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 relationship of part to whole is one of the most fundamental there is; this is the first and only full-length study of this concept. This book shows that mereology, the formal theory of part and whole, is essential to ontology. Peter Simons surveys and criticizes previous theories, especially the standard extensional view, and proposes a more adequate account which encompasses both temporal and modal considerations in detail. 'Parts could easily be the standard book on mereology for the next twenty (...) or thirty years.' Timothy Williamson, Grazer Philosophische Studien. (shrink)

It has been widely argued that words are analogous to species such that words, like species, are natural kinds. In this paper, I consider the metaphysics of word-kinds. After arguing against an essentialist approach, I argue that word-kinds are homeostatic property clusters, in line with the dominant approach to other biological and psychological kinds.

This article investigates the hitherto under-examined relations between affirmative action, paternalism and respect. We provide three main arguments. First, we argue that affirmative action initiatives are typically paternalistic and thus disrespectful towards those intended beneficiaries who oppose the initiatives in question. Second, we argue that not introducing affirmative action can also be disrespectful towards these potential beneficiaries because such inaction involves a failure to adequately recognize their moral worth. Third, we argue that the paternalistic disrespect involved in affirmative action is (...) alleviated when the potential beneficiaries’ preferences against such initiatives are adaptive. We conclude that although there is a relevant sense in which paternalistic affirmative action is disrespectful, it may well be more disrespectful not to pursue such policies. (shrink)

The aim of this paper is to bring recent work on metaphysical grounding to bear on the phenomenon of social construction. It is argued that grounding can be used to analyze social construction and that the grounding framework is helpful for articulating various claims and commitments of social constructionists, especially about social identities, e.g., gender and race. The paper also responds to a number of objections that have been leveled against the application of grounding to social construction from Elizabeth Barnes, (...) Mari Mikkola, and Jessica Wilson. (shrink)

I defend the following version of the ought-implies-can principle: (OIC) by virtue of conceptual necessity, an agent at a given time has an (objective, pro tanto) obligation to do only what the agent at that time has the ability and opportunity to do. In short, obligations correspond to ability plus opportunity. My argument has three premises: (1) obligations correspond to reasons for action; (2) reasons for action correspond to potential actions; (3) potential actions correspond to ability plus opportunity. In the (...) bulk of the paper I address six objections to OIC: three objections based on putative counterexamples, and three objections based on arguments to the effect that OIC conflicts with the is/ought thesis, the possibility of hard determinism, and the denial of the Principle of Alternate Possibilities. (shrink)

The aim of this paper is to evaluate the critical success factors and investigate the benefits that might be gained once implementing Electronic Customer Relationship Management at HEI from employee perspective. The study conducted at Al Quds Open University in Palestine and data collected from (300) employee through a questionnaire which consist of four variables. A number of statistical tools were intended for hypotheses testing and data analysis, including Spearman correlation coefficient for Validity, reliability correlation using Cronbach’s alpha, and Frequency (...) and Descriptive analysis. The overall findings of the current study show that all the features were important for staff and it was critical success factors, at the same time, websites were providing all the features discussed by the theory whereas staff showed their willingness to use those features if provided. It is also discovered that implementing Electronic Customer Relationship Management can cause staff retention, were provided efficiently and needed to be improved. Research limitations: The survey findings were based on QOU employee in Palestine, UAE and KSA branches not included in the study. (shrink)

Some modern cosmological models predict the appearance of Boltzmann Brains: observers who randomly fluctuate out of a thermal bath rather than naturally evolving from a low-entropy Big Bang. A theory in which most observers are of the Boltzmann Brain type is generally thought to be unacceptable, although opinions differ. I argue that such theories are indeed unacceptable: the real problem is with fluctuations into observers who are locally identical to ordinary observers, and their existence cannot be swept under the rug (...) by a choice of probability distributions over observers. The issue is not that the existence of such observers is ruled out by data, but that the theories that predict them are cognitively unstable: they cannot simultaneously be true and justifiably believed. (shrink)

This paper will be broken down into four sections. In §1, I try to assuage a worry that intellectual humility is not really an intellectual virtue. In §2, we will consider the two dominant accounts of intellectual humility in the philosophical literature—the low concern for status account the limitations-owing account—and I will argue that both accounts face serious worries. Then in §3, I will unpack my own view, the doxastic account of intellectual humility, as a viable alternative and potentially a (...) better starting place for thinking about this virtue. And I’ll conclude in §4 by trying to defend the doxastic account against some possible objections. (shrink)

In this article, I explore Seth Farber’s critique in _The Spiritual Gift of Madness_ that the leaders of the Mad Pride movement are failing to realize his vision of the mad as spiritual vanguard of sociopolitical transformation. First, I show how, contra Farber’s polemic, several postmodern theorists are well suited for this leadership (especially the Argentinian post-Marxist philosopher Ernesto Laclau). Second, I reinterpret the first book by the Icarus Project, _Navigating the Space between Brilliance and Madness_, by reimagining its central (...) metaphor of Icarus in the context of late capitalism as a prison world. Finally, I conclude with four strategies derived therefrom for higher functioning mad leaders to transform our penitentiary world. (shrink)

The Principle of Sufficient Reason (PSR) holds that, for everything that exists or occurs or holds true, there is a reason why that is the case. I consider three possible ways of relating physics to the PSR: past states as reasons for present states, reasons why the laws of physics take the form that they do, and reasons why there is anything at all. In each case I suggest that the PSR is not the best way of thinking about how (...) and why physics works. -/- Invited reflection for The Principle of Sufficient Reason (Oxford Philosophical Concepts), Eds. F. Amijee and M. Della Rocca (forthcoming 2024). (shrink)

A consensus exists among contemporary philosophers of biology about the history of their field. According to the received view, mainstream philosophy of science in the 1930s, 40s, and 50s focused on physics and general epistemology, neglecting analyses of the 'special sciences', including biology. The subdiscipline of philosophy of biology emerged (and could only have emerged) after the decline of logical positivism in the 1960s and 70s. In this article, I present bibliometric data from four major philosophy of science journals (Erkenntnis, (...) Philosophy of Science, Synthese, and the British Journal for the Philosophy of Science), covering 1930-59, which challenge this view. (shrink)

Recently, Intelligent Tutoring Systems (ITS) got much attention from researchers even though ITS educational technology began in the late 1960s and ITS is just embryonic from laboratories into the field. In this paper we outline an intelligent tutoring system for teaching basics of the databases system called (MDB). The MDB was built as education system by using the authoring tool (ITSB). MDB contains learning materials as a group of lessons for beginner level which include relational database system and lessons in (...) the process to install and set up a database. MDB system has exams for each level of the Lessons. An evaluation was done to see the effectiveness the MDB among learners and instructors. The outcome of the evaluation was promising. (shrink)

I argue that an individual has aspects numerically identical with it and each other that nonetheless qualitatively differ from it and each other. This discernibility of identicals does not violate Leibniz's Law, however, which concerns only individuals and is silent about their aspects. They are not in its domain of quantification. To argue that there are aspects I will appeal to the internal conflicts of conscious beings. I do not mean to imply that aspects are confined to such cases, but (...) the best way to start is to recognize them experientially. We can feel the conflicts within ourselves. In doing so we can feel some of our aspects. I will try to enhance our understanding of the concept of aspect by listing and formalizing some principles for its use. After that I will argue that all sorts of individual things have aspects, not just people who are conflicted. (shrink)

How should we choose between uncertain prospects in which different possible people might exist at different levels of wellbeing? Alex Voorhoeve and Marc Fleurbaey offer an egalitarian answer to this question. I give some reasons to reject their answer and then sketch an alternative, which I call person-affecting prioritarianism.

Slurs such as spic, slut, wetback, and whore are linguistic expressions that are primarily understood to derogate certain group members on the basis of their descriptive attributes and expressions of this kind have been considered to pack some of the nastiest punches natural language affords. Although prior scholarship on slurs has uncovered several important facts concerning their meaning and use –including that slurs are potentially offensive, are felicitously applied towards some targets yet not others, and are often flexibly used not (...) only derogatorily to convey offense towards out-group members but also non-derogatorily to convey affiliation with in-group members– the literature remains largely focused on slurs that typically target African Americans, male homosexuals, and sexually active females. Since no account of slurs that typically target Hispanics or Mexican-Americans has so far been proposed, here I offer the first systematic and empirically informed analysis of these that accounts for both their derogatory and appropriative use. Importantly, this article reviews over a dozen Spanish stereotypes and slurs and explains how the descriptive attributes involved in a stereotype associated with a slur can contribute to the predication of certain content in the application of that slur toward its target in context. This article further explains how the psychological effects of stereotype threat and stereotype lift can be initiated through the application of a relevant slur towards its target in context as well. -/- ----- -/- Las expresiones peyorativas tales como spic (‘spic’), slut (‘zorra’), wetback (‘espalda mojada’) y whore (‘puta’) son expresiones lingüísticas que se entienden principalmente para minusvalorar ciertos miembros de un grupo sobre la base de sus atributos descriptivos (como la raza o el sexo). Se ha considerado que las expresiones de este tipo conllevan algunos de los puñetazos más desagradables que el lenguaje natural puede proporcionar. Aunque la literatura especializada sobre expresiones peyorativas ha descubierto varios hechos importantes en cuanto a significado y uso –entre los que se incluyen que tales expresiones son potencialmente ofensivas, apuntan efectivamente hacia unos objetivos pero no hacia otros, y con frecuencia se utilizan con flexibilidad no sólo despectivamente para ofender a miembros por fuera de un grupo, sino que también de forma no despectiva para afiliar con miembros dentro de un mismo grupo–, tal literatura sigue centrada en gran medida en las expresiones peyorativas que típicamente apuntan contra los afroamericanos (nigger ‘negro’), los homosexuales varones (fagot ‘maricón’), y las mujeres sexualmente activas (slut ‘zorra’). En tanto que no se ha propuesto al momento dar cuenta de expresiones peyorativas dirigidas contra hispanos o mexicano-americanos, en este trabajo se ofrece el primer análisis sistemático y empíricamente informado de tales expresiones, tanto en sus usos despectivos y de apropiación. Es importante destacar que en este artículo se revisan más de una docena de estereotipos y expresiones peyorativas en español, además de explicar cómo los atributos descriptivos que participan de un estereotipo asociado con una difamación pueden contribuir a la predicación de determinados contenidos en la aplicación de esa expresión hacia su objetivo en contexto. Asimismo, en este artículo se explica cómo comienzan los efectos psicológicos de la amenaza estereotipada y el realce estereotipado cuando se emplea una expresión peyorativa relevante contra un objetivo en contexto. (shrink)

In Flourish, the positive psychologist Martin Seligman (2011) identifies five commonly recognized factors that are characteristic of human flourishing or wellbeing: (1) “positive emotion,” (2) “relationships,” (3) “engagement,” (4) “achievement,” and (5) “meaning” (p. 24). Although there is no settled set of necessary and sufficient conditions neatly circumscribing the bounds of human flourishing (Seligman, 2011), we would mostly likely consider a person that possessed high levels of these five factors as paradigmatic or prototypical of human flourishing. Accordingly, if we wanted (...) to go about the practical task of actually increasing our level of wellbeing, we ought to do so by focusing on practically increasing the levels of the five factors that are characteristic of wellbeing. If, for instance, an activity such as musical engagement can be shown to positively influence each or all of these five factors, this would be compelling evidence that an activity such as musical engagement can positively contribute to one’s living a flourishing life. I’m of the belief that psychological research can and should be used, not only to identify and diagnose maladaptive psychological states, but identify and promote adaptive psychological states as well. In this article I advance the hypothesis and provide supporting evidence for the claim that musical engagement can positively contribute to one’s living a flourishing life. Since there has not yet been a substantive and up-to-date investigation of the possible role of music in contributing to one’s living a flourishing life, the purpose of this article is to conduct this investigation, thereby bridging the gap and stimulating discussion between the psychology of music and the psychology of wellbeing. (shrink)

Alasia Nuti’s important recent book, Injustice and the Reproduction of History: Structural Inequalities, Gender and Redress, makes many persuasive interventions. Nuti shows how structural injustice theory is enriched by being explicitly historical; in theorizing historical-structural injustice, she lays bare the mechanisms of how the injustices of history reproduce themselves. For Nuti, historical-structural patterns are not only shaped by habitual behaviors that are or appear to be morally permissible, but also by individual wrongdoing and wrongdoing by powerful group agents like states. (...) In this article, I extend Nuti’s rich analysis, focusing on two questions that arise from her theory of historical-structural injustice: Beyond being blameworthy for wrongful acts themselves, are culpable wrongdoers blameworthy for contributing to structural injustice? Does historical moral ignorance mitigate moral responsibility for past injustice? Regarding, I distinguish between the local and societal structural effects of wrongdoing. Though I think this distinction is well-founded, it ultimately leads to tensions with structural injustice theory’s idea of ordinary individuals being blameless for reproducing unjust structures. Regarding, I argue that even though it is natural for the question of historical moral ignorance to arise in considering past wrongdoing, at least in the case of powerful group agents, we should not overlook forms of cruelty which present-day moral concepts are not needed to condemn. (shrink)

The paper considers contemporary models of presumption in terms of their ability to contribute to a working theory of presumption for argumentation. Beginning with the Whatelian model, we consider its contemporary developments and alternatives, as proposed by Sidgwick, Kauffeld, Cronkhite, Rescher, Walton, Freeman, Ullmann-Margalit, and Hansen. Based on these accounts, we present a picture of presumptions characterized by their nature, function, foundation and force. On our account, presumption is a modal status that is attached to a claim and has the (...) effect of shifting, in a dialogue, a burden of proof set at a local level. Presumptions can be analysed and evaluated inferentially as components of rule-based structures. Presumptions are defeasible, and the force of a presumption is a function of its normative foundation. This picture seeks to provide a framework to guide the development of specific theories of presumption. (shrink)

Conceptions of acceptability-based moral or political justification take it that authoritative acceptability constitutes, or contributes to, validity, or justification. There is no agreement as to what bar for authoritativeness such justification may employ. The paper engages the issue in relation to (i) the level of idealization that a bar for authoritativeness, ψ, imparts to a standard of acceptability-based justification, S, and (ii) the degree of discursive purchase of the discursive standing that S accords to people when it builds ψ. I (...) argue that (i) and (ii) are interdependent: high idealization values entail low discursive purchase, while high degrees of purchase require low idealization values. I then distinguish between alethic conceptions of justification that prioritize ends that commit to high idealization values, and recognitive conceptions that favour high discursive purchase. On this basis, I argue for a moderately recognitivist constraint on idealization. To render the recognitive discursive minimum available to relevant people at the site of justification, S should set ψ low enough so that it is a genuine option for actual people to reject relevant views in ways that S recognizes as authoritative. (shrink)

A evolução da seleção genética de aves e suínos proporcionou aumento no crescimento muscular e no desempenho produtivo, bem como na produção intensiva. Os premixes proporcionam ingredientes, como vitaminas e minerais que são essenciais para o crescimento muscular, redução do estresse, eficiência de diversos metabolismos e o bem-estar animal, contribuindo para uma produção mais sustentável. Deste modo, os premixes desempenham um papel fundamental na otimização do desempenho produtivo e reprodutivo de aves, equinos e suínos. Para formular uma dieta balanceada é (...) necessária a inclusão de vitaminas e minerais, os quais são inseridos em baixas concentrações, em função disto é necessário incluí-los por meio de premix para garantir uma boa homogeneidade dos microingredientes na ração. Os premixes podem ser classificados como: ➢ Vitamínicos, ➢ Minerais e ➢ Minerais-vitamínicos ➢ e conter aminoácidos, antibióticos ou enzimas. (shrink)

Multicellular organisms contain numerous symbiotic microorganisms, collectively called microbiomes. Recently, microbiomic research has shown that these microorganisms are responsible for the proper functioning of many of the systems (digestive, immune, nervous, etc.) of multicellular organisms. This has inclined some scholars to argue that it is about time to reconceptualise the organism and to develop a concept that would place the greatest emphasis on the vital role of microorganisms in the life of plants and animals. We believe that, unfortunately, there is (...) a problem with this suggestion, since there is no such thing as a universal concept of the organism which could constitute a basis for all biological sciences. Rather, the opposite is true: numerous alternative definitions exist. Therefore, comprehending how microbiomics is changing our understanding of organisms may be a very complex matter. In this paper we will demonstrate that this pluralism proves that claims about a change in our understanding of organisms can be treated as both true and untrue. Mainly, we assert that the existing concepts differ substantially, and that only some of them have to be reconsidered in order to incorporate the discoveries of microbiomics, while others are already flexible enough to do so. Taking into account the plurality of conceptualisations within different branches of modern biology, we will conduct our discussion using the developmental and the cooperation–conflict concepts of the organism. Then we will explain our results by referring to the recent philosophical debate on the nature of the concept of the organism within biology. (shrink)

We provide a derivation of the Born Rule in the context of the Everett (Many-Worlds) approach to quantum mechanics. Our argument is based on the idea of self-locating uncertainty: in the period between the wave function branching via decoherence and an observer registering the outcome of the measurement, that observer can know the state of the universe precisely without knowing which branch they are on. We show that there is a uniquely rational way to apportion credence in such cases, which (...) leads directly to the Born Rule. Our analysis generalizes straightforwardly to cases of combined classical and quantum self-locating uncertainty, as in the cosmological multiverse. (shrink)

This Discussion Piece is a response to Mark Windsor's Discussion Piece (2023) 'Photographic Registers are Latent Images', which is a response to my article, (2021) 'Invisible Images and Indeterminacy: Why we need a Multi-stage Account of Photography' JAAC 79(2) 161-174.. -/- I argue that a photosensitive surface does not produce invisible pictorial features when it is exposed to light, and conclude, contra Windsor, that a photographic register is not a latent image. I argue that Windsor does not succeed in defending (...) a single-stage account of photography and I reconfirm that a multi-stage account is correct. (shrink)

Imperatives cannot be true, but they can be obeyed or binding: `Surrender!' is obeyed if you surrender and is binding if you have a reason to surrender. A pure declarative argument — whose premisses and conclusion are declaratives — is valid exactly if, necessarily, its conclusion is true if the conjunction of its premisses is true; similarly, I suggest, a pure imperative argument — whose premisses and conclusion are imperatives — is obedience-valid (alternatively: bindingness-valid) exactly if, necessarily, its conclusion is (...) obeyed (alternatively: binding) if the conjunction of its premisses is. I argue that there are two kinds of bindingness, and that a vacillation between two corresponding variants of bindingness-validity largely explains conflicting intuitions concerning the validity of some pure imperative arguments. I prove that for each of those two variants of bindingness-validity there is an equivalent variant of obedience-validity. Finally, I address alternative accounts of pure imperative inference. (shrink)

There is growing concern that a global economic system fueled predominately by financial incentives may not maximize human flourishing and social welfare externalities. If so, this presents a challenge of how to get economic actors to adopt a more virtuous motivational mindset. Relying on historical, psychological, and philosophical research, we show how such a mindset can be instilled. First, we demonstrate that historically, financial self-interest has never in fact been the only guiding motive behind free markets, but that markets themselves (...) are representations of our individual and collective moral identities. Building on this understanding, we review the research on how economic incentives crowd out virtue-oriented concerns. We then introduce the concept of moral self-awareness (MSA), an evolving mindset informed by reflection on moral identity, namely what one’s actions say about oneself given the impacts on others or society that one’s action may effect. MSA comprises three fundamental aspects of virtue-oriented reasoning: pride, shame, and guilt. Finally, we offer a four-stage model anchored in systems theory, yielding ever more refined motivating strategies for maximizing human flourishing and social welfare externalities. (shrink)

Philosophers of action of different persuasions have suggested that there is a tight connection between the phenomenon of intending and the phenomena of “being settled on” and of “settling” a course of action. For many, this connection supports an important constraint on intention: one may only intend what one takes one’s so intending as settling. Traditionally, this has been understood as a doxastic constraint on intention: what one takes one’s intention as settling is what one believes one’s so intending as (...) settling. This paper proposes an alternative conception of such a constraint. The idea is to conceive of it in terms of the attitude of reliance, rather than of belief. The aim of the paper is three-fold: to clarify the connection between intending to act and the phenomena of being settled on and of settling a course of action, to provide support for the reliance conception of the cited constraint, and to show that this conception drives a wedge in the familiar dispute, between doxastic and conative accounts of intention, as to whether intending to act necessarily involves the belief that one will so act. (shrink)

Are living organisms--as Descartes argued--just machines? Or is the nature of life such that it can never be fully explained by mechanistic models? In this thought-provoking and controversial book, eminent geophysicist Walter M. Elsasser argues that the behavior of living organisms cannot be reduced to physico-chemical causality. Suggesting that molecular biology today is at the same point as Newtonian physics on the eve of the quantum revolution, Elsasser lays the foundation for a theoretical biology that points the way toward a (...) natural philosophy of organic life. Explicitly repudiating "vitalism" (the notion that the laws of nature need to be modified when applied to living organisms), Elsasser argues instead that the structural complexity of even a single living cell is "transcomputational"--that is, beyond the power of any imaginable system to compute. Beginning from this insight, Elsasser leads the reader through a step-by-step process that ultimately arrives at the conclusion that living and non-living matter are separated by "a no-man's land of irrationality." Trained in Germany as a physicist, Elsasser first pondered the implications of quantum mechanics for biology as early as 1951. The more closely he studied the inherent complexity of life, the more skeptical he became of the reductionist view of organisms as tiny machines. "An organism," he concluded, "is a source of causal chains which cannot be traced beyond a terminal point because they are lost in the unfathomable complexity of the organism." Like the physicist who works within the bounds of an unfathomable universe, Elsasser argues, the biologist must seek answers within a system that is no less unfathomable. (shrink)

The paper argues that applications of the principle that “ought” implies “can” (OIC) depend on normative considerations even if the link between “ought” and “can” is logical in nature. Thus, we should reject a common, “factualist” conception of OIC and endorse weak “normativism”. Even if we use OIC as the rule ““cannot” therefore “not ought””, applying OIC is not a mere matter of facts and logic, as factualists claim, but often draws on “proto-ideals” of moral agency.

Intelligent Tutoring Systems (ITS) has a wide influence on the exchange rate, education, health, training, and educational programs. In this paper we describe an intelligent tutoring system that helps student study computer networks. The current ITS provides intelligent presentation of educational content appropriate for students, such as the degree of knowledge, the desired level of detail, assessment, student level, and familiarity with the subject. Our Intelligent tutoring system was developed using ITSB authoring tool for building ITS. A preliminary evaluation of (...) the ITS was done by a group of students and teachers. The results were acceptable. (shrink)

The purpose of this research is to identify the extent of the efficiency of the internal control environment in the Palestinian higher educational institutions in Gaza Strip from the perspective of employees in the Palestinian universities in Gaza Strip, where researchers used in the study five universities. The researchers adopted in their study the descriptive and analytical approach. The research community consists of administrative employees and academic employees with administrative duties. Senior management or the University Council was excluded. The study (...) population compromises of (392) employees. A stratified random sample was chosen and (197) questionnaires were distributed. (160) questionnaires were received back with a return rate of (81.2%).The researchers used a questionnaire to collect that which then was analyzed using (SPSS) to get the results. The research found the following results: the absence of a fundamental difference between the responses of males and females. The lack of significant difference between the responses of the respondents attributed to the variable age. The lack of significant difference between the responses of the respondents attributed to the variable of years of service. And the existence of a fundamental difference between the responses of the respondents attributed to the university variable. The existence of a fundamental difference between the responses of the respondents attributed to the Qualification variable. The existence of a fundamental difference between the responses of the respondents attributed to the administrative level variable. The research found a group of recommendations including: the need to raise awareness of censorship as the basis for the protection of employees in all administrative levels from making mistake.Updating the systems and instructions of control periodically and parallel with the scientific progress and technology.Benefit from regional and international experiences in the application of internal control standards which commensurate with the administrative system of the institution. (shrink)

Hubert Dreyfus has argued that cases of absorbed bodily coping show that there is no room for self-awareness in flow experiences of experts. In this paper, I argue against Dreyfus’ maxim of vanishing self-awareness by suggesting that awareness of agency is present in expert bodily action. First, I discuss the phenomenon of absorbed bodily coping by discussing flow experiences involved in expert bodily action: merging into the flow; immersion in the flow; emergence out of flow. I argue against the claim (...) that flow experience does not involve an awareness of agency for each of these features, while conceding that fluent agency does not involve self-awareness in the thetic sense. I challenge the assumption that the awareness of fluent agency must be understood in terms of a thetic awareness of agency. Instead, I develop an Anscombean account of the awareness of fluent agency in terms of the phenomenal character of knowing one’s aims. I respond to the challenge that if an Anscombean account of the awareness of agency is to succeed, then agents must be able to answer Anscombean questions. I consider the objection that awareness of agency is not a form of self-awareness by outlining an account of self-awareness as self-synthesis that is distinct from self-perception and self-ascription, but which makes room for self-awareness in expert bodily action. (shrink)

PHILOSOPHY OF SCIENCE, vol. 52, number 1, pp.44-63. R.M. Nugayev, Kazan State |University, USSR. -/- THE HISTORY OF QUANTUM THEORY AS A DECISIVE ARGUMENT FAVORING EINSTEIN OVER LJRENTZ. -/- Abstract. Einstein’s papers on relativity, quantum theory and statistical mechanics were all part of a single research programme ; the aim was to unify mechanics and electrodynamics. It was this broader program – which eventually split into relativistic physics and quantummmechanics – that superseded Lorentz’s theory. The argument of this paper is (...) partly historical and partly methodological. A notion of “crossbred objects” – theoretical objects with contradictory properties which are part of the domain of application of two different research programs – is developed that explains the dynamics of revolutionary theory change. (shrink)

In Rawls’s political liberalism, legitimate exercises of political power must be publicly justifiable to reasonable citizens on grounds each can coherently accept, where citizens count as “reasonable” only if they can accept certain values of public culture. Other citizens have no say in public justification, or no equal say. For Rawls, then, legitimate political power must accord with a subset of cultural values, and can be legitimate even if it is not (equally) justifiable to people who cannot accept them. Does (...) this mean that Rawls permits that such people be dominated? What kind of domination, if any, would this involve, and would it involve “cultural” domination? This chapter takes its lead from these questions. It offers a reading of the role of public justification in political liberalism that foregrounds differences in the discursive standing of reasonable and unreasonable people, and interpret these differences in domination-theoretic terms. I suggest that there is reason to believe that Rawls’s view would subject the unreasonable–a mixed group that also includes respectable people–to forms of discursive and political domination, and this in a manner that attracts the worry that cultural domination is involved. (shrink)

This discussion treats a set of familiar social derelictions as consequences of the perversion of a universalistic moral theory in the service of an ill-considered or insufficiently examined personal agenda.The set includes racism, sexism, anti-Semitism, homophobia, and class elitism, among other similar pathologies, under the general heading of discrimination. The perversion of moral theory from which these derelictions arise, I argue, involves restricting its scope of application to some preferred subgroup of the moral community of human beings. -/- The following (...) analysis of higher-order discrimination suggests that we often select the individuals who constitute such subgroups for reasons that we ourselves would reject on moral grounds were we to examine them carefully, but that we choose instead to put our rational resources in the service of avoiding any such examination at all costs. The implication is that arguments that truncate the scope of moral theory in fact justify bestowing the gift of moral treatment on a select few who deserve it no more than the many from whom we withhold it. Therefore, it would be precipitous to conclude that universalistic moral theory can be legitimately restricted in its practical scope of application in any way at all. (shrink)

I want to argue that self-deception is a species of a more general phenomenon, which I shall call pseudorationality, which in turn is necessitated by what I shall describe as our highest-order disposition to literal self-preservation. By "literal self-preservation," I mean preservation of the rational intelligibility of the self, in the face of recalcitrant facts that invariably threaten it.

In Who's Afraid of Idealism? the philosophical concept of idealism, the extent to which reality is mind-made, is examined in new light. Author Luis M. Augusto explores epistemological idealism, at the source of all other kinds of idealism, from the viewpoints of Immanuel Kant and Friedrich Nietzsche, two philosophers who spent a large part of their lives denigrating the very concept. Working from Kant and Nietzsche's viewpoints that idealism was a scandal to philosophy and the cause of nihilism, Augusto evaluates (...) these philosophers and their role in shaping epistemological idealism. Using textual evidence from their writings and their reactions to western philosophers such as Plato, Descartes, and Hegel, Who's Afraid of Idealism? argues that in fact Kant and Nietzsche were really idealists at heart. In accessible prose, this text puts forward a theory that goes against current scholarly opinion, and even Kant and Nietzsche's opinions of themselves. (shrink)

Contemporary studies in unconscious cognition are essentially founded on dissociation, i.e., on how it dissociates with respect to conscious mental processes and representations. This is claimed to be in so many and diverse ways that one is often lost in dissociation. In order to reduce this state of confusion we here carry out two major tasks: based on the central distinction between cognitive processes and representations, we identify and isolate the main dissociation paradigms; we then critically analyze their key tenets (...) and reported findings. (shrink)

A moral code consists of principles that assign moral status to individual actions – principles that evaluate acts as right or wrong, prohibited or obligatory, permissible or supererogatory. Many theorists have held that such principles must serve two distinct functions. On the one hand, they serve a theoretical function, insofar as they specify the characteristics in virtue of which acts possess their moral status. On the other hand, they serve a practical function, insofar as they provide an action-guide: a standard (...) by reference to which a person can choose which acts to perform and which not. Although the theoretical and practical functions of moral principles are closely linked, it is not at all obvious that what enables a principle to fill one of these roles automatically equips it to fill the other. In this paper I shall briefly examine some of the reasons why a moral principle might fail to fill its practical role, i.e., be incapable of guiding decisions. I shall then sketch three common responses to this kind of failure, and examine in some detail the adequacy of one of the most popular of these responses. (shrink)

An increasing vaccine hesitancy among parents, which has resulted in insufficient rates of immunization, provides reason to reconsider childhood vaccination practices. Studies suggest that parents' decision-making process concerning whether to vaccinate their child is highly influenced by cognitive biases. These biases can be utilized to increase vaccination uptake via changes in the choice context. This article considers childhood vaccination programmes, which involve children being vaccinated in school or daycare unless their parents actively ‘opt out’. We suggest that such programmes reconcile (...) parents' decisional authority and vaccination duties. First, opt-out childhood vaccination based in schools or daycare centres are not disrespectful of parental authority. Second, the programme aligns the default setting with a moral obligation to vaccinate one's child that most parents have. (shrink)

Criticism of big data has focused on showing that more is not necessarily better, in the sense that data may lose their value when taken out of context and aggregated together. The next step is to incorporate an awareness of pitfalls for aggregation into the design of data infrastructure and institutions. A common strategy minimizes aggregation errors by increasing the precision of our conventions for identifying and classifying data. As a counterpoint, we argue that there are pragmatic trade-offs between precision (...) and ambiguity that are key to designing effective solutions for generating big data about biodiversity. We focus on the importance of theory-dependence as a source of ambiguity in taxonomic nomenclature and hence a persistent challenge for implementing a single, long-term solution to storing and accessing meaningful sets of biological specimens. We argue that ambiguity does have a positive role to play in scientific progress as a tool for efficiently symbolizing multiple aspects of taxa and mediating between conflicting hypotheses about their nature. Pursuing a deeper understanding of the trade-offs and synthesis of precision and ambiguity as virtues of scientific language and communication systems then offers a productive next step for realizing sound, big biodiversity data services. (shrink)

This paper offers an analysis of work on human development in evolutionary anthropology from a Thomist perspective. I show that both fields view care for others as fundamental to human nature and interpret cooperative breeding as expression of the virtue of charity. I begin with an analysis of different approaches to the relationship between evolutionary anthropology and moral theory. I argue that ethical naturalism is the approach best suited to interdisciplinary dialogue, since it holds that natural facts are useful for (...) moral theory but do not encompass it. This forms the basis for a Thomist analysis of some key features of human evolution including bipedalism, higher encephalisation and extended childhood. In each case I explain how these parts of our nature contributed to the evolution of modern humans, and how each is reliant upon communal care. Finally, I offer three observations on these facts from a Thomist perspective. Firstly, that a good human life necessarily involves caring for others and being cared for ourselves. Secondly, that this is exemplified in the virtue of charity, which is the ground of all virtue. Finally, that the need for such care shows that human flourishing cannot be attained without divine aid. (shrink)

From folk tales to movies, stories possess features which naturally suit them to contribute to the growth of virtue. In this article I show that the fictional exemplars help the learner to grasp the moral importance of internal states and resolves a tension between existing kinds of exemplars discussed by virtue ethicists. Stories also increase the information conveyed by virtue terms and aid the growth of prudence. Stories can provide virtuous exemplars, inform learners as to the nature of the virtues (...) and offer practice in developing situational judgement. As such they are a significant resource for virtue ethics and moral education. (shrink)

2nd edition. Many-valued logics are those logics that have more than the two classical truth values, to wit, true and false; in fact, they can have from three to infinitely many truth values. This property, together with truth-functionality, provides a powerful formalism to reason in settings where classical logic—as well as other non-classical logics—is of no avail. Indeed, originally motivated by philosophical concerns, these logics soon proved relevant for a plethora of applications ranging from switching theory to cognitive modeling, and (...) they are today in more demand than ever, due to the realization that inconsistency and vagueness in knowledge bases and information processes are not only inevitable and acceptable, but also perhaps welcome. The main modern applications of (any) logic are to be found in the digital computer, and we thus require the practical knowledge how to computerize—which also means automate—decisions (i.e. reasoning) in many-valued logics. This, in turn, necessitates a mathematical foundation for these logics. This book provides both these mathematical foundation and practical knowledge in a rigorous, yet accessible, text, while at the same time situating these logics in the context of the satisfiability problem (SAT) and automated deduction. The main text is complemented with a large selection of exercises, a plus for the reader wishing to not only learn about, but also do something with, many-valued logics. (shrink)

We develop a theory about the metaphysics of time and modality that combines the conceptual resources devised in recent sympathetic work on ontological pluralism (the thesis that there are fundamentally distinct kinds of being) with the thought that what is past, future, and merely possible is less real than what is present and actual (albeit real enough to serve as truthmakers for statements about the past, future, and merely possible). However, we also show that despite being a coherent, distinctive, and (...) prima facie appealing position, the theory succumbs to what we call the “problem of mixed ontological status”. We conclude that the proponents of the theory can only evade these problems by developing ontological pluralism in a radically different way than it has been by its recent sympathizers. (shrink)

Perhaps the greatest impediment to a viable libertarianism is the provision of a satisfactory explanation of how actions that are undetermined by an agent's character can still be under the control of, or ‘up to’, the agent. The ‘luck problem’ has been most assiduously examined by Robert Kane who supplies a detailed account of how this problem can be resolved. Although Kane's theory is innovative, insightful, and more resourceful than most of his critics believe, it ultimately cannot account for the (...) type of control that moral responsibility and (ultimate) agency legitimately require. (shrink)

Upshot: In our target article we claimed that, at least since Weber and Varela, enactivism has incorporated a theoretical commitment to one important aspect of Jonas’s philosophical biology, namely its anthropomorphism, which is at odds with the methodological commitments of modern science. In this general reply we want to clarify what we mean by anthropomorphism, and explain why we think it is incompatible with science. We do this by spelling out what we call the “Jonasian inference,” i.e., the idea that (...) we are entitled, based on our first-person experience of teleology, to take the appearance of teleology in other living beings at face value. (shrink)

Existing institutions do not seem well-designed to address paradigmatically global, intergenerational and ecological problems, such as climate change. 1 In particular, they tend to crowd out intergenerational concern, and thereby facilitate a “tyranny of the contemporary” in which successive generations exploit the future to their own advantage in morally indefensible ways (albeit perhaps unintentionally). Overcoming such a tyranny will require both accepting responsibility for the future and meeting the institutional gap. I propose that we approach the first in terms of (...) a traditional “delegated responsibility” model of the transmission of individual responsibility to collectives, and the second with a call for a global constitutional convention focused on future generations. In this paper, I develop the delegated responsibility model by suggesting how it leads us to understand both past failures and prospective responsibility. I then briefly defend the call for a global constitutional convention. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Epistemic Leaks and Epistemic Meltdowns: A Response to William Morris on Scepticism with Regard to Reason Mikael M. Karlsson I. In an excellent paper which appeared in the April, 1989 issue of this journal,2 William Morris attemptsto demonstrate thatthe arguments which make up Hume's notorious chapter, "Of scepticism with regard to reason, are, in the first place, coherent—both internally and with the overall strategy of the Treatise—and, in the (...) second place, successful. Morris' paper is an exercise in the noble art of what I style constructive exegesis, an enterprise to which many readers of Hume Studies, and myself as much as any, are committed. It is a guiding principle ofthis art that we donotunderstandaphilosophical textuntil we can interpret it in such a way as to render it both coherent and correct. From this point ofview, coherence and correctness are not as independent of one another as they may seem to be to others who are differently committed. Some texts, such as Hume's chapter, "Ofscepticism with regard to reason," are notoriously resistant to constructive exegesis, despite the formidable bag of tricks which scholars and interpreters have developed; so resistant, that in gloomier moments we may be brought to wonder about our interpretative enterprise itself. Constructive exegesis is indeed a strange, and peculiarly optimistic, enterprise. Someday, I imagine, in a leisurely moment, I will think more reflectively about the principles ofour art. But not now.6 As a fellow practitioner of constructive exegesis, I am in full sympathy with what Morris tries to do in his paper; and I think that he does contribute substantially to our understanding of what Hume is up to in the chapter, "Ofscepticism with regard to reason." The third section of Morris' paper is, in my judgement, particularly successful in showing how Hume's chapter fits into the larger framework of the Treatise: Hume is, we see, attacking both what Morris labels "intellectualist rationalism" and its counterpart, which we may call 'unmitigated scepticism', although the chapter's two main arguments go primarily to the former. I also think that Morris gives very helpful, Volume XVI Number 2 121 MIKAEL M. KARLSSON and to my mind accurate, accounts of these two arguments, which I dub, respectively, the epistemic leak argument, and the epistemic meltdown argument. However, I have personally never found either of these arguments remotely convincing; and I still do not, despite Morris' clarification and defense. In what follows, I shall indicate some ofthe reasons for my dissatisfaction.?. Theepistemicleakargumentpurportsto"prove"(in Hume's sense)that reason or demonstration cannot support knowledge. Morris rightlyreminds us that whatHume meansby knowledge is perfect assurance or conviction: Knowledge is, in short, subjective certainty. This has caused confusion, for this is not what we usually mean nowadays by knowledge; nor was it what people, philosophers included, generally meant prior to Descartes. In Hume itis the product ofthe attempttoresolve all epistemic statesintomental eventsorwhat he calls "perceptions." In any case, we must—as Morris rightly explains—be clear that the epistemic leak argument is aimed at showing that demonstration cannot supportperfect conviction. Inoutline, the argumentissimple: Itworks, asMorrismakes clear, by shifting attention away from the subject-matter or "objects" of demonstration, that is, relations of ideas, to the exercise of demonstrative reason by human agents. The necessity of relations of ideas may suggest to us that we can be certain about them. Against this, one may point out that people do err in the conclusions arrived at by demonstration; this presumably shows that our (rational) understandingis fallible. And once we recognize this, our confidence in any conclusion produced by exercising this facultyislessened—thus do we move from knowledge, or subjective certainty, toprobability: belief, or imperfect conviction. Arguments ofthis general type (we can call them, using Descartes' famous figure, Totten-apple arguments ) were around long before Hume, although they were more commonly directed against the senses than against reason. We find them in antiquity—in Plato and Sextus Empiricus, for instance —and in Descartes, in parallel passages in the Discourse on Method, the First Meditation and the Principles of Philosophy, wherein one can discern a version directed precisely against reason and demonstration.12 To find out what, if anything, Hume has... (shrink)

In the literature on transitional justice, there is disagreement about whether countries like the United States can be characterized as transitional societies. Though it is widely recognized that transitional justice mechanisms such as truth commissions and reparations can be used by Global North nations to address racial injustice, some consider societies to be transitional only when they are undergoing a formal democratic regime change. We conceptualize the political situation of low-income Black communities under the U.S. imprisonment and policing regime in (...) terms of three criteria for identifying transitional contexts: normalized collective and political wrongdoing, pervasive structural inequality, and the failure of the rule of law. That these criteria are met, however, does not necessarily mean that a transition is taking place. Drawing on the American political development and abolition democracy literatures, we discuss what it would mean for the United States to transition out of its present imprisonment and policing regime. A transitional justice perspective shows the importance of not only pushing for truth and reparation, but for an actual transition. (shrink)