture de- bate has been one of its key disputes. Are human individuals malleable by environmental factors (such as psychiatric treatments or disciplinary regimes), or do they rather display inborn predispositions for (...) delin- quency and other forms of antisocial behaviour? In the current era of genetic testing, in behavioural genomics and neuroscience, this issue is as controversial and topical as ever. Büchner’s unfinished drama Woyzeck (written in 1836) is a remarkable anticipation of this debate, staging the birth of the human individual as a research subject. It is the story of a destitute soldier who, according to his superiors, displays er- rant behaviour and is therefore recruited to serve as a research subject in an experiment. His army physician turns him into a ‹case›, which can be meticulously monitored and studied so as to record the genesis of a crime. In this paper, Büchner’s unsettling play is analysed in detail as one of the great anticipatory literary documents of the 19th century, ex- ploring the idea of predictive psychiatry and the quest for genetic pre- dispositions: a primal scene as it were of the nature-nurture debate as it unfolds from predictive criminology up to behavioural genomics. (shrink)

I argue, first, that the deprived individuals whose predicaments Nussbaum cites as examples of "adaptive preference" do not in fact prefer the conditions of their lives to what we should regard as more desirable alternatives, indeed that we believe they are badly off precisely because they are not living the lives they would prefer to live if they had other options and were aware of them. Secondly, I argue that even where individuals in deprived circumstances acquire tastes for conditions that (...) we regard as bad, they are typically better off having their acquired preferences satisfied. If they are badly off it is because they cannot get what we and they, would regard as more desirable alternatives. Preference utilitarianism explains why individuals in such circumstances are badly off whether they have adapted to their deprived circumstances or not. Even if they prefer the conditions of their lives to all other available alternatives, most would prefer alternatives that are not available to them which would, on the preferentist account, make them better off. And that, on the preferentist account, is the basis for a radical critique of unjust institutions that limit people's options and prevent them from getting what they want. (shrink)

A social planner who evaluates risky public policies in light of the other risks with which their society will be faced should judge favourably some such policies even though they would deem them too risky when considered in isolation. I suggest that a longtermist would—or at least should—evaluate risky polices in light of their prediction about future risks; hence, longtermism supports social risk-taking. I consider two formal versions of this argument, discuss the conditions needed for the argument to be valid, (...) and briefly compare these conditions to some risky policy options with which actual public decision-makers are faced. (shrink)

In a given polity, interactions between the Governed and the Governing Strata are symbiotic. The Governed desire, and indeed need, infrastructure services organized. If such basic foundations are not provided, the economic activity so deeply cherished by both groups cannot be realized. The Governing Strata cannot function without the Governed. After all, without the Governed, there will not be a polity; hence nothing to govern. Regardless of the politico-economic system in effect, this co-dependence is inevitable, inescapable, indenturing both groups to (...) each other. This is the case, regardless of the designation, functions, or the style of the governance system. It matters not if the designation or philosophy of the said governance is a variation of pluralism or authoritarianism by a minority. (shrink)

I defend a weak version of the Pigou-Dalton principle for chances. The principle says that it is better to increase the survival chance of a person who is more likely to die rather than a person who is less likely to die, assuming that the two people do not differ in any other morally relevant respect. The principle justifies plausible moral judgements that standard ex post views, such as prioritarianism and rank-dependent egalitarianism, cannot accommodate. However, the principle can be justified (...) by the same reasoning that has recently been used to defend the core axiom of ex post prioritarianism and egalitarianism, namely, Pigou-Dalton for well-being. The arguably biggest challenge for proponents of Pigou-Dalton for chances is that it violates State Dominance for social prospects. However, I argue that we have independent reason for rejecting State Dominance for social prospects, since it prevents a social planner from properly respecting people's preferences. (shrink)

The main aim of this book is to introduce the topic of limited awareness, and changes in awareness, to those interested in the philosophy of decision-making and uncertain reasoning.

This book is a thesis submitted to the Faculty of Arts of the University of Utrecht. It was prepared under the supervision of Prof. Dr. H. Schultink. I would like to express my gratitude to him for his criticisms of earlier versions which led to many improvements, in particular with respect to the exposition of the argument. To my co-referent Dirk van Dalen, reader in the Department of Philo sophy (,Centrale Interfaculteit') of the University of Utrecht, I am greatly indebted (...) for his valuable and fruitful suggestions about problems relevant to both linguistics and logic. Several ideas developed in this study owe their present concrete form to our many discussions. This thesis originates in syntactic research into the Aspects carried out in 1967 under the supervision of Albert Kraak, professor at the University of Nijmegen, who ever since gave much attention to my work in progress. I am very grateful to him for his careful and stimulating criticism as well as for the continuous support he gave me during these years. The present study closely relates to the work of my colleague Wim Klooster with regard to both its theoretical framework and its subject matter. Our joint work on the measurement of duration in Dutch is an integral part of the argument. I have greatly profited from the numerous discussions we have had. (shrink)