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)

According to proponents of the extended mind, bio-external resources, such as a notebook or a smartphone, are candidate parts of the cognitive and mental machinery that realises cognitive states and processes. The present chapter discusses three areas of ethical concern associated with the extended mind, namely mental privacy, mental manipulation, and agency. We also examine the ethics of the extended mind from the standpoint of three general normative frameworks, namely, consequentialism, deontology, and virtue ethics.

All parties involved in researching, developing, manufacturing, and distributing COVID-19 vaccines need guidance on their ethical obligations. We focus on pharmaceutical companies' obligations because their capacities to research, develop, manufacture, and distribute vaccines make them uniquely placed for stemming the pandemic. We argue that an ethical approach to COVID-19 vaccine production and distribution should satisfy four uncontroversial principles: optimising vaccine production, including development, testing, and manufacturing; fair distribution; sustainability; and accountability. All parties' obligations should be coordinated and mutually consistent. For (...) instance, companies should not be obligated to provide host countries with additional booster shots at the expense of fulfilling bilateral contracts with countries in which there are surges. Finally, any satisfactory approach should include mechanisms for assurance that all parties are honouring their obligations. This assurance enables countries, pharmaceutical companies, global organisations, and others to verify compliance with the chosen approach and protect ethically compliant stakeholders from being unfairly exploited by unethical behaviour of others. (shrink)

Recent studies indicate that indicative conditionals like "If people wear masks, the spread of Covid-19 will be diminished" require a probabilistic dependency between their antecedents and consequents to be acceptable (Skovgaard-Olsen et al., 2016). But it is easy to make the slip from this claim to the thesis that indicative conditionals are acceptable only if this probabilistic dependency results from a causal relation between antecedent and consequent. According to Pearl (2009), understanding a causal relation involves multiple, hierarchically organized conceptual dimensions: (...) prediction, intervention, and counterfactual dependence. In a series of experiments, we test the hypothesis that these conceptual dimensions are differentially encoded in indicative and counterfactual conditionals. If this hypothesis holds, then there are limits as to how much of a causal relation is captured by indicative conditionals alone. Our results show that the acceptance of indicative and counterfactual conditionals can become dissociated. Furthermore, it is found that the acceptance of both is needed for accepting a causal relation between two co-occurring events. The implications that these findings have for the hypothesis above, and for recent debates at the intersection of the psychology of reasoning and causal judgment, are critically discussed. Our findings are consistent with viewing indicative conditionals as answering predictive queries requiring evidential relevance (even in the absence of direct causal relations). Counterfactual conditionals in contrast target causal relevance, specifically. Finally, we discuss the implications our results have for the yet unsolved question of how reasoners succeed in constructing causal models from verbal descriptions. (shrink)

‘Shallow’ and ‘deep’ versions of scientific realism may be distinguished as follows: the shallow realist is satisfied with belief in the existence of the posits of our best scientific theories; by contrast, deep realists claim that realism can be legitimate only if such entities are described in metaphysical terms. We argue that this methodological discussion can be fruitfully applied in Everettian quantum mechanics, specifically on the debate concerning the existence of worlds and the recent dispute between Everettian actualism and quantum (...) modal realism. After presenting what is involved in such dispute, we point to a dilemma for realists: either we don’t have the available metaphysical tools to answer the deep realist’s demands, and realism is not justified in this case, or such demands of metaphysical dressing are not mandatory for scientific realism, and deep versions of realism are not really required. (shrink)

This study aims to find out the factors that hinder students in learning Integrated Art Education. A descriptive research design was utilized in the conduct of the study. The researcher prepared a questionnaire with 15 closed-ended- questions that could be answered objectively. The study discovered that the students would learn more when they feel that they belong to a certain group. Interests in a subject also matter, the more you are interested in a particular subject, the more you will learn (...) the material. Parent support marks an impact on the student's interest in learning Arts. Therefore, personal interest in a subject must be given attention and managed properly. Parent's support also plays a vital role in reinforcing the students on what to pursue in order to maintain their motivation. (shrink)

Technological advancement makes translation convenient due to the emergence of various translation tools. This Explanatory-Sequential study aims to determine the preference and the factors affecting the preference of Filipino and Foreign college students toward the Online Translation Tool. Likewise, it also aimed to identify if there is a significant difference between the respondents' choices. To acquire the data, the researchers used a survey conducted on 15 Filipino and foreign collegiate students enrolled in universities in Manila and a focus group discussion (...) among 3 Filipino students. The transcribed data were analyzed using Thematic Analysis. Moreover, the results of the quantitative data revealed that Google Translate was the preferred Online Translation Tool of Filipino and Foreign students for the reason of accessibility, user-friendliness, and the tendency of users to brand bias. The reasons presented in quantitative data are strengthened by the themes identified in the qualitative data. The three prevailing themes of Brand Bias, Accessibility, and Accuracy constituted the central theme of User Friendliness. It was identified through the Chi-Square Test that there is no significant difference among respondents' preferences (0.345 P-Value) toward online Translation software. (shrink)

Shortages of new therapeutics to treat coronavirus disease (COVID-19) have forced clinicians, public health officials, and health systems to grapple with difficult questions about how to fairly allocate potentially life-saving treatments when there are not enough for all patients in need (1). Shortages have occurred with remdesivir, tocilizumab, monoclonal antibodies, and the oral antiviral Paxlovid (2) -/- Ensuring equitable allocation is especially important in light of the disproportionate burden experienced during the COVID-19 pandemic by disadvantaged groups, including Black, Hispanic/Latino and (...) Indigenous communities, individuals with certain disabilities, and low-income persons. However, many health systems have resorted to first-come, first-served approaches to allocation, which tend to disadvantage individuals with barriers in access to care (3). There is mounting evidence of racial, ethnic, and socioeconomic disparities in access to medications for COVID-19 (4, 5). -/- One potential method to promote equitable allocation is to use a weighted lottery, which is an allocation strategy that gives all eligible patients a chance to receive the scarce treatment while also allowing the assignment of higher or lower chances according to other ethical considerations (6). We sought to assess the feasibility of implementing a weighted lottery to allocate scarce COVID-19 medications in a large U.S. health system and to determine whether the weighted lottery promotes equitable allocation. (shrink)

This is part 1 of 6 of the dossier What Do We Talk about when We Talk about Queer Death?, edited by M. Petricola. The contributions collected in this article sit at the crossroads between thanatology and queer theory and tackle questions such as: how can we define queer death studies as a research field? How can queer death studies problematize and rethink the life-death binary? Which notions and hermeneutic tools could be borrowed from other disciplines in order to better (...) define queer death studies? The present article includes the following contributions: – MacCormack P., What does queer death studies mean?; – Radomska M., On queering death studies; – Lykke N., Death as vibrancy; – Hillerup Hansen I., What concreteness will do to resolve the uncertain; – Olson P., Queer objectivity as a response to denials of death; – Manganas N., The queer lack of a chthonic instinct. (shrink)

Interactions are important in establishing deep and meaningful learning experiences for learners in a distance education setup. Of all the activities in an online classroom, the discussion forum proved to be the one that had the most interactions. A discussion forum lets learners interact with the content, peers, and teachers. Participation in these learning activities is one important factor. The more the learners participate, the more they learn. This paper uses the researcher’s experience in determining what participation is in an (...) online learning experience. After reviewing the experience, participation in a discussion forum is defined as a self-induced connection to the learning community to receive and share knowledge to bring a deeper understanding of a certain theory or phenomenon.” There are conditions for a behavior or action that can be considered participation. The more conditions the behavior met, the higher the level of participation it led. The conditions are the learner analyzes an abstract theory or concept and relates it to practice or experience; the learner views other people’s perspectives regarding the subject and synthesizes a stronger and deeper understanding of the acquired knowledge; the learner communicates the acquired understanding of a certain subject that induces a validation or further inquiry; lastly, the learner constructed a train of premeditated discourse that leads to the understanding of a certain subject. (shrink)

Although an inverse relationship between religion and deviance is empirically well-established in the western context, previous studies on Islam and deviance conducted in non-western countries are limited. To address this gap in deviance research, we hypothesized that individual religiosity would be inversely related to deviance with the inverse relationship being more likely for ascetic than anti-ascetic or secular deviance. To test this hypothesis, we applied ordinary least squares and logistic regression methods to analyze data collected from 2,005 survey participants of (...) a Turkish public university student population. Regression results provided partial support for the hypothesis, as we found that religiosity was inversely related to both ascetic and secular deviance. The observed inverse relationship is noteworthy in that it was found in an institutionally secular, Muslim country. Implications of our findings are discussed. (shrink)

Our investigative question is what part of the human psyche is active when we are sleeping. We use the single-counter-example method, extracted from Classical Logic, to prove that it could not be the case that one of our existing models for the human psyche could explain the human sleep. The models of the human psyche that we consider are the Freudian, the Jungian, and our own. By proving that no known part could be active whilst we sleep, and we prove (...) all by presenting known facts, we reach the conclusion that we need a new model of psyche to account for the entire complexity of our beings. We associate sleep with dreams. Upon discussing the human dreams in more details, we end up applying the principles of the inference to the best explanation to explain the human dreams by means of references to the spiritual world. That makes us think about how the spiritists would describe our psyche, and we then present a new model. The new model is obviously a fruit of speculation. This time, the model involves all Freudian elements, our extensional elements, body, and soul. We use the synthetic method to construct our new model. Since our sleep time is so important, to the point of obliging us to build a new model for the human psyche, we worry about protecting it. We then use studies on the impact of noise on humans to talk about how bad the consequences of having a person speaking to us during sleep are. This trivially extends to people that are in hypnotic state. We try to make a case against hypnosis and interference with the sleep of human beings by referring to health, spiritual, and world consequences. Our main result is then a new model for the human psyche, and this time a model that has to do with what is beyond what has already been formally acknowledged by us. A secondary result is that we should not allow people to hypnotize others or to speak to them as they sleep. Our conclusions are that there is definitely something beyond our rationality that happens during our sleep time and this something has not been identified by Freud, Jung or us this far. Besides, that we should not allow people to hypnotize others or speak to them as they sleep. (shrink)

The God Experiment – Let there be Light -/- The question “What is real?” can be traced back to the shadows in Plato’s cave. Two thousand years later, Rene Descartes lacked knowledge about arguing against an evil´ deceiver feeding us the illusion of sensation. Descartes’ epistemological concept later led to various theories of what our sensory experiences actually are. The concept of ”illusionism”, proposing that even the very conscious experience we have – our qualia – is an illusion, is not (...) only a red-pill scenario found in the 1999 science fiction movie ”The Matrix” but is also a philosophical concept promoted by modern tinkers, most prominently by Daniel Dennett. He describes his argument against qualia as materialistic and scientific. Reflection upon a possible simulation and our perceived reality was beautifully visualized in “The Matrix”, bringing the old ideas of Descartes to coffee houses around the world. Irish philosopher Bishop Berkeley was the father of what has later been coined as “subjective idealism”, basically stating that “what you perceive is real” (e.g., ”The Matrix” is real because its population perceives it). Berkeley then argued against Isaac Newton’s absolutism of space, time, and motion in 1721, ultimately leading to Ernst Mach and Albert Einstein’s respective views. Several neuroscientists have rejected Dennetts’ perspective on the illusion of consciousness, and idealism is often dismissed as the notion that people want to pick and choose the tenets of reality. Even Einstein ended his life on a philosophical note, pondering the very foundations of reality. With the advent of quantum technologies based on the control of individual fundamental particles, the question of whether our universe is a simulation isn’t just intriguing. Our ever-advancing understanding of fundamental physical processes will likely lead us to build quantum computers utilizing quantum effects for simulating nature quantum-mechanically in all complexity, as famously envisioned by Richard Feynman. Finding an answer to the simulation question will potentially alter our very definition and understanding of life, reshape theories on the evolution and fate of the universe, and impact theology. No direct observations provide evidence in favor or against the simulation hypothesis, and experiments are needed to verify or refute it. In this paper, we outline several constraints on the limits of computability and predictability in/of the universe, which we then use to design experiments allowing for first conclusions as to whether we participate in a simulation chain. We elaborate on how the currently understood laws of physics in both complete and small-scale universe simulations prevent us from making predictions relating to the future states of a universe, as well as how every physically accurate simulation will increase in complexity and exhaust computational resources as global thermodynamic entropy increases. Eventually, in a simulation in which the computer simulating a universe is governed by the same physical laws as the simulation and is smaller than the universe it simulates, the exhaustion of computational resources will halt all simulations down the simulation chain unless an external programmer intervenes or isn’t limited by the simulation’s physical laws, which we may be able to observe. By creating a simulation chain and observing the evolution of simulation behavior throughout the hierarchy taking stock of statistical relevance, as well as comparing various least complex simulations under computability and predictability constraints, we can gain insight into whether our universe is part of a simulation chain. -/- Index Terms—Simulation, simulation hypothesis, quantum computing, universe, life, intelligence. (shrink)

This reply to an ongoing debate between conspiracy theory researchers from different disciplines exposes the conceptual confusions that underlie some of the disagreements in conspiracy theory research. Reconciling these conceptual confusions is important because conspiracy theories are a multidisciplinary topic and a profound understanding of them requires integrative insights from different fields. Specifically, we distinguish research focussing on conspiracy *theories* (and theorizing) from research of conspiracy *belief* (and mindset, theorists) and explain how particularism with regards to conspiracy theories does not (...) mean we cannot define a problematic subclass of conspiracy beliefs, while avoiding the problems of generalism. We hope this reply helps conspiracy theory researchers recognize the differences between studying conspiracy theories and conspiracy beliefs and appreciate the possibilities for fruitful, integrative, and interdisciplinary research. (shrink)

A longish (12 page) discussion of Richard Sorabji's excellent book, with a further discussion of what it means for a theory of emotions to be a cognitive theory.

Toni Rønnow-Rasmussen | : This paper explores a novel metaethical theory according to which value judgments express conditional beliefs held by those who make them. Each value judgment expresses the belief that something is the case on condition that something else is the case. The paper aims to reach a better understanding of this view and to highlight some of the challenges that lie ahead. The most pressing of these revolves around the correct understanding of the nature of the relevant (...) cognitive attitudes. It is suggested that the distinction between “dormant attitudes” and “occurrent attitudes” helps us to understand these conditional beliefs. | : Cet article explore une nouvelle théorie méta-éthique selon laquelle les jugements de valeur expriment les croyances conditionnelles des sujets qui les font. Chaque jugement de valeur exprimerait la croyance selon laquelle quelque chose est le cas à la condition que quelque chose d’autre le soit. L’objectif de cet article est de parvenir à une meilleure compréhension de ce point de vue et de souligner certaines de ses difficultés. La plus urgente d’entre elles concerne la compréhension adéquate de la nature des attitudes cognitives pertinentes. Nous suggérons que la distinction entre « attitudes dormantes » et « attitudes occurrentes » permettrait de mieux comprendre les croyances conditionnelles. (shrink)

Walter S. Athearn's "An Introduction to the Study of the Mind" delves into the essence and functions of the human mind, exploring its immaterial, unitary, self-active, self-conscious, and abiding attributes. Athearn emphasizes the mind's immortality and constancy despite bodily changes, underscoring the importance of effective study habits and emotional management for cognitive efficiency. The work highlights the significant impact of early experiences on mental development and stresses the need for balanced growth in knowledge, appreciation, and conduct to prevent mental disorders. (...) Through insightful examples and practical guidance, Athearn provides a comprehensive framework for understanding the mind's role in shaping individual destiny and the importance of listening to the voice of conscience. (shrink)

R.J. Barnes (chapter 3) takes up the ways in which Sicilian comedy engaged current intellectual fashions, especially philosophy. Sicily was the home of rich and influential poetic and philosophical traditions that Epicharmus held up for comic examination and ridicule.

We show that five important elements of the ‘nomological package’— laws, counterfactuals, chances, dispositions, and counterfactuals—needn’t be a problem for the Growing-Block view. We begin with the framework given in Briggs and Forbes (in The real truth about the unreal future. Oxford studies in metaphysics. Oxford University Press, Oxford, 2012 ), and, taking laws as primitive, we show that the Growing-Block view has the resources to provide an account of possibility, and a natural semantics for non-backtracking causal counterfactuals. We show (...) how objective chances might ground a more fine-grained concept of feasibility, and furnished a places in the structure where causation and dispositions might fit. The Growing-Block view, thus understood, provides the resources to explain the close link between modality and tense, so that it predicts modal change as time passes. This account lets us capture not only what the future might hold for us, and also what might have been. (shrink)

This paper explores the nature of hate, forgiveness, and interconnectedness in human relationships. Hatred often arises from conflicts with personal expectations but can be transformed into forgiveness by adopting an impersonal, holistic perspective. Drawing on evolutionary theory, psychological insights, and Buddhist philosophy, the paper argues that forgiveness is essential for individual mental well-being and societal harmony. The Buddhist concept of “two arrows” illustrates that while pain is unavoidable, suffering stems from emotional reactions and can be mitigated. Embracing the interconnected nature (...) of events allows individuals to transcend psychological suffering and cultivate compassion. Forgiveness, distinct from condoning or forgetting, is a profound process of healing and self-liberation with significant implications for mental and physical health. By integrating philosophical and psychological perspectives, the paper highlights forgiveness as a biological and psychological necessity, improving mental health, life satisfaction, and fostering both personal and communalistic harmony. (shrink)

The exploration of the mind is a fundamental pursuit spanning philosophy and psychology, with implications reaching into diverse practical realms. This paper delves into the intricacies of mental states, examining historical perspectives from ancient philosophers to modern theorists. Philosophical inquiries into intentionality, consciousness, and the nature of mental phenomena are scrutinized, alongside empirical investigations by psychologists. The discourse navigates through contrasting theories such as dualism, materialism, and functionalism, shedding light on the challenges of reconciling subjective experiences with objective observations. The (...) problem of other minds and the tension between internalism and externalism are dissected, revealing the complex interplay between individual cognition and external influences. Ultimately, this analysis underscores the intricate nature of philosophical inquiries into consciousness and the mind. (shrink)

This essay explores the psychological freedom that emerges from the acceptance of death, arguing that it should not be seen as merely a one-sided freedom of death without the complementary freedom of life. While death is often met with dread and fear, it can foster a sense of authenticity and alignment with personal values. However, this realization must also emphasize the importance of life, as the goal of psychological well-being lies in living, not just acknowledging death. This balance allows us (...) to live fully, prioritize meaningful experiences, and discard trivial concerns. By drawing on Carl Sagan’s reflections on humanity’s insignificance within the cosmos, this essay encourages empowered and responsible living that embraces both life and death. (shrink)

This paper explores the philosophical question of whether a meaningful difference exists between living in a simulation and living in what we call “reality.” Drawing from the simulation hypothesis and discussions of consciousness and subjective experience, the investigation considers whether the subjective experiences of a simulated entity could be indistinguishable from those of a human being. The central argument is that while metaphysical differences between simulation and reality exist, from the standpoint of subjective experience, the distinction may be inconsequential. We (...) examine the implications of this idea for personal identity, free will, and the authenticity of experience. The paper concludes that, although important philosophical differences exist between simulation and reality, subjective experience and the sense of self may remain fundamentally the same in both scenarios. (shrink)

This essay explores the inherent blankness of life, describing it as devoid of fixed meaning, purpose, or morality. It discusses how humans struggle with this blankness, often attempting to avoid or fill it through various activities and pursuits. The essay distinguishes between natural biological activities and those driven by fear and anxiety, emphasizing how societal conditioning contributes to the latter. It delves into the role of rationality in avoiding blankness, the discomfort of silence, and the vibrancy that this blankness holds. (...) Ultimately, it advocates for embracing this blankness as a source of freedom, vitality, and profound insight into the nature of existence. (shrink)

There is an intuitive difference in how we think about pluralism and attitudinal diversity in epistemological contexts versus political contexts. In an epistemological context, it seems problematically arbitrary to hold a particular belief on some issue, while also thinking it perfectly reasonable to hold a totally different belief on the same issue given the same evidence. By contrast, though, it doesn’t seem problematically arbitrary to have a particular set of political commitments, while at the same time thinking it perfectly reasonable (...) for someone in a similar position have a totally different set of political commitments. This chapter examines three explanatory theses that might be used to make sense of this difference: (1) that practical commitments are desire dependent in a way that beliefs are not; (2) that there are reasons to be resolute in practical commitments, but not in beliefs; and (3) that compromise in the face of practical political disagreement doesn’t mitigate controversy, whereas compromise in the face of disagreement about mere beliefs does mitigate controversy. (shrink)

Phenomenal conservatives claim that seemings are sui generis mental states and can thus provide foundational non-doxastic justification for beliefs. Many of their critics deny this, claiming, instead, that seemings can be reductively analyzed in terms of other mental states—either beliefs, inclinations to believe, or beliefs about one’s evidence—that cannot provide foundational non-doxastic justification. In this paper, I argue that no tenable semantic reduction of ‘seems’ can be formulated in terms of the three reductive analyses that have been proposed by critics (...) of phenomenal conservatism. This is because Moore-paradoxical statements are generated when each of the reductive analyses is substituted for ‘seems’ in statements like ‘The stick is straight, but it does not seem to me that it’s straight.’ Since the latter statement is not Moore-paradoxical, the three proposed reductive analyses of ‘seems’ are unsuccessful. Absent a successful semantic reduction, however, there is no good reason to think a successful metaphysical reduction of seemings is forthcoming. Thus, there is an additional reason, unnoticed in the existing literature, to think that seemings are sui generis mental states. (shrink)

Within contemporary evangelical theology, a peculiar controversy has been brewing over the past few decades with regard to the doctrine of the Trinity. A good number of prominent evangelical theologians and philosophers are rejecting the doctrine of divine processions within the eternal life of the Trinity. In William Hasker’s recent Metaphysics and the Tri-Personal God, Hasker laments this rejection and seeks to offer a defense of this doctrine. This paper shall seek to accomplish a few things. In section I, I (...) shall first set the stage for a proper understanding of the discussion. Section II will articulate the basic Trinitarian desiderata that must be satisfied by any model of the doctrine of the Trinity. This will help one understand the debate between Hasker and the procession deniers. Section III will offer an articulation of what the doctrine of divine processions teaches. Section IV will examine Hasker’s defense of the doctrine point by point. I shall argue that his defense of the doctrine of the divine processions fails. (shrink)

The concept of the mind in philosophy encompasses a diverse range of theories and perspectives, examining its immaterial nature, unitary function, self-activity, self-consciousness, and persistence despite bodily changes. This paper explores the attributes of the mind, addressing classical materialism, dualism, and behaviorism, along with contemporary theories like functionalism and computational functionalism. Key philosophical debates include the mind-body problem, the subjectivity of mental states, and the epistemological and conceptual challenges in understanding other minds. Contrasting views from Aristotle, Descartes, Wittgenstein, and modern (...) philosophers like U.T. Place, Gilbert Ryle, and Hilary Putnam are analyzed. The paper also discusses the implications of these theories on our understanding of mental phenomena, consciousness, and the nature of human experience. (shrink)

This essay challenges the notion of avoiding uncomfortable thoughts and emotions in mental health. It argues that accepting these experiences, as supported by therapies like Exposure and Response Prevention for Pure OCD, promotes greater wellbeing. By cultivating a compassionate relationship with inner experiences, individuals can foster resilience amidst challenges.

The article “Philosophy is crucial in the age of AI” by Anthony Grayling and Brian Ball explores the significant role philosophy has played in the development of Artificial Intelligence (AI) and its continuing relevance in guiding the future of AI technologies. The authors trace the historical contributions of philosophers and logicians, such as Gottlob Frege, Kurt Godel, and Alan Turing, in shaping the foundational principles of AI. They argue that philosophical inquiry remains essential, especially in addressing complex issues like consciousness, (...) creativity, and the alignment of AI with human values. The article emphasizes the interdisciplinary collaboration needed to navigate the ethical and societal challenges posed by advancing AI systems, suggesting that philosophy is crucial in ensuring these technologies develop responsibly and ethically. (shrink)

World Mental Health Day serves as a timely reminder of the need to recognize and prioritize mental well-being amidst the growing complexities of modern life. Despite advancements in technology that have created comfort and convenience, these external developments often overshadow our inner well-being, leading to a neglect of mental health. This letter underscores the importance of nurturing our mental and emotional states, which serve as the foundation for overall health and a harmonious existence. Acknowledging the interplay between technology, distraction, and (...) mental stability is crucial in redefining what it means to lead a balanced life today. -/- . (shrink)

Hermann von Helmholtz’s work on perceptual science had a fundamental impact on Neo-Kantian movements in the late nineteenth century, and his influence continues to be felt in psychology and analytic philosophy of perception. As is widely acknowledged, Helmholtz denied that we can perceive mind-independent properties of external objects, a view I label Ignorance. Given his commitment to Ignorance, Helmholtz might seem to be committed to a subjectivism according to which we only perceive properties of our own representations. Against this, I (...) argue that for Helmholtz, the properties we perceive are not monadic properties of either the subject or the object. Rather, Helmholtz endorsed a relationalism about the properties we perceive: the properties of objects we perceive are all relational properties. I then suggest that once we take into account oft-neglected terminological distinctions in Helmholtz’s corpus, we are better able to make sense of his commitment to relationalism. (shrink)

Philosophers who work on desert-adjustment within axiology often articulate the concept of desert as follows: x deserves y on the basis of z. This formulation allows for a focused examination that encompasses deservers, deservings, and desert bases. I call this first-order desert. This paper posits that axiology grounded solely in first-order desert fails to adequately capture our nuanced intuitions concerning desert. I contend that to construct an axiology that more effectively aligns with our desert-sensitive intuitions, we must incorporate considerations of (...) second-order desert. Second-order desert is defined as follows: x deserves to live a life in which x deserves y on the basis of z. Initially, I provide a definition of first-order desert, followed by an elucidation of second-order desert. Subsequently, I explore various counter-arguments against my proposition. I defend my proposal against potential counter-arguments, demonstrating that a desert-adjusted axiological theory will be significantly better-off by incorporating second-order desert considerations. (shrink)

In the quest for mental peace and philosophical insight, the most profound approach is to let the mind function freely, without the interference of a controlling thinker. This essay explores the philosophical and cognitive implications of an unimpeded mind, drawing from Eastern traditions such as Zen Buddhism and Taoism, alongside contemporary cognitive science. It argues that the natural rhythm of thought is disrupted by the ego’s need for control, leading to mental fragmentation and turbulence. By embracing the concept of “no-mind” (...) or non-interference, individuals can achieve a harmonious flow of consciousness. Contemporary cognitive science supports this view, showing that reducing self-referential thinking enhances cognitive flexibility and emotional regulation. This harmonious state, akin to the flow experienced by top athletes and artists, offers a path to greater psychological well-being and deeper philosophical understanding. (shrink)

Belief in conspiracy theories is typically considered irrational, and as a consequence of this, conspiracy theorists––those who dare believe some conspiracy theory––have been charged with a variety of epistemic or psychological failings. Yet recent philosophical work has challenged the view that belief in conspiracy theories should be considered as typically irrational. By performing an intra-group analysis of those people we call “conspiracy theorists”, we find that the problematic traits commonly ascribed to the general group of conspiracy theorists turn out to (...) be merely a set of stereotypical behaviours and thought patterns associated with a purported subset of that group. If we understand that the supposed prob- lem of belief in conspiracy theories is centred on the beliefs of this purported sub- set––the conspiracists––then we can reconcile the recent philosophical contribu- tions to the wider academic debate on the rationality of belief in conspiracy theories. (shrink)

Looking at the recent spate of claims about “fake news” which appear to be a new feature of political discourse, I argue that fake news presents an interesting problem in epistemology. Te phenomena of fake news trades upon tolerating a certain indiference towards truth, which is sometimes expressed insincerely by political actors. Tis indiference and insincerity, I argue, has been allowed to fourish due to the way in which we have set the terms of the “public” epistemology that maintains what (...) is considered “rational” public discourse. I argue one potential salve to the problem of fake news is to challenge this public epistemology by injecting a certain ethical consideration back into the discourse. (shrink)

The thesis of this article is that there has never been any ground for the controversy between the doctrine of free will and determinism, that it is based upon a misapprehension, that the two assertions are entirely consistent, that one of them strictly implies the other, that they have been opposed only because of our natural want of the analytical imagination. In so saying I do not tamper with the meaning of either phrase. That would be unpardonable. I mean free (...) will in the natural and usual sense, in the fullest, the most absolute sense in which for the purposes of the personal and moral life the term is ever employed. I mean it as implying responsibility, merit and demerit, guilt and desert. I mean it as implying, after an act has been performed, that one " could have done otherwise " than one did. I mean it as conveying these things also, not in any subtly modified sense but in exactly the sense in which we conceive them in life and in law and in ethics. These two doctrines have been opposed because we have not realised that free will can be analysed without being destroyed, and that determinism is merely a feature of the analysis of it. And if we are tempted to take refuge in the thought of an "ultimate ", an "innermost" liberty that eludes the analysis, then we have implied a deterministic basis and constitution for this liberty as well. For such a basis and constitution lie in the idea of liberty. -/- The thesis is not, like that of Green or Bradley, that the contending opinions are reconciled if we adopt a certain metaphysic of the ego, as that it is timeless, and identifies itself with a desire by a " timeless act". This is to say that the two are irreconcilable, as they are popularly supposed to be, except by a theory that delivers us from the conflict by taking us out of time. Our view on the contrary is that from the natural and temporal point of view itself there never was any need of a reconciliation but only of a comprehension of the meaning of terms. (The metaphysical nature of the self and its identity through time is a problem for all who confront memory, anticipation, etc.; it has no peculiar difficulties arising from the present problem.) -/- I am not maintaining that determinism is true; only that it is true insofar as we have free will. That we are free in willing is, broadly speaking, a fact of experience. That broad fact is more assured than any philosophical analysis. It is therefore surer than the deterministic analysis of it, entirely adequate as that in the end appears to be. But it is not here affirmed that there are no small exceptions, no slight undetermined swervings, no ingredient of absolute chance. All that is here said is that such absence of determination, if and so far as it exists, is no gain to freedom, but sheer loss of it; no advantage to the moral life, but blank subtraction from it. -- When I speak below of "the indeterminist" I mean the libertarian indeterminist, that is, him who believes in free will and holds that it involves indetermination. (shrink)

In Open Minded: Searching for Truth about the Unconscious Mind, Ben R. Newell & David R. Shanks (henceforth, N&S) challenge the popular claim that much of human judgment and decision-making is explained by unconscious processes...

l. There is an antinomy in Hare's thought between Ought-Implies-Can and No-Indicatives-from-Imperatives. It cannot be resolved by drawing a distinction between implication and entailment. 2. Luther resolved this antinomy in the l6th century, but to understand his solution, we need to understand his problem. He thought the necessity of Divine foreknowledge removed contingency from human acts, thus making it impossible for sinners to do otherwise than sin. 3. Erasmus objected (on behalf of Free Will) that this violates Ought-Implies-Can which he (...) supported with Hare-style ordinary language arguments. 4. Luther a) pointed out the antinomy and b) resolved it by undermining the prescriptivist arguments for Ought-Implies-Can. 5. We can reinforce Luther's argument with an example due to David Lewis. 6. Whatever its merits as a moral principle, Ought-Implies-Can is not a logical truth and should not be included in deontic logics. Most deontic logics, and maybe the discipline itself, should therefore be abandoned. 7. Could it be that Ought-Conversationally-Implies-Can? Yes - in some contexts. But a) even if these contexts are central to the evolution of Ought, the implication is not built into the semantics of the word; b) nor is the parallel implication built into the semantics of orders; and c) in some cases Ought conversationally implies Can, only because Ought-Implies-Can is a background moral belief. d) Points a) and b) suggest a criticism of prescriptivism - that Oughts do not entail imperatives but that the relation is one of conversational implicature. 8. If Ought-Implies-Can is treated as a moral principle, Erasmus' argument for Free Will can be revived (given his Christian assumptions). But it does not 'prove' Pelagianism as Luther supposed. A semi-Pelagian alternative is available. (shrink)

Two systems of belief change based on paraconsistent logics are introduced in this article by means of AGM-like postulates. The first one, AGMp, is defined over any paraconsistent logic which extends classical logic such that the law of excluded middle holds w.r.t. the paraconsistent negation. The second one, AGMo , is specifically designed for paraconsistent logics known as Logics of Formal Inconsistency (LFIs), which have a formal consistency operator that allows to recover all the classical inferences. Besides the three usual (...) operations over belief sets, namely expansion, contraction and revision (which is obtained from contraction by the Levi identity), the underlying paraconsistent logic allows us to define additional operations involving (non-explosive) contradictions. Thus, it is defined external revision (which is obtained from contraction by the reverse Levi identity), consolidation and semi-revision, all of them over belief sets. It is worth noting that the latter operations, introduced by S. Hansson, involve the temporary acceptance of contradictory beliefs, and so they were originally defined only for belief bases. Unlike to previous proposals in the literature, only defined for specific paraconsistent logics, the present approach can be applied to a general class of paraconsistent logics which are supraclassical, thus preserving the spirit of AGM. Moreover, representation theorems w.r.t. constructions based on selection functions are obtained for all the operations. (shrink)

The meaning of “information and communication technologies (ICT)”, “market of information and communication technologies” were clarified in the article. Components and priority areas for capital investment in the ICT market were determined. The relativity of relationship between the placement of supercomputers in the countries and their level of innovation was revealed. The tendencies of world ICT market development were defined. The place of Ukraine in the world ICT market was established.

The potential for Large Language Models (LLMs) to attain technological singularity—the point at which artificial intelligence (AI) surpasses human intellect and autonomously improves itself—is a critical concern in AI research. This paper explores the feasibility of current LLMs achieving singularity by examining the philosophical and practical requirements for such a development. We begin with a historical overview of AI and intelligence amplification, tracing the evolution of LLMs from their origins to state-of-the-art models. We then proposes a theoretical framework to assess (...) whether existing LLM technologies could satisfy the conditions for singularity, with a focus on Recursive Self-Improvement (RSI) and autonomous code generation. We integrate key component technologies, such as Reinforcement Learning from Human Feedback (RLHF) and Direct Preference Optimization (DPO), into our analysis, illustrating how these could enable LLMs to independently enhance their reasoning and problem-solving capabilities. By mapping out a potential singularity model lifecycle and examining the dynamics of exponential growth models, we elucidate the conditions under which LLMs might self-replicate and rapidly escalate their intelligence. We conclude with a discussion of the ethical and safety implications of such developments, underscoring the need for responsible and controlled advancement in AI research to mitigate existential risks. Our work aims to contribute to the ongoing dialogue on the future of AI and the critical importance of proactive measures to ensure its beneficial development. (shrink)

In psychology, stress is a feeling of emotional strain and pressure. Stress is a type of psychological pain. Small amounts of stress may be beneficial, as it can improve athletic performance, motivation and reaction to the environment. Excessive amounts of stress, however, can increase the risk of strokes, heart attacks, ulcers, and mental illnesses such as depression and also aggravation of a pre-existing condition. Psychological stress can be external and related to the environment but may also be caused by internal (...) perceptions that cause an individual to experience anxiety or other negative emotions surrounding a situation, such as pressure, discomfort, etc., which they then deem stressful. (shrink)

Since the advent of computers, humans have pursued automata with superior information-processing capabilities. In the endeavor to create new entities that converge toward intellectual functions, the emergence of large language models (LLMs) that emulate AI surpassing ourselves has become a reality. With the intelligence explosion triggered by AI and the consequent emergence of superintelligence, the improvement of simulation capabilities accelerates. As this surpasses humans’ discriminative perceptual abilities between reality and unreality, a paradox arises wherein, from a modern scientific standpoint, science (...) becomes unscientific. It is thought that as our controllability over the reality we perceive is ultimately enhanced by superintelligence, even whether we ourselves exist, what happiness is, what ethics are, and whether concepts themselves ever existed become matters of uncertainty. -/- Note: In the creation of this paper, we have undertaken all writing ourselves and have not used generative AI for text generation except for translation purposes. (shrink)

Practical reason is the general human capacity for resolving, through reflection, the question of what one is to do. Deliberation of this kind is practical in at least two senses. First, it is practical in its subject matter, insofar as it is concerned with action. But it is also practical in its consequences or its issue, insofar as reflection about action itself directly moves people to act. Our capacity for deliberative self-determination raises two sets of philosophical problems. For one thing, (...) there are questions about how deliberation can succeed in being practical in its issue. What do we need to assume—both about agents and about the processes of reasoning they engage in—to make sense of the fact that deliberative reflection can directly give rise to action? Can we do justice to this dimension of practical reason while preserving the idea that practical deliberation is genuinely a form of reasoning? For another, there are large issues concerning the content of the standards that are brought to bear in practical reasoning. Which norms for the assessment of action are binding on us as deliberating agents? Do these norms provide resources for critical reflection about our ends, or are they exclusively instrumental? Under what conditions do moral norms yield valid standards for reasoning about action? The first set of issues is addressed in sections §§1–3 of the present article, while sections §§4–6 cover the second set of issues. (shrink)

The COVID-19 crisis opened up discussions on using online tools and platforms for academic work, e.g. for research (management) events that were originally designed as face-to-face interactions. As social scientists working in the domain of responsible research and innovation (RRI), we draft this paper to open up a dialogue on Responsible online Research and Innovation (RoRI), and deliberate particular socioethical opportunities and challenges of the onlineification in collaborative theoretical and empirical research. An RRI-inspired ‘going online’ approach would mean, we suggest, (...) trying to make academic events and research activities more inclusive, researchers’ attitude to their work more reflective and suggest processes that are more responsive to societal needs and ethical concerns. For such systematic reflection, we suggest using the RRI-heuristic provided by Owen et al., and applying the dimensions of ‘Anticipation, Inclusion, Reflection and Responsiveness’ (AIRR) in order to identify and reflect on the dilemmas involved in ‘going online’ in one’s research. (shrink)

Political liberals ask citizens not to appeal to certain considerations, including religious and philosophical convictions, in political deliberation. We argue that political liberals must include a demanding requirement of intellectual modesty in their ideal of citizenship in order to motivate this deliberative restraint. The requirement calls on each citizen to believe that the best reasoners disagree about the considerations that she is barred from appealing to. Along the way, we clarify how requirements of intellectual modesty relate to moral reasons for (...) deliberative restraint. And we argue against attempts to weaken our requirement of intellectual modesty by emphasizing those moral reasons. (shrink)