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)

Elite women seized the public health campaign during the 1900 plague outbreak to assert political influence and advocate for sanitation reform grounded in their domestic experiences. These women advocated for their inclusion in the political sphere by valuing their domestic experiences as knowledge relevant for public health initiatives. This reframing of experience positioned them as viable citizens in the imminent Federation. Applying Laura Zanotti's concept of relational ontology, this analysis frames their actions as not simply a battle against institutional authority (...) but as careful and strategic interactions with their era's political context, exploiting aspects of it that were beneficial to them. Their ambivalent involvement in the public health campaign illustrates a complex chapter in Australian medical history. Women used the opportunity of plague to reevaluate their experience of the home as a form of knowledge relevant to public health. At the same time, they leveraged their growing status as political subjects to oppress others. (shrink)

When the third global plague pandemic reached Sydney in 1900, theories regarding the ecology and biology of disease transmission were transforming. Changing understandings led to conflicts over the appropriate response. Medical and government authorities employed symbols like dirt to address gaps in knowledge. They used these symbols strategically to compel emotional responses and to advocate for specific political and social interventions, authorising institutional actions to shape social identity and the city in preparation for Australia's 1901 Federation. Through theoretical and historical (...) analysis, this Element argues that disgust and aversion were effectively mobilised to legitimise these actions. As an intervention in contemporary debates about the impact of knowledge on emotion and affect, it presents a case for the plasticity of emotions like disgust, and for how both emotion and affect can change with new medical information. (shrink)

It is commonly assumed that the expression “an sich selbst” (“in itself”) in Kant combines with terms to form complex nouns such as “thing in itself” and “end in itself.” I argue that the basic use of “an sich selbst” in Kant’s German is as a sentence adverb, which has the role of modifying subject-predicate combinations, rather than either subject or predicate on their own. Expressions of the form “S is P an sich selbst” mean roughly that S is P (...) ‘in its own right’ or without some further ‘condition’. Accordingly, “an sich selbst” should not be treated as forming complex nouns. This analysis has significant consequences for the interpretation of “thing in itself” in particular, for it implies that the latter is not a complete nominal expression. Instead, one must treat ‘an sich selbst’ as expressing how some S is a ‘thing’, looking to the wider sentential context. I conclude with a brief account of the new significance granted to the concept of a ‘thing’ (Ding) according to the present interpretation. (shrink)

Ausgangspunkt ist die Frage, was Masse ist, wodurch sie insbesondere befähigt ist, Dauer zu konstituieren und deshalb - im Sinn des kinematischen Relativitätsprinzips - ebenso als bewegt wie als ruhend betrachtet werden kann. In einem Gedankenexperiment wird diese Frage, in Umkehrung der Perspektive, hier nicht von der Masse selbst, sondern von einer stehenden Lichtwelle her angegangen. In diesem Modell lassen sich masse-analoge Strukturen rekonstruieren, die in relativer Bewegung sein können. Die (empirisch bekannte) Unabhängigkeit der Lichtgeschwindigkeit vom Bezugssystem ist dabei nicht (...) vorausgesetzt. Doch kann gezeigt werden, dass die Lichtgeschwindigkeit Grenzgeschwindigkeit solcher relativer Bewegungen ist, dass dies für alle durch masse-analoge Strukturen konstituierte, relativ zueinander gleichförmig bewegten Bezugssysteme gilt und dass die Lichtgeschwindigkeit selbst in allen diesen Systemen gleich ist. Die Absolutheit der Lichtgeschwindigkeit und die Relativität der Massebewegungen erweisen sich so als zwar differente, aber intrinsisch zusammengehörende Momente des kinematischen Relativitätsprinzips: ein Beitrag zu einer Philosophie der Relativitätstheorie. - Die mathematischen Zusammenhänge werden im Anhang ausführlicher dargelegt. (shrink)

European Journal of Philosophy, Volume 29, Issue 4, Page 1026-1038, December 2021.

ArgumentIn the United States, scientific knowledge is brought before the courts by way of testimony – the testimony of scientific experts. We argue that this expertise is best understoodfirstas related to the quality of the underlying scienceand thenin terms of who delivers it. Bloodstain pattern analysis (BPA), a contemporary forensic science, serves as the vaulting point for our exploration of objectivity as a metric for the quality of a science in judicial contexts. We argue that BPA fails to meet the (...) minimal standard set by Helen Longino’s social-procedural account of objectivity (1990, 2002). In light of some pressing issues for social-procedural accounts, we offer an infrastructural account of objectivity. This account offers what amounts to a friendly amendment to Longino’s account and adds to the ways in which we might analyze social-procedural objectivity. Finally, we address an issue that is pressing in the legal context: given that scientific knowledge is delivered by individuals, not communities, at least in U.S. courts, we (may) need a way to evaluate individual scientific and epistemic agents. We suggest a means for making this evaluation that is derived from our infrastructural account of objectivity. (shrink)

The Swiss psychologist Jean Piaget contends that children below the age of 12 see no necessity for the logical law of non-contradiction. I argue this view is problematic. First of all, Piaget's dialogues with children which are considered supportive of this position are not clearly so. Secondly, Piaget underestimates the necessary nature of following the logical law of non-contradiction in everyday discourse. The mere possibility of saying something significant and informative at all presupposes that the law of non-contradiction is enforced.

Nudging works through dispositions to decide with specific heuristics, and has three component parts. A nudge is a feature of an environment that enables such a disposition; a person is nudged when such a disposition is triggered; and a person performs a nudged action when such a disposition manifests in action. This analysis clarifies an autonomy-based worry about nudging as used in public policy or for private profit: that a person’s ability to reason well is undermined when she is nudged. (...) Reasoning well is a component of self-guidance, which is an aspect of autonomy and so something there is reason to promote, preserve, or respect. However, a person can reason well when she is nudged: Many of these heuristics are good rules to reason with, and she can be flexible with respect to them when she takes there to be a better way to reason. Along the way, this paper uncovers several design specifications for responsible nudging, and discusses open empirical questions. However, nudging’s being compatible with reasoning well crystallizes a distinct worry about manipulation: that nudge designers can rely on nudged people guiding themselves toward the designers’ own ends. Manipulation of this sort exploits one aspect of autonomy (namely, self-guidance) to undermine autonomy in other respects. (shrink)

Stephen Yablo’s notion of proportionality, despite controversies surrounding it, has played a significant role in philosophical discussions of mental causation and of high-level causation more generally. In particular, it is invoked in James Woodward’s interventionist account of high-level causation and explanation, and is implicit in a novel approach to constructing variables for causal modeling in the machine learning literature, known as causal feature learning (CFL). In this article, we articulate an account of proportionality inspired by both Yablo’s account of proportionality (...) and the CFL account of variable construction. The resulting account has at least three merits. First, it illuminates an important feature of the notion of proportionality, when it is adapted to a probabilistic and interventionist framework. The feature is that at the center of the notion of proportionality lies the concept of “determinate intervention effects.” Second, it makes manifest a virtue of (common types of) high-level causal/explanatory statements over low-level ones, when relevant intervention effects are determinate. Third, it overcomes a limitation of the CFL framework and thereby also addresses a challenge to interventionist accounts of high-level causation. (shrink)

As automating technologies are increasingly integrated into workplaces, one concern is that many of the human workers who remain will be relegated to more dull and less positively impactful work. This paper considers two rival theories of meaningful work that might be used to evaluate particular implementations of automation. The first is achievementism, which says that work that culminates in achievements to workers’ credit is especially meaningful; the other is the practice view, which says that work that takes the form (...) of an open-ended practice is especially meaningful. Of the two, the practice view is the better tool for assessing the future of meaningful work, because achievementism is explanatorily inadequate in two ways. Moreover, the practice view can explain why the most meaningful forms of work cannot be automated. A procedure can only be automated as long as the steps are defined, whereas, in such work, which steps to take is indefinitely open to redefinition. This reveals the real threat to meaningful work to be a political-economic one. The relevant ethical questions there have to do with how much creative control workers retain in crafting their own jobs, when those jobs involve meaningful work in collaboration with machines; and how to liberate workers from jobs that do not involve meaningful work, which should be left to machines anyway. (shrink)

In this essay I suggest that we view design principles in systems biology as minimal models, for a design principle usually exhibits universal behaviors that are common to a whole range of heterogeneous (living and nonliving) systems with different underlying mechanisms. A well-known design principle in systems biology, integral feedback control, is discussed, showing that it satisfies all the conditions for a model to be a minimal model. This approach has significant philosophical implications: it not only accounts for how design (...) principles explain, but also helps clarify one dispute over design principles, e.g., whether design principles provide mechanistic explanations or a distinct kind of explanations called design explanations. (shrink)

In this paper, I contest increasingly common "realist" interpretations of Hegel's theory of "the concept" (der Begriff), offering instead a "isomorphic" conception of the relation of concepts and the world. The isomorphism recommended, however, is metaphysically deflationary, for I show how Hegel's conception of conceptual form creates a conceptually internal standard for the adequacy of concepts. No "sideways-on" theory of the concept-world relationship is envisioned. This standard of conceptual adequacy is also "graduated" in that it allows for a lack of (...) fit between concept and world. The possibility for a "maximally isomorphic" fit between concept and world obtains through the teleological realization of concepts, which marks especially the "artificial" world of human culture (law, art, religion, etc.). Some of the most seemingly exaggerated claims Hegel makes about the concept, I contend, can be understood when we consider the significance Hegel ascribes to human making, which is provided for in his conceptual theory. But my framework provides an interpretive key for the way Hegel sees concepts imperfectly realized in the natural world as well. (shrink)

Some cognitive processes appear to have “phenomenal” properties that are directly revealed to the subject and not determined by physical properties. I suggest that the source of this appearance is the method by which our brain processes sensory information. The appearance is an illusion. Nonetheless, we are not mistaken when we judge that people sometimes fee lpain.

Tractatus Politico-Philosophicus (Political-Philosophical Treatise) of W. Julian Korab-Karpowicz proposes a new idea-system. Ideas concerning different topics related to politics are introduced. The work aims to establish the principles of good governance and of a happy society, and to open up new directions for the future development of humankind. It is also in part a critique of the epistemology of early Wittgenstein as presented in his Tractatus Logico-Philosophicus. It argues that one can speak about politics and ethics with sense, and that (...) political philosophy is still a viable enterprise for us. This explanation is provided in response to the review of Tractatus Politico-Philosophicus by Katarzyna Heremska and a critical note of Pawel Kloczowski that were both published in Argument 6(1), 2016. (shrink)

This is an encyclopedia entry on consequentializing. It explains what consequentializing is, what makes it possible, why someone might be motivated to consequentialize, and how to consequentialize a non-consequentialist theory.

In the Transcendental Aesthetic (TA), Kant is typically held to make negative assertations about “things in themselves,” namely that they are not spatial or temporal. These negative assertions stand behind the “neglected alternative” problem for Kant’s transcendental idealism. According to this problem, Kant may be entitled to assert that spatio-temporality is a subjective element of our cognition, but he cannot rule out that it may also be a feature of the objective world. In this paper, I show in a new (...) way how Kant’s view (focusing on his conclusions about space) is not subject to this objection, by showing that he does not make the denial about mind-independent reality that he is typically held to make. The argument develops consequences of a new reading of Kant’s expression “an sich selbst” (‘in itself’; ‘in themselves’). I argue that “an sich selbst” or “per se” has a special, judgment-level role, so that this expression does not form new noun-terms adjectivally. It follows that the conceptual unit of Kant’s “Conclusions” in the TA is simply “things” (Dinge), since “things in themselves” is not a nominal expression; Kant adopts the Wolffian ontological use of “thing” as the basic kind-term for any existent. The arguments that things per se are not in space are arguments that space cannot be a necessary property or relations of things as a kind. I show that this does not involve the positive claim about mind-independent reality that inspires the neglected alternative objection. (shrink)

The current study is a pilot trial to examine the effects of a nonelective, classroom-based, teacher-implemented, mindfulness meditation intervention on standard clinical measures of mental health and affect in middle school children. A total of 101 healthy sixth-grade students (55 boys, 46 girls) were randomized to either an Asian history course with daily mindfulness meditation practice (intervention group) or an African history course with a matched experiential activity (active control group). Self-reported measures included the Youth Self Report (YSR), a modified (...) Spielberger State-Trait Anxiety Inventory, and the Cognitive and Affective Mindfulness Measure –Revised. Both groups decreased significantly on clinical syndrome subscales and affect but did not differ in the extent of their improvements. Meditators were significantly less likely to develop suicidal ideation or thoughts of self-harm than controls. These results suggest that mindfulness training may yield both unique and non-specific benefits that are shared by other novel activities. (shrink)

Things and Their Place in Theories Our talk of external things, our very notion of things, is just a conceptual apparatus that helps us to foresee and ...

ABSTRACTThe close connection often cited between Hegel and Wilfrid Sellars is not only said to lie in their common negative challenges to the ‘framework of givenness,’ but also in the positive less...

This book extends the concept of linguistic coordinate geometry using linguistic planes or semi-linguistic planes. In the case of coordinate planes, we are always guaranteed of the distance between any two points in that plane. However, in the case of linguistic and semi-linguistic planes, we can not always determine the linguistic distance between any two points. This is the first limitation of linguistic planes and semi-linguistic planes.

In this book, authors, for the first time, introduce the new notion of special subset linguistic topological spaces using linguistic square matrices. This book is organized into three chapters. Chapter One supplies the reader with the concept of ling set, ling variable, ling continuum, etc. Specific basic linguistic algebraic structures, like linguistic semigroup linguistic monoid, are introduced. Also, algebraic structures to linguistic square matrices are defined and described with examples. For the first time, non-commutative linguistic topological spaces are introduced. The (...) notion of a linguistic special subset of doubly non-commutative topological spaces of linguistic topological spaces is introduced in this book. (shrink)

Traditionally, the ideas of “intuitive” and “discursive” forms of understanding have been seen as near opposites. Whereas an intuitive understanding could have a direct grasp of something, a discursive understanding would always depend on what is given to it, as mediated by concepts. In this essay, I suggest that Paul Ricoeur’s conception of analogy presents a way of overcoming this opposition. For Ricoeur, an analogy works within discursive understanding, but it depends on an eventful insight that leads beyond what is (...) merely given in discourse. The analogy “gives more” for thought. Yet, as I argue, what analogy gives for thought is always explicable in conceptual terms: any intuitive understanding is commensurate with a discursive one. I illustrate Ricoeur’s mediation of discursive and intuitive understanding in particular with his conception of metaphor, which vividly depends on overcoming a discursive contradiction by analogical and intuitive means. Before introducing Ricoeur’s conception, I discuss the Kantian background of the intuitive/discursive distinction. In particular, I suggest how Goethe’s attempt to revitalize a notion of intuitive understanding can be compared to Ricoeur’s conception, though Ricoeur improves upon Goethe by grounding intuition in the specific phenomenon of analogy. (shrink)

The study of teleology is challenging in many ways, but there is a particular challenge that makes matters worse, distorting the conceptual space that has set the terms of debate. And that is the tendency to think about teleology in terms of certain long-established dichotomies. In this paper, we examine four such dichotomies prevalent in the literature on teleology, the notions that: 1) Teleological explanations are opposed to mechanistic explanations; 2) teleology must arise from processes operating either internal to an (...) organism or external to it; 3) systems are either alive and teleological, or nonliving and not teleological; 4) humans are teleological, on account of our ability to intend, seek, prefer, etc., while other systems without these capacities are not. Here, we use our own view of goal directedness, field theory, to show for each dichotomy that there is an alternative, a view of teleology that either violates these dichotomies or demands revision of them. What this reveals is not only the dangers of dichotomous thinking, but a widespread lack of clarity about what teleology is. (shrink)

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)

In the world of philosophy of science, the dominant theory of confirmation is Bayesian. In the wider philosophical world, the idea of inference to the best explanation exerts a considerable influence. Here we place the two worlds in collision, using Bayesian confirmation theory to argue that explanatoriness is evidentially irrelevant.

In this essay I propose that what design principles in systems biology and systems neuroscience do is to present abstract characterizations of mechanisms, and thereby facilitate mechanistic explanation. To show this, one design principle in systems neuroscience, i.e., the multilayer perceptron, is examined. However, Braillard (2010) contends that design principles provide a sort of non-mechanistic explanation due to two related reasons: they are very general and describe non-causal dependence relationships. In response to this, I argue that, on the one hand, (...) all mechanisms are more or less general (or abstract), and on the other, many (if not all) design principles are causal systems. (shrink)

Pada musim semi, entah kenapa, tidak banyak ikan. Karena tangkapannya sangat tidak stabil, Pekakak mulai berpikir. Lalu membuat beberapa rencana. Dengan otoritas komandonya, dia memanggil Bangau: – Ini adalah musim penangkapan ikan yang sangat sulit. Jika kita ingin kenyang, kita harus membuat usaha patungan. Bangau mengangguk, menambahkan: - Saya setuju; mari kita beternak ikan kakap putih dan ikan mas krusia. Jenis ini berumur panjang dan sangat produktif. Pekakak dan Bangau sepakat untuk berbagi tugas beternak, dan tidak ada diskriminasi yang diizinkan. (...) Namun imbalannya berbeda: Pekakak bertanggung jawab untuk ikan kakap putih dan, dengan demikian, dapat memiliki lebih banyak ikan kakap putih, sedangkan Bangau mendapat ikan mas krusia. Siapapun yang memelihara ikan mana yang lebih banyak akan menikmati 80% dari panen akhir ikan tersebut. Keduanya akan mengevaluasi dan membagi produk ternak pada akhir musim beternak. Ini berarti mengantongi sendiri ikan hasil usaha patungan untuk diri sendiri itu dilarang. (shrink)

Suatu pagi di musim panas, desa burung diselimuti keheningan. Semua orang sibuk mendengarkan pengembara baru. Burung pengembara ini berasal dari keluarga yang tidak jelas; bulunya berwarna-warni, gerak-geriknya lucu, dan ilmunya baru. Dia bercerita seolah-olah sedang memberi ceramah, tepat sekali, warga desa memanggilnya burung Guru – orang yang menjawab setiap pertanyaan aneh warga desa yang rajin belajar. Burung pelatuk telah belajar menangkap cacing di sore hari, sehingga mereka tidak perlu bangun pagi. Burung pipit sekarang tahu cara mencuri beras dari gudang saat (...) sawah mulai kering. Bulbul, sementara itu, telah mengambil kesempatan berkumpul untuk memamerkan kecantikan dan fashion mereka… . (shrink)

Pekakak selama ini tinggal di gua galiannya sendiri di tepi kolam, tapi sekarang dia memutuskan bahwa dia membutuhkan rumah baru. Dia melakukan tur keliling desa untuk melihat bagaimana burung-burung lain membangun rumah mereka. Dia mengunjungi Tuan Pipit, yang tinggal di pohon pinus yang bersiul. Bagian depan bangunannya tampak indah, dan lokasinya yang tinggi memberikan ventilasi yang baik. Tapi, semakin lama dia menginap, dia jadi semakin pusing. Hembusan angin apa pun yang menerpa membuat seluruh struktur bangunan bergetar seolah-olah akan hancur berantakan.

I develop an expressivist account of verbal disagreements as practical disagreements over how to use words rather than factual disagreements over what words actually mean. This account enjoys several advantages over others in the literature: it can be implemented in a neo-Stalnakerian possible worlds framework; it accounts for cases where speakers are undecided on how exactly to interpret an expression; it avoids appeals to fraught notions like subject matter, charitable interpretation, and joint-carving; and it naturally extends to an analysis of (...) metalinguistic negotiations. (shrink)

A common objection to the very idea of conceptual engineering is the topic continuity problem: whenever one tries to “reengineer” a concept, one only shifts attention away from one concept to another. Put differently, there is no such thing as conceptual revision: there’s only conceptual replacement. Here, I show that topic continuity is compatible with conceptual replacement. Whether the topic is preserved in an act of conceptual replacement simply depends on what is being replaced (a conceptual tool or a conceptual (...) role) and what the topic under discussion is. Thus, the topic continuity problem only arises from a failure to specify these two things. (shrink)

While the idea of philosophy as conceptual analysis has attracted many adherents and undergone a number of variations, in general it suffers from an authority problem with two dimensions. First, it is unclear why the analysis of a concept should have objective authority: why explicating what we mean should express how things are. Second, conceptual analysis seems to lack intersubjective authority: why philosophical analysis should apply to more than a parochial group of individuals. I argue that Hegel’s conception of social (...) ontology, focused on his concept of “ethical life” (Sittlichkeit), helps to explain how concepts (and their explication) have both objective and intersubjective authority in the social domain. Hegel claims that modern institutions are the product of self-conscious purposes, so that they are conceptually constituted. Concepts do not just represent these objects and so depend on a contingent relation to them. As many contemporary social ontologists agree, this means that our concepts of these institutions are uniquely epistemically “transparent.” They have objective authority. Concepts have intersubjective authority in the modern world as well, according to Hegel. However, I show that this feature of Hegel’s account does not rely on the solution to a philosophical problem. Rather, since the concepts of modern ethical life are “essentially contested,” their content depends on the practical and political agreement of modern subjects. This means that concepts can only have objective authority if some prior intersubjective agreement has been reached. The role of philosophy as conceptual analysis is thus importantly dependent on political developments. (shrink)

Hegel often says that his "logic" is meant to replace metaphysics. Since Hegel's Science of Logic is so different from a standard logic, most commentators have not treated the portion of that work devoted to logical forms as relevant to this claim. This paper argues that Hegel's discussion of logical forms of judgment and syllogism is meant to be the foundation of his reformation of metaphysics. Implicit in Hegel's discussion of the logical forms is the view that the metaphysical concepts (...) discussed in Books I and II of the Science of Logic supervene on the role of subject and predicate terms in the logical forms discussed in Book III. Hegel thus has an explanation for the nature and significance of metaphysical concepts that resembles Kant's "metaphysical deduction," according to which the categories can be derived from the table of judgments. Though Hegel's metaphysics is often supposed to be influenced by Kant, prevailing interpretations do not show how Hegel's fine-grained treatment of logical forms is relevant to his critical view of metaphysics. The present interpretation provides a model for Hegel's explanation of metaphysical concepts, as well as a new picture of the structure of his Science of Logic that emphasizes the priority of its Doctrine of the Concept. (shrink)

Is moral responsibility essentially historical, or does an agent's moral responsibility for an action depend only on their psychological structure at that time? In previous work, I have argued that the two main (non‐skeptical) views on moral responsibility and agents’ histories—historicism and standard structuralism—are vulnerable to objections that are avoided by a third option, namely history‐sensitive structuralism. In this paper, I develop this view in greater detail and evaluate the view by comparing it with its three dialectical rivals: skepticism about (...) moral responsibility, historicism, and standard structuralism. Each comparison includes discussion of new work on moral responsibility and agents’ histories, and along the way I offer new arguments for preferring history‐sensitive structuralism, paying special attention to the view's explanatory power. (shrink)

This is the second part of a two-part series on the logic of hyperlogic, a formal system for regimenting metalogical claims in the object language (even within embedded environments). Part A provided a minimal logic for hyperlogic that is sound and complete over the class of all models. In this part, we extend these completeness results to stronger logics that are sound and complete over restricted classes of models. We also investigate the logic of hyperlogic when the language is enriched (...) with hyperintensional operators such as counterfactual conditionals and belief operators. (shrink)

The method of reflective equilibrium (MRE) is a method of justification popularized by John Rawls and further developed by Norman Daniels, Michael DePaul, Folke Tersman, and Catherine Z. Elgin, among others. The basic idea is that epistemic agents have justified beliefs if they have succeeded in forming their beliefs into a harmonious system of beliefs which they reflectively judge to be the most plausible. Despite the common reference to MRE as a method, its mechanisms or rules are typically expressed in (...) a metaphorical or simplified manner and are therefore criticized as too vague. Recent efforts to counter this criticism have been directed towards the attempt to provide formal explications of MRE. This paper aims to supplement these efforts by providing an informal working definition of MRE. This approach challenges the view that MRE can adequately be characterized only in the negative as a set of anti-essentialisms. I argue that epistemic agents follow MRE iff they follow four interconnected rules, which are concerned with a minimalistic form of foundationalism, a minimalistic form of fallibilism, a moderate form of holism, and a minimalistic form of rationality. In the critical spirit of MRE, the corresponding working definition is, of course, provisional and revisable. In general, the aim is to contribute to a reflective equilibrium (RE) concerning MRE. If it is successful, this working definition provides a better grasp of the most basic elements of the method and thereby enhances our understanding of it. (shrink)

In this paper, a modified form of Collatz conjecture for neutrosophic numbers n ∈ (Z U I) is defined. We see for any n ∈ (Z U I) the related sequence using the formula (3a + 1) + (3b + 1)I converges to any one of the 55 elements mentioned in this paper. Using the akin formula of Collatz conjecture viz. (3a- 1) + (3b -1)I the neutrosophic numbers converges to any one of the 55 elements mentioned with appropriate modifications. (...) Thus, it is conjectured that every n ∈ (Z U I) has a finite sequence which converges to any one of the 55 elements. (shrink)

This study investigates all available literature related to critical thinking in business education in a survey of publications in the field produced from 1990-2019. It conducts a thematic analysis of 787 articles found in Web of Science and Google Scholar, including a specific focus on 55 highly-cited articles. The aim is to investigate the importance of critical thinking in business education, how it is conceptualised in business education research, the business contexts in which critical thinking is situated, and the key (...) and more marginal themes related to critical thinking outlined in the business and business education literature. The paper outlines six key areas and topics associated with those areas. It suggests future directions for further scholarly work in the area of critical thinking in business education. (shrink)

While more species are being identified as cultural on a regular basis, stark differences between human and animal cultures remain. Humans are more richly cultural, with group-specific practices and social norms guiding almost every element of our lives. Furthermore, human culture is seen as cumulative, cooperative, and normative, in contrast to animal cultures. One hypothesis to explain these differences is grounded in the observation that human children across cultures appear to spontaneously over-imitate silly or causally irrelevant behaviors that they observe. (...) The few studies on over-imitation in other species are largely taken as evidence that spontaneous over-imitation is not present in other species. This leads to the over-imitation hypothesis – that the differences between human culture and animal cultures can be traced to the human unique tendency to over-imitate. In this paper, we analyze the current state of the literature on animal over-imitation and challenge the adequacy of the over-imitation hypothesis for the differences between humans and animal cultures. To make this argument, we first argue that the function of human over-imitation is norm-learning and that over-imitation, like skill-learning, should be subject to selective social learning effects. Then we review the empirical evidence against animal over-imitation and argue that these studies do not take into account the relevant variables given the normative and selective nature of over-imitation. We then analyze positive empirical evidence of over-imitation in great apes and canids from the experimental literature and conclude that the current body of evidence suggests that some canids and primates may have the capacity for over-imitation. This paper offers a methodological suggestion for how to study animal over-imitation, and a theoretical suggestion that over-imitation might be much more widely found among species. The larger implication for claims about human uniqueness suggests that if we do find widespread evidence of over-imitation across species, many of the current theories of human uniqueness that focus on human hyper-cooperation or social norms may have only identified a difference of degree, not of kind, between humans and other animals. (shrink)

The fructose 6-phosphate (Fru-6P) saturation curve for phosphofructokinase (PFK) from E. coli is sigmoidal in the presence of saturating MgATP levels, while the corresponding curve for B. stearothermophilus PFK is essentially hyperbolic. Sigmoidality can be due to apparent cooperativity arising from the kinetic mechanism of an enzyme. We have determined the kinetic mechanism of B. stearothermophilus PFK (BsPFK). BsPFK was found to obey a non rapid-equilibrium random mechanism similar to the one E. coli PFK (EcPFK) follows. Substrate inhibition by MgATP (...) was observed. We propose that substrates bind to BsPFK through two alternative pathways, one of which is slower. The substrate inhibition arises in part from reaction flux through the slower pathway. Although EcPFK and BsPFK obey similar kinetic mechanisms, they are inhibited differently by MgATP: EcPFK is profoundly inhibited, BsPFK only weakly. The structural basis for this difference could be closure of the active site via a conformational transition that occurs in EcPFK, but not BsPFK. To investigate the importance of this transition for MgATP inhibition of EcPFK, we have constructed a chimeric enzyme (ChiPFK) that contains the "rigid" ATP-binding domain of BsPFK grafted onto the remainder of the EcPFK subunit. Our results indicate that ChiPFK is locked in an "open" structure resembling the activated form of EcPFK. It is insensitive to heterotropic regulation. Nevertheless, ChiPFK exhibits residual cooperativity. Possible explanations for the cooperativity are discussed. The 6F loop is proposed to be important in PFK allosteric behavior. Residues along the loop are largely conserved between BsPFK and EcPFK, except for 161, which is a glutamate in BsPFK, and a glutamine in EcPFK. Using site-directed mutagenesis, Glu 161 of BsPFK has been changed to glutamine and alanine. Similarly, Gin 161 of EcPFK has been changed to glutamate, arginine and alanine. Of the five mutants, one, QA161, was particularly interesting. Though activated normally by GDP, it was completely insensitive to PEP inhibition. This indicates that the hydrogen-bonding ability of residue 161 is critical for PEP inhibition of EcPFK, and that GDP activation and PEP inhibition follow different structural pathways. (shrink)

[A. W. Moore] Criteria of ineffability are presented which, it is claimed, preclude the possibility of truths that are ineffable, but not the possibility of other things that are ineffable—not even the possibility of other things that are non-trivially ineffable. Specifically, they do not preclude the possibility of states of understanding that are ineffable. This, it is argued, allows for a reappraisal of the dispute between those who adopt a traditional reading of Wittgenstein’s Tractatus and those who adopt the new (...) reading recently championed by Cora Diamond, James Conant, and others. By maintaining that what the nonsense in the Tractatus is supposed to convey is ineffable understanding, rather than ineffable truth, we can do considerable justice to each of these readings. We can also do considerable justice to the Tractatus. /// [Peter Sullivan] Moore proposes to cut between 'traditional' and 'new' approaches to the Tractatus, suggesting that Wittgenstein's intention is to convey, through the knowing use of nonsense, ineffable understanding. I argue, first, that there is indeed room for a proposal of Moore's general kind. Secondly, though, I question whether Moore's actual proposal is not more in tune with Wittgenstein's later thought than with the attitude of the Tractatus. (shrink)

First put forth in June 2005, the altered nuclear transfer-oocyte assisted reprogramming (ANT-OAR) proposal has been promoted as an ethically-acceptable alternative to the embryo-destructive methods now used to obtain embryonic stem cells. According to its proponents, the goal of ANT-OAR is to use the cloning process to create a pluripotent stem cell. This would be achieved through overexpression of the transcription factor Nanog (or a hypothetical substitute) both in the enucleated egg cell and in the somatic cell prior to transfer (...) of its nucleus. Although the ethical acceptability of ANT-OAR has been publicly debated, its scientific feasibility has not. This paper aims to help rectify this situation. It argues that ANT-OAR, as currently conceived, cannot realistically work. It presents evidence from the scientific literature showing that Nanog cannot single-handedly establish pluripotency in cells, but rather works together with a network of other transcription factors to maintain pluripotency. It argues that ANT-OAR is based on a flawed understanding of stem cell biology, and emphasizes that, in this debate about embryonic stem cells, scientists must strive to accurately and realistically assess the feasibility of the embryo research strategies they propose. (shrink)

I argue that any account attempting to do away with resultant or circumstantial moral luck is inconsistent with a natural response to the problem of constitutive moral luck. It is plausible to think that we sometimes contribute to the formation of our characters in such a way as to mitigate our constitutive moral luck at later times. But, as I argue here, whether or not we succeed in bringing about changes to our characters is itself a matter of resultant and (...) circumstantial moral luck. I conclude with a dilemma, both horns of which require accepting some form of moral luck. (shrink)

The articles included in this issue represent some of the most recent thinking in the area of critical thinking in higher education. While the emphasis is on work being done in the Australasian region, there are also papers from the USA and UK that demonstrate the international interest in advancing research in the area. -/- ‘Critical thinking’ in the guise of the study of logic and rhetoric has, of course, been around since the days of the ancient Greeks and the (...) early beginnings of universities. In a narrower sense, critical thinking has been central to higher education as a desirable attribute of graduates since at least the beginning of the twentieth century. The work of John Dewey, and others, emphasised the importance of ‘good habits of thinking’ as early as 1916. In 1945, the Harvard Committee placed emphasis on the importance of ‘thinking effectively’ as one of three desirable educational abilities in their General education in a free society. This was later endorsed in 1961 by the US-based Educational Policies Commission: ‘The purpose which runs through and strengthens all other educational purposes … is the development of the ability to think’ (Kennedy, Fisher, & Ennis, 1991, pp. 11–12). -/- In recent times, universities have made a point of emphasising the importance of critical thinking as a ‘generic skill’ that is central to most, if not all, subjects. There is not a university today (in Australia at least) that does not proudly proclaim that their graduates will – as a result of a degree program in their institution – learn to think critically. Further, there is rarely a subject taught that does not offer the opportunity to acquire skills in critical thinking. However, where is the evidence that we teach critical thinking in higher education? Disturbingly, despite our best intentions, it appears we may be teaching very little of it. (shrink)

'The arrow of time' refers to the curious asymmetry that distinguishes the future from the past. Reversing the Arrow of Time argues that there is an intimate link between the symmetries of 'time itself' and time reversal symmetry in physical theories, which has wide-ranging implications for both physics and its philosophy. This link helps to clarify how we can learn about the symmetries of our world, how to understand the relationship between symmetries and what is real, and how to overcome (...) pervasive illusions about the direction of time. Roberts explains the significance of time reversal in a way that intertwines physics and philosophy, to establish what the arrow of time means and how we can come to know it. This book is both mathematically and philosophically rigorous yet remains accessible to advanced undergraduates in physics and the philosophy of physics. This title is also available as Open Access on Cambridge Core. (shrink)