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 paper provides a historical take on Filipino populism particularly former President Rodrigo Duterte’s leadership. The study contends that Duterte’s populism relies on his charisma as a strongman, where he frames his image as the father of the nation. The study relates this to Filipino philosopher Leonardo Mercado’s concept of sakop. This notion is best seen in the Filipinos’ harmonization of familial relations into other areas of society.

This article asserts that Philippine journalism practices parrhesia by exploring the present situation of the Philippine press vis-à-vis Foucault's concept of Parrhesia (fearless speech). Foucault's concept of Parrhesia is a feasible practice that gives a description as to why the Philippine press experience a curtailment of their rights in their duty to speak truth to power. Foucault claims that the practice of parrhesia is a critique of present circumstances, or what Foucault calls 'history of the present,' where a specific regime (...) of truth is imposed by power via a variety of strategies that run through both institutional and non-institutional practices. In contrast, the Philippine press battles the Duterte administration and its machinery of misinformation in social media amidst the repercussions they might face, all in the name of their duty and obligation to the truth. At present, as the Philippine press continues to do the duty of monitoring Duterte's political power, journalists and press workers continually face dangers and harassments in striving to fulfill their duties as independent monitors of power, and resisting the fascistic tendency of the present government that does everything in its power to control and repress anyone that dares to challenge his power. (shrink)

Nghiên cứu nhằm xác định các yếu tố ảnh hưởng đến quyết định mua các sản phẩm thân thiện với môi trường của cư dân trong đại đô thị Vinhomes Grand Park. Kết quả nghiên cứu chỉ ra 6 nhân tố: (1) Thái độ hướng đến bảo vệ môi trường; (2) Chuẩn chủ quan; (3) Chất lượng sản phẩm tốt; (4) Giá cả sản phẩm; (5) Truyền thông xã hội đều có ảnh hưởng đến quyết định mua các sản phẩm (...) thân thiện với môi trường. Qua đó, tác giả đề xuất hàm ý quản trị nhằm nâng cao chiến lược phát triển thị trường sản phẩm thân thiện với môi trường của cư dân. (shrink)

Many corporations are large, powerful, and wealthy. There are massive shortfalls of global justice, with hundreds of millions of people in the world living below the threshold of extreme poverty, and billions more living not far above that threshold. Where injustice and needs shortfalls must be remediated, we often look towards agents’ capabilities to determine who ought to bear the costs of rectifying the situation. The combination of these three claims grounds what I call a ‘linkage-based’ account of why corporations (...) have demanding positive duties to the global poor. In this paper, I put forward a distinctive linkage-based account of corporations’ positive duties centred on the idea of dependence and the importance of meeting agents’ core needs. In addition to outlining and defending this account, I will show that we can utilise its basic conceptual components to make headway on questions that have received insufficient attention in the business ethics literature; specifically, we can say something substantive about the weighting of needy agents’ competing claims to assistance, and about the limits to the demands that can be lodged against corporations on the basis of others' unmet needs. Having integrated considerations of duties' grounding, their comparative weight, and the limits of their demandingness into a single account of corporate positive duty, I conclude by discussing a challenge to attributing to corporations duties owed to the worst-off amongst the global poor. (shrink)

Đánh giá chất lượng công chức nói chung và công chức quản lý nhà nước về kinh tế cấp huyện nói riêng là khâu mở đường quan trọng trong các hoạt động quản lý công chức và kết quả thực thi công vụ là tiêu chí cơ bản trong đánh giá. Nghiên cứu tiếp thu kết quả các nghiên cứu đi trước để xây dựng mô hình lý thuyết các nhân tố ảnh hưởng đến kết quả thực thi công vụ (...) của công chức quản lý nhà nước về kinh tế cấp huyện ở TP. Hà Nội gồm 8 nhân tố: (1) Đào tạo, bồi dưỡng công chức; (2) Chính sách đãi ngộ; (3) Đánh giá công chức; (4) Bố trí, sử dụng công chức; (5) Kỷ cương, kỷ luật; (6) Phong cách lãnh đạo; (7) Đổi mới, sáng tạo của công chức; (8) Gắn kết với công việc của công chức. (shrink)

Biologists and philosophers of biology have argued that learning rules that do not lead organisms to play evolutionarily stable strategies (ESSes) in games will not be stable and thus not evolutionarily successful. This claim, however, stands at odds with the fact that learning generalization---a behavior that cannot lead to ESSes when modeled in games---is observed throughout the animal kingdom. In this paper, I use learning generalization to illustrate how previous analyses of the evolution of learning have gone wrong. It has (...) been widely argued that the function of learning generalization is to allow for swift learning about novel stimuli. I show that in evolutionary game theoretic models learning generalization, despite leading to suboptimal behavior, can indeed speed learning. I further observe that previous analyses of the evolution of learning ignored the short term success of learning rules. If one drops this assumption, I argue, it can be shown that learning generalization will be expected to evolve in these models. I also use this analysis to show how ESS methodology can be misleading, and to reject previous justifications about ESS play derived from analyses of learning. (shrink)

To hold an environmental ethic is to hold that non-human beings and states of affairs in the natural world have intrinsic value. This seemingly straightforward claim has been the focus of much recent philosophical discussion of environmental issues. Its clarity is, however, illusory. The term ‘intrinsic value’ has a variety of senses and many arguments on environmental ethics suffer from a conflation of these different senses: specimen hunters for the fallacy of equivocation will find rich pickings in the area. This (...) paper is largely the work of the underlabourer. I distinguish different senses of the concept of intrinsic value, and, relatedly, of the claim that non-human beings in the natural world have intrinsic value; I exhibit the logical relations between these claims and examine the distinct motivations for holding them. The paper is not however merely an exercise in conceptual underlabouring. It also defends one substantive thesis: that while it is the case that natural entities have intrinsic value in the strongest sense of the term, i.e., in the sense of value that exists independently of human valuations, such value does not as such entail any obligations on the part of human beings. The defender of nature’s intrinsic value still needs to show that such value contributes to the well-being of human agents. (shrink)

The Cyrenaics assert that (1) particular pleasure is the highest good, and happiness is valued not for its own sake, but only for the sake of the particular pleasures that compose it; (2) we should not forego present pleasures for the sake of obtaining greater pleasure in the future. Their anti-eudaimonism and lack of future-concern do not follow from their hedonism. So why do they assert (1) and (2)? After reviewing and criticizing the proposals put forward by Annas, Irwin and (...) Tsouna, I offer two possible reconstructions. In the first reconstruction, I explain claim (1) as follows: happiness has no value above and beyond the value of the particular pleasures that compose it. Also, there is no "structure" to happiness. The Cyrenaics are targeting the thesis that happiness involves having the activities of one's life forming an organized whole, the value of which cannot be reduced to the value of the experiences within that life. I explain claim (2) as follows: a maximally pleasant life is valuable, but the best way to achieve it is to concentrate heedlessly on the present. In the second reconstruction, the good is radically relativized to one's present preferences. The Cyrenaics assert that we desire some particular pleasure, e.g., the pleasure that results from having this drink now. Thus, our telos -- which is based upon our desires -- is this particular pleasure, not (generic) 'pleasure' or the maximization of pleasure over our lifetime. As our desires change, so does our telos. I conclude that the scanty texts we have do not allow us to decide conclusively between these reconstructions, but I give some reasons to support the second over the first. (shrink)

Đánh giá chất lượng công chức nói chung và công chức quản lý nhà nước về kinh tế cấp huyện nói riêng là khâu mở đường quan trọng trong các hoạt động quản lý công chức và kết quả thực thi công vụ là tiêu chí cơ bản trong đánh giá. Nghiên cứu tiếp thu kết quả các nghiên cứu đi trước để xây dựng mô hình lý thuyết các nhân tố ảnh hưởng đến kết quả thực thi công vụ (...) của công chức quản lý nhà nước về kinh tế cấp huyện ở TP. Hà Nội gồm 8 nhân tố: (1) Đào tạo, bồi dưỡng công chức; (2) Chính sách đãi ngộ; (3) Đánh giá công chức; (4) Bố trí, sử dụng công chức; (5) Kỷ cương, kỷ luật; (6) Phong cách lãnh đạo; (7) Đổi mới, sáng tạo của công chức; (8) Gắn kết với công việc của công chức. (shrink)

China’s rise to global power status is set to be amongst the primary shapers of politics and life more broadly in the 21st century. Yet despite its immense significance, political philosophers have been surprisingly quiet on the normative implications of China’s rise. This, I will argue, is a mistake. Not only does China’s rise generate interesting normative questions in its own right; it also upends some basic assumptions that many of us have hitherto adopted in our thinking about international distributive (...) justice. In the philosophical literature, the international order is often characterised by two sorts of states – developed and developing – with the former owing demanding duties and the latter having expansive permissions to further their own development. China’s status as both a genuine superpower and a middle-income country facing significant development challenges calls into question the continued functionality of such simplifying assumptions. Against the backdrop of China’s rise – and, to a lesser extent, that of other large emerging economies – this paper develops a more fine-grained account of how to conceive of states’ differential levels of advantage, distinguishing between states that are incapable, precariously capable, and robustly capable of realizing a minimally decent standard of domestic justice. This account reaffirms the assignment of the most onerous international duties to developed states, but also assigns duties and claims to developing states in a scalar fashion, with the upshot that better-off developing states in particular bear positive duties of international justice, owed to least-developed countries (LDCs). (shrink)

Socialist republicans advocate public ownership and control of the means of production in order to achieve the republican goal of a society without endemic domination. While civic republicanism is often attacked for its conservatism, the relatively neglected radical history of the tradition shows how a republican form of socialism provides powerful conceptual resources to critique capitalism for leaving workers and citizens dominated. This analysis supports a programme of public ownership and economic democracy intended to reduce domination in the workplace and (...) wider society. I defend this socialist republicanism from both the Marxist objection that it overlooks the impersonal nature of domination under capitalism and the left-liberal objections that property-owning democracy or worker codetermination are sufficient to suppress dominating relationships. The resulting position identifies the need for more ambitious institutional grounds for republican liberty than is often supposed, while offering us a distinctive emancipatory justification for socialism. (shrink)

Observers inspected normal, high quality color displays of everyday visual scenes while their eye movements were recorded. A large display change occurred each time an eye blink occurred. Display changes could either involve "Central Interest" or "Marginal Interest" locations, as determined from descriptions obtained from independent judges in a prior pilot experiment. Visual salience, as determined by luminance, color, and position of the Central and Marginal interest changes were equalized. -/- The results obtained were very similar to those obtained in (...) prior experiments showing failure to detect changes occurring simultaneously with saccades, flicker, or “mudsplashes” in the visual scene: Many changes were very hard to detect, and Marginal Interest changes were harder to detect than Central Interest changes. -/- Analysis of eye movements showed, as expected, that the probability of detecting a change depended on the eye’s distance from the change location. However a surprising finding was that both for Central and Marginal Interest changes, evenwhen observers were directly fixating the change locations (within 1 degree),more than 40% of the time they still failed to see the changes. It seems that looking at something does not guarantee you “ see” it. (shrink)

Unlike mainstream Cyrenaics, the Annicereans deny that friendship is chosen only because of its usefulness. Instead, the wise person cares for her friend and endures pains for him because of her goodwill and love. Nonetheless, the Annicereans maintain that your own pleasure is the telos and that a friend’s happiness isn’t intrinsically choiceworthy. Their position appears internally inconsistent or to attribute doublethink to the wise person. But we can avoid these problems. We have good textual grounds to attribute to the (...) Annicereans a doctrine of “non-hedonic habits,” which allows them to abandon psychological hedonism while still maintaining hedonism regarding well-being. (shrink)

This paper canvasses the various dimensions along which theories of truth may disagree about the extent to which truth is minimal.

Socrates has an implicit argument for his afterlife story that concludes the Gorgias, with two key premises. One is at 527a-c, where he summarizes the ethical position he has been arguing for through most of the dialogue, regarding the intrinsic goodness of justice, the intrinsic badness of injustice, and the desirability of rehabilitative punishments. The second occurs at 507e-508a, where Socrates asserts that the universe is held together by justice. This argument explains why Socrates regards his story as a logos, (...) not merely a muthos. It also helps us understand the nature of the rewards and punishments in his story. (shrink)

It is widely thought that functionalism and the qualia theory are better positioned to accommodate the ‘affective’ aspect of pain phenomenology than representationalism. In this paper, we attempt to overturn this opinion by raising problems for both functionalism and the qualia theory on this score. With regard to functionalism, we argue that it gets the order of explanation wrong: pain experience gives rise to the effects it does because it hurts, and not the other way around. With regard to the (...) qualia theory, we argue that it fails to capture the sense in which pain 's affective phenomenology rationalises various bodily-directed beliefs, desires, and behaviours. Representationalism, in contrast, escapes both of these problems: it gets the order of explanation right and it explains how pain 's affective phenomenology can rationalise bodily-directed beliefs, desires, and behaviours. For this reason, we argue that representationalism has a significant advantage in the debates about pain 's affective phenomenology. We end the paper by examining objections, including the question of what representationalists should say about so-called ‘disassociation cases’, such as pain asymbolia. (shrink)

A minimal truthmaker for a given proposition is the smallest portion of reality which makes this proposition true. Minimal truthmakers are frequently mentioned in the literature, but there has been no systematic account of what they are or of their importance. In this article we shall clarify the notion of a minimal truthmaker and argue that there is reason to think that at least some propositions have minimal truthmakers. We shall then argue that the notion can play a useful role (...) in truthmaker theory, by helping to explain the truth of certain propositions as precisely as possible. (shrink)

Looks into evaluation of information provision probability from different sources, based on use of linguistic variables. Formation of functions appurtenant for its unclear variables provides for adoption of decisions by the decision maker, in conditions of nonprobabilistic equivocation. The development of market relations in Ukraine increases the independence and responsibility of enterprises in justifying and making management decisions that ensure their effective, competitive activities. As a result of the analysis, it is determined that the condition of economic facilities can be (...) described and determined by the decision-maker, in the presence of the necessary information. The confidence of the decision-maker in the information received is different and the decisions made have a correspondingly different level of information risk. It is important to substantiate the procedure for assessing the numerical extent of information risk in decision-making based on the information obtained in conditions of uncertainty. The use of a linguistic variable in the processing of expert data presented in the form of a matrix of binary relations of values of the membership function, which allowed to move to further processing of knowledge to support decision-making in the management of industrial, commercial, financial and other activities. As a mathematical model for estimating the numerical measure of information risk when making decisions based on the information obtained in conditions of non-stochastic uncertainty, a model has been developed to model natural language uncertainties, which differs from existing ones by formalizing knowledge taking into account uncertainty of input information. Making such a clear decision in a fuzzy environment has appropriate values of effectiveness and risk. The paper proposes all the functions and accessories of indicators of both quantitative nature and qualitative nature to bring their values in the field of definition to one scale. Then the indicator of the effectiveness of decision-making will be a measure of the clarity of the cross-section of fuzzy subsets, which correspond to the introduced indicators of information risk. The condition of economic facilities can be described and determined by the decision-maker, if the necessary information is available. Decision-making on thenumerical measure of information risk must be determined by a set of basic indicators, which can be both quantitative and qualitative in nature. Predictive values of indicators should be determined in conditions of nonstochastic uncertainty. In this case, the indicators of a quantitative nature can be determined by fuzzy triangular numbers, which implement a high level of confidence in the subjective judgments of experts. Indicators of qualitative nature should be presented in linguistic variables. The values of the indicators of qualitative nature that are predicted must be considered for all fuzzy variable terms-sets of linguistic variables introduced into consideration. For any fuzzy variable, the introduction to the consideration of a clear set of values as carriers of the α-level of its membership function allows to reduce to a single interpretation of the predicted values of indicators of quantitative and qualitative nature in terms of non-stochastic uncertainty. (shrink)

Anaxarchus accompanied Pyrrho on Alexander the Great’s expedition to India and was known as “the Happy Man” because of his impassivity and contentment. Our sources on his philosophy are limited and largely consist of anecdotes about his interactions with Pyrrho and Alexander, but they allow us to reconstruct a distinctive ethical position. It overlaps with several disparate ethical traditions but is not merely a hodge-podge; it hangs together as a unified whole. Like Pyrrho, he asserts that things are indifferent in (...) value and that realizing this indifference leads to contentment. But this doctrine of indifference is rooted in Democritean atomism. And in his pursuit of pleasure and dismissiveness of conventional standards of what is just, noble, and pious, Anaxarchus is closer to fifth century thinkers such as Aristippus, Antiphon, and Critias. (shrink)

Proclus and Aquinas envision a plurality of divine beings organized hierarchically under the aegis of a first principle: respectively, the One and the henads, and God and His angels. While the differences rule out a wholescale application of Procline henadology to Thomas’ angelology, Aquinas, nevertheless, incorporates Proclus’ henadology into his angelology in two ways. First, Aquinas borrows from Procline henadology when explaining the differences between angels: these can be known in an approximate way from their observable effects. Second, Aquinas incorporates (...) Proclus’ understanding of henadic hierarchy, which focuses on power and activity over ontology, into his conception of angelic hierarchy. (shrink)

Over 1000 companies have either curtailed or else completely ceased operations in Russia as a response to its invasion of Ukraine, a mass corporate exodus of a speed and scale which we’ve never seen. While corporate withdrawal appears to have considerable public support, it’s not obvious that it has done anything to hamper the Russian war effort, nor is it clear what the long-run effects of corporate withdrawal as a regularised response to war might be. Given this, it’s important the (...) evaluate the ethical merits of such a response. In this paper I critique what I take to be the two most common arguments given in favour of voluntary corporate withdrawal, which I label ‘the instrumental argument’ and ‘the clean hands argument’ respectively. After illustrating their shortcomings, I reframe corporations’ predicament as a ‘spattered hands’ case—one where they may do good by remaining in a war-waging state, but where they contribute indirectly to grave wrongdoing by doing so. Drawing on ideas from the ‘Business for Peace’ and ‘Business and Human Rights’ literature, I highlight the potentially positive role of corporate presence within war-waging countries, before highlighting four considerations which corporations ought to bear in mind when determining whether to withdraw, or whether it is the lesser evil to stay and to let their hands be spattered. (shrink)

Each of the standard outlooks in the philosophy of perception --phenomenalism, direct realism, indirect realism, scepticism -- has thus been viewed as Hume's own considered position in the eyes of informed commentators. I argue that Hume does not ascribe univocally to any one of the traditional stances in the philosophy of perception, nor does he leave us only a schizophrenic or 'mood' scepticism. Hume attempted to resolve the traditional philosophical problem (or perhaps more accurately, to set it aside on principled (...) grounds) by transforming the issue from one of theoretical consistency to one of pragmatic coherence. Hume's moderate scepticism and his systematic naturalism entail a reflective 'return' to the vulgar (cp. T 223), a qualified normative endorsement of the directly realist beliefs of common life. The interpretive challenge is to understand the subtle nature of that endorsement, and to explain how it arises out of genuinely Humean doctrines. The account offered here attempts both to capture Hume's own considered position and to explain the attractions and shortcomings of each of the competing interpretations. After laying out the elements of Hume's account of perceptual belief (section I), I proceed to examine in some detail two recent attempts to interpret Hume as a realist (sections II-III). I contend that these revisionary accounts ascribe unHumean doctrines to Hume. The interpretation of Hume as an irreducible 'mood' sceptic or as a phenomenalist are in that respect both closer to the mark, but Hume's reflective return to the vulgar has recast the nature of the problem and leaves us with a position that is not reflected in the more traditional interpretations (section IV). (shrink)

This chapter examines the possibility of using AI technologies to improve human moral reasoning and decision-making, especially in the context of purchasing and consumer decisions. We characterize such AI technologies as artificial ethics assistants (AEAs). We focus on just one part of the AI-aided moral improvement question: the case of the individual who wants to improve their morality, where what constitutes an improvement is evaluated by the individual’s own values. We distinguish three broad areas in which an individual might think (...) their own moral reasoning and decision-making could be improved: one’s actions, character, or other evaluable attributes fall short of one’s values and moral beliefs; one sometimes misjudges or is uncertain about what the right thing to do is in particular situations, given one’s values; one is uncertain about some fundamental moral questions or recognizes a possibility that some of one’s core moral beliefs and values are mistaken. We sketch why one might think that AI tools could be used to support moral improvement in those areas, and describe two types of assistance: preparatory assistance, including advice and training supplied in advance of moral deliberation; and on-the-spot assistance, including on-the-spot advice and facilitation of moral functioning over the course of moral deliberation. Then, we turn to some of the ethical issues that AEAs might raise, looking in particular at three under-appreciated problems posed by the use of AI for moral self-improvement: namely, reliance on sensitive moral data; the inescapability of outside influences on AEAs; and AEA usage prompting the user to adopt beliefs and make decisions without adequate reasons. (shrink)

The few people familiar with the pseudo-Platonic dialogue Axiochus generally have a low opinion of it. It's easy to see why: the dialogue is a mish-mash of Platonic, Epicurean and Cynic arguments against the fear of death, seemingly tossed together with no regard whatsoever for their consistency. As Furley notes, the Axiochus appears to be horribly confused. Whereas in the Apology Socrates argues that death is either annihilation or a relocation of the soul, and is a blessing either way, "the (...) Socrates of the Axiochus wants to have it both ways": death is both annihilation and a release of the soul from the body into a better realm. This may be used to construct a valid argument for the conclusion that death is not evil, but at the expense of having a contradiction as one of its premises. But D. S. Hutchinson has recently proposed that these inconsistencies shouldn't surprise us if we view the Axiochus as "an unconventional version of a very conventional genre--the consolation letter." In this paper I expand on Hutchinson's brief suggestion and argue that the Axiochus can be rehabilitated by paying attention to its genre. Although the Axiochus does display many similarities to the consolation letter, the shift from letter to dialogue does--pace Hutchinson--significantly affect what's going on. Within the dialogue, Socrates behaves toward Axiochus in a way similar to the way the author of a consolation letter behaves towards the letter's reader: he is willing to use inconsistent arguments, borrowed from any source, in order to soothe the patient. However, in depicting this type of consolatory relationship between Socrates and Axiochus, the dialogue itself is not aiming at consoling its readers. Instead, it should be seen as displaying for the reader's consideration a certain type of consolatory argumentative practice. -/- Socrates notes that Axiochus is "very much in need of consolation" (365a), and he uses any means necessary to accomplish this task. Socrates exhibits many ways in which he is willing to sacrifice argumentative hygiene for the sake of therapeutic effectiveness. These include: -/- * Use of arguments with inconsistent premises, presented in propria persona. * Appeals to emotion * Tailoring arguments to the audience. * Presenting invalid arguments so as to induce unjustified but comforting beliefs. * Evasion. In these respects, I think that Socrates' argumentative practice is best compared to PH III 280-1, where Sextus Empiricus says that the skeptic will deliberately use logically weak arguments as long as they work. Dorothy Tarrant claims that what links the Socrates of the Axiochus to Socrates as he appears elsewhere in the Platonic corpus is his evident care for the welfare of his interlocutor's psyche. But this concern takes a quite different form in the Axiochus than it usually does. As with Sextus, psychic therapy in the Axiochus involves relief from pain. The primary difference between them is that Socrates, unlike Sextus, is not aiming at producing epochê in his patient. (shrink)

The representational theory of phenomenal experience is often stated in terms of a supervenience thesis: Byrne recently characterises it as the thesis that “there can be no difference in phenomenal character without a difference in content”, while according to Tye, “[a]t a minimum, the thesis is one of supervenience: necessarily, experiences that are alike in their representational contents are alike in their phenomenal character.” Consequently, much of the debate over whether representationalism is true centres on purported counter-examples – that is (...) to say, purported failures of supervenience. The refutation of putative counter-examples has been, it seems to me, by and large successful. But there is a certain class of these for which the representationalist response has been something less than completely convincing. These are the cross-modality cases. I will explain what I mean, and then argue that the response in question is not only unconvincing but actually undermines the representationalist position. (shrink)

Bài viết đề xuất mô hình nghiên cứu các yếu tố ảnh hưởng tới Truyền thông mạng xã hội trong việc nâng cao nhận diện thương hiệu quốc gia, đặc biệt trong bối cảnh Cách mạng Công nghiệp 4.0. Dựa trên các lý thuyết và nghiên cứu trước đó, nhóm tác giả đề xuất mô hình gồm các yếu tố: Trí tuệ nhân tạo (AI); Dữ liệu lớn (Big Data); Nội dung do người dùng tạo (UGC); Tương tác thời gian (...) thực (Real-Time Engagement); Quản lý danh tiếng số (Digital Reputation Management). Các yếu tố này được khám phá để tìm hiểu tác động của chúng đến vai trò của truyền thông mạng xã hội trong việc định hình và thúc đẩy bản sắc thương hiệu của một quốc gia. (shrink)

This paper focuses on 3 features of Freyenhagen's Aristotelian version of Adorno. (a) It challenges the strict negativism Freyenhagen finds in Adorno. If we have morally relevant interests in ourselves, it is implicit that we have a standard by which to understand what is both good and bad for us (our interests). Because strict negativism operates without reference to what is good, it seems to be detached from real interests too. Torture, it is argued, is, among other things, a violation (...) of those interests. (b) Freyenhagen identifies the “impulse” in Adorno as an untutored yet moral reaction to morally demanding situations. The plausibility of this primitivism and its compatibility with Adorno's general worries about immediacy are considered. (c) The disruptive character of Adorno's version of the categorical imperative, its willingness to complicate action through wholesale reflection on the norms of what we are committing ourselves to, is set in contrast with Freyenhagen's Aristotelian claim that certain notions, such as “humanity,” cannot be intelligibly questioned. (shrink)

The republican ideal of non-domination identifies the capacity for arbitrary interference as a fundamental threat to liberty that can generate fearful uncertainty and servility in those dominated. I argue that republican accounts of domination can provide a powerful analysis of the nature of legal and institutional power that is encountered by people with mental disorders or cognitive disabilities. In doing so, I demonstrate that non-domination is an ideal which is pertinent, distinctive, and desirable in thinking through psychological disability. Finally, I (...) evaluate republican strategies for contesting domination, focusing on the limits of contestatory democracy, and proposing a participatory alternative which better addresses problems of political agency in the mentally disordered and cognitively disabled. (shrink)

Biomedical diagnostic science is a great deal less successful than we've been willing to acknowledge in bioethics, and this fact has far-reaching ethical implications. In this article I consider the surprising prevalence of medically unexplained symptoms, and the term's ambiguous meaning. Then I frame central questions that remain answered in this context with respect to informed consent, autonomy, and truth-telling. Finally, I show that while considerable attention in this area is given to making sure not to provide biological care to (...) patients without a need, comparatively little is given to the competing, ethically central task of making sure never to obstruct access to biological care for those with diagnostically confusing biological conditions. I suggest this problem arises from confusion about the philosophical value of vagueness when it comes to the line between biological and psychosocial needs. (shrink)

In ‘The Epistemic Goals of the Humanities’, Stephen Grimm (2024) argues for epistemic continuities between the humanities, on one hand, and the social and natural sciences, on the other. This paper focuses on discontinuities. Drawing inspiration from Svetlana Alexievich’s literary non-fiction, I argue that if a reader is to gain a specific kind of understanding of the actions of the agents who appear in such work, they must engage in a rational evaluation of those agents’ reasons and actions. This epistemic (...) process may yield, not just understanding of another’s action, but a grip on the evaluative distance between the reader and the agents she reads about, together with a greater appreciation of normative matters. These epistemic gains are, I suggest, central to the value of the humanities, and play a key role in its corrective power. (shrink)

Nowhere in the works of what is called Aristotle is there a discussion of anything named Natural Law. Everywhere in the works of what is called Aristotle there are discussions of principles and there are discussion of laws; separately. And for this reason: Nature abides by principles. Humans make laws. By nature, aggression is the principle. Since aggression impedes each particular person in the same way, a universal manner, this universal offense is the impetus for a prescription of any law (...) at all. Law was first prescribed to prohibit that natural aggression. Hence, there is no non-aggression principle. Aggression is the principle, non-aggression is the law. The purpose of good law is to protect and maintain this natural justice of equality before any law. Unjust laws are an attempt to establish some other sort of equality that is not universal. Seeing this distinction of principles and laws as separate makes clear what is right by nature and wrong by law. However, at some places in the works of what is called Aristotle there is a discussion of what may be named natural rights, political rights, and natural justice. The preceding paragraph is the application of Aristotle’s CATEGORIES, INTERPRETATION, ANALYTICS, TOPICS, and RHETORIC as the means of separating the true from the false. (shrink)

This paper criticizes the assumptions behind Robert Brandom’s reading of Hegel’s Phenomenology, contending that Hegel’s concern with the rational structure of experience, his valorization of reflection over ordinary experience and his idea of the necessit y of progress in knowledge cannot be accommodated within the framework of semantic pragmatism. The central contentions are that Brandom’s pragmatism never comes to terms with Hegel’s idea of truth as a result, leading to a historicist distortion, and also that Brandom’s failure to deal with (...) Hegel’s distinction between natural consciousness and the phenomenological observer collapses Hegel’s phenomenology into a philosophy restricted to the level of natural consciousness. (shrink)

This article undertakes a republican analysis of power in the workplace and labour market in order to determine whether workers are dominated by employers. Civic republicans usually take domination to be subjection to an arbitrary power to interfere with choice. But when faced with labour disputes over what choices it is normal for workers to make for themselves, these accounts of domination struggle to determine whether employers possess the power to interfere. I propose an alternative capabilitarian conception of domination as (...) the arbitrary power to determine access to capabilities necessary for relationships of equality between citizens. This approach allows us to diagnose domination in the workplace and the labour market but does not capture unfreedom arising from the wider socio-structural position of workers. Thus, I supplement this capabilitarian account of the domination of workers with a structural account of dominating power, which reveals a richer set of conditions under which employers dominate workers. (shrink)

Economic liberty is best understood in opposition to economic domination. This article develops a radical republican conception of such domination. In particular, I argue that radical republicanism provides a more satisfactory account of individual economic freedom than the market-friendly liberties of working, transacting, holding, and using championed by Nickel and Tomasi. So too, it avoids the pitfalls of other conceptions of economic liberty which emphasize real freedom, alternatives to immiserating work, or unalienated labor. The resulting theory holds that economic domination (...) occurs when someone’s access to civic capabilities is contingent on the arbitrary economic power of others. Socialist institutions—suitably configured—can deliver on this individual economic freedom, allowing the dominating power of proprietors, shareholders, landlords, and managers to be kept in check, and providing an unconditional minimum that allows individual citizens to be less beholden to others in meeting many of their most fundamental civic needs. Thus, I conclude that socialism can be championed as a politics of individual economic liberty. (shrink)

Bài viết đánh giá thực trạng hoạt động hệ thống ngân hàng Việt Nam trong bối cảnh thực hiện đề án cơ cấu lại hệ thống các tổ chức tín dụng (TCTD). Kết quả nghiên cứu cho thấy, hoạt động tái cấu trúc ngân hàng đã diễn ra mạnh mẽ với chỉ đạo quyết liệt của Chính phủ và Ngân hàng nhà nước, đặc biệt trong phê duyệt chủ trương chuyển giao bắt buộc 4 ngân hàng diện kiểm soát đặc (...) biệt nhằm lành mạnh và ổn định hệ thống ngân hàng. Tuy nhiên, với thực trạng nền kinh tế suy thoái, những vấn đề về nợ xấu gia tăng vượt qua ngưỡng an toàn 3%, tỷ lệ bao phủ nợ xấu giảm xuống dưới 100%, tín dụng tăng trưởng chậm, biên lợi nhuận thu hẹp đang trở thành nguy cơ dẫn dến rủi ro hoạt động của hệ thống ngân hàng Việt Nam. Trước thực trạng đó, tác giả đưa ra một số khuyến nghị chính sách nhằm nâng cao hiệu quả tái cơ cấu hệ thống ngân hàng. (shrink)

For anyone approaching the Encheiridion of Epictetus for the first time, this book provides a comprehensive guide to understanding a complex philosophical text. Including a full translation and clear explanatory commentaries, Epictetus's 'Encheiridion' introduces readers to a hugely influential work of Stoic philosophy. Scott Aikin and William O. Stephens unravel the core themes of Stoic ethics found within this ancient handbook. Focusing on the core themes of self-control, seeing things as they are, living according to nature, owning one's roles and (...) fulfilling the responsibilities that those roles entail, the authors elucidate the extremely challenging ideas in Epictetus's brisk chapters. Divided into five distinct parts, this book provides readers with: -/- - A new translation of the Encheiridion by William O. Stephens. - A new introduction to ancient Stoicism, its system of concepts, and the ancient figures who shaped it. - A fresh treatment of the notorious and counter-intuitive 'Stoic paradoxes'. - An accessible overview of the origin and historical context of the Encheiridion. - Detailed commentaries on each chapter of the Encheiridion that clarify its recurring themes and highlight their interconnections. - Careful attention to the presentation of the arguments embedded in Epictetus's aphoristic style. - A thoughtful discussion of serious criticisms of Epictetus's Stoicism and replies to these objections. -/- Written with clarity and authority, Epictetus's 'Encheiridion' provides a foundation from which readers can understand this important text and engage with the fundamental questions of Stoic philosophy and ethics. This guide will aid teachers of Epictetus, students encountering Stoicism for the first time, and readers seeking a greater understanding of Stoic ethics. (shrink)

This article argues that political injustices can arise from the distribution and character of our sexual desires and that we can be held responsible for correcting these injustices. It draws on a conception of structural injustice to diagnose unjust patterns of sexual attraction, which are taken to arise when socio-structural processes shaping the formation of sexual desire compound systemic domination and capacity-deprivation for the occupants of a social position. Individualistic and structural solutions to the problem of unjust patterns of sexual (...) attraction are assessed in the context of racialised sexual aversion, racial fetishism, and the desexualisation of people with disabilities. While both forms of intervention can help in principle, some of the advantages of structural approaches are laid out. A schema for assigning political responsibilities for addressing this injustice is proposed, with some limits identified to the kinds of state and social responses that are justified. Finally, the status of the merely aesthetically unappealing is considered, with a relational egalitarian approach concluding that they are subject to structurally unjust patterns of sexual desire only when exposed to oppression or second-class citizenship as a result. (shrink)

This paper explains what an infinite regress argument is. Part 1 contains some examples of infinite regress arguments. Part 2 presents a schema for all such arguments an defines an infinite regress argument as one that approximates to the schema. Part 3 tests the schema on the examples. Part 4 contrasts my account of infinite regress arguments with that given by Passmore and shows that Passmore's theory succumbs to objections. Part 5 distinguishes an infinite regress argument from an infinite regress (...) and defines an infinite regress. Part 6 explains the dyslogistic force of 'infinite regress'. (shrink)

Most commonplace moral failure is not conditioned by evil intentions or the conscious desire to harm or humiliate others. It is more banal and ubiquitous – a form of moral stupidity that gives rise to rationalization, self‐deception, failures of due moral consideration, and the evasion of responsibility. A kind of crude, perception‐distorting self‐absorption, moral stupidity is the cause of many moral missteps; moral development demands the development of self‐knowledge as a way out of moral stupidity. Only once aware of the (...) presence or absence of particular desires and beliefs can an agent have authority over them or exercise responsibility for their absence. But what is the connection between self‐knowledge and moral development? I argue that accounts (such as Kant's and Richard Moran's) which construe instances of self‐knowledge as like the verdicts of a judge cannot explain its potential role in moral development, and claim that it must be conceived of in a way that makes possible a process of self‐refinement and self‐regulation. Making use of Buddhist moral psychology, I argue that when self‐knowledge plays a role in moral development, it includes a quality of attention to one's experience best modeled as the work of the craftsperson, not as judge. (shrink)

This article develops a civic republican approach to medical ethics. It outlines civic republican concerns about the domination that arises from subjection to an arbitrary power of interference, while suggesting republican remedies to such domination in healthcare. These include proposals for greater review, challenge and pre-authorisation of medical power. It extends this analysis by providing a civic republican account of assistive arbitrary power, showing how it can create similar problems within both formal and informal relationships of care, and offering strategies (...) for tackling it. Two important objections to civic republican medical ethics—that it overvalues independence and political participation in healthcare—are also considered and rebutted. (shrink)

Epicurus is strongly committed to psychological and ethical egoism and hedonism. However, these commitments do not square easily with many of the claims made by Epicureans about friendship: for instance, that the wise man will sometimes die for his friend, that the wise man will love his friend as much as himself, feel exactly the same toward his friend as toward himself, and exert himself as much for his friend's pleasure as for his own, and that every friendship is worth (...) choosing for its own sake. These claims have led some scholars to assert that Epicurus inconsistently affirms that friendship has an altruistic element. I argue that the Epicurean claims about friendship can be reconciled with egoism and hedonism in psychology and ethics. Friendship is valuable because having friends provides one with security more effectively than any other means, and having confidence that one will be secure in the future either is identical to ataraxia, or the grounds on which one has it. (shrink)

Adorno and Heidegger are frequently aligned because of apparent similarities in their critiques of modern epistemology. This alignment fails, however, to appreciate the substantial differences in the philosophical presuppositions that inform those very critiques. I distinguish Adorno's negative dialectic from Heidegger's fundamental ontology under the respective designations of critical versus phenomenological forms of transcendental philosophy. I argue that only by understanding Adorno's negative dialectic as a revised version of epistemology (namely a dialectical epistemology, committed to subject-object and transcendental argument) can (...) we make sense of, first, the profound differences between Adorno and Heidegger on the question of epistemology and, second, the philosophical motivations behind Adorno's trenchant rejection of Heidegger. Key Words: being-in-the-world • - dialectics • - empiricism • - epistemology • - idealism • - identity • - immediacy • - irrationalism • - mediation • - project • - subject • -object • - transcendental. (shrink)

In Just Fodder, Milburn argues for a relational account of our duties to animals. Following Clare Palmer, he argues that, though all animals have negative rights that we have a duty not to violate, we only gain positive obligations towards animals in the contexts of our relationships with them, which can be personal or political. He argues that human beings have collective positive duties towards domesticated animals, in virtue of the kind of relationship between us established by domestication. However, when (...) it comes to wild animals, he argues that we have no such morally relevant relationships, and so we have only negative duties towards them. I argue that throughout history and even prehistory human beings have morally entangled themselves with wild animals sufficiently that we may in fact have collective positive duties towards many, if not all, wild animals. (shrink)