DIFERENCIAÇÃO SEXUAL -/- Emanuel Isaque Cordeiro da Silva Instituto Agronômico de Pernambuco Embrapa Semiárido -/- • _____OBJETIVO -/- Os estudantes de Veterinária e de Zootecnia estão ligados à disciplina Reprodução Animal, um pelos mecanismos fisiológicos para evitar e tratar as possíveis patologias do trato reprodutivo dos animais domésticos, e outro para o entendimento dos processos fisiológicos visando o manejo reprodutivo e a procriação para a formação de um plantel geneticamente melhorado. Sendo assim, a finalidade do presente trabalho é apresentar os (...) mecanismos que regulam as diferenças sobre o desenvolvimento embrionário relativos à diferenciação e determinação sexual de machos e fêmeas, que também incluem o desenvolvimento dos órgãos envolvidos na reprodução e a origem das diferenças entre ambos os sexos. -/- •____INTRODUÇÃO -/- Os organismos que se reproduzem sexualmente são descendentes de organismos ao qual não existia a diferenciação sexual. Em algum momento da evolução surgiu a reprodução sexual como um mecanismo para incrementar a diversidade genética e facilitar a troca de informações genéticas mediante o material genético da fêmea com o do macho. Devido sua origem comum, na maioria das espécies, tanto os machos como as fêmeas possuem todos os genes necessários para desenvolverem-se em qualquer dos sexos. O que efetivamente faz diferença entre os sexos é a forma e a ordem ao qual se expressam os genes durante o processo de desenvolvimento. A diferenciação sexual é regulada principalmente por mecanismos epigenéticos, mais do que as diferenças genéticas de grande magnitude entre os sexos. Todo o controle epigenético de qualquer processo de desenvolvimento depende basicamente de uma série de expressões gênicas, através da qual a expressão de certa combinação de genes resulta na presença de determinadas proteínas, conhecidas como os fatores de transcrição, que induzem ou reprimem a expressão de outro(os) gene(es), a partir dos quais se produzem novas proteínas, que em certos casos também atuam como fatores de transcrição para outros genes, e assim sucessivamente. Logo, a expressão ou falta de expressão de um gene ao início da série pode resultar em um ladrão totalmente diferente da expressão de outros genes subsequentes, o que pode ocasionar profundas mudanças no processo de desenvolvimento e até a mutações indesejáveis. O padrão predeterminado de expressões gênica relativo a diferenciação sexual na maioria das espécies tanto domésticas quanto selvagens, leva ao desenvolvimento de um dos sexos (o padrão predeterminado dos mamíferos é o sexo feminino). Em consequência, a diferenciação faz com que um indivíduo do sexo oposto exija a expressão de um gene de determinação sexual que desvie a subsequente série de expressões gênica em direção ao dito sexo. Nos mamíferos, a expressão do gene SRY, localizado no cromossomo Y (e portanto ausente nas fêmeas), redige o padrão de diferenciação sexual de sua via pré-estabelecida feminina em direção ao padrão masculino. A existência de uma única diferença genética (presença do gene SRY nos machos e ausentes nas fêmeas), vai se amplificando e termina resultando no desenvolvimento de indivíduos diferentes entre si. Esse é um mecanismo de diferenciação sexual cromossômica. O primeiro passo de uma série de diferenciação sexual, em sentido estrito, não depende nem requer necessariamente a presença de um gene diferente em algum dos sexos. O gene “disparador” da diferenciação sexual pode estar presente em todos os embriões, porém pode expressar-se somente em algum deles, devido a fatores ambientais que formam parte da sua regulação epigenética, isto é, uma determinação sexual ambiental. Em algumas espécies de tartarugas ou de lagartos a expressão ou falta de expressão do gene “disparador”, por exemplo, depende da temperatura existente durante a incubação dos ovos, pelo qual alguns embriões desenvolvem-se como machos e outros como fêmeas, apesar de não existir diferença genética entre eles, simplesmente como consequência da temperatura: a determinação sexual depende da temperatura a que cada um deles foi submetido durante a incubação. Em certas espécies as temperaturas mais elevadas facilitam o desenvolvimento de fêmeas e outras de machos, enquanto que em outras espécies as temperaturas amenas (intermediárias) resultam em machos, e as inferiores como as superiores induzem o desenvolvimento de fêmeas. A existência dessa diversidade indica que a temperatura por si mesma não é a que induz ou a que provoca o desenvolvimento do macho e da fêmea, senão a que atua somente como um regulador inicial da diferenciação sexual. Em outras espécies o fator ambiental que regula a determinação sexual pode ser distinto. A densidade populacional, por exemplo, pode atuar como um regulador. Podemos concluir que a determinação sexual dependente da temperatura ou de outros fatores ambientais estabelece-se antes da determinação sexual cromossômica, a qual evoluiu depois como um método que oferece maior certeza e resultado, já que a proporção de machos e fêmeas não é afetada por mudanças ambientais ou de hábitat. -/- •___FORMAÇÃO INICIAL DA GÔNADA -/- Basicamente em todos os embriões, inicialmente se formam as chamadas gônadas indiferenciadas (com o potencial de desenvolver-se em ovários ou testículos) a partir da invasão das cristas genitais pelas células germinais primordiais, que migram desde seu local de origem no epiblasto, perto do lugar onde o saco vitelino se une com o intestino primitivo e que chegam até às cristas genitais que são engrossamentos de tecido situados na região mesonéfrica do embrião. A migração das células germinais primordiais ocorre muito cedo sobre o processo de desenvolvimento do embrião (dia 26 nos bovinos). Ao chegas as cristas genitais, as células germinativas proliferam-se e se organizam com as células somáticas já existentes nas cristas para ir formando a gônada (figura 1). Para regular essa remodelação e conformação adequada da gônada vários genes se expressam, como o OCT-4 (que aparentemente mantém a totipotencialidade da gônada), assim como o SF-1 (Fator esteroidogênico 1) e o WT-1 (gene associado ao tumor de Wilms). Esses dois últimos genes estimulam a proliferação celular e estabelecimento dos cordões sexuais. Nessa etapa inicial do desenvolvimento todos esses genes se expressam sem distinção de sexo, pelo que a gônada em formação mantém a capacidade de se diferenciar em testículo ou em ovário. -/- Figura 1: migração das células germinais primordiais em direção a crista gonodal. Diferenciação das gônadas femininas e masculinas. Fonte: ZARCO, 2018. -/- •___SEXO CROMOSSÔMICO -/- Têm-se observado que nos mamíferos a determinação sexual depende diretamente dos cromossomos. As fêmeas possuem dois cromossomos sexuais X (um contribuído do óvulo e o outro por um espermatozoide “X”). Os machos, por sua vez, possuem um cromossomo sexual X(proveniente do óvulo) e um cromossomo sexual Y, que provém de um espermatozoide “Y” (figura 2). A metade dos espermatozoides produzidos por um macho são X e a metade Y, isso porque durante a espermatogênese a divisão meiótica provoca que a partir de cada espermatócito primário, célula diploide que por pertencer a um indivíduo macho tem um cromossomo X e um Y, se originem das espermátides haploides a cada um das que eles tocam cromossomos X, e outras espermátides haploides as que eles tocam os cromossomos Y. Dessa forma, de acordo com o tipo do espermatozoide que fertilize o ovócito, se originará um indivíduo com cariótipo feminino “XX” ou um cariótipo masculino “XY” (figura 2). Esse processo é conhecido como sexo cromossômico, ao qual se determina o momento da fertilização. Figura 2: nos mamíferos todos os óvulos produzidos pelas fêmeas possuem um cromossomo sexual X. A metade dos espermatozoides produzidos pelos machos possuem um cromossomo X e a outra metade possui um cromossomo Y. Dependendo do cromossomo presente no espermatozoide que fertilize o óvulo pode-se gerar um indivíduo XX (fêmea) ou um XY (macho). Fonte: ZARCO, 2018. -/- O cromossomo “Y” é uma “invenção” relativamente recente na história da evolução das espécies e do estudo da genética. Surgiu a partir de uma mutação de um cromossomo “X”, que resultou na perda de um de seus braços, que é por onde se originou a morfologia do cromossomo Y. A maioria dos genes presentes no cromossomo Y também existem no cromossomo X; assim mesmo somente alguns genes do cromossomo Y foram evoluídos até ser diferentes dos genes do cromossomo X. Embora os machos possuam um cromossomo que não está presente nas fêmeas, esse mesmo cromossomo não aporta toda a informação genética original. Todos os genes existentes nas fêmeas estão também presentes nos dos machos, já que eles também possuem um cromossomo X. Uma particularidade do cromossomo Y, ao existir somente uma cópia nos machos, é que ele sofre um entrecruzamento com um cromossomo análogo durante o processo de meiose, pelo que o cromossomo Y de um macho é idêntico ao de seu progenitor e ao de seus descendentes, exceto no caso em que ocorra uma mutação espontânea. Em contraste, os cromossomos X das fêmeas (um proveniente do pai e outro da mãe) se entrecruzam durante a meiose, por onde cada óvulo produzido pela fêmea terá uma combinação de alelos distinta em seu cromossomo X. Ao estudar as diferenças presentes na sequência de DNA do cromossomo Y, é possível identificar a distância filogenética entre os indivíduos (quanto mais diferenças existirem entre os cromossomos significa que seu ancestral comum está mais longe). Algo análogo ocorre com o DNA das mitocôndrias, que sempre são aportados pela mãe e nunca sofrem recombinação genética. Gene SRY -/- Um dos poucos genes do cromossomo Y que não possuem correspondência com o cromossomo X é o gene SRY (Sex-determining Region of the Y chromossome – região do cromossomo Y determinante do sexo). Esse gene se expressa somente na gônada em formação nos embriões machos, em particular em células precursoras das células de Sertoli; ele codifica uma proteína da família SOX (SRY-like Box) que é uma família formada por proteínas que possuem um domínio de união ao DNA e que atuam como fatores de transcrição. Ao produzir-se a proteína SRY nas células precursoras das células de Sertoli estimula-se a expressão (transcrição) de outro gene análogo, denominado SOX-9 que, por sua vez, atua como um fator de transcrição que ativa a expressão de outros genes, como o FGF-9 (Fibroblast Growth Factor-9), ou seja ele é o estimulante de ativação dos demais. Os produtos dos genes SOX-9 e FGF-9 iniciam uma cascata de expressões que provocam a diferenciação das células de suporte da gônada indiferenciada (crista genital) em células de Sertoli. Em seguida, essas células dirigem a diferenciação das células intersticiais da crista genital em células de Leydig, o que finalmente resulta na formação de um testículo. Outro dos efeitos da proteína codificada por SOX-9 é um estímulo maior da expressão de seu próprio gene, pelo qual é produzido um ciclo de retroalimentação positiva que favorece a continuidade do processo de formação testicular. Como nos embriões da fêmea não existe o gene SRY, a gônada indiferenciada não é estimulada para expressar os genes SOX-9 nem o FGF-9 nas células de suporte (que nesse caso serão precursoras de células da granulosa). A gônada, em mudança, expressa em forma constitutiva, isto é, sem a necessidade de estimulação, outra cascata de genes que incluem o WNT4 (Wingless-integration Factor 4) e o RAPO1 (Respondina-1), que por sua vez iniciam uma cascata de expressão gênica, a qual provoca a diferenciação das células somáticas da gônada indiferenciada para formação das células da granulosa e células da teca, esse feito conduz, por sua vez, a formação de um ovário. No embrião macho a proteína SOX-9 inibe a expressão dos genes WNT4 e RSPO-1, pelo que a presença do gene SRY, e portanto de SOX-9, inibem a formação de um ovário ao mesmo tempo que estimulam a formação do testículo (figura 3). Em suma, se o embrião possui genótipo XY (um embrião macho), o gene SRY começa a expressar-se sobre as células precursoras da gônada imediatamente depois da formação da mesma, quando os cordões sexuais primários estão se desenvolvendo na medula. A expressão do gene, assim como a presença subsequente das proteínas SOX-9 e FGF-9 estimula a distinção das células de Sertoli e que se organizem os tubos seminíferos a partir dos cordões sexuais primários. Em contrapartida, em um embrião com genótipo XX (fêmea) não existe o gene SRY, pelo qual é impossível que se elevem os níveis das proteínas SOX-9 e FGF-9 e as células precursoras não se diferenciam em células de Sertoli, e portanto os cordões sexuais primários sofrem regressão. Depois de alguns dias, começam a organizar-se os cordões sexuais secundários e as células precursoras iniciam a expressão do gene WNT4, o que leva as mesmas a diferenciar-se em células da granulosa, que serão a base para a conformação dos folículos ovarianos. Se em um embrião XY, macho, a expressão do gene SRY demora, é formada um ovo-testículo devido a que algumas das células somáticas das cristas gonodais começam a expressar o gene WNT4, e a diferenciar-se em células da granulosa, enquanto que em outras a proteína SRY chega a tempo para dirigir a diferenciação para formação das células de Sertoli. No ovário em formação é expressado um gene denominado DAX-1 (Dosage-sensitive Sex Reversal). Esse gene, localizado no cromossomo X, codifica uma proteína que é um membro da família dos receptores nucleares ao que lhe falta o domínio de união ao DNA, pelo que parece atuar no bloqueio de diversos fatores de transcrição, entre os que se encontra o SRY. Como a proteína DAX-1 impede a ação da proteína SRY, um excesso de expressão do gene DAX-1 pode provocar a feminilização gonodal de indivíduos XY, macho, embora tenham SRY. Em condições normais, a expressão adequada do gene DAX-1 não é capaz de evitar a masculinização gonodal de embriões com o gene SRY, daqui o nome de reversão sexual dependente da dose. Figura 3: série de expressão gênica para a determinação gonodal. SRY (Região do cromossomo Y determinante do sexo), SOX-9 (SRY-like Box-9), FGF-9 (Fator de crescimento de fibroblastos-9), WNT4 (Wingless-integration Factor-4), RSPO-1 (Respondina-1). Uma vez que o SRY induz a expressão de SOX-9 na gônada masculina, inicia-se um processo de feedback positivo mediante o qual os níveis de expressão de SOX-9 e FGF-9 vão aumentando, ao mesmo tempo que inibem a expressão de WNT-4 e RSPO-1. Na gônada feminina não se expressam SRY, SOX-9 e nem FGF-9, o que permite que se expressem os genes WNT-4 e RSPO-1, que iniciam uma cascata de sinalização que dirige a formação de um ovário. Fonte: ZARCO, 2018. -/- • ___DIFERENCIAÇÃO SEXUAL DOS GENITAIS -/- Uma vez que se formam os testículos, todo o desenvolvimento subsequente dos órgãos e as características “masculinas” em lugar das femininas é em consequência dos hormônios produzidos pelos testículos em formação, incluindo os andrógenos e o hormônio inibidor dos ductos de Müller. Mediante a ausência de testículos todo o desenvolvimento dos órgãos genitais internos e externos segue um padrão feminino, sem levar em conta se estão presentes os ovários; o que significa a ausência de hormônios gonodais determina que o embrião se desenvolva como fêmea, uma vez que não requerem hormônios ovarianos para desencadear o padrão feminino. Por sua vez, as gônadas masculinas (os testículos), produzem substâncias que desviam o desenvolvimento em direção ao padrão masculino. Sob etapas relativamente rápidas da diferenciação todos os embriões possuem dois pares de dutos sexuais, os dutos de Wolff ou mesonéfricos e os dutos de Müller ou paramesonéfricos (figura 4). A testosterona secretada pelos testículos do feto macho em desenvolvimento atua sobre os dutos de Wolff, o que induz a formação posterior dos dutos deferentes, do epidídimo e das glândulas seminais (figura 4). Figura 4: formação dos órgãos genitais internos a partir dos dutos de Wolff no macho e dos dutos de Müller na fêmea. Fonte: ZARCO, 2018. -/- Os testículos produzem ao mesmo tempo, uma glicoproteína chamada Hormônio Inibidor dos Dutos de Müller (Müllerian Inhibiting Hormone, MIH, também chamado de Anti-Müllerian Hormone, AMH); como o seu nome indica, inibe o desenvolvimento dos dutos de Müller ou paramesonéfricos, provocando sua regressão, que impede a formação dos órgãos genitais característicos da fêmea como os ovidutos, o útero, a cérvix e a porção cranial da vagina (figura 4). O MIH é uma glicoproteína da família dos fatores de crescimento transformativo β (TGFβ). O gene MIH possui locais de união para os produtos dos genes SOX-9 e SF-1, pelo que a presença simultânea de ambos fatores de transcrição é necessária para a secreção do MIH e leva a cabo sua função de iniciação dos dutos de Müller sobre o embrião macho (vale lembrar que nessa etapa tanto a gônada de embriões machos como de embriões fêmeas expressam o gene SF-1, mas somente o macho expressa o SOX-9, para que unicamente esse último produza MIH). O certo é que na gônada do embrião fêmea não se produzem quantidades importantes da proteína SOX-9, além de que se produz a proteína DAX-1, mesma que antagoniza tanto a SOX-9 como a SF-1, todo o qual impede a produção de MIH e resulta no desenvolvimento dos dutos de Müller até a formação dos ovidutos, útero, cérvix e a porção cranial da vagina (figura 4). Assim, na fêmea, ao não haver testículos não circulam concentrações elevadas de andrógenos, o que impedirá o desenvolvimento dos dutos de Wolff, enquanto que os dutos de Müller se desenvolvem já que não haverá a presença do MIH para impedi-lo. O desenvolvimento dos genitais internos e externos femininos não requerem a presença de nenhum hormônio ovariano o que levará a cabo de maneira predeterminada (ou pré-estabelecida) na ausência de testículos. Outra estrutura interna que também se desenvolve de forma distinta nos machos e nas fêmeas é o seio urogenital, que no embrião macho é estimulado pela testosterona para formação da próstata, das glândulas bulbouretrais e da uretra peniana, enquanto que na fêmea forma a porção caudal da vagina. A respeito dos órgãos genitais externos (figura 5), nos embriões de ambos os sexos existem estruturas precursoras chamadas de tubérculo genital e pregas vestibulares. Na fêmea o tubérculo genital da origem ao clitóris e as pregas vestibulares dão origem aos lábios vulvares sem a necessidade da atuação de hormônios ovarianos, já que o padrão “por via pré-estabelecida” é feminino. Em contrapartida, no macho, tanto o tubérculo genital quanto as pregas vestibulares respondem ao hormônio 5α-dehidro-testosterona (DHT), ao qual se formam as células da pele da zona genital a partir da testosterona que é secretada pelos testículos. Para isso existem nas células a enzima 5α-reductasa, que transforma a testosterona em DHT. Uma vez formada, a DHT atua sobre as pregas vestibulares do embrião macho para que se fusionem e formem o escroto (em lugar dos lábios vulvares), e sobre o tubérculo genital para formar o pênis (em lugar do clitóris). Figura 5: estruturas que se desenvolvem nos embriões de cada sexo a partir do seio urogenital, o tubérculo genital e as pregas vestibulares. A cor do né de cada estrutura final corresponde com a cor do nome da estrutura a partir da qual se originou. Fonte: ZARCO, 2018. -/- • ___DIFERENCIAÇÃO SEXUAL DO SISTEMA NERVOSO -/- Existem inúmeras diferenças funcionais entre o sistema nervoso da fêmeas e o do machos, em humanos podem incluir diferenças tão complexas como a maior capacidade de verbal da mulher ou a maior capacidade de orientação espacial do homem. Nessa parte será abordada aquelas diferenças que influenciam diretamente sobre a função reprodutiva, como as diferenças na regulação da secreção de gonadotropinas ou as diferenças na capacidade de comportamento sexual masculino ou feminino. É necessário lembrar que, apesar de que essas diferenças se originem durante um período crítico da vida fetal ou neonatal (dependendo da espécie), geralmente se fazem presentes até que o animal chegue a vida adulta e demonstre obter ou não a capacidade para se comportar como macho ou como fêmea uma vez que é exposto aos hormônios sexuais que são secretada depois da puberdade. Igualmente aos processos acima citados, podemos afirmar que nos mamíferos o padrão pré-estabelecido de comportamento sexual e de secreção de gonadotropinas é o feminino. Se durante os primeiros dias de vida neonatal uma rata fêmea não é exposta a nenhum hormônio gonodal, ao chegar a vida adulta ela terá a capacidade de se comportar como fêmea na presença de estrógenos, assim como de secretar um pico pré-ovulatório de GnRH/LH em resposta aos mesmos (figura 6). Essa rata, portanto, não poderá se comportar como macho embora que em sua vida adulta seja exposta a testosterona. O sistema nervoso do rato macho recém-nascido que é exposto aos andrógenos produzidos pelos testículos, em detrimento, faz com que adquiram o potencial para se comportar como machos em sua vida adulta e que perdem o potencial para ter conduta de fêmeas na presença e/ou administração de estrógenos (processo conhecido como desfeminização do SNC). Se por meios de experimentos injetamos testosterona em uma rata fêmea recém-nascida, essa rata não poderá se comportar como fêmea em sua vida adulta, e passará a se comportar como macho. A castração neonatal de um rato (visando evitar a exposição de seu SNC a andrógenos testiculares), assim mesmo, resultará em sua vida adulta um padrão feminino (SNC feminizado e não masculinizado). O hipotálamo das ratas adultas possui uma área em que o número, características e densidade dos corpos neurais difere em machos e fêmeas, essa área é denominada como “núcleo sexualmente dimórfico do hipotálamo”, e tem demonstrado que quando as ratas são tratadas com testosterona na vida neonatal, a morfologia de seu núcleo sexualmente dimórfico será masculinizado em sua vida adulta, enquanto que a castração neonatal de ratos resulta em um núcleo sexualmente dimórfico feminizado em sua vida adulta. Isso significa que a exposição ou não a testosterona na vida neonatal é o que determina que tipo de núcleo sexualmente dimórfico se desenvolverá, o que por sua vez está relacionado com o tipo de conduta que o animal poderá expressar em sua vida adulta. Não deixa de ser um paradoxo que ao injetar uma dose elevada de estrógenos nos primeiros dias de vida de uma rata, os núcleos sexualmente dimórficos da mesma se desenvolverão como macho e em sua vida adulta seu potencial de conduta estará masculinizado e desfeminizado. O hormônio “feminino” conhecido como estradiol, masculiniza o hipotálamo e a conduta do animal. Logo, se a rata neonatal for exposta a injeção de andrógeno não-aromatizado (que não pode ser transformado em estrógenos pelas células) ela não se masculiniza. A masculinização e desfeminização dos ratos ou das ratas tratados com testosterona, na realidade, não são provocados pela própria testosterona, senão pelos estrógenos que se formam dentro dos neurônios quando absorvem a testosterona do sangue e a aromatizam para transformá-la em estrógenos (figura 6). Figura 6: desfeminização e masculinização do sistema nervoso central por meio da testosterona, que quando não absorvida pela α-fetoproteína pode entrar nos neurônios, onde se aromatizam para serem transformados em estrógenos, hormônio que é responsável pela desfeminização. Fonte: ZARCO, 2018. Por que as ratas, que possuem ovários funcionalmente produtores de estrógenos, não se masculinizam? A resposta está em uma proteína denominada α-fetoproteína que circula em altas concentrações nos fetos e nos recém-nascidos. Essa proteína possui a capacidade de unir-se aos estrógenos, ao qual impede seu entrada nas células. Os ratos, em desenvolvimento, produzem testosterona, no entanto não possui afinidade pela α-fetoproteína, o que permite com que ela circule livremente. Ao chegar ao SNC, a testosterona (que não foi absorvida) pode entrar nos neurônios e dentro deles se aromatizam e transformam-se em estrógenos, que finalmente masculinizam o SNC. A diferenciação sexual do hipotálamo depende, em síntese, da presença ou ausência dos testículos, o que permite que se produza ou não o hormônio testosterona que pode não ser absorvida por parte da α-fetoproteína, transformar-se em estrógenos e masculinizar o SNC. -/- •___CONCLUSÃO -/- Nos mamíferos todo o processo que se requerem para o desenvolvimento de um macho depende da existência de somente um gene do cromossomo Y, o gene SRY; a ausência desse gene resulta no desenvolvimento de uma fêmea. A presença ou ausência do gene SRY determina, então, a cadeia de eventos morfogênicos que ocorrerá em sua expressão ou não, para desenvolver todos os órgãos e características de um macho ou de uma fêmea. Por essa razão, os indivíduos com uma monossomia XOA (síndrome de Turner) são fêmeas (por não possuir o cromossomo Y nem o gene SRY), enquanto que os indivíduos triploides XXY (síndrome de Kleinefelter) são machos embora possuam dois cromossomos X. Em algumas espécies, no entanto, têm-se identificado machos que são cromossomicamente XX; nesses casos é determinado invariavelmente que por ser um erro durante a meiose a região do cromossomo Y em que reside o gene SRY tem sido transloucada ao cromossomo X. Da mesma forma, em alguns casos tem sido encontrado fêmeas com cariótipo XY; que nelas se identifica uma mutação inabilitante do gene SRY. Isso demonstra experimentalmente que por meio da engenharia genética é possível produzir machos com cariótipo XY mas com o gene SRY eliminado (knockout). Como é de se esperar, esses machos desenvolvem ovários e todos seus órgãos genitais, tanto internos quanto externos, e se desenvolvem como fêmeas. Os machos cromossomicamente XX transgênicos aos que se insertam uma cópia do gene SRY, desenvolvem testículos e um fenótipo masculino, embora sejam estéreis por causa da ausência de alguns genes do cromossomo Y que são necessários para a realização de uma espermatogênese normal. As falhas nos mecanismos de diferenciação sexual podem, diretamente, ocasionar anormalidades como as observadas nas bezerras Freemartin, que são bezerras originadas de uma gestação gemelar em que seu gêmeo era macho. O que sucede é que na espécie bovina, quando há uma gestação gemelar, é produzido um certo grau de anastomose entre as placentas dos fetos, o que permite a troca de sangue e de células entre ambos. Os produtos recebem, então, algumas células de seu gêmeos, que encontram seu lugar no órgão correspondente e se integram a ele. No caso particular das gônadas, quando o ovário primitivo de um embrião fêmea é colonizado por algumas células gonodais de seu gêmeo macho, essas células expressam o gene SRY, o que fará com que essa região da gônada se diferencie como testículo. Como resultado, se desenvolve um ovo-testículo (com maior ou menor proporção de tecido testicular dependendo do grau de colonização da gônada em formação por células provenientes do gêmeo macho). Ademais, ao haver certa quantidade de tecido testicular produtor de MIH, circularão sobre o feto fêmea níveis desse hormônio que, embora baixos, afetarão o desenvolvimento normal dos dutos de Müller, fazendo com que as bezerras Freemartin possuam genitálias internas ausentes ou pouco desenvolvidas. Os andrógenos produzidos pelas zonas de tecido testicular, por fim, são suficientes para causar um certo grau de masculinização, que se manifesta como um clitóris mais grande que o normal ou um desenvolvimento corporal masculinizado. -/- REFERÊNCIAS BIBLIOGRÁFICAS -/- ARNOLD, Arthur P.; CHEN, Xuqi; ITOH, Yuichiro. What a difference an X or Y makes: sex chromosomes, gene dose, and epigenetics in sexual differentiation. In: Sex and gender differences in pharmacology. Springer, Berlin, Heidelberg, 2013. p. 67-88. CUNNINGHAM, James. Tratado de fisiologia veterinária. Elsevier Health Sciences, 2011. DERIVAUX, Jules; BARNABÉ, Renato Campanarut. Reprodução dos animais domésticos. Zaragoza: Acribia, 1980. DA SILVA, Emanuel Isaque Cordeiro. Desenvolvimento Embrionário e Diferenciação Sexual nos Animais Domésticos. Disponível em:. Acesso em: Julho de 2020. HAFEZ, Elsayed Saad Eldin; HAFEZ, Bahaa. Reprodução animal. São Paulo: Manole, 2004. HIDALGO, C. Galina et al. Reproducción de animales domésticos. México: Limusa, 2008. MACLAUGHLIN, David T.; DONAHOE, Patricia K. Sex determination and differentiation. New England Journal of Medicine, v. 350, n. 4, p. 367-378, 2004. MCCARTHY, Margaret M.; ARNOLD, Arthur P. Reframing sexual differentiation of the brain. Nature neuroscience, v. 14, n. 6, p. 677, 2011. PLANT, Tony M.; ZELEZNIK, Anthony J. (Ed.). Knobil and Neill's physiology of reproduction. Academic Press, 2014. REY, Rodolfo. Diferenciación sexual embrio-fetal: De las moléculas a la anatomía. Revista chilena de anatomía, v. 19, n. 1, p. 75-82, 2001. SENGER, P. L. Embryogenesis of the pituitary gland and male or female reproductive system. In. Pathways to Pregnancy and Parturition. Current Conception Inc, v. 1, p. 8-76, 1997. ZARCO, L. Diferenciación sexual. In. PORTA, L. R.; MEDRANO, J. H. H. Fisiología reproductiva de los animales domésticos. Cidade do México: FMVZ-UNAM, 2018. -/- REALIZAÇÃO -/- . (shrink)

In 2009, we celebrated the bicentennial of the birth of Charles Darwin and the sesquicentennial of the publication of his book The Origin of Species. This seems to be a good opportunity to evaluate the importance of Darwin’s work for the social sciences, mainly for philosophical anthropology. The aim of this paper is to discuss the traditional anthropocentric conceptions of man, which consider our biological species to be exceptional – qualitatively higher than other living organisms. Over the course of the (...) 20th century, philosophers have argued for the claim in a number of ways: man is supposed to be the only animal capable of laughter, love, thought or language. It has also been claimed that only members of Homo sapiens have free will, morality or religion. The paper refutes these arguments on the basis of contemporary studies by M. Davila Ross, H. Fischer, K. Arnold, K. Zuberbühler, G. Konopka, B. Libet, F. De Waal, M. Bekoff, P. Boyer, B. Hood, G. Paul and others. The author argues that the only differences between man and other animals are quantitative, and therefore the nature of humans should be studied using the methods of naturalized philosophy, with respect to the natural sciences. (shrink)

This paper draws together as many as possible of the clues and pieces of the puzzle surrounding T. S. Eliot’s “infamous” literary term “objective correlative”. Many different scholars have claimed many different sources for the term, in Pound, Whitman, Baudelaire, Washington Allston, Santayana, Husserl, Nietzsche, Newman, Walter Pater, Coleridge, Russell, Bradley, Bergson, Bosanquet, Schopenhauer and Arnold. This paper aims to rewrite this list by surveying those individuals who, in different ways, either offer the truest claim to being the source (...) of the term, or contributed the most to Eliot’s development of it: Allston, Husserl, Bradley and Bergson. What the paper will argue is that Eliot’s possible inspiration for the term is more indebted to the idealist tradition, and Bergson’s aesthetic development of it, than to the phenomenology of Husserl. (shrink)

Joseph Butler was an Anglican priest and later a bishop who wrote about ethics, religion, and other philosophical themes. He is not well known today. During his lifetime and into the early part of the twentieth century he was better known especially for his major work the Analogy of Religion (1736). Today he is known mostly for his sermons which are interpreted as essays on ethics and for his essay on identity. Butler had a profound effect on J. H. Newman, (...) Matthew Arnold, and W. E. Gladstone and some effect on many other popular, academic, and professional readers. This book is as much about Butler’s sources and his reception as it is about the way he arranged and presented the evidence in the first half of the 18th century. He was a good man and is recognized by the Anglican church as a divine. We have no interest in taking a nostalgic look at a quaint figure in English church history. To those who claim Butler is unknown, that he was “blown out of the water” by John Wesley or Karl Barth, or Cornelius van Til, we can only say Butler is not as well known in the 20th and 21st centuries as in the 19th, but he is certainly not unknown to those who have taken any interest in philosophy, religion, or ethics. Today there has been a revival of interest in Bishop Butler. Our concern is to build and maintain a bridge that will help to keep this momentum. He offers an ethic that is universal and clearly Christian, yet it is based on the nature of man. Kant had a similar project, but in our opinion, Butler makes more compelling arguments. What is of interest to the Christian apologist is Butler’s work in this area. The purpose of this book is to present Butler’s ideas. We believe that his ethics have a universality that is applicable to people of all religious faiths and those that have none. It is common sense way of looking at ethics for everyday interaction. This book is a narrative argument presenting in detail how Butler’s creative arrangement of the evidence served as a bridge between the ancients as known in the Greek, Latin, and Hebrew originals, and the moderns, mostly Anglophone, who constituted Butler’s work environment and his reception in the latter day down to the present. We can hardly expect everyone to agree with Butler on all points, we certainly do not. The point at issue is rather whether he merits a seat at the present-day round table of deliberation on matters pertaining to philosophy, religion, and ethics. (shrink)

What should we believe when epistemic and practical reasons pull in opposite directions? The traditional view states that there is something that we ought epistemically to believe and something that we ought practically to (cause ourselves to) believe, period. More recent accounts challenge this view, either by arguing that there is something that we ought simpliciter to believe, all epistemic and practical reasons considered (the weighing view), or by denying the normativity of epistemic reasons altogether (epistemic anti‐normativism). I argue against (...) both accounts and defend the traditional view. An agent can be blameworthy in doxastic dilemmas for complying with their practical but not their epistemic reasons. This reveals how epistemic reasons are normative: the concept of epistemic blame helps us track epistemic normativity. (shrink)

Sebastian Schmidt (Zürich) fragt in seinem Beitrag »Wie vernünftig sind Verschwörungstheoretiker?«, wie es um die Vernunft derjenigen steht, die einer Verschwörungstheorie über die Corona-Pandemie anhängen. Im Umgang mit Corona scheint sich zu bestätigen, was die Psychologie seit Jahrzehnten lehrt: Menschen unterliegen in ihrem Denken kognitiven Fehlern und Verzerrungen. Doch ist verschwörungstheoretisches Denken, das solche Fehler ebenfalls begeht, deshalb irrational? Schmidt warnt davor, einander zu leichtfertig als irrational zu betrachten, und verweist auf die wichtige Rolle, die intellektuelles Vertrauen in (...) Wissensgemeinschaften spielt. Am Beispiel des sogenannten Bestätigungsfehlers führt er aus, dass Menschen, die ihre Überzeugungen nicht fortwährend kritisch prüfen, in diesem Verhalten durchaus rational sein können. (shrink)

Eva Schmidt argues that facts about incoherent beliefs can be non-evidential epistemic reasons to suspend judgment. In this commentary, I argue that incoherence-based reasons to suspend are epistemically superfluous: if the subjects in Schmidt’s cases ought to suspend judgment, then they should do so merely on the basis of their evidential reasons. This suggests a more general strategy to reduce the apparent normativity of coherence to the normativity of evidence. I conclude with some remarks on the independent interest (...) that reasons-first epistemology might have within an evidentialist framework. (shrink)

Proponents of the reasoning view analyze normative reasons as premises of good reasoning and explain the normativity of reasons by appeal to their role as premises of good reasoning. The aim of this paper is to cast doubt on the reasoning view by providing counterexamples to the proposed analysis of reasons, counterexamples in which premises of good reasoning towards φ‐ing are not reasons to φ.

The Pessimistic Induction over the history of science argues that because most past theories considered empirically successful in their time turn out to be not even approximately true, most present ones probably aren’t approximately true either. But why did past scientists accept those incorrect theories? Kyle Stanford’s ‘Problem of Unconceived Alternatives’ is one answer to that question: scientists are bad at exhausting the space of plausible hypotheses to explain the evidence available to them. Here, I offer another answer, which I (...) call the ‘Problem of Misleading Evidence.’ I argue that this proposal is, in important respects, superior to Stanford’s. (shrink)

It is often argued that there are no practical reasons for belief because we could not believe for such reasons. A recent reply by pragmatists is that we can often believe for practical reasons because we can often cause our beliefs for practical reasons. This paper reveals the limits of this recently popular strategy for defending pragmatism, and thereby reshapes the dialectical options for pragmatism. I argue that the strategy presupposes that reasons for being in non-intentional states are not reducible (...) to reasons to act. Pragmatists who want to preserve a motivational constraint on reasons therefore have exactly two options: either arguing that there are irreducible reasons for being in non-intentional states ; or arguing that we can believe directly for practical reasons. I argue that the prospects for the former option are dim because irreducible reasons to be in states are hard to square with the motivational constraint on reasons. Returning to the more traditional route of arguing for pragmatism by defending a version of doxastic voluntarism therefore seems to be the more promising way for pragmatists to go. (shrink)

I argue that the problem of responsibility for attitudes is best understood as a puzzle about how we are responsible for responding to our object-given reasons for attitudes – i.e., how we are responsible for being (ir)rational. The problem can be solved, I propose, by understanding the normative force of reasons for attitudes in terms of blameworthiness. I present a puzzle about the existence of epistemic and mental blame which poses a challenge for the very idea of reasons for attitudes. (...) We are left with three options: denying that there are any reasons for attitudes, opting for pragmatism about reasons for attitudes, or arguing that the challenge rests on a misunderstanding of the normative force of reasons for attitudes. I finally suggest a version of the last strategy. We can understand the normative force of reasons for attitudes, and thereby solve the problem of mental responsibility, by acknowledging that the way we blame each other for failing to respond correctly to our reasons for attitudes is different from the way we blame each other when one failed to respond correctly to reasons for action. (shrink)

Broome takes the debate on rationality to be concerned with the ordinary use of 'rational'. I argue that this is at best misleading. For the object of current theories of rationality is determined by a specific use of 'rational' that is intimately connected to blame and praise. I call the property it refers to 'rationalityRESP'. This focus on rationalityRESP, I argue, has two significant implications for Broome's critique of theories of rationality as reasons-responsiveness. First, rationalityRESP is plausibly conceived of as (...) a kind of reasons-responsiveness. Secondly, Broome's dispute with internalists about normativity as well as his dispute with externalists about rationality both hinge on questions regarding the concept of responsibility. I conclude that philosophers should integrate discussions about responsibility in their debates about rationality. (shrink)

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

In this paper, I defend a reasons-first view of epistemic justification, according to which the justification of our beliefs arises entirely in virtue of the epistemic reasons we possess. I remove three obstacles for this view, which result from its presupposition that epistemic reasons have to be possessed by the subject: the problem that reasons-first accounts of justification are necessarily circular; the problem that they cannot give special epistemic significance to perceptual experience; the problem that they have to say that (...) implicit biases provide epistemic. The first problem will be overcome by introducing presentational attitudes that are not in need of justification as basic ways of possessing epistemic reasons. The latter two problems will be solved by introducing epistemic rational capacities of two different kinds, which are exercised in mental states that are ways of possessing epistemic reasons, and by distinguishing these from mental states that are not exercises of epistemic rational capacities. (shrink)

The semeiotic of Charles Sanders Peirce is irreducibly triadic, positing that a sign mediates between the object that determines it and the interpretant that it determines. He eventually holds that each sign has two objects and three interpretants, standardizing quickly on immediate and dynamical for the objects but experimenting with a variety of names for the interpretants. The two most prominent terminologies are immediate/dynamical/final and emotional/energetic/logical, and scholars have long debated how they are related to each other. This paper seeks (...) to shed new light on the matter by reviewing the numerous manuscript drafts where Peirce develops the latter nomenclature while attempting to introduce his pragmatism to a general audience. It then goes on to examine an additional set of interpretants, intentional/effectual/communicational, and shows that the three different trichotomies can be understood as complementary, rather than redundant or conflicting. (shrink)

Many of our attitudes are non-culpable: there was nothing that we should have done to avoid holding them. I argue that we can still be blameworthy for non-culpable attitudes: they can impair our relationships in ways that make our full practice of apology and forgiveness intelligible. My argument poses a new challenge to indirect voluntarists, who attempt to reduce all responsibility for attitudes to responsibility for prior actions and omissions. Rationalists, who instead explain attitudinal responsibility by appeal to reasons-responsiveness, can (...) make sense of blameworthiness for non-culpable attitudes. In response, voluntarists could propose a revision of our actual practices. This would lead us into a quite different debate. (shrink)

While Thomas Kuhn's theory of scientific revolutions does not specifically deal with validation, the validation of simulations can be related in various ways to Kuhn's theory: 1) Computer simulations are sometimes depicted as located between experiments and theoretical reasoning, thus potentially blurring the line between theory and empirical research. Does this require a new kind of research logic that is different from the classical paradigm which clearly distinguishes between theory and empirical observation? I argue that this is not the case. (...) 2) Another typical feature of computer simulations is their being ``motley'' (Winsberg 2003) with respect to the various premises that enter into simulations. A possible consequence is that in case of failure it can become difficult to tell which of the premises is to blame. Could this issue be understood as fostering Kuhn's mild relativism with respect to theory choice? I argue that there is no need to worry about relativism with respect to computer simulations, in particular. 3) The field of social simulations, in particular, still lacks a common understanding concerning the requirements of empirical validation of simulations. Does this mean that social simulations are still in a pre-scientific state in the sense of Kuhn? My conclusion is that despite ongoing efforts to promote quality standards in this field, lack of proper validation is still a problem of many published simulation studies and that, at least large parts of social simulations must be considered as pre-scientific. (shrink)

I present an explanatory argument for the reasons-first view: It is superior to knowledge-first views in particular in that it can both explain the specific epistemic role of perception and account for the shape and extent of epistemic justification.

Do non-human animals have an interest in sociopolitical freedom? Cochrane has recently taken up this important yet largely neglected quest ion. He argues that animal freedom is not a relevant moral concern in itself, because animals have a merely instrumental but not an intrinsic interest in freedom (Cochrane 2009a, 2012). This paper will argue that even if animals have a merely instrumental interest in freedom, animal freedom should nonetheless be an important goal for our relationships with animals. Drawing on recent (...) work on the value of freedom, it will be argued that freedom is non-specifically instrumentally valuable. Accordingly, freedom is a means to other goods, but often it is not possible to identify those goods in advance or aim for them directly. Some of the reasons that make freedom non-specifically valuable for human relationships, it will be argued, also apply to relationships between humans and animals. Amongst other implications, it will be shown how this argument provides a response to those who fear that stricter animal protection policies might undermine people’s freedom: A concern for freedom actually requires stricter protection policies rather than speak against them. (shrink)

Modern philosophy recognizes two major ethical theories: deontology, which encourages adherence to rules and fulfillment of duties or obligations; and consequentialism, which evaluates morally significant actions strictly on the basis of their actual or anticipated outcomes. Both involve the systematic application of universal abstract principles, reflecting the culturally dominant paradigm of technical rationality. Professional societies promulgate codes of ethics with which engineers are expected to comply, while courts and the public generally assign liability to engineers primarily in accordance with the (...) results of their work, whether intended or unintended. A third option, prominent in ancient philosophy, has reemerged recently: virtue ethics, which recognizes that sensitivity to context and practical judgment are indispensable in particular concrete situations, and therefore rightly focuses on the person who acts, rather than the action itself. Beneficial character traits—i.e., virtues—are identified within a specific social practice in light of the internal goods that are unique to it. This paper proposes a comprehensive framework for implementing virtue ethics within engineering. (shrink)

Peirce is best known as the founder of pragmatism, but his dissatisfaction with how others understood and appropriated it prompted him to rename his own doctrine “pragmaticism” and to compose several variants of his original maxim defining it, as well as numerous restatements and elaborations. This paper presents an extensive selection of such formulations, followed by analysis and commentary demonstrating that for Peirce the ultimate meaning of an intellectual concept is properly expressed as a conditional proposition about the deliberate, self-controlled (...) conduct of its interpreters, not the law-governed behavior of its object. (shrink)

Confused terms appear to signify more than one entity. Carnap maintained that any putative name that is associated with more than one object in a relevant universe of discourse fails to be a genuine name. Although many philosophers have agreed with Carnap, they have not always agreed among themselves about the truth-values of atomic sentences containing such terms. Some hold that such atomic sentences are always false, and others claim they are always truth-valueless. Field maintained that confused terms can still (...) refer, albeit partially, and offered a supervaluational account of their semantic properties on which some atomic sentences with confused terms can be true. After outlining many of the most important theoretical considerations for and against various semantic theories for such terms, we report the results of a study designed to investigate which of these accounts best accords with the truth-value judgments of ordinary language users about sentences containing these terms. We found that naïve participants view confused names as capable of successfully referring to one or more objects. Thus, semantic theories that judge them to involve total reference failure do not comport well with patterns of ordinary usage. (shrink)

It has been argued that rationality consists in responding correctly to reasons. Recent defenses of the normativity of rationality assume that this implies that we always ought to be rational. However, this follows only if the reasons rationality requires us to correctly respond to are normative reasons. Recent meta-epistemological contributions have questioned whether epistemic reasons are normative. If they were right, then epistemic rationality wouldn’t provide us with normative reasons independently of wrong-kind reasons to be epistemically rational. This paper spells (...) out this neglected challenge for the normativity of epistemic rationality by connecting the two bodies of literature. Moreover, it generalizes this challenge to the rationality of desire, intention, and emotion. The upshot is that we can only answer the normative question about rationality if we debate about blame and accountability for holding different kinds of irrational attitudes, as well as about the sources of mental normativity. (shrink)

Although Peirce frequently insisted that continuity was a core component of his philosophical thought, his conception of it evolved considerably during his lifetime, culminating in a theory grounded primarily in topical geometry. Two manuscripts, one of which has never before been published, reveal that his formulation of this approach was both earlier and more thorough than most scholars seem to have realized. Combining these and other relevant texts with the better-known passages highlights a key ontological distinction: a collection is bottom-up, (...) such that the parts are real and the whole is an ens rationis, while a continuum is top-down, such that the whole is real and the parts are entia rationis. Accordingly, five properties are jointly necessary and sufficient for Peirce’s topical continuum: rationality, divisibility, homogeneity, contiguity, and inexhaustibility. (shrink)

Since anonymous agents can spread misinformation with impunity, many people advocate for greater accountability for internet speech. This paper provides a veritistic argument that accountability mechanisms can cause significant epistemic problems for internet encyclopedias and social media communities. I show that accountability mechanisms can undermine both the dissemination of true beliefs and the detection of error. Drawing on social psychology and behavioral economics, I suggest alternative mechanisms for increasing the trustworthiness of internet communication.

I argue that a certain type of naturalist should not accept a prominent version of the no-miracles argument (NMA). First, scientists (usually) do not accept explanations whose explanans-statements neither generate novel predictions nor unify apparently disparate established claims. Second, scientific realism (as it appears in the NMA) is an explanans that makes no new predictions and fails to unify disparate established claims. Third, many proponents of the NMA explicitly adopt a naturalism that forbids philosophy of science from using any methods (...) not employed by science itself. Therefore, such naturalistic philosophers of science should not accept the version of scientific realism that appears in the NMA. (shrink)

Employing computer simulations for the study of the evolution of altruism has been popular since Axelrod's book "The Evolution of Cooperation". But have the myriads of simulation studies that followed in Axelrod's footsteps really increased our knowledge about the evolution of altruism or cooperation? This book examines in detail the working mechanisms of simulation based evolutionary explanations of altruism. It shows that the "theoretical insights" that can be derived from simulation studies are often quite arbitrary and of little use for (...) the empirical research. In the final chapter of the book, therefore, a set of epistemological requirements for computer simulations is proposed and recommendations for the proper research design of simulation studies are made. (shrink)

Wenn wir Peter Singers Konklusion in „Famine, Affluence, and Morality“ (1972) akzeptieren, dann handeln wir im Alltag sehr viel häufiger falsch, als es uns lieb ist. Anstatt über die Natur von Altruismus zu philosophieren, könnten wir auch möglichst effektiv Hungerleidenden helfen. Ist es daher etwa moralisch verwerflich – weil egoistisch – zu philosophieren? In diesem Beitrag beleuchte ich die Gründe, die wir haben, Philosophie in den Mittelpunkt unseres Lebens zu stellen. Ich argumentiere, dass Philosophieren – genauso wie die Beschäftigung mit (...) Kunst und Wissenschaft – nur dann gerechtfertigt sein kann, wenn es praktische Gründe jenseits von Gründen des persönlichen Nutzens und der Moral gibt. Dabei schliesse ich an Susan Wolfs Idee an, dass diese Tätigkeiten ein Leben mit Sinn erfüllen können. Es bleibt jedoch offen, ob in einer Welt voller Ungerechtigkeit die moralischen Gründe gegen das Philosophieren (und für andere Handlungsoptionen) nicht dennoch überwiegen. (shrink)

This paper tries to answer the question why the epistemic value of so many social simulations is questionable. I consider the epistemic value of a social simulation as questionable if it contributes neither directly nor indirectly to the understanding of empirical reality. To examine this question, two classical social simulations are analyzed with respect to their possible epistemic justification: Schelling’s neighborhood segregation model and Axelrod’s reiterated Prisoner’s Dilemma simulations of the evolution of cooperation. It is argued that Schelling’s simulation is (...) useful because it can be related to empirical reality, while Axelrod’s simulations and those of his followers cannot and thus that their scientific value remains doubtful. I relate this findingto the background beliefs of modelers about the superiority of the modeling method as expressed in Joshua Epstein’s keynote address “Why model?”. (shrink)

An epistemology of art has seemed problematic mainly because of arguments claiming that an essential element of a theory of knowledge, truth, has no place in aesthetic contexts. For, if it is objectively true that something is beautiful, it seems to follow that the predicate “is beautiful” expresses a property – a view asserted by Plato but denied by Hume and Kant. But then, if the belief that something is beautiful is not objectively true, we cannot be said to know (...) that something is beautiful and the path to an epistemology of art is effectively blocked. The article places the existence aesthetic properties in the proper context; presents a logically correct argument for the existence of such properties; identifies strategies for responding to this argument; explains why objections by Hume, Kant, and several other philosophers fail; and sketches a realization account of beauty influenced by Hogarth. (shrink)

Why, if at all, should we object to economic inequality? Some central arguments – the argument from decreasing marginal utility for example – invoke instrumental reasons and object to inequality because of its effects. Such instrumental arguments, however, often concern only the static effects of inequality and neglect its intertemporal conse- quences. In this article, we address this striking gap and investigate income inequality’s intertemporal consequences, including its potential effects on humanity’s (very) long-term future. Following recent arguments around future generations (...) and so-called longtermism, those effects might arguably matter more than inequality’s short-term con- sequences. We assess whether we have instrumental reason to reduce economic inequality based on its intertemporal effects in the short, medium, and the very long term. We find a good short and medium-term instrumental case for lower economic inequality. We then argue, somewhat speculatively, that we have instrumental reasons for inequality reduction from a longtermist perspective too, primarily because greater inequality could increase existential risk. We thus have instrumental reasons to reduce inequality, regardless of which time-horizon we take. We then argue that from most consequentialist perspectives, this pro tanto reason also gives us all-things-considered reason. And even across most non-consequentialist views in philosophy, this argument gives us either an all-things-considered or at least weighty pro tanto reason against inequality. (shrink)

Suppose one believes that the historical record of discarded scientific theories provides good evidence against scientific realism. Should one adopt Kyle Stanford’s specific version of this view, based on the Problem of Unconceived Alternatives? I present reasons for answering this question in the negative. In particular, Stanford’s challenge cannot use many of the prima facie strongest pieces of historical evidence against realism, namely: superseded theories whose successors were explicitly conceived, and superseded theories that were not the result of elimination-of-alternatives inferences. (...) Attempts to accommodate and within Stanford’s framework are incompatible with other commitments Stanford holds, such as anti-realism being piecemeal instead of global. As separate lines of criticism, I argue that there are problems with Stanford’s claim that the PUA is the most important challenge to realism, and with his view of instrumentalist theory endorsement. (shrink)

I argue that believing at will – i.e. believing for practical reasons – is in some sense possible and in some sense impossible. It is impossible insofar as we think of belief formation as a re-sult of our exercise of certain capacities (perception, memory, agency). But insofar as we think of belief formation as an action that might lead to such a result (i.e. a deliberation or an in-quiry), believing at will is possible. First I present and clarify the problem (...) and its philosophical relevance (section 1). I then argue that a belief formation as an immediate reaction to practical reasons is not necessarily equivalent to believing at will because the causal mechanism that leads to the formation might be deviant (section 2). Finally, I explain the difference between the two above mentioned meanings of “belief formation” in order to clarify the possibility and impossibility of believing at will (section 3). (shrink)

Imagine that you and a duplicate of yourself are lying unconscious, next to each other, about to undergo a complete step-by-step exchange of bits of your bodies. It certainly seems that at no stage in this exchange of bits will you have thereby switched places with your duplicate. Yet it also seems that the end-result, with all the bits exchanged, will be essentially that of the two of you having switched places. Where will you awaken? I claim that one and (...) the same person possesses both bodies, occupies both places and will experience both awakenings, just as a person whose brain has been bisected must at once experience both of the unconnected fields of awareness, even though each of these will falsely appear to him as the entirety of his experience. I also claim that the more usual apparent boundaries of persons are as illusory as those in brain bisection; personal identity remains unchanged through any variation or multiplication of body or mind. In all conscious life there is only one person - I - whose existence depends merely on the presence of a quality that is inherent in all experience - its quality of being mine, the simple immediacy of it for whatever is having experience. One powerful argument for this is statistical: on the ordinary view of personhood it is an incredible coincidence for you (though not for others) that out of 200,000,000 sperm cells the very one required on each occasion for your future existence was first to the egg in each of the begettings of yourself and all your ancestors. The only view that does not make your existence incredible, and that is not therefore (from your perspective) an incredible view, is that any conscious being would necessarily have been you anyway. It is a consequence that self-interest should extend to all conscious organisms. (shrink)

In a recent Philosophy of Science article Gerhard Schurz proposes meta-inductivistic prediction strategies as a new approach to Hume's. This comment examines the limitations of Schurz's approach. It can be proven that the meta-inductivist approach does not work any more if the meta-inductivists have to face an infinite number of alternative predictors. With his limitation it remains doubtful whether the meta-inductivist can provide a full solution to the problem of induction.

Many commentators on Alfred Tarski have, following Hartry Field, claimed that Tarski's truth-definition was motivated by physicalism—the doctrine that all facts, including semantic facts, must be reducible to physical facts. I claim, instead, that Tarski did not aim to reduce semantic facts to physical ones. Thus, Field's criticism that Tarski's truth-definition fails to fulfill physicalist ambitions does not reveal Tarski to be inconsistent, since Tarski's goal is not to vindicate physicalism. I argue that Tarski's only published remarks that speak approvingly (...) of physicalism were written in unusual circumstances: Tarski was likely attempting to appease an audience of physicalists that he viewed as hostile to his ideas. In later sections I develop positive accounts of: (1) Tarski's reduction of semantic concepts; (2) Tarski's motivation to develop formal semantics in the particular way he does; and (3) the role physicalism plays in Tarski's thought. (shrink)

Ecology has become a popular conceptual model in numerous fields of inquiry and it seems especially appropriate for environmental philosophy. Apart from its literal employment in biology, ecology has served as a useful metaphor that captures the interdependence of factors in a field of research. At the same time as ecology is suggestive, it cannot be followed literally or blindly. This paper considers the appropriateness of the uses to which ecology has been put in some recent discussions of architectural and (...) environmental aesthetics, and develops a critique of the differing ecological aesthetics of Jusuck Koh and Xiangzhan Cheng. (shrink)

I critically examine Nietzsche’s argument in The Will to Power that all the detailed events of the world are repeating infinite times (on account of the merely finite possible arrangements of forces that constitute the world and the inevitability with which any arrangement of force must bring about its successors). Nietzsche celebrated this recurrence because of the power of belief in it to bring about a revaluation of values focused wholly on the value of one’s endlessly repeating life. Belief in (...) recurrence would bring joy to those who had achieved excellence in this life and crush those who had not. I point out, however, that this significance of recurrence must be spoiled by the consideration that within each of the long cycles of recurrence there would have to be, as well, countless variations of this life. And I consider the issue of personal identity within such recurrences. Is it the same person or merely resembling but distinct persons in the recurrences or the variations? If it is the same person in precise recurrences, should the subjectively identical experience be thought of as really additional for that person? (shrink)

Many have tackled the question ‘What (if anything) is analytic philosophy?’ I will not attempt to answer this vexed question. Rather, I address a smaller, more manageable set of interrelated questions: first, when and how did people begin using the label ‘analytic philosophy’? Second, how did those who used this label understand it? Third, why did many philosophers we today classify as analytic initially resist being grouped together under the single category of ‘analytic philosophy’? Finally, for the first generation who (...) described themselves as analytic philosophers, what was their intended contrast class? Relatedly, when did ‘continental philosophy’ become the standard opposition? Some evidence I present justifies received answers to these questions; other evidence supports surprising and unorthodox answers to these questions. (shrink)

To investigate cultural lifestyle preferences in different cultural contexts, a forced-choice questionnaire was constructed, based on Thurstone's Law of Comparative Judgement, an almost forgotten statistical method of 1927, which is a useful tool for assessing groups. This study's questionnaire items targeted job and living conditions in the spectrum from traditional to globalised lifestyles. Subjects were indigenous representatives at the UNO in Geneva, and students in Nigeria, Cameroon, South Africa and Germany. The preferences ascertained reflect attitudes on a scale ranging from (...) very traditional to very globalised lifestyles. Although being an uncommon assessment tool, Thurstone's Comparative Judgement indicates to yield highly valid outcomes, as the results of the African university students, though from three different countries, resembled each other, but were complementary to the results of the indigenous representatives, which, in turn, mirrored the Berlin controls' profiles, according to expectations. Findings are discussed in light of the Symbolic Self-Completion Theory. (shrink)

In the progress of globalisation, the human being is exposed to effects of cultural dominance. For the individual, this exposure can be the stronger, the more autonomous his or her culture of origin used to be before the confrontation. Global consent with regard to behaviour patterns and cogni¬tive styles leads to the obliteration of traditional knowledge and behaviour upon which identity has been defined. The loss of identity in favour of belonging to the global society brings about a number of (...) problems, which can be demonstrated in functional models. These models, in turn, may sup¬port the planning of interventional strategies and rescue work. (shrink)

We set out longtermist political philosophy as a research field by exploring the case for, and the implications of, ‘institutional longtermism’: the view that, when evaluating institutions, we should give significant weight to their very long-term effects. We begin by arguing that the standard case for longtermism may be more robust when applied to institutions than to individual actions or policies, both because institutions have large, broad, and long-term effects, and because institutional longtermism can plausibly sidestep various objections to individual (...) longtermism. We then address points of contact between longtermism and some central values of mainstream political philosophy, focusing on justice, equality, freedom, legitimacy, and democracy. While each value initially seems to conflict with institutional longtermism, we find that these conflicts are less clear-cut upon closer inspection, and that some political values might even provide independent support for institutional longtermism. We end with a grab bag of related questions that we lack space to explore here. (shrink)

Mit einer virtuellen Welt kann sehr Verschiedenes und Mannigfaltiges assoziiert werden, unter anderem ein weiterer schillernder Begriff: Die Utopie. Sind nun virtuelle Welten allesamt Utopien? Oder müsste man vielmehr umgekehrt die Utopie als eine besondere virtuelle Welt hervorheben? Dass es überhaupt einen engen Zusammenhang zwischen den beiden Begriffen gibt, scheint nicht einmal selbstverständlich: Es gibt ihn sicherlich nicht, wenn man unter einer virtuellen Welt lediglich ein mit Hilfe von Computertechnik generiertes Szenario und unter einer Utopie schlicht und einfach eine der (...) Wirklichkeit unangemessene Wunschvorstellung versteht oder aber die Utopie als die literarische Konzeption einer für ideal befundenen Gesellschaftsform begreift und ideengeschichtlich demgemäß mit Platons „Staat“ beginnen lässt. Damit das begriffliche Verhältnis zwischen den heute durchaus auch im allgemeinen Sprachgebrauch verwurzelten Ausdrücken „Utopie“ und „Virtualität“ untersucht werden kann, soll der Versuch unternommen werden, anschaulich zu machen, wie sie verwendet werden könnten. (shrink)

Aesthetics is fundamentally a theory of sensible experience. Its scope has expanded greatly from an initial centering on the arts and scenic nature to the full range of appreciative experience. Expanding the range of aesthetics raises challenging questions about the experience of appreciation. Traditional accounts are inadequate in their attempt to identify and illuminate the perceptual experiences that these new applications evoke. Considering the range of environmental and everyday occasions aesthetically changes aesthetics into a descriptive and not necessarily celebratory study (...) of sensible experience, for it must now accommodate a complete range of negative as well as positive values. Th is paper develops an analysis of the multiple dimensions of environmental sensibility. (shrink)

The underdetermination of theory by data obtains when, inescapably, evidence is insufficient to allow scientists to decide responsibly between rival theories. One response to would-be underdetermination is to deny that the rival theories are distinct theories at all, insisting instead that they are just different formulations of the same underlying theory; we call this the identical rivals response. An argument adapted from John Norton suggests that the response is presumptively always appropriate, while another from Larry Laudan and Jarrett Leplin suggests (...) that the response is never appropriate. Arguments from Einstein for the special and general theories of relativity may fruitfully be seen as instances of the identical rivals response; since Einstein’s arguments are generally accepted, the response is at least sometimes appropriate. But when is it appropriate? We attempt to steer a middle course between Norton’s view and that of Laudan and Leplin: the identical rivals response is appropriate when there is good reason for adopting a parsimonious ontology. Although in simple cases the identical rivals response need not involve any ontological difference between the theories, in actual scientific cases it typically requires treating apparent posits of the various theories as mere verbal ornaments or computational conveniences. Since these would-be posits are not now detectable, there is no perfectly reliable way to decide whether we should eliminate them or not. As such, there is no rule for deciding whether the identical rivals response is appropriate or not. Nevertheless, there are considerations that suggest for and against the response; we conclude by suggesting two of them. (shrink)

Strawson's view on punishment has been either neglected or recoiled from in contemporary scholarship on ‘Freedom and Resentment’ (FR). Strawson's alleged retributivism has made his view suspect and troublesome. In this article, we first argue, against the mainstream, that the punishment passage is an indispensable part of the main argument in FR (section 1) and elucidate in what sense Strawson can be called ‘a retributivist’ (section 2). We then elaborate our own hypothesis of symbolic retribution to explain the continuum between (...) moral reactive attitudes and punishment that Strawson only adumbrates (section 3). After this justification of the punitive response to wrongdoing, we compare and contrast our specific kind of retributivist hypothesis with other positions in the so-called ‘new retributivism’ (section 4). Our hypothesis differs from other subvarieties of expressive retributivism in putting centre stage the idea of punishment as taking up a reverential stance towards the victim. (shrink)

Most people will agree that if my brain were made to have within it precisely the same pattern of activity that is in it now but through artificial means, as in its being fed all its stimulation through electrodes as it sits in a vat, an experience would result for me that would be subjectively indistinguishable from that I am now having. In ‘The Story of a Brain’ I ask whether the same subjective experience would be maintained in variations like (...) these: The hemispheres are in different vats but interacting with each other through radio transmission. Smaller chunks - and eventually the individual neurons - are interacting in this way. The hemispheres or the smaller chunks undergo internally the same pattern of activity but without interacting with each other. (shrink)

Definitions I presented in a previous article as part of a semantic approach in epistemology assumed that the concept of derivability from standard logic held across all mathematical and scientific disciplines. The present article argues that this assumption is not true for quantum mechanics (QM) by showing that concepts of validity applicable to proofs in mathematics and in classical mechanics are inapplicable to proofs in QM. Because semantic epistemology must include this important theory, revision is necessary. The one I propose (...) also extends semantic epistemology beyond the ‘hard’ sciences. The article ends by presenting and then refuting some responses QM theorists might make to my arguments. (shrink)

Repentance is central to the message of Christianity. Yet, repentance has received little analysis in recent scholarship despite being emphasized by the church fathers. In particular, there has been minimal effort to understand the necessity of repentance in light of Christ’s atoning work. With this as the background, I explore fundamental questions such as repentance’s definition, scope, and role in salvation history. Furthermore, I attempt to more precisely outline repentance’s role in Christ’s salvific work. Underpinning the project is my view (...) that repentance should be understood as metanoia or transformation. This transformation of repentance is ordered toward divine metanoia – participation in Christ. In developing repentance, I put forward a synthesis of Thomas Aquinas’s framework of penance and John McLeod Campbell’s account of Christ’s vicarious repentance. Through this synthesis, I attempt to make sense of the relationship between repentance and atonement. I finish by suggesting that it would be appropriate to conclude that Thomas would endorse a vicarious repentance account of the atonement and hint at how it might fit into broader soteriologies. (shrink)

This paper proposes a radical re-examination of the foundations of modern aesthetics. It urges that we replace the tradition of eighteenth century aesthetics, with its insistence on disinterestedness and the separateness of the aesthetic, and its problematic oppositions, such as the separation of sense from cognition. In their place it appeals to a more process-oriented, pluralistic account, one that takes note of varying cultural traditions in aesthetics, that recognizes the aesthetic as a complex of many forces and factors, and that (...) considers the aesthetic as part of a complexity of values, including moral, practical, social, and political ones. It urges, further, an aesthetic-based criticism, not only of the arts, but of culture and knowledge. Central to this account is the idea of aesthetic engagement, which not only recognizes and extends the many connections of and in aesthetic experience, but invites our total involvement as active participants. (shrink)