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)

Gila Sher interviewed by Chen Bo: -/- I. Academic Background and Earlier Research: 1. Sher’s early years. 2. Intellectual influence: Kant, Quine, and Tarski. 3. Origin and main Ideas of The Bounds of Logic. 4. Branching quantifiers and IF logic. 5. Preparation for the next step. -/- II. Foundational Holism and a Post-Quinean Model of Knowledge: 1. General characterization of foundational holism. 2. Circularity, infinite regress, and philosophical arguments. 3. Comparing foundational holism and foundherentism. 4. A post-Quinean model of (...) knowledge. 5. Intellect and figuring out. 6. Comparing foundational holism with Quine’s holism. 7. Evaluation of Quine’s Philosophy -/- III. Substantive Theory of Truth and Relevant Issues: 1. Outline of Sher’s substantive theory of truth. 2. Criticism of deflationism and treatment of the Liar. 3. Comparing Sher’s substantive theory of truth with Tarski’s theory of truth. -/- IV. A New Philosophy of Logic and Comparison with Other Theories: 1. Foundational account of logic. 2. Standard of logicality, set theory and logic. 3. Psychologism, Hanna’s and Maddy’s conceptions of logic. 4. Quine’s theses about the revisability of logic. -/- V. Epilogue. (shrink)

Harry Frankfurt had insightfully pointed out that an agent acts freely when he acts in accord with the mental states with which he identifies. The concept of identification rightly captures the ownership condition (something being one’s really own), which plays a significant role in the issues of freedom and moral responsibility. For Frankfurt, identification consists of one’s forming second-order volitions, endorsing first-order desires, and issuing in his actions wholeheartedly. An agent not only wants to φ but also fully embraces his (...) desire to φ (and φ). Frankfurt’s official theory above encounters some serious problems, especially since it is believed that his concept of wholehearted identification is too strong to be necessary for freedom. In this paper, I propose that we can uncouple identification from wholeheartedness and thus get two different senses of identification: weak identification and strong identification. Then, I argue that this distinction does a better job than Frankfurt’s official theory. On the one hand, weak identification is enough for ownership and freedom and thus more promising than strong identification; on the other hand, this distinction has an attractive implication that it fits well with our intuition about the degree of freedom and responsibility. (shrink)

This paper examines the relationship of ethical decision-making by individuals to corporate business ethics and organizational performance of three groups: SMEs, Outstanding SMEs and Large Enterprises, in order to provide a reference for Taiwanese entrepreneurs to practice better business ethics. The survey method involved random sampling of 132 enterprises within three groups. Some 524 out of 1320 questionnaires were valid. The survey results demonstrated that ethical decision-making by individuals, corporate business ethics and organizational performance are highly related. In summary, then, (...) high levels of organizational performance were directly attributable to high levels of applied corporate and individual ethics. Furthermore, there is a demonstrable tendency for Outstanding SMEs to reject ethically unsound practices such as padded expense accounts, tax evasion and misleading advertising. The measurement criteria used to assess organizational performance, however, did not include an objective evaluation of financial performance. (shrink)

Item response theory (IRT) is a modern psychometric framework for estimating respondents’ latent traits (e.g., ability, attitude, and personality) based on their responses to a set of questions in psychological tests. The current study adopted an item response tree (IRTree) method, which combines the tree model with IRT models for handling the sequential process of responding to a test item, to score individual moral inclination for the CNI test—a broadly adopted model for examining humans’ moral decision-making with three parameters generated: (...) sensitivity to moral norms, sensitivity to consequences, and inaction preference. Compared to previous models for the CNI test, the resulting EIRTree-CNI Model is able to generate individual scores without increasing the number of items (thus, less subject fatigue or compromised response quality) or employing a post hoc approach that is deemed statistically suboptimal. The model fits the data well, and the subsequent test also supported the concurrent validity and the predictive validity of the model. Limitations are discussed further. (shrink)

In the contemporary epistemological literature, peer disagreement is often taken to be an instance of a more general phenomenon of “higher-order evidence.” Correspondingly, its epistemic significance is often thought to turn on the epistemic significance of higher-order evidence in general. This chapter attempts to evaluate this claim, and in doing so to clarify some points of unclarity in the current literature – both about what it is for evidence to be “higher-order,” and about the relationship between disagreement and higher-order evidence. (...) We will begin by considering some candidate definitions of “higher-order evidence,” and offering our own definition that attempts to capture the phenomenon of interest. We will then consider, in light of this definition, whether disagreement and its epistemic significance are best-understood as a kind of higher-order evidence. We’ll argue that although peer disagreement can be epistemically significant qua higher-order evidence, this role doesn’t exhaust its significance, and that it can also serve as straightforward first-order evidence. Finally, we’ll suggest that inattention to this latter point has made broadly conciliatory views about peer disagreement seem somewhat easier to resist than they in fact are. (shrink)

Wang Yangming’s discussions concerning evil mainly appear in two sets of texts, i.e., Chuanxilu 传习录 (Instructions for Practical Living) and gongyi 公移 (documents transferred to vertically unrelated departments). The former addresses evil in metaphysical terms, and the latter in social terms. These subtly different approaches show the nuance between self-cultivation and governance of others.

This correlational study investigated the relationship between preservice teachers’ math self-concept, self-efficacy, and attitude with their math achievement. Participants were chosen using stratified random sampling from BEEd and BSEd mathematics majors (n = 117). From the findings, preservice teachers had moderate to high math self-concept, self-efficacy, and attitude. These variables were statistically correlated with each other and with math achievement. The inclusion of training programs for developing the preservice teachers’ math self-concept, self-efficacy, and attitude, as well as designing curricula that (...) engage and encourage them to do mathematics and problem-solving, must be considered among teacher education institutions. (shrink)

This article explores the profound impact of Artificial Intelligence (AI) on the realm of religion, exploring the potential for AI to catalyze the birth of new world religions and break the "Solomon's Cycle." Drawing inspiration from King Solomon's timeless declaration, "There is nothing new under the sun," the article examines the challenges faced by new religions in a world dominated by established faiths and traditions. By leveraging the transformative capabilities of AI to inspire creativity, foster cross-cultural dialogue, provide ethical guidance, (...) build virtual communities, and personalize spiritual experiences, individuals are empowered to transcend historical barriers and forge new paths of spiritual exploration. The fusion of AI and human ingenuity holds the promise of birthing diverse, inclusive, and dynamic belief systems that resonate with the complexities of our contemporary world. (shrink)

This article delves into the concept of "Egocloism," a term that amalgamates an inflated sense of self-importance ("ego") with a disposition towards isolation and resistance to external influences ("cloister"). It explores how this mindset manifests not only in individuals but also at the communal level, leading to insularity and a reluctance to embrace diversity and progress. Drawing inspiration from Anton Chekhov's narrative of "The Man in a Case," the article introduces the metaphor of "The Race in a Case" to critique (...) communities entrenched in their historical narratives and cultural identities to the detriment of inclusivity and growth. Through historical examples such as the Spanish Inquisition, the Tokugawa Shogunate’s Sakoku Policy, the Ottoman Empire’s late reforms, and the fall of the Qing Dynasty, the article illustrates the adverse effects of Egocloism. It concludes with strategies for individuals and communities to overcome this mindset, advocating for a shift towards an open horizon that embraces diversity, inclusivity, and global interconnectedness. (shrink)

Compatibilism claims that a person is a free agent when no external circumstances prevent an action; internal factors such as unconscious thoughts and conditioned responses do not prevent free agency. Contemporary psychology and neuroscience reveal, however, that complex internal factors are involved in our decision-making process and invite new criticisms of compatibilism. I introduce the dual-system theory and implicit bias and discuss the case of mental illness as a disability to decision making. I argue that compatibilist accounts of free will (...) ascribe free will to agents who should not be considered free agents. (shrink)

In a quantum universe with a strong arrow of time, we postulate a low-entropy boundary condition to account for the temporal asymmetry. In this paper, I show that the Past Hypothesis also contains enough information to simplify the quantum ontology and define a unique initial condition in such a world. First, I introduce Density Matrix Realism, the thesis that the quantum universe is described by a fundamental density matrix that represents something objective. This stands in sharp contrast to Wave Function (...) Realism, the thesis that the quantum universe is described by a wave function that represents something objective. Second, I suggest that the Past Hypothesis is sufficient to determine a unique and simple density matrix. This is achieved by what I call the Initial Projection Hypothesis: the initial density matrix of the universe is the normalized projection onto the special low-dimensional Hilbert space. Third, because the initial quantum state is unique and simple, we have a strong case for the \emph{Nomological Thesis}: the initial quantum state of the universe is on a par with laws of nature. This new package of ideas has several interesting implications, including on the harmony between statistical mechanics and quantum mechanics, the dynamic unity of the universe and the subsystems, and the alleged conflict between Humean supervenience and quantum entanglement. (shrink)

A century after the discovery of quantum mechanics, the meaning of quantum mechanics still remains elusive. This is largely due to the puzzling nature of the wave function, the central object in quantum mechanics. If we are realists about quantum mechanics, how should we understand the wave function? What does it represent? What is its physical meaning? Answering these questions would improve our understanding of what it means to be a realist about quantum mechanics. In this survey article, I review (...) and compare several realist interpretations of the wave function. They fall into three categories: ontological interpretations, nomological interpretations, and the sui generis interpretation. For simplicity, I will focus on non-relativistic quantum mechanics. (shrink)

If there are fundamental laws of nature, can they fail to be exact? In this paper, I consider the possibility that some fundamental laws are vague. I call this phenomenon 'fundamental nomic vagueness.' I characterize fundamental nomic vagueness as the existence of borderline lawful worlds and the presence of several other accompanying features. Under certain assumptions, such vagueness prevents the fundamental physical theory from being completely expressible in the mathematical language. Moreover, I suggest that such vagueness can be regarded as (...) 'vagueness in the world.' For a case study, we turn to the Past Hypothesis, a postulate that (partially) explains the direction of time in our world. We have reasons to take it seriously as a candidate fundamental law of nature. Yet it is vague: it admits borderline (nomologically) possible worlds. An exact version would lead to an untraceable arbitrariness absent in any other fundamental laws. However, the dilemma between fundamental nomic vagueness and untraceable arbitrariness is dissolved in a new quantum theory of time's arrow. (shrink)

The view of embodied cognition believes that cognition is embodied in nature, only the dynamics involved in the interaction between cognitive activities and the nervous system, body and environment, only by closely linking the correct evaluation of time-dependent and relationship, then only can make a correct understanding of cognitive activities. The core concepts of body and environment involved in embodied cognition are different from the body and environment in the usual sense. In terms of research methods, dynamic research methods that (...) are different from traditional computer simulations are also adopted. The article first integrates and analyzes the basic position and general propositions in the discipline, then the embodied cognition are explained based on author's understanding. In addition, the suitability of dynamic research methods, its advantages and disadvantages is analyzed, and finally, a brief summary of the current status of embodied cognition research. (shrink)

The Great Divide in metaphysical debates about laws of nature is between Humeans, who think that laws merely describe the distribution of matter, and non-Humeans, who think that laws govern it. The metaphysics can place demands on the proper formulations of physical theories. It is sometimes assumed that the governing view requires a fundamental / intrinsic direction of time: to govern, laws must be dynamical, producing later states of the world from earlier ones, in accord with the fundamental direction of (...) time in the universe. In this paper, we propose a minimal primitivism about laws of nature (MinP) according to which there is no such requirement. On our view, laws govern by constraining the physical possibilities. Our view captures the essence of the governing view without taking on extraneous commitments about the direction of time or dynamic production. Moreover, as a version of primitivism, our view requires no reduction / analysis of laws in terms of universals, powers, or dispositions. Our view accommodates several potential candidates for fundamental laws, including the principle of least action, the Past Hypothesis, the Einstein equation of general relativity, and even controversial examples found in the Wheeler-Feynman theory of electrodynamics and retrocausal theories of quantum mechanics. By understanding governing as constraining, non-Humeans who accept MinP have the same freedom to contemplate a wide variety of candidate fundamental laws as Humeans do. (shrink)

If an asymmetry in time does not arise from the fundamental dynamical laws of physics, it may be found in special boundary conditions. The argument normally goes that since thermodynamic entropy in the past is lower than in the future according to the Second Law of Thermodynamics, then tracing this back to the time around the Big Bang means the universe must have started off in a state of very low thermodynamic entropy: the Thermodynamic Past Hypothesis. In this paper, we (...) consider another boundary condition that plays a similar role, but for the decoherent arrow of time, i.e. the subsystems of the universe are more mixed in the future than in the past. According to what we call the Entanglement Past Hypothesis, the initial quantum state of the universe had very low entanglement entropy. We clarify the content of the Entanglement Past Hypothesis, compare it with the Thermodynamic Past Hypothesis, and identify some challenges and open questions for future research. (shrink)

The mathematical structure of realist quantum theories has given rise to a debate about how our ordinary 3-dimensional space is related to the 3N-dimensional configuration space on which the wave function is defined. Which of the two spaces is our (more) fundamental physical space? I review the debate between 3N-Fundamentalists and 3D-Fundamentalists and evaluate it based on three criteria. I argue that when we consider which view leads to a deeper understanding of the physical world, especially given the deeper topological (...) explanation from the unordered configurations to the Symmetrization Postulate, we have strong reasons in favor of 3D-Fundamentalism. I conclude that our evidence favors the view that our fundamental physical space in a quantum world is 3-dimensional rather than 3N-dimensional. I outline lines of future research where the evidential balance can be restored or reversed. Finally, I draw lessons from this case study to the debate about theoretical equivalence. (shrink)

If the Past Hypothesis underlies the arrows of time, what is the status of the Past Hypothesis? In this paper, I examine the role of the Past Hypothesis in the Boltzmannian account and defend the view that the Past Hypothesis is a candidate fundamental law of nature. Such a view is known to be compatible with Humeanism about laws, but as I argue it is also supported by a minimal non-Humean "governing'' view. Some worries arise from the non-dynamical and time-dependent (...) character of the Past Hypothesis as a boundary condition, the intrinsic vagueness in its specification, and the nature of the initial probability distribution. I show that these worries do not have much force, and in any case they become less relevant in a new quantum framework for analyzing time's arrows---the Wentaculus. Hence, the view that the Past Hypothesis is a candidate fundamental law should be more widely accepted than it is now. (shrink)

In a quantum universe with a strong arrow of time, it is standard to postulate that the initial wave function started in a particular macrostate---the special low-entropy macrostate selected by the Past Hypothesis. Moreover, there is an additional postulate about statistical mechanical probabilities according to which the initial wave function is a ''typical'' choice in the macrostate. Together, they support a probabilistic version of the Second Law of Thermodynamics: typical initial wave functions will increase in entropy. Hence, there are two (...) sources of randomness in such a universe: the quantum-mechanical probabilities of the Born rule and the statistical mechanical probabilities of the Statistical Postulate. I propose a new way to understand time's arrow in a quantum universe. It is based on what I call the Thermodynamic Theories of Quantum Mechanics. According to this perspective, there is a natural choice for the initial quantum state of the universe, which is given by not a wave function but by a density matrix. The density matrix plays a microscopic role: it appears in the fundamental dynamical equations of those theories. The density matrix also plays a macroscopic / thermodynamic role: it is exactly the projection operator onto the Past Hypothesis subspace. Thus, given an initial subspace, we obtain a unique choice of the initial density matrix. I call this property "the conditional uniqueness" of the initial quantum state. The conditional uniqueness provides a new and general strategy to eliminate statistical mechanical probabilities in the fundamental physical theories, by which we can reduce the two sources of randomness to only the quantum mechanical one. I also explore the idea of an absolutely unique initial quantum state, in a way that might realize Penrose's idea of a strongly deterministic universe. (shrink)

A strongly deterministic theory of physics is one that permits exactly one possible history of the universe. In the words of Penrose (1989), "it is not just a matter of the future being determined by the past; the entire history of the universe is fixed, according to some precise mathematical scheme, for all time.” Such an extraordinary feature may appear unattainable in a world like ours. In this paper, I show that it can be achieved in a simple way and (...) discuss its implications for metaphysics and philosophy of science, including natural properties, free will, explanation, and modality. First, I propose a precise definition of strong determinism. Next, I discuss its philosophical ramifications and a toy example. Finally, I provide a realistic example of a strongly deterministic (and simple) physical theory---the Everettian Wentaculus. A surprising consequence is that whether or not our world is strongly deterministic may be empirically underdetermined. (shrink)

Although expected utility theory has proven a fruitful and elegant theory in the finite realm, attempts to generalize it to infinite values have resulted in many paradoxes. In this paper, we argue that the use of John Conway's surreal numbers shall provide a firm mathematical foundation for transfinite decision theory. To that end, we prove a surreal representation theorem and show that our surreal decision theory respects dominance reasoning even in the case of infinite values. We then bring our theory (...) to bear on one of the more venerable decision problems in the literature: Pascal's Wager. Analyzing the wager showcases our theory's virtues and advantages. To that end, we analyze two objections against the wager: Mixed Strategies and Many Gods. After formulating the two objections in the framework of surreal utilities and probabilities, our theory correctly predicts that (1) the pure Pascalian strategy beats all mixed strategies, and (2) what one should do in a Pascalian decision problem depends on what one's credence function is like. Our analysis therefore suggests that although Pascal's Wager is mathematically coherent, it does not deliver what it purports to, a rationally compelling argument that people should lead a religious life regardless of how confident they are in theism and its alternatives. (shrink)

What is the quantum state of the universe? Although there have been several interesting suggestions, the question remains open. In this paper, I consider a natural choice for the universal quantum state arising from the Past Hypothesis, a boundary condition that accounts for the time-asymmetry of the universe. The natural choice is given not by a wave function but by a density matrix. I begin by classifying quantum theories into two types: theories with a fundamental wave function and theories with (...) a fundamental density matrix. The Past Hypothesis is compatible with infinitely many initial wave functions, none of which seems to be particularly natural. However, once we turn to density matrices, the Past Hypothesis provides a natural choice---the normalized projection onto the Past Hypothesis subspace in the Hilbert space. Nevertheless, the two types of theories can be empirically equivalent. To provide a concrete understanding of the empirical equivalence, I provide a novel subsystem analysis in the context of Bohmian theories. Given the empirical equivalence, it seems empirically underdetermined whether the universe is in a pure state or a mixed state. Finally, I discuss some theoretical payoffs of the density-matrix theories and present some open problems for future research. (Bibliographic note: the thesis was submitted for the Master of Science in mathematics at Rutgers University.). (shrink)

Two of the most difficult problems in the foundations of physics are (1) what gives rise to the arrow of time and (2) what the ontology of quantum mechanics is. I propose a unified 'Humean' solution to the two problems. Humeanism allows us to incorporate the Past Hypothesis and the Statistical Postulate into the best system, which we then use to simplify the quantum state of the universe. This enables us to confer the nomological status to the quantum state in (...) a way that adds no significant complexity to the best system and solves the ''supervenient-kind problem'' facing the original version of the Past Hypothesis. We call the resultant theory the Humean unification. It provides a unified explanation of time asymmetry and quantum entanglement. On this theory, what gives rise to time's arrow is also responsible for quantum phenomena. The new theory has a separable mosaic, a best system that is simple and non-vague, less tension between quantum mechanics and special relativity, and a higher degree of theoretical and dynamical unity. The Humean unification leads to new insights that can be useful to Humeans and non-Humeans alike. (shrink)

The present study aims to examine the relationship between the cortical midline structures (CMS), which have been regarded to be associated with selfhood, and moral decision making processes at the neural level. Traditional moral psychological studies have suggested the role of moral self as the moderator of moral cognition, so activity of moral self would present at the neural level. The present study examined the interaction between the CMS and other moral-related regions by conducting psycho-physiological interaction analysis of functional images (...) acquired while 16 subjects were solving moral dilemmas. Furthermore, we performed Granger causality analysis to demonstrate the direction of influences between activities in the regions in moral decision-making. We first demonstrate there are significant positive interactions between two central CMS seed regions—i.e., the medial prefrontal cortex (MPFC) and posterior cingulate cortex (PCC)—and brain regions associated with moral functioning including the cerebellum, brainstem, midbrain, dorsolateral prefrontal cortex, orbitofrontal cortex and anterior insula (AI); on the other hand, the posterior insula (PI) showed significant negative interaction with the seed regions. Second, several significant Granger causality was found from CMS to insula regions particularly under the moral-personal condition. Furthermore, significant dominant influence from the AI to PI was reported. Moral psychological implications of these findings are discussed. The present study demonstrated the significant interaction and influence between the CMS and morality-related regions while subject were solving moral dilemmas. Given that, activity in the CMS is significantly involved in human moral functioning. (shrink)

In this short survey article, I discuss Bell’s theorem and some strategies that attempt to avoid the conclusion of non-locality. I focus on two that intersect with the philosophy of probability: (1) quantum probabilities and (2) superdeterminism. The issues they raised not only apply to a wide class of no-go theorems about quantum mechanics but are also of general philosophical interest.

Physical laws are strikingly simple, although there is no a priori reason they must be so. I propose that nomic realists of all types (Humeans and non-Humeans) should accept that simplicity is a fundamental epistemic guide for discovering and evaluating candidate physical laws. The proposal addresses several problems of nomic realism and simplicity. A consequence is that the oft-cited epistemic advantage of Humeanism over non-Humeanism disappears, undercutting an influential epistemological argument for Humeanism. Moreover, simplicity is shown to be more tightly (...) connected to lawhood than to mere truth. (shrink)

This paper is about the epistemology of quantum theory. We establish a new result about a limitation to knowledge of its central object---the quantum state of the universe. We show that, if the universal quantum state can be assumed to be a typical unit vector from a high-dimensional subspace of Hilbert space (such as the subspace defined by a low-entropy macro-state as prescribed by the Past Hypothesis), then no observation can determine (or even just narrow down significantly) which vector it (...) is. Typical state vectors, in other words, are observationally indistinguishable from each other. Our argument is based on a typicality theorem from quantum statistical mechanics. We also discuss how theoretical considerations that go beyond the empirical evidence might bear on this fact and on our knowledge of the universal quantum state. (shrink)

We consider two ways one might use algorithmic randomness to characterize a probabilistic law. The first is a generative chance* law. Such laws involve a nonstandard notion of chance. The second is a probabilistic* constraining law. Such laws impose relative frequency and randomness constraints that every physically possible world must satisfy. While each notion has virtues, we argue that the latter has advantages over the former. It supports a unified governing account of non-Humean laws and provides independently motivated solutions to (...) issues in the Humean best-system account. On both notions, we have a much tighter connection between probabilistic laws and their corresponding sets of possible worlds. Certain histories permitted by traditional probabilistic laws are ruled out as physically impossible. As a result, such laws avoid one variety of empirical underdetermination, but the approach reveals other varieties of underdetermination that are typically overlooked. (shrink)

The Purpose of this study was to investigate the effect of cloud mobile learning and creative environment on college student’s creativity performance. A nonequivalent pretest-posttest quasi-experimental design was used in this research. The objects were two freshman classes selected from a public university and randomly assigned to the experimental group and the control group. A learning activity named Amphibious Mechanical Beast was conducted in this teaching experiment. The experimental was taught using cloud mobile learning, while the control group was taught (...) using the traditional (usual) way. Participant student’s design performances before and after the experiment were evaluated. Creative Environment Scale was used to collect data of student’s perception of creative environment. Additionally, an open ended questionnaire was used to realize student’s learning processes. The one-way analysis of covariance (ANCOVA) and the two-way analysis of covariance were performed in this research. After data coding, relative concepts, themes, and theories were integrated and developed. Finally, the findings were proposed according to result of qualitative data analysis. Those main results of this research were: 1.Cloud mobile learning had a positive effect on student’s creative process. Most participant students thought cloud mobile device using convenient and prompt while learning. Cloud mobile learning improved student active participation, and was student-centered rather than teacher-centered. Participant student’s high order thinking abilities could be improved by receiving information and discussing anytime and anywhere. Those high order thinking included problem solving, critical thinking, and creative thinking. Nevertheless, minor participant students’ learning was influenced by past learning habits and insufficient devices. 2. Cloud mobile learning had positive effects on newness, elaborateness, and total aspect of creative products. 3. Perceptions of creative environment had positive effects on preparation stage and reaction stage of creative process. 4. Perceptions of creative environment which were above a certain level had positive effects on creative products. 5. Cloud mobile learning had positive effects on preparation stage of students’ creative process who had lower perceptions of creative environment. 6. Cloud mobile learning had positive effects on value of students’ creative products who had lower perceptions of creative environment. 7. Cloud mobile learning had positive effects on total aspect of students’ creative products who had higher perceptions of creative environment. Finally, recommendations and suggestions were addressed for implementation of cloud mobile learning and future studies based on results of this research. (shrink)

To reject skepticism and lay the foundation for the certainty of knowledge, Kant raised the question of how synthetic a priori proposition is possible. In his solution, the new content of knowledge comes from the syntheses of experience a posteriori, and the universal necessity of knowledge is guaranteed by it’s a priority. Under the influence of Kant, the concept of a priori and necessity has long been regarded as coextensive. But Saul Kripke believes that this will confuse different philosophical fields: (...) a priori is an epistemological concept, which involves the way or means of acquiring knowledge, and necessity is a metaphysical concept, which involves the possible ways or states of the world. The key point is that, on Kripke, there is no necessary connection between these two fields. He raised some famous examples of the necessary a posteriori. More remarkably, in his explanation of necessary a posteriori, although he did not clearly propose the distinction between epistemic possibility and metaphysical possibility, he had laid the foundation for this distinction. Furthermore, on Manuel Garcia-Carpintero and Josep Macia, when Kripke talks about necessary a posteriori by appealing to two relevant expressions, what he proposed can be taken as kind of ‘blueprint for 2-D accounts’. (Manuel Garcia-Carpintero and Josep Macia, 2006, p.2) There are different forms of two-dimensionalism in semantics. I will focus on David Chalmers’s epistemic version and Scott Soames’ criticism. With the framework of possible world semantics established by Kripke and others, David Chalmers’ epistemic two-dimensionalism deals with the relationship between epistemic and metaphysical modalities from a quite different perspective, and then gives an elegant definition to necessary a posteriori and other modal concepts. Scott Soames criticized two-dimensionalism based on Kripke's modal realism and essentialism, and developed Kripke's account of necessary a posteriori. But according to Chalmers, Soames also uses a two-dimensional system himself to analyze cases of the necessary a posteriori. In the first two part of this paper I will briefly introduce the epistemic two-dimensionalism and specify the similarities between Kripke-Soames and Chalmers when they interpret necessary a posteriori. In the third part I turn to their difference by the analysis of relationship between epistemic possibility and metaphysical possibility which is the key issue for illuminating necessary a posteriori. (shrink)

In this paper, I introduce an intrinsic account of the quantum state. This account contains three desirable features that the standard platonistic account lacks: (1) it does not refer to any abstract mathematical objects such as complex numbers, (2) it is independent of the usual arbitrary conventions in the wave function representation, and (3) it explains why the quantum state has its amplitude and phase degrees of freedom. -/- Consequently, this account extends Hartry Field’s program outlined in Science Without Numbers (...) (1980), responds to David Malament’s long-standing impossibility conjecture (1982), and establishes an important first step towards a genuinely intrinsic and nominalistic account of quantum mechanics. I will also compare the present account to Mark Balaguer’s (1996) nominalization of quantum mechanics and discuss how it might bear on the debate about “wave function realism.” In closing, I will suggest some possible ways to extend this account to accommodate spinorial degrees of freedom and a variable number of particles (e.g. for particle creation and annihilation). -/- Along the way, I axiomatize the quantum phase structure as what I shall call a “periodic difference structure” and prove a representation theorem as well as a uniqueness theorem. These formal results could prove fruitful for further investigation into the metaphysics of phase and theoretical structure. -/- (For a more recent version of this paper, please see "The Intrinsic Structure of Quantum Mechanics" available on PhilPapers.). (shrink)

One of the most difficult problems in the foundations of physics is what gives rise to the arrow of time. Since the fundamental dynamical laws of physics are (essentially) symmetric in time, the explanation for time's arrow must come from elsewhere. A promising explanation introduces a special cosmological initial condition, now called the Past Hypothesis: the universe started in a low-entropy state. Unfortunately, in a universe where there are many copies of us (in the distant ''past'' or the distant ''future''), (...) the Past Hypothesis is not enough; we also need to postulate self-locating (de se) probabilities. However, I show that we can similarly use self-locating probabilities to strengthen its rival---the Fluctuation Hypothesis, leading to in-principle empirical underdetermination and radical epistemological skepticism. The underdetermination is robust in the sense that it is not resolved by the usual appeal to 'empirical coherence' or 'simplicity.' That is a serious problem for the vision of providing a completely scientific explanation of time's arrow. (shrink)

Contextualist accounts of “woman,” including Saul (2012), Diaz-Leon (2016), and Ichikawa (2020), aim to capture the variability of the meaning of the term, and do justice to the rights of trans women. I argue that (i) there is an internal tension between a contextualist stance and the commitment to trans-inclusive language, and that (ii) we should recognize and tackle the broader and deeper theoretical and practical difficulties implicit in the semantic debates, rather than collapsing them all into semantics. Moving on, (...) I sketch three strategies to help us advance feminist philosophical endeavors, including how attending to contextual matters can lead us to further reflect on the meta-contextual, such as our role in shaping contexts and whether the working of language is indicative of a larger oppressive social structure. (shrink)

Mystical religious experiences typically purport to engage with the transcendent and often claim to involve encounters with spiritual entities or a detachment from the material world. Daoism diverges from this paradigm. This paper examines Daoist mystical experiences of bodily transformations and explores their epistemological implications. Specifically, we defend the justificatory power of Daoist somatic experiences against the disanalogy objection. The disanalogy objection posits that mystical experiences, in contrast to sense perceptions, are not socially verifiable and thereby lack prima facie epistemic (...) value. We argue that some Daoist mystical bodily states, being essentially spatiotemporal, are exempt from this challenge. This leads to a broader understanding of mysticism and offers a partial resolution to the disanalogy objection. (shrink)

What exists at the fundamental level of reality? On the standard picture, the fundamental reality contains (among other things) fundamental matter, such as particles, fields, or even the quantum state. Non-fundamental facts are explained by facts about fundamental matter, at least in part. In this paper, I introduce a non-standard picture called the "cosmic void” in which the universe is devoid of any fundamental material ontology. Facts about tables and chairs are recovered from a special kind of laws that satisfy (...) strong determinism. All non-fundamental facts are completely explained by nomic facts. I discuss a concrete example of this picture in a strongly deterministic version of the many-worlds theory of quantum mechanics. I discuss some philosophical and scientific challenges to this view, as well as some connections to ontological nihilism. (shrink)

Mystical experiences are often regarded as potential sources of epistemic justification for religious beliefs. However, the ‘disanalogy objection’ maintains that, in contrast to sense perceptions, mystical experiences lack social verifiability and are thus merely subjective states that cannot substantiate objective truths. This article explores a novel externalist response that involves the concept of angels. As spiritual beings, angels can directly perceive God and verify these perceptions in their celestial community. Thus, the ‘direct perception of God’ is not inherently incapable of (...) social verification. While invoking angels might appear contentious, it coheres with the externalist approach of conceptualising cognitive states under hypothetical settings. Despite the differences between humans and angels and their lack of interaction for verification purposes, our approach remains valid because mystics not only exemplify the same general type of ‘direct perception of God’ as angels but can also be preliminary members of a wider celestial community. (shrink)

Reluctance to adopt mask-wearing as a preventive measure is widely observed in many Western societies since the beginning of the COVID-19 pandemics. This reluctance toward mask adoption, like any other complex social phenomena, will have multiple causes. Plausible explanations have been identified, including political polarization, skepticism about media reports and the authority of public health agencies, and concerns over liberty, amongst others. In this paper, we propose potential explanations hitherto unnoticed, based on the framework of epistemic injustice. We show how (...) testimonial injustice and hermeneutical injustice may be at work to shape the reluctant mask adoption at both the societal and individual levels. We end by suggesting how overcoming these epistemic injustices can benefit the global community in this challenging situation and in the future. (shrink)

Since 2019, Northeastern post-industrial culture has been a popular topic of discussion; the general public refers to it as the Northeastern Renaissance. Crises of identity, honor, and faith have been recurring themes in several Northeastern films released in recent years. Furthermore, these cinematic narratives frequently generate somber humor by presenting an enormous contrast between ideals and actuality. The article examines how the post-industrial narrative context of Northeast China has influenced audio-visual cultural products and contemporary Chinese popular culture. To elucidate the (...) fundamental aspect of the Northeast narrative, the article’s author employs the absurd theory of Albert Camus. The main structure and viewpoints of the article are as follows: The first is after presenting individuals’ contemplations on the Northeastern Renaissance-instigated post-industrial narrative of the Northeast. In the following sections, the article explores the narrative context of post-industrial audio-visual works in Northeast China, focusing on the absurdity depicted in the documentary Tie Xi Qu: West of the Tracks (2002). The authors’ analysis reveals how the documentary captures the socio-economic decline and the resulting human experiences of absurdity and dislocation. Key findings indicate that the narrative structure and visual style effectively convey the bleak realities of post-industrial life, offering critical insights into the region’s socio-cultural transformation. These findings suggest that future research should explore the intersection of visual media and social change in other post-industrial contexts. -/- . (shrink)

One famous debate in contemporary epistemology considers whether there is always one unique, epistemically rational way to respond to a given body of evidence. Generally speaking, answering “yes” to this question makes one a proponent of the Uniqueness thesis, while those who answer “no” are called “permissivists”. Another influential recent debate concerns whether non-truth-related factors can be the basis of epistemic justification, knowledge, or rational belief. Traditional theories answer “no”, and are therefore considered “purists”. However, more recently many theorists have (...) argued to the contrary, claiming that impurist factors, such as practical stakes, can sometimes encroach or even override truth-related considerations. This paper bridges the two debates by presenting and defending what I call “Impurist Permissivism”. I support Impurist Permissivism by showing how it can resist Roger White’s famous Argument from Arbitrariness (2005). (shrink)

Realism about quantum theory naturally leads to realism about the quantum state of the universe. It leaves open whether it is a pure state represented by a wave function, or an impure (mixed) one represented by a density matrix. I characterize and elaborate on Density Matrix Realism, the thesis that the universal quantum state is objective but can be impure. To clarify the thesis, I compare it with Wave Function Realism, explain the conditions under which they are empirically equivalent, consider (...) two generalizations of Density Matrix Realism, and answer some frequently asked questions. I end by highlighting an implication for scientific realism. (shrink)

This paper presents a formalization of the classical proof of completeness in Henkin-style developed by Troelstra and van Dalen for intuitionistic logic with respect to Kripke models. The completeness proof incorporates their insights in a fresh and elegant manner that is better suited for mechanization. We discuss details of our implementation in the Lean theorem prover with emphasis on the prime extension lemma and construction of the canonical model. Our implementation is restricted to a system of intuitionistic propositional logic with (...) implication, conjunction, disjunction, and falsity given in terms of a Hilbert-style axiomatization. As far as we know, our implementation is the first verified Henkin-style proof of completeness for intuitionistic logic following Troelstra and van Dalen's method in the literature. (shrink)

We expect the laws of nature that describe the universe to be exact, but what if that isn't true? In this popular science article, I discuss the possibility that some candidate fundamental laws of nature, such as the Past Hypothesis, may be vague. This possibility is in conflict with the idea that the fundamental laws of nature can always and faithfully be described by classical mathematics. -/- [Bibliographic note: this article is featured on the magazine website under a different title (...) as "The fuzzy law that could break the idea of a mathematical universe" and on the magazine cover as "The Flaw at the Heart of Reality: Why precise mathematical laws can never fully explain the universe." It is a popular version of the article "Nomic Vagueness" that can be found on arXiv: 2006.05298.]. (shrink)

The experience of embarrassment was explored in two experiments comparing monolingual and bilingual speakers from cultures varying in the degree of elabo- ration of the embarrassment lexicon. In Experiment 1, narratives in English or Korean depicting three types of embarrassing predicaments were to be rated on their embarrassability and humorousness by Korean-English bilinguals, Korean monolinguals, and Euro-American monolinguals. All groups judged certain predicaments (involving social gaffes) to be the most embarrassing. However, significant group and language differences occurred in judgments of (...) the inten- sity of embarrassment and amusement judgments evoked. Euro-Americans ex- hibited higher overall levels of amusement than the two Korean groups who, in turn, reported higher levels of embarrassment, particularly for certain predica- ment types and contexts (ingroup members present). Further, for the bilinguals, inept performance predicaments in English were judged more embarrassing than those in Korean, whereas all predicament types were judged more amusing when framed with English emotion labels. Bilinguals also appeared to show a heightened embarrassability relative to both monolingual groups. Experiment 2 found lexical selection differences in open-ended responses to embarrassing predicaments depicted in each language, with Euro-Americans preferring to give justifications or use humor to minimize the embarrassment and Korean-English bilinguals preferring to give apologies or say nothing. The findings are interpret- ed to reflect the influence of culturally-mediated schemas guiding the activation and processing of emotion vocabulary. (shrink)

What is gender and on what should gender classification be based? Dembroff (2018) has recently claimed that, for reasons of social justice, gender classification should not track extant gender kinds. They further argue for ontological pluralism—the existence of many gender kinds, and recommend that we combat oppression by imitating the gender kinds and classification practices in non-oppressive communities. Contra Dembroff, I argue that the analysis is subject to a number of internal problems, including a misguided self-characterization and a tension between (...) ontological pluralism and imitation. In addition, I sketch a different perspective on the relation between gender kinds and gender classification practices that upholds Dembroff’s intended goal but ameliorates the unintended complications. (shrink)

Oceanic languages typically make a grammatical contrast between expres- sions of alienable and inalienable possession. Moreover, further distinctions are made in the alienable category but not in the inalienable category. The present research tests the hypothesis that there is a good motivation for such a development in the former case. As English does not have a grammaticalized distinction between alienable and inalienable possession, it provides a good testing ground. Three studies were conducted. In Study 1, participants were asked to write (...) down the first interpretation that came to mind for possessive phrases, some of which contained inherently relational possessums, while o thers contained possessums that are not inherently relational. Phrases with non-relational possessums elicited a broader range of interpretations and a lower consistency of a given interpretation across possessor modifiers than those with relational possessums. Study 2 demonstrated that users assign a default interpretation to a possessive phrase containing a relational possessum even when another reading is plausible. Study 3, a corpus-based analysis of possessive phrase use, showed that phrases with relational possessums have a narrower range of interpretations than those with other possessums. Taken together, the findings strongly suggest that grammatical distinctions between different types of alienable possession are motivated. (shrink)

Compared with Western Philosophy, Chinese Philosophy seldom talks about "the other world". This difference can be further proved in language categories. What exists in language text is different from what exists in language structure or language categories. Language categories reflect the styles of deep thinking. The lacking of subjunctive in Chinese language reflects the indifference between facts and ultra-facts in Chinese minds. There is a pan-fact attention in Chinese culture, while an ultra-fact attention in Western culture. This difference also embodies (...) in the activities of religion, logic, mathematics and science. (shrink)

What is the proper metaphysics of quantum mechanics? In this dissertation, I approach the question from three different but related angles. First, I suggest that the quantum state can be understood intrinsically as relations holding among regions in ordinary space-time, from which we can recover the wave function uniquely up to an equivalence class (by representation and uniqueness theorems). The intrinsic account eliminates certain conventional elements (e.g. overall phase) in the representation of the quantum state. It also dispenses with first-order (...) quantification over mathematical objects, which goes some way towards making the quantum world safe for a nominalistic metaphysics suggested in Field (1980, 2016). Second, I argue that the fundamental space of the quantum world is the low-dimensional physical space and not the high-dimensional space isomorphic to the ``configuration space.'' My arguments are based on considerations about dynamics, empirical adequacy, and symmetries of the quantum mechanics. Third, I show that, when we consider quantum mechanics in a time-asymmetric universe (with a large entropy gradient), we obtain new theoretical and conceptual possibilities. In such a model, we can use the low-entropy boundary condition known as the Past Hypothesis (Albert, 2000) to pin down a natural initial quantum state of the universe. However, the universal quantum state is not a pure state but a mixed state, represented by a density matrix that is the normalized projection onto the Past Hypothesis subspace. This particular choice has interesting consequences for Humean supervenience, statistical mechanical probabilities, and theoretical unity. (shrink)

In this popular article, I suggest that the task of interpreting quantum mechanics becomes easier if we reject the view that the quantum universe must be described by a wave function. We should zoom out from the wave function and represent the universe with something more coarse-grained, one that naturally arises from considerations about the Past Hypothesis. The new proposal is called the Wentaculus.