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 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)

In this paper, we highlight some problems for accounts of disability and enhancement that have not been sufficiently addressed in the literature. The reason, we contend, is that contemporary debates that seek to define, characterise or explain the normative valence of disability and enhancement do not pay sufficient attention to a wide range of cases, and the transition between one state and another. In section one, we provide seven cases that might count as disability or enhancement. We explain why each (...) case might count, and on what basis, and why it is been neglected. Each case is explained as a transition in what we call capacity space. We then argue that no definition of disability or enhancement addresses all of these cases, except for strict welfarist accounts of disability that do not rely on a depiction of any particular capacity. We argue further, however, that this is a serious deficiency of welfarist conceptions of disability. We then address objections to our account. (shrink)

The embedding and promotion of social change is faced with aparadoxical challenge. In order to mainstream an approach to socialchange such as responsible research and innovation and makeit into a practical reality rather than an abstract ideal, we need tohave conceptual clarity and empirical evidence. But, in order to beable to gather empirical evidence, we have to presuppose that theapproach already exists in practice. This paper proposes a social labmethodology that is suited to deal with this circularity. Themethodology combines the (...) defining features of social labs emergingfrom the literature such as agility and real-world focus withestablished theories and approaches such as action research andexperiential learning. Thereby it enables the parallel investigationand propagation of RRI. The framework thus constructed provides atheoretical embedding of sociallabs and overcomes some of theknown limitations of the constitutive approaches. (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)

As engineering applications require management of ever larger volumes of data, ontologies offer the potential to capture, manage, and augment data with the capability for automated reasoning and semantic querying. Unfortunately, considerable barriers hinder wider deployment of ontologies in engineering. Key among these is lack of a shared top-level ontology to unify and organise disparate aspects of the field and coordinate co-development of orthogonal ontologies. As a result, many engineering ontologies are limited to their scope, and functionally difficult to extend (...) or interoperate with other engineering ontologies. This paper demonstrates how the use of a top-level ontology, specifically the Basic Formal Ontology (BFO), greatly facilitates interoperability of multiple engineering-related ontologies. We constructed a system of formal linked ontologies by re-engineering legacy ontologies to be conformant with BFO and developing new BFO-conformant ontologies to capture knowledge in the engineering design, enterprise, human factors, manufacturing, and application domain of additive manufacturing. The resulting Integrated Framework for Additively Manufactured Products (IFAMP), including the body knowledge instantiated on its basis, serve as the basis for a proposed Design with Additive Manufacturing Method (DWAM), which we believe can support the design of innovative products with semantically enhanced ideation tools and enhanced access to application domain knowledge. The method and its facilitation through the ontological framework are demonstrated using a case study in medicine. (shrink)

Background: Community-based education (CBE) involves educating the head (cognitive), heart (affective), and the hand (practical) by utilizing tools that enable us to broaden and interrogate our value systems. This article reports on the use of virtue ethics (VE) theory for understanding the principles that create, maintain and sustain a socially accountable community placement programme for undergraduate medical students. Our research questions driving this secondary analysis were; what are the goods which are internal to the successful practice of CBE in medicine, (...) and what are the virtues that are likely to promote and sustain them? -/- Methods: We conducted a secondary theoretically informed thematic analysis of the primary data based on MacIntyre’s virtue ethics theory as the conceptual framework. -/- Results: Virtue ethics is an ethical approach that emphasizes the role of character and virtue in shaping moral behavior; when individuals engage in practices (such as CBE), goods internal to those practices (such as a collaborative attitude) strengthen the practices themselves, but also augment those individuals’ virtues, and that of their community (such as empathy). We identified several goods that are internal to the practice of CBE and accompanying virtues as important for the development, implementation and sustainability of a socially accountable community placement programme. A service-oriented mind-set, a deep understanding of community needs, a transformed mind, and a collaborative approach emerged as goods internal to the practice of a socially accountable CBE. The virtues needed to sustain the identified internal goods included empathy and compassion, connectedness, accountability, engagement [sustained relationship], cooperation, perseverance, and willingness to be an agent of change. -/- Conclusion: This study found that MacIntyre’s virtue ethics theory provided a useful theoretical lens for understanding the principles that create, maintain and sustain CBE practice. (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)

This paper explores the profound teachings of the Yoga Sutras and their application in modern psychological and therapeutic contexts. Yoga, as defined by Patanjali, aims to tranquil the fluctuations of the mind and achieve spiritual liberation through the integration of conscious and unconscious processes. The critique of Western dualism (more specifically Cartesian’ dualism) in favor of a unified perspective with Samkhya philosophy is discussed, emphasizing the role of the intellect, karma, and self- awareness in achieving mental calm and freedom from (...) suffering. Modern challenges such as social media’s impact on identity and the rise of mental as well as psychological disorders are examined through the lens of the methods of Yoga Philosophy, highlighting the efficacy of mindfulness and yoga therapies in promoting self-regulation, inner well-being, and peace. (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)

In his Encomium of Helen and On Not Being, Gorgias of Leontinoi discusses the nature and function of speech more extensively than any other surviving author before Plato. His discussions are not only surprising in the way they characterize the power of logos and its effects on a listener but also in how the two descriptions of speech seem to contradict one another. In the Helen, Gorgias claims that logos is a very powerful entity, capable of affecting a listener in (...) whatever way it wants. In On Not-Being, he makes the very different (but no less exaggerated) claim that logos is a non-entity, incapable of referring to anything other than itself. In this essay I show how these apparently contradictory accounts might be brought into harmony with one another.2 In the first part I address some of the interpretive difficulties with the text of Gorgias’s On Not Being (henceforth ONB) and the role that irony plays in the work. In particular I argue (as others have before) that Gorgias’s remarks about the impotency of speech are not meant to be taken seriously. Instead, they are aimed more squarely at raising questions about how exactly speech is thought to function and, more specifically, how linguistic reference works—i.e., how words somehow correspond to things, on one level, and to our ideas about things, on another. In the second and third parts of this paper, I illustrate how Gorgias’s concern with linguistic reference in ONB goes on to inform his notion of logos in the Encomium of Helen. I point specifically to evidence found in an important and often overlooked exit clause at the close of ONB regarding the difference between words and things. There, Gorgias insists that if words manifest meaning at all, they must appeal to their own sort of sense organ. In the Helen, he draws on the concepts of soul (psychē) and opinion (doxa) in order to construct this alternative, psychagogic account in which utterances are actually apprehended in ways akin to sense perception. Whether or not one is convinced by Gorgias’s alternative account of how speech works, the description he gives of logos does notionally circumvent the problem of linguistic reference and, in doing so, pushes one to think beyond the potentially constrictive framework of nomen et nominatum. I argue that, when read in this way, these two early discussions of logos represent a unified progression of serious thought about how speech works. (shrink)

We consider the varieties and directions of influence that the source and target domains involved in a conceptual metaphor can have on each other during the course of understanding metaphorical utterances based on the metaphor. Previous studies have been restricted both as to direction of influence and as to type of influence. They have been largely confined to the “forward” (source to target) direction of influence, and they have concentrated on the transfer of features or propositions and (to some extent) (...) the highlighting of aspects of a domain. By contrast, this article stresses the importance both of other varieties of influence (e.g., transfer of queries and uncertainty effects) and of “reverse” influence (target to source). We seek to curb the natural tendency to think that, because metaphor involves an overall move from source to target, therefore all inter-domain influences in the course of understanding go in that direction. The bulk of the article explores the theoretical issues involved. These issues have arisen out of a reasoning-based approach to metaphor, seeking to make best use of information from metaphorical utterance, context, source and target domains, and known metaphorical mappings, by applying a complex overall reasoning process. The article briefly explains the thorough implementation of reverse influence in a computer program for metaphorical reasoning called ATT-Meta, although the theoretical considerations are relevant to all disciplines concerned with metaphor. We make some suggestions for further computational and psychological research on metaphor. (shrink)

This presentation discusses a notion encountered across disciplines, and in different facets of human activity: autonomous activity. We engage it in an interdisciplinary way. We start by considering the reactions and behaviors of biological entities to biotechnological intervention. An attempt is made to characterize the degree of freedom of embryos & clones, which show openness to different outcomes when the epigenetic developmental landscape is factored in. We then consider the claim made in programming and artificial intelligence that automata could show (...) self-directed behavior as to the determination of their step-wise decisions on courses of action. This question remains largely open and calls for some important qualifications. We try to make sense of the presence of claims of freedom in agency, first in common sense, then by ascribing developmental plasticity in biology and biotechnology, and in the mapping of programmed systems in the presence of environmental cues and self-referenced circuits as well as environmental coupling. This is the occasion to recall attempts at working out a logical and methodological approach to the openness of concepts that are still to be found, and assess whether they can operate the structuring intelligibility of a yet undeveloped or underdeveloped field of study, where a “bisociation" and a unification of knowledge might be possible. (shrink)

In real-time, Twitter strongly imprints world events, popular culture, and the day-to-day; Twitter records an ever growing compendium of language use and change; and Twitter has been shown to enable certain kinds of prediction. Vitally, and absent from many standard corpora such as books and news archives, Twitter also encodes popularity and spreading through retweets. Here, we describe Storywrangler, an ongoing, day-scale curation of over 100 billion tweets containing around 1 trillion 1-grams from 2008 to 2020. For each day, we (...) break tweets into 1-, 2-, and 3-grams across 150+ languages, record usage frequencies, and generate Zipf distributions. We make the data set available through an interactive time series viewer, and as downloadable time series and daily distributions. We showcase a few examples of the many possible avenues of study we aim to enable including how social amplification can be visualized through ‘contagiograms’. (shrink)

New trends in the economic systems management in the context of modern global challenges: collective monograph / scientific edited by M. Bezpartochnyi, in 2 Vol. // VUZF University of Finance, Business and Entrepreneurship. – Sofia: VUZF Publishing House “St. Grigorii Bogoslov”, 2020. – Vol. 1. – 309 p.

Data security is, protecting data from ill- conceived get to, utilize, introduction, intrusion, change, examination, recording or destruction. Cloud computing is a sort of Internet-based computing that grants conjoint PC handling resources and information to PCs what's more, different gadgets according to necessity. It is a model that empowers universal, on-request access to a mutual pool of configurable computing resources. At present, security has been viewed as one of the best issues in the improvement of Cloud Computing. The key issue (...) in effective execution of Cloud Computing is to adequately deal with the security in the cloud applications. This paper talks about the part of cryptography in cloud computing to improve the data security. The expectation here is to get bits of knowledge another security approach with the usage of cryptography to secure information at cloud data centers. (shrink)

Applied to evaluative properties the supervenience thesis is customarily understood as expressing two intuitions: (i) the idea that there is some kind of dependence between the (supervenient) value of an object and some (or all) of the natural properties of the object; (ii) the idea that if you assert that x is valuable and if you agree that y is relevantly similar to x, with regard to natural properties, you must be prepared to assert that y too is valuable. It (...) is argued that the influential account of supervenience by R. M. Hare is problematic in that it only expresses the latter but not the former intuition. Two solutions to this problem are outlined, one of which ought to be endorsable by a prescriptivist such as Hare. (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.

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)

Objectives: To explore individuals’ perception of the personal, family and societal educational needs following a spinal cord injury. Methods: Sixty-one patients who sustained a traumatic SCI between March 2015 and June 2016 referred to Brain and Spinal Cord Injury Research Center were included in a cross sectional study and completed an online survey containing open-and closed-ended questions, in Iran. Participants’ responses were analyzed i using a qualitative approach with a thematic analysis. Results: Following a thematic analysis of the patient’s perceived (...) educational needs, 3 themes and 14 subthemes were identified. The 3 themes included personal, family, and societal educational perceived needs. Within personal educational needs, there were 7 subthemes which included personal independence and transportation, financial independence, life skills modification, knowledge about SCI, prevention of SCI complications, relationships and sexual function, and psychological adjustments. Among family educational needs, the 3 subthemes were caregiver skills and communication, first aid and emergency skills, and emotional and psychological support. For societal educational needs, the 4 subthemes described were social integration, interpersonal communication skills, SCI awareness and injury prevention, sympathize while avoiding pity. Conclusion: According to our findings, people with SCI have various needs that need to be addressed. Educational support should be a part of a comprehensive rehabilitation program and geared towards addressing the patients’ personal and family needs, while educating the community about SCI in order to allow for reintegration into society. (shrink)

Commentary in reply to an article by Jeff McMahan and Julian Savulescu.

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.

Background: Exposomics, the study of the exposome, is flourishing, but the field is not well defined. The term “exposome” refers to all environmental influences and associated biological responses throughout the lifespan. However, this definition is very similar to that of the term “environment”—the external elements and conditions that surround and affect the life and development of an organism. Consequently, the exposome seems to be nothing more than a synonym for the environment, and exposomics a synonym for environmental research. As a (...) result, some have rebranded their “standard” environmental health research with the neologistic exposome term, whereas others ignore or seek to abandon the seemingly redundant concept of the exposome. -/- Objectives: We argue that exposomics needs to sharpen its mission focus to counteract this apparent redundancy. Exposomics should be defined as a research program in environmental health aimed at enabling a comprehensive and discovery-driven approach to identifying environmental determinants of human health. Similar to the aim of the Human Genome Project, exposomics aims to analyze the complete complexity of exposures and their corresponding biological responses. Exposomics’ primary premise is that the existence of undiscovered, potentially interconnected, nongenetic (environmental) risk factors for health necessitates a comprehensive discovery-driven analysis approach. -/- Discussion: We argue that exposomics researchers should adopt our reconceptualization of exposomics and focus on the productiveness and integrity of their research program: its purpose and principles. We suggest that exposomics researchers should coordinate the writing of reviews that assess the program’s productiveness and integrity, as well as provide a platform for exposomics researchers to define their vision for the field. (shrink)

Standpoint theorists have long been clear that marginalization does not make better understanding a given. They have been less clear, though, that social dominance does not make ignorance a given. Indeed, many standpoint theorists have implicitly committed themselves to what I call the strong epistemic disadvantage thesis. According to this thesis, there are strong, substantive limits on what the socially dominant can know about oppression that they do not personally experience. I argue that this thesis is not just implausible but (...) politically pernicious; it is an excuse for ignorance and silence that stifles our ability to address many injustices. Moreover, I argue that if we are to avoid lending support to the SEDT while working within a standpoint theory framework, we must hold that the socially dominant can achieve marginalized standpoints. So, we must hold that men can achieve feminist standpoints, that white women (and men) can achieve black feminist standpoints, and so on. (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)

The role of intuition in Kant’s account of experience receives perennial philosophical attention. In this essay, I present the textual case that Kant also makes extensive reference to what he terms “images” that are generated by the imagination. Beyond this, as I argue, images are fundamentally distinct from empirical and pure intuitions. Images and empirical intuitions differ in how they relate to sensation, and all images (even “pure images”) actually depend on pure intuitions. Moreover, all images differ from intuitions in (...) their structure or format. I then turn to a question that naturally arises on the resulting view: if the imagination produces images, and if images are fundamentally distinct from intuitions, then how do intuitions relate to the imagination? I outline reasons for thinking that intuitions and their essential features do not depend on the imagination at all. Though this essay does not decisively argue for this thesis, the resulting view provides a clear account of the distinction between the senses and the imagination in Kant’s theory of sensibility. (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...

The potential for vaccines to prevent the spread of infectious diseases is crucial for vaccination policy and ethics. In this paper, I discuss recent evidence that the current COVID-19 vaccines have only a modest and short-lived effect on reducing SARS-CoV-2 transmission and argue that this has at least four important ethical implications. First, getting vaccinated against COVID-19 should be seen primarily as a self-protective choice for individuals. Second, moral condemnation of unvaccinated people for causing direct harm to others is unjustified. (...) Third, the case for a harm-based moral obligation to get vaccinated against COVID-19 is weak. Finally, and perhaps most significantly, coercive COVID-19 vaccination policies (e.g., measures that exclude unvaccinated people from society) cannot be directly justified by the harm principle. (shrink)

DECODING THE MENO The truth the dialectic Meno attempts to search for is human excellence or virtue. Part of this process is defining exactly what each concept really means. In truth, however, Plato has given the reader the answer – the greatest human virtue or excellence is imagination. The answer is subtly weaved into the dialogue itself. Plato has subliminally communicated the pattern of excellence.

Vaccination can protect vaccinated individuals and often also prevent them from spreading disease to other people. This opens up the possibility of getting vaccinated for the sake of others. In fact, altruistic vaccination has recently been conceptualized as a kind of vaccination that is undertaken primary for the benefit of others. In order to better understand the potential role of altruistic motives in people’s vaccination decisions, we conducted two focus group studies with a total of 37 participants. Study 1 included (...) three focus groups on the subject of HPV vaccination for boys. Study 2 included three focus groups on the subject of pertussis and measles vaccination for childcare workers. We found substantial evidence of other-regarding motives across all focus groups, which suggests that altruistic motives could be an important factor when it comes to people’s vaccination decisions. We address the significance of these findings for vaccination policy surrounding HPV vaccination for boys and vaccination for childcare workers. We also extend the findings to normative work on vaccination for the sake of others more generally. (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)

Computational Functionalism is a subfield of philosophy of mind most relevant to the subject of cognitive science as well as to artificial intelligence (AI). The analysis of this paper focuses on Hilary Putnam’s and Gualtiero Piccinini’s standpoints regarding the molecular understanding of computation. Finally, Putnam’s argument of the functionalism in notion of the mental states is based on the positive definition of those states by their functions, while Piccinini, and on the other hand suggest that an understanding of the mechanism (...) of computation will go a long way to explaining cognition. This research also points out shortcomings of functionalism in their theories especially in regards to connectivity with physicality of AI structures. Therefore, the paper identifies the following gaps: The first gap holds that although both theorists have important insights, the two approaches put forward by the respective theorists are flawed and a better proposal is required, then a new proposal is suggested In identifying these gaps, the paper seeks to contribute to the literature by arguing for the need to develop a composite of the two theorists. The results show that the big ideas are important in present-day AI debate and analysis, which helps to explain the mind as computation. (shrink)

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)

In recent years, exposome research has been put forward as the next frontier for the study of human health and disease. Exposome research entails the analysis of the totality of environmental exposures and their corresponding biological responses within the human body. Increasingly, this is operationalized by big-data approaches to map the effects of internal as well as external exposures using smart sensors and multiomics technologies. However, the ethical implications of exposome research are still only rarely discussed in the literature. Therefore, (...) we conducted a systematic review of the academic literature regarding both the exposome and underlying research fields and approaches, to map the ethical aspects that are relevant to exposome research. We identify five ethical themes that are prominent in ethics discussions: the goals of exposome research, its standards, its tools, how it relates to study participants, and the consequences of its products. Furthermore, we provide a number of general principles for how future ethics research can best make use of our comprehensive overview of the ethical aspects of exposome research. Lastly, we highlight three aspects of exposome research that are most in need of ethical reflection: the actionability of its findings, the epidemiological or clinical norms applicable to exposome research, and the meaning and action–implications of bias. (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)

The main objective of our project is to construct a fully functional voice-based home automation system that uses the Internet of Things and Natural Language Processing. The home automation system is user-friendly to smartphones and laptops. A set of relays is used to connect the Node MCU to homes under controlled appliances. The user sends a command through the speech to the mobile devices, which interprets the message and sends the appropriate command to the specific appliance. The voice command given (...) by the user is interpreted by the mobile device using Natural Language Processing. The system utilizes a node microcontroller unit (Node MCU) as a Wi-Fi-based gateway to connect to the Google Assistant. It determines operation must be completed by which the appliance to fulfill the user’s request. The user increased mobile capabilities we will be using a smart phone in this project. A smartphone application as nearly all of the data transferred can be processed by cloud. The user increased mobile capabilities we will be using a smart phone in this project. The IoT -based system for home automation can easily and efficiently control appliances. The Node MCU is interfaced with the appliances and programmed in a manner that they respond to mobile inputs. (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)

The psychology of reasoning uses norms to categorize responses to reasoning tasks as correct or incorrect in order to interpret the responses and compare them across reasoning tasks. This raises the arbitration problem: any number of norms can be used to evaluate the responses to any reasoning task and there doesn’t seem to be a principled way to arbitrate among them. Elqayam and Evans have argued that this problem is insoluble, so they call for the psychology of reasoning to dispense (...) with norms entirely. Alternatively, Stupple and Ball have argued that norms must be used, but the arbitration problem should be solved by favouring norms that are sensitive to the context, constraints, and goals of human reasoning. In this paper, I argue that the design of reasoning tasks requires the selection of norms that are indifferent to the factors that influence human responses to the tasks—which aren’t knowable during the task design phase, before the task has been given to human subjects. Moreover, I argue that the arbitration problem is easily dissolved: any well-designed task will contain instructions that implicitly or explicitly specify a single determinate norm, which specifies what would count as a solution to the task—independently of the context, constraints, and goals of human reasoning. Finally, I argue that discouraging the use of these a priori task norms may impair the design of novel reasoning tasks. (shrink)

If we are to escape reification—a sort of cogni- tive neutrality of basic, gnosic apprehension of the world plus a fundamental disrespect of the other as free agent—we should recognize our mode of existence as always already one of existential engagement with and within experience, aiming at articulating and expressing this engagement. One way of fully inhabiting this, let’s call it the proper human stance, is through recognizing a pendular space between the basic attitudes of acknowledging lived, shared interests and (...) values and avoiding being bound to and dependent on the values of others. Both philosophy as radical critical re- flection, and art, or artistic processes of production and re- ception, can be seen as invitations to inhabit this pendular space of human experience, by way of continually opening up our habits of sensibility to new engagements in thought and life, and successfully articulating and expressing these engagements in public forms. I take Cavell’s reading of Wittgenstein’s mature philosophy as an attuning to an apt attitude towards this invitation. Is this attitude one possible, non-procedural meaning of “liberalism”? (shrink)

A woman and a man desire to come together stirred by the primal fire of Kama and the man deposits his egg in the womb of the woman. This egg develops into a human undergoing nine or ten months of evolution. This process is the microscopic replication of the method evolved by God to create the universe. Rigveda (10.121) mentions Hiranyagarbha, the Golden Egg as the source of the creation of the universe. It is said that God, wishing to create (...) the world, produced an egg as big as the cosmos. God meditated for a thousand years sitting inside the egg and when the egg burst, the Lord himself was born out of the egg as the Progenitor of the universe (“He made Himself by Himself.”, Taitiriya Upanishad: 2.7.1). The Rishis called the Egg Brahmanda (the Cosmic Egg), and the Progenitor Manu. Scientists have discovered that the universe has an oval shape. Like the nine months of the evolution of the human egg, the Cosmic Egg also undergoes nine stages of evolution before it gets dissolved during what we call ‘Maha Pralaya’. The Puranas mention that Brahmanda has 14 biospheres, seven nether and seven upper inhabited by different types of souls. If we count from the human world, there are ten dimensions of consciousness. Rishis called these astral biospheres Mandalas/Lokas with different wavelengths and colours. Sri Karunakara Guru referred to them as Avasthas, or spiritual stages. The Buddhists and Hindu esoteric sects such as the Theosophical Society explain these levels of the Absolute in terms of Physical plane, Astral plane, Mental plane, Buddhic plane, Atmic plane, Anupadaka plane, Adi plane and Shiv and Shakti. These Avasthas are related to the expanding consciousness reaching up to the core of the Cosmic Egg, the Paramatma. Like a spider which creates a web around it sitting in the centre, and withdraws it in the end, Paramatma creates and withdraws webbed multi-dimensional universes. Nobody can say when it started and when it will end as it is a beginningless and endless process. (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)

The study’s goal was to provide an educational intervention in Algebra through GeoGebra that would boost students’ confidence, improve their learning, and correct their most minor mastered skills, allowing them to improve their Algebra performance. The research design was quasi-experimental, with 40 nonrandomly chosen participants comprising the GeoGebra and control groups. Mean and standard deviation was employed to describe the algebra performance and confidence of the respondents. At the same time, independent and dependent t-tests were used to determine the students’ (...) significant difference in algebra performance and confidence in the pre-and post-test between the control and GeoGebra groups. GeoGebra effectively improved algebra confidence, enhanced learning, and remedied the students’ least mastered skills. GeoGebra is recommended as an instructional material in teaching and learning Algebra and can be extended to other mathematics content areas. (shrink)

In Galileo's Error, Philip Goff sets out a manifesto for a post-Galilean science of consciousness. Article four of the manifesto reads: 'Anti-Dualism: Consciousness is not separate from the physical world; rather consciousness is located in the intrinsic nature of the physical world.' I argue that there is an important sense of ‘dualism’ in which Goff’s arguments are not only compatible with but entail dualism, and not only dualism but substance dualism. Substance dualism, in the sense I have in mind, is (...) the view that (i) there are two sides to reality, a fundamentally mental side and a fundamentally nonmental side; and (ii) the fundamentally mental side consists of mental substances resembling Cartesian souls. I do not suggest that this is bad news for post-Galilean science of consciousness. My aim is rather to push for a certain view about what a theory of consciousness motivated by Goff’s arguments must look like. (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)

This paper examines Plato’s conception of shame and the role intoxication plays in cultivating it in the Laws. Ultimately, this paper argues that there are two accounts of shame in the Laws. There is a public sense of shame that is more closely tied to the rational faculties and a private sense of shame that is more closely tied to the non-rational faculties. Understanding this division between public and private shame not only informs our understanding of Plato’s moral psychology, but (...) his political and ethical theory as well. (shrink)