The COVID-19 pandemic revealed numerous weaknesses in pandemic preparedness and response, including underfunding, inadequate surveillance, and inequitable distribution of countermeasures. To overcome these weaknesses for future pandemics, WHO released a zero draft of a pandemic treaty in February, 2023, and subsequently a revised bureau's text in May, 2023. COVID-19 made clear that pandemic prevention, preparedness, and response reflect choices and value judgements. These decisions are therefore not a purely scientific or technical exercise, but are fundamentally grounded in ethics. The latest (...) treaty draft reflects these ethical considerations by including a section entitled Guiding Principles and Approaches. Most of these principles are ethical—they establish core values that undergird the treaty. Unfortunately, the treaty draft's set of principles are numerous, overlapping, and show inadequate coherence and consistency. We propose two improvements to this section of the draft pandemic treaty. First, key guiding ethical principles should be clearer and more precise than they currently are. Second, the link between ethical principles and policy implementation should be clearly established and define boundaries on acceptable interpretation, ensuring that signatories abide by these principles. (shrink)

This paper is a defense of moral evidentialism, the view that we have a moral obligation to form the doxastic attitude that is best supported by our evidence. I will argue that two popular arguments against moral evidentialism are weak. I will also argue that our commitments to the moral evaluation of actions require us to take doxastic obligations seriously.

There is no uniquely standard concept of an effectively decidable set of real numbers or real n-tuples. Here we consider three notions: decidability up to measure zero [M.W. Parker, Undecidability in Rn: Riddled basins, the KAM tori, and the stability of the solar system, Phil. Sci. 70(2) (2003) 359–382], which we abbreviate d.m.z.; recursive approximability [or r.a.; K.-I. Ko, Complexity Theory of Real Functions, Birkhäuser, Boston, 1991]; and decidability ignoring boundaries [d.i.b.; W.C. Myrvold, The decision problem for entanglement, in: (...) R.S. Cohen et al. (Eds.), Potentiality, Entanglement, and Passion-at-a-Distance: Quantum Mechanical Studies fo Abner Shimony, Vol. 2, Kluwer Academic Publishers, Great Britain, 1997, pp. 177–190]. Unlike some others in the literature, these notions apply not only to certain nice sets, but to general sets in Rn and other appropriate spaces. We consider some motivations for these concepts and the logical relations between them. It has been argued that d.m.z. is especially appropriate for physical applications, and on Rn with the standard measure, it is strictly stronger than r.a. [M.W. Parker, Undecidability in Rn: Riddled basins, the KAM tori, and the stability of the solar system, Phil. Sci. 70(2) (2003) 359–382]. Here we show that this is the only implication that holds among our three decidabilities in that setting. Under arbitrary measures, even this implication fails. Yet for intervals of non-zero length, and more generally, convex sets of non-zero measure, the three concepts are equivalent. (shrink)

**No longer the current version available on SEP; see revised version by Sharon Crasnow** -/- Feminists have a number of distinct interests in, and perspectives on, science. The tools of science have been a crucial resource for understanding the nature, impact, and prospects for changing gender-based forms of oppression; in this spirit, feminists actively draw on, and contribute to, the research programs of a wide range of sciences. At the same time, feminists have identified the sciences as a source (...) as well as a locus of gender inequalities: the institutions of science have a long tradition of excluding women as practitioners; feminist critics of science find that women and gender (or, more broadly, issues of concern to women and sex/gender minorities) are routinely marginalized as subjects of scientific inquiry, or are treated in ways that reproduce gender-normative stereotypes; and, closing the circle, scientific authority has frequently served to rationalize the kinds of social roles and institutions that feminists call into question. -/- Feminist perspectives on science therefore reflect a broad spectrum of epistemic attitudes toward and appraisals of science. Some urge the reform of gender inequities in the institutions of science and call for attention to neglected questions with the aim of improving the sciences in their own terms; they do not challenge the standards and practices of the sciences they engage. Others pursue jointly critical and constructive programs of research that, to varying degrees, aim at transforming the methodologies, substantive content, framework assumptions, and epistemic ideals that animate the sciences. The content of these perspectives, and the degree to which they generate transformative critique, depends not only on the types of philosophical and political commitments that inform them but also on the nature of the sciences and subject domains on which they bear. Feminist perspectives have had greatest impact on sciences that deal with inherently gendered subjects—the social and human sciences—and, secondarily, on sciences that study subjects characterized in gendered terms, metaphorically or by analogy (projectively gendered subjects), chiefly the biological and life sciences. Feminist perspectives are relevant to sciences that deal with non-gendered subject matters, but perspectives vary substantially in content and in critical import depending on the sciences and the particular research programs they engage. (shrink)

This twelfth volume of Collected Papers includes 86 papers comprising 976 pages on Neutrosophics Theory and Applications, published between 2013-2021 in the international journal and book series “Neutrosophic Sets and Systems” by the author alone or in collaboration with the following 112 co-authors (alphabetically ordered) from 21 countries: Abdel Nasser H. Zaied, Muhammad Akram, Bobin Albert, S. A. Alblowi, S. Anitha, Guennoun Asmae, Assia Bakali, Ayman M. Manie, Abdul Sami Awan, Azeddine Elhassouny, Erick González-Caballero, D. Dafik, Mithun Datta, Arindam Dey, (...) Mamouni Dhar, Christopher Dyer, Nur Ain Ebas, Mohamed Eisa, Ahmed K. Essa, Faruk Karaaslan, João Alcione Sganderla Figueiredo, Jorge Fernando Goyes García, N. Ramila Gandhi, Sudipta Gayen, Gustavo Alvarez Gómez, Sharon Dinarza Álvarez Gómez, Haitham A. El-Ghareeb, Hamiden Abd El-Wahed Khalifa, Masooma Raza Hashmi, Ibrahim M. Hezam, German Acurio Hidalgo, Le Hoang Son, R. Jahir Hussain, S. Satham Hussain, Ali Hussein Mahmood Al-Obaidi, Hays Hatem Imran, Nabeela Ishfaq, Saeid Jafari, R. Jansi, V. Jeyanthi, M. Jeyaraman, Sripati Jha, Jun Ye, W.B. Vasantha Kandasamy, Abdullah Kargın, J. Kavikumar, Kawther Fawzi Hamza Alhasan, Huda E. Khalid, Neha Andalleb Khalid, Mohsin Khalid, Madad Khan, D. Koley, Valeri Kroumov, Manoranjan Kumar Singh, Pavan Kumar, Prem Kumar Singh, Ranjan Kumar, Malayalan Lathamaheswari, A.N. Mangayarkkarasi, Carlos Rosero Martínez, Marvelio Alfaro Matos, Mai Mohamed, Nivetha Martin, Mohamed Abdel-Basset, Mohamed Talea, K. Mohana, Muhammad Irfan Ahamad, Rana Muhammad Zulqarnain, Muhammad Riaz, Muhammad Saeed, Muhammad Saqlain, Muhammad Shabir, Muhammad Zeeshan, Anjan Mukherjee, Mumtaz Ali, Deivanayagampillai Nagarajan, Iqra Nawaz, Munazza Naz, Roan Thi Ngan, Necati Olgun, Rodolfo González Ortega, P. Pandiammal, I. Pradeepa, R. Princy, Marcos David Oviedo Rodríguez, Jesús Estupiñán Ricardo, A. Rohini, Sabu Sebastian, Abhijit Saha, Mehmet Șahin, Said Broumi, Saima Anis, A.A. Salama, Ganeshsree Selvachandran, Seyed Ahmad Edalatpanah, Sajana Shaik, Soufiane Idbrahim, S. Sowndrarajan, Mohamed Talea, Ruipu Tan, Chalapathi Tekuri, Selçuk Topal, S. P. Tiwari, Vakkas Uluçay, Maikel Leyva Vázquez, Chinnadurai Veerappan, M. Venkatachalam, Luige Vlădăreanu, Ştefan Vlăduţescu, Young Bae Jun, Wadei F. Al-Omeri, Xiao Long Xin.‬‬‬‬‬‬. (shrink)

DESENVOLVIMENTO EMBRIONÁRIO E DIFERENCIAÇÃO SEXUAL -/- E. I. C. da Silva Departamento de Agropecuária – IFPE Campus Belo Jardim Departamento de Zootecnia – UFRPE sede -/- 1.1 INTRODUÇÃO O sexo foi definido como a soma das diferenças morfológicas, fisiológicas e psicológicas que distinguem o macho da fêmea permitindo a reprodução sexual e assegurando a continuidade das espécies. Os processos de diferenciação sexual são realizados durante o desenvolvimento embrionário, onde ocorre a proliferação, diferenciação e maturação das células germinativas e primordiais, precursoras (...) de ovócitos e espermatozoides em fêmeas e machos, respectivamente. Assim, os embriões machos e fêmeas iniciam o seu desenvolvimento de forma semelhante, de modo que em ambos os sexos se estabelecem em estruturas idênticas a partir das quais se formarão os órgãos reprodutores correspondentes a cada sexo. O conhecimento da origem e do desenvolvimento do aparelho genital é indispensável para entender sua função e as alterações que produzem infertilidade ou esterilidade. 1.2 DETERMINAÇÃO DO SEXO CROMOSSÔMICO Nos mamíferos, o sexo cromossômico é determinado no momento da fertilização, quando um óvulo, que contém um cromossomo X, é fecundado por um espermatozoide portador de um cromossomo X ou um cromossomo Y. No primeiro caso, o complemento cromossômico seria XX, o que originaria uma fêmea (sexo homogamético), e no segundo daria como resultado um macho com a fórmula cromossômica XY (sexo heterogâmico). 1.3 A GÔNADA INDIFERENCIADA A primeira manifestação das gônadas se aprecia no embrião em forma de um par de eminências longitudinais chamadas cristas ou dobras gonodais, situadas em ambos os lados da linha média entre os mesonefros (rins em desenvolvimento) e do mesentério dorsal. Nos embriões dos mamíferos, as células germinativas primordiais (CGP) manifestam-se em estágios precoces do desenvolvimento, podendo ser detectadas pela primeira vez na metade da gastrulação. As CGP são células grandes, de citoplasma claro e núcleo grande e redondo, localizadas na parede do saco vitelino, perto do alantoide. Essas células possuem grande capacidade de proliferação e vão migrar desde o endoderma do intestino e o epitélio do saco vitelino, através do mesentério, até as cristas gonodais. Isso ocorre por volta do 26° dia da gestação no bovino. Sua migração realiza-se graças aos movimentos de translocação passiva e deslocamento ameboide ativo. Desconhece-se o mecanismo pelo qual estas células são dirigidas para as cristas gonodais, porém foram estudadas algumas moléculas que se expressam durante sua migração e que poderiam desempenhar um papel importante na diferenciação deste tipo celular. A fosfatase alcalina é uma enzima que tem sido usada como marcador de CGP para determinar a sua origem e migração. Num estudo recente, foi inserido um marcador fluorescente que se exprime unicamente nas células germinativas primordiais de embriões transgênicos, e utilizando este marcador e a fosfatase alcalina determinou-se a origem e o padrão de migração destas células. O primeiro sinal de diferenciação das células germinativas primordiais é a expressão de fosfatase alcalina, e esta apareceu pela primeira vez na parte mais posterior da linha primitiva. No sétimo dia de desenvolvimento no embrião do camundongo, o endoderma visceral (AF+) é substituído pelo endoderma definitivo (AF-) originado na parte anterior da linha primitiva. O fator de transcrição Oct-4 é expresso nas CGP de ambos os sexos, pelo que acredita-se estar envolvido na mantença a totipotêncialidade das células. O receptor tirosina quinase, cujo ligante é o fator de Steel, é outra das moléculas que expressam as CGP. Tem sido demonstrado que este receptor possui um papel muito importante na sobrevivência deste tipo celular. Existem outros fatores que promovem a sobrevivência e/ou proliferação de CGP in vitro. Em experiências realizadas com o fator de transformação beta I (TGFβ-I), observou-se que este tem um efeito negativo sobre a proliferação das CGP. Outra atividade que tem sido postulada a este fator é o de um agente quimioatraente que possivelmente possa direcionar a migração destas células para a gônada. a) Um formado pelas células germinativas primordiais (precursoras dos gametas masculinos ou femininos), rodeadas de células somáticas das quais posteriormente se derivarão as células de Sertoli no macho e as células da granulosa na fêmea. b) O tecido que formará o estroma da gônada: tecido conjuntivo, vasos sanguíneos e as células intersticiais com atividade esteroidogênica (células de Leydig no testículo e a teca interna do ovário). As células somáticas do primórdio gonodal originam-se do mesoderma. Inicialmente são de três tipos: mesenquimáticas, mesoteliais e endoteliais. As células mesenquimáticas e mesoteliais iniciam grande atividade proliferativa ao chegar as CGP. Observa-se então uma condensação de células de origem mesotelial e mesenquimatoso que forma um agregado compacto denominado "blastema gonodal". A partir deste primórdio embrionário, diferenciam-se dois tecidos gonodais: os cordões sexuais e o estroma. Os cordões sexuais são arranjos epiteliais que se encontram delimitados por uma folha basal, e dentro deles encontramos as CGP. Por sua vez, no estroma encontram-se células do tipo mesenquimático e vasos sanguíneos. Neste momento, as gônadas são indiferenciadas e bipotencialmente sexuais, sendo impossível diferenciar, morfologicamente, uma gônada masculina de uma feminina, mas no caso dos machos genéticos já existe uma diferenciação da gônada a nível molecular. Nesta fase já se encontram presentes as estruturas das quais se desenvolvem os dutos mesonéfricos ou de Wolff precursores do aparelho genital masculino e os dutos paramesonéfricos ou de Müller que darão origem ao aparelho reprodutor feminino. Há uma série de fatores envolvidos no desenvolvimento precoce da gônada, entre os quais o fator esteroidogênico I (SFI: Steroidogenic fator l), que é um membro da subfamília de receptores nucleares, receptores órfãos. Este fator de transcrição tem um local de ligação ao DNA composto por dois dedos-de-Zinc. O SFI foi identificado como um ativador de genes envolvidos na biossíntese de esteroides em diferentes células. O SFI está presente durante o desenvolvimento embrionário em regiões associadas com funções endócrinas como gônadas, adrenais, pituitárias e hipotálamos. Os animais homozigotos para o gene SFI defeituoso, necessitam de gônadas e adrenais e têm a função gonadotrófica alterada. Os ratos sem SFI carecem de gonadotrofos e têm um desenvolvimento anormal do núcleo ventro-medial do hipotálamo; em particular as gônadas deixam de se desenvolver entre os dias 11 a 15 e degeneram-se por apoptose. No entanto, a crista genital forma-se e é colonizada pelas células germinativas, o que indica que estas continuam a receber o sinal adequado para a sua migração. Portanto, o SFI não está envolvido no desenvolvimento precoce da gônada e do sistema urogenital, mas parece estar envolvido na manutenção do crescimento das células somáticas presentes na gônada indiferenciada. O gene associado ao tumor de Wilms (WTI: Wilm's tumor Associated) está envolvido no desenvolvimento da gônada e do rim. Durante o desenvolvimento embrionário, WTI se expressa em todo o mesoderma intermediário e posteriormente na gônada indiferenciada, bem como no rim em formação. WTI regula o sinal indutivo do mesênquima para o epitélio celômico dos mesonefros. Se este for o caso, então WTI é responsável pelo crescimento da crista genital ao dirigir a entrada do epitélio celômico. Dado que estas células darão origem às células de Sertoli, a carência de WTI pode causar o desenvolvimento de embriões XY como fêmeas simplesmente porque não se formam as células de Sertoli. Em geral, todos os genes importantes na diferenciação do mesoderma intermediário e do sistema urogenital intervêm no desenvolvimento da gônada precoce. 1.4 DIFERENCIAÇÃO GONODAL O desenvolvimento das gônadas e ductos genitais descritos até o momento, é o mesmo para ambos os sexos. Igualmente, os genes descritos, que estão envolvidos no desenvolvimento das gônadas, ductos genitais e migração das células germinativas, afetam igualmente os embriões com genótipo XX ou XY. A gônada primitiva consiste anatomicamente de uma medula (interna) e uma crosta (externa), e de acordo com o local onde ocorre a colonização das células germinativas, diferenciara em testículo ou um ovário, respectivamente. Nos mamíferos, a primeira manifestação estrutural de diferenciação sexual é detectada na gônada dos machos, onde as células germinativas estão localizadas na medula. A diferenciação do testículo inicia-se quando os cordões sexuais se separam do epitélio celômico como consequência dos arranjos produzidos por uma invasão do mesênquima e vasos sanguíneos que provoca a compactação dos cordões, agora denominados cordões testiculares. As células que rodeiam os cordões se achatam e formam as células mioides, que são responsáveis pela formação das membranas basais. As células do epitélio interno, ou seja, as células de Sertoli, têm duas funções principais: o suporte das CGP e a síntese da hormona antimulleriana, responsável pela regressão dos ductos de Müller e secretada durante o período de diferenciação sexual. As células do estroma que rodeiam os cordões testiculares diferenciam-se para formar vários tipos de células: células mioides, fibroblastos, endotélio e células de Leydig, que são as mais importantes pela sua atividade endócrina. Posteriormente, os cordões testiculares dão origem aos túbulos seminíferos, que contêm o epitélio que produzirá os espermatozoides ao chegar à puberdade. Na fêmea, durante os estágios iniciais de diferenciação gonodal, não se observam mudanças em relação à gônada indiferenciada, só pode-se observar um certo crescimento devido à proliferação de células somáticas e germinativas. As células germinativas iniciam um período de proliferação, que termina com o início da meiose. Iniciada a meiose, dá-se o processo de foliculogênese; neste momento os cordões epiteliais se fragmentam, de tal maneira que cada ovócito fica rodeado de células epiteliais cobertas por uma folha basal fina (figura 1). Para que a gônada primitiva se desenvolva em testículo é indispensável a presença do cromossoma Y, independentemente do número de cromossomas X que contenha o genoma de um indivíduo. O gene determinante do testículo encontra-se localizado no cromossoma Y, denominado sry em ratos e SRY em humanos. O gene sry se expressa durante o desenvolvimento embrionário na crista genital de embriões de camundongos. A expressão é detectável no dia 10,5, pouco depois do aparecimento das cristas genitais, atinge o seu máximo durante o dia 11,5 e mantém-se até pouco depois de ocorrerem os primeiros sinais morfológicos de diferenciação testicular no dia 12,5. Este padrão de expressão é compatível com a teoria de que sry atua induzindo a ativação dos genes (figura 2) que conduzem ao desenvolvimento testicular, sem que exista a necessidade da expressão contínua de sry para manter a diferenciação do testículo após o dia 12,5. Como mencionado anteriormente, a gônada primitiva é composta por vários tipos de células. No entanto, as células germinativas primordiais não são o local de expressão do sry, já que os embriões que necessitam de células germinativas mantêm a expressão de sry e desenvolvem o sexo gonodal normalmente. As células somáticas na gônada em desenvolvimento incluem também as células de suporte. Sabe-se que é nestas células que o sry é expresso para que se diferenciem em células de Sertoli, e a expressão transitória de sry indica que deve ativar a outros genes para a manutenção das células de Sertoli. Uma vez diferenciadas as células de Sertoli, elas se encarregarão da diferenciação do resto das células na gônada. -/- Figura 1: Representação da diferenciação dos órgãos genitais internos. Adaptado de BRONSON, 1989. Figura 2: Cascada de genes envolvidos na diferenciação sexual, adaptado de KOOPMAN, 1999. O fator sry é necessário para a diferenciação do testículo. Embora não se conheçam os genes que provavelmente regulam esse gene, estudos realizados em camundongos demonstram que este gene parece coordenar-se com certos genes autossômicos. Entre estes genes autossômicos, o sox9, que é produzido pelas células de Sertoli uma vez que são estimuladas por sry, de modo que sox9 é um dos genes relacionados estruturalmente com sry. O Sox9 funciona como um fator de transcrição, mas não se sabe se a proteína tem qualquer outra função estrutural; este gene exprime-se abundantemente nos condrócitos e está relacionado com defeitos do aparelho ósseo chamados displasia campomélica. Curiosamente, os pacientes XY com esta condição sofrem frequentemente de reversão do sexo. O Sox9 é um dos poucos genes, além do SRY, do qual as mutações demonstraram interferir com a determinação sexual masculina. No entanto, apenas 75% dos pacientes com anomalias esqueléticas de tipo displasia campomélica têm reversão sexual e não foram encontrados casos de reversão sexual devido a um defeito de Sox9 que não seja acompanhado de defeitos esqueléticos. Isso indica que o Sox9 é apenas um membro da rede de genes que são ativados para determinar a diferenciação sexual, enquanto a rota que rege a condrogênese é mais sensível a perturbações deste. O momento em que se detecta a expressão do gene Sox9 (11dpc em ratos) coincide com a máxima expressão de sry, o que poderia indicar a possibilidade de que sry regule positivamente a Sox9. De fato, na região do promotor de Sox9 há um local de união ao que potencialmente se pode unir o sry. A expressão de Sox9 durante a diferenciação sexual sugere um papel abaixo de sry na diferenciação das células de Sertoli. O cromossoma X também é importante na diferenciação gonodal. O gene DAX-I foi isolado do lócus DSS (Dosage sensitive sex reversal) do cromossoma X. DAX-I é parte da cascata de determinação sexual, mas não é necessário para a formação do testículo. DAX-I é um membro dos receptores nucleares conhecidos como receptores órfãos. Este gene demonstrou ser um poderoso repressor da transcrição de SFI e de vários genes. Os padrões de expressão de DAX-I são complementares daqueles de SFI, ambos expressos nas cristas genitais. Em resumo, dada a evidência exposta, desenvolveu-se a hipótese de que DAX-I é um antagonista de sry; esse antagonismo é dependente dos níveis relativos de DAX-I e sry e de um limiar que varia de espécie para espécie. A DAX-I foi classificada como o gene antitestículo. Na fêmea (cariótipo XX) é importante que ocorra a inativação de um dos cromossomas sexuais X para que se mantenha o equilíbrio genético ao igualar o conteúdo de DNA dos cromossomas. Esse cromossoma inativado constitui o chamado corpúsculo de Barr. No entanto, para que a meiose se realize, é necessário dos dois cromossomas X ativos nos ovócitos para assegurar a diferenciação ovárica e a fertilidade. 1.5 DIFERENCIAÇÃO DOS DUCTOS SEXUAIS O embrião possui, além das gônadas indiferenciadas, dois sistemas de ductos: os de potencialidade masculina denominam-se ductos de Wolff ou mesonéfricos, e os de potencialidade feminina se chamam ductos de Müller ou paramesonéfricos (figura 1). Se a diferenciação gonodal levou à formação de um testículo, a partir do ducto mesonéfrico ou de Wolff se desenvolverão os ductos eferentes, o epidídimo, os ductos deferentes e as vesículas seminais. As hormonas importantes no desenvolvimento do aparelho genital masculino são a testosterona, produzida pelas células de Leydig, e sua forma 5α reduzida, a 5α di-hidrotestosterona. Acredita-se que a testosterona é responsável pela virilização dos ductos de Wolff, e a di-hidrotestosterona dos órgãos genitais externos. No macho, os canais de Müller atrofiam-se devido à ação de uma hormona fetal de origem testicular denominada hormona inibidora das estruturas de Müller (HIM) ou hormona antimulleriana. Este processo começa assim que os cordões espermáticos se formam e se diferenciam as células de Sertoli. A existência de HIM foi proposta baseada em estudos realizados em bezerras freemartin, devido à existência de uma hormona responsável pela atresia dos ductos de Müller que na fêmea dá origem ao útero e aos ovidutos. Essa hormona provoca a involução do aparelho genital do bovino nas gestações gemelares nas quais os produtos de diferente sexo têm comunicação sanguínea por ter ocorrido a anastomose dos vasos de ambas as placentas (figura 3). A HIM é uma glicoproteína pertencente à subfamília de TGFβ, é expressa pelas células que darão origem às células de Sertoli e é um dos primeiros marcadores de diferenciação nestas células. A HIM é secretada na vida adulta pelas células de Sertoli no testículo e por células da granulosa no ovário. No rato a HIM é expressa-se no 12° dia em um teste padrão que segue muito de perto o aumento na expressão de sry. No macho, esta secreção de HIM continua durante a vida fetal e adulta, contudo os níveis de HIM declinam na puberdade devido a um aumento na secreção de testosterona. Vários fatores intervêm na regulação do gene de HIM, incluindo os acima descritos SFI e Sox9. O gene HIM contém segmentos de DNA que são conservados em várias espécies de vertebrados. Existe um nexo de ligação para SFI, que ativa a transcrição de HIM. A mutação no local de ligação de SFI resulta em reversão do sexo em indivíduos XY incluindo genitais femininos normais, presença de um útero formado enfatizando a importância de SFI na determinação sexual e na expressão de HIM. Embora SFI seja um bom candidato como regulador de HIM, é expresso em outras células, como as de Leydig e adrenais, que não expressam HIM. Em contrapartida, Sox9 é expresso unicamente nas células de Sertoli que são as produtoras de HIM. O gene HIM também tem um nexo de ligação para Sox9. Além disso, Sox9 pode atuar sinergicamente com SFI para promover a secreção de HIM. Ao contrário destes dois fatores de transcrição, DAX-I antagoniza a ação de Sox9 e provavelmente SFI sobre o promotor de HIM. Assim, para que as células de Sertoli secretem HIM, a transcrição de DAX-I deve diminuir. Figura 3: Representação da diferenciação dos órgãos genitais externos. Adaptado de BRONSON, 1989. Os ductos de Wolff tornam-se o sistema de ejaculação do macho. A porção mais próxima dos testículos dá origem ao epidídimo, a parte central ao ducto deferente e a porção mais distal às vesículas seminais. A próstata e a parte membranosa da uretra do macho desenvolvem-se a partir da porção pélvica do seio urogenital. A virilização e diferenciação dos ductos de Wolff dependem da produção de testosterona pelo testículo. Quanto aos órgãos genitais externos do macho, o tubérculo genital é ampliado e as dobras uretrais se fundem para formar a uretra peniana. A fusão das dobras uretrais aproxima os tubérculos genitais para formar o escroto (figura 4). Figura 4: Diferenciação do aparelho genital da fêmea e do macho. Adaptado de KOOPMAN, 1989. A diferenciação dos órgãos genitais da fêmea ocorre de forma passiva, já que a ausência de testículos e por isso da hormona inibidora dos ductos de Müller (HIM), assim como dos andrógenos virilizantes, favorece o desenvolvimento dos ductos de Müller, enquanto os de Wolff sofrem atrofia. A porção cefálica dos ductos de Müller dá origem aos ovidutos, que na sua terminação caudal se fundem com o útero. O contato dos ductos de Müller com o seio urogenital induz uma intensa proliferação celular que resulta na formação da área uterovaginal localizado entre o seio urogenital e os ductos de Müller. As células do prato uterovaginal proliferam e aumentam a distância entre as duas estruturas criando o espaço que formará a vagina quando o prato é canalizado e forma um lúmen. Em contraste com o que ocorre no macho, na fêmea a maior parte do seio urogenital se mantém exposta na superfície da abertura onde desembocam a vagina e a uretra. O tubérculo urogenital da fêmea tem um crescimento limitado e forma o clitóris. A sequência de passos da diferenciação sexual do aparelho genital é resumida na tabela 1. Tabela 1: Destino em desenvolvimento dos rudimentos sexuais dos fetos macho e fêmea dos mamíferos -/- Rudimento sexual Macho Fêmea Gônada Testículo Ovário Ductos de Müller (Paramesonéfricos) Vestígios Útero, parte da vagina, ovidutos Ductos de Wolff (Mesonéfricos) Ductos eferentes deferentes, epidídimo, vesículas seminais Vestígios Seio urogenital Uretra, próstata, glândulas bulbouretrais Parte da vagina, uretra, vestíbulo, glândulas vestibulares Tubérculo genital Pênis Clitóris Pregas vestibulares Escroto Lábios vulvares Fonte: HAFEZ, 2004. 1.6 DIFERENCIAÇÃO SEXUAL DO HIPOTÁLAMO Os processos de diferenciação sexual não se limitam apenas às células somáticas do organismo do feto, mas incluem também os centros nervosos superiores do cérebro. Assim, da mesma maneira que a gônada e os ductos sexuais se desenvolvem para o tipo feminino ou masculino, propôs-se que o cérebro pode ser "masculinizado" ou permanecer "Feminizado". A diferenciação do hipotálamo vai depender do ambiente esteroidal do neonato e ocorre na fase perinatal. Estes eventos serão de grande transcendência na vida reprodutiva do indivíduo. Tanto a fêmea como o macho nascem com a capacidade de secreção de gonadotropinas de acordo com um padrão cíclico; contudo, no macho, a exposição do hipotálamo à ação dos andrógenos testiculares durante os primeiros dias da vida extrauterina provoca a masculinização, com o qual o hipotálamo do macho é programado para que a secreção de gonadotropinas se realize a um ritmo relativamente constante por parte da hipófise (secreção tônica). Na fêmea, tanto a secreção tônica como a cíclica se conservam. No entanto, observou-se que a injeção de testosterona ou o transplante de testículo na rata fêmea durante os primeiros dias de vida, suprime a sua futura atividade estral (secreção cíclica). Por outro lado, se os ovários forem transplantados para o rato macho normal castrado na idade adulta, o animal não desenvolve qualquer atividade cíclica, mas se os machos transplantados forem castrados ao nascer, o ovário é capaz de efetuar mudanças cíclicas e ovulações. Isto foi demonstrado em roedores, mas não em animais domésticos ou na espécie humana. Portanto, o padrão de secreção de gonadotropinas, seja cíclico ou tônico, não depende da hipófise, mas do hipotálamo e sua correta diferenciação. 1.7 CONCLUSÕES A maioria dos conhecimentos no campo da biologia do desenvolvimento e, muito especificamente, dos processos de diferenciação sexual têm sido originados de estudos relacionados com desordens congênitas, que na sua maioria devem-se a defeitos de genes específicos. A análise detalhada destas desordens permitiu entender alguns mecanismos endócrinos, moleculares e genéticos envolvidos na diferenciação sexual. A identificação do gene sry como determinante do testículo foi uma contribuição crucial e abriu as portas à compreensão dos mecanismos moleculares e celulares relacionados com o desenvolvimento do testículo. Se este gene não estiver presente, é criado um programa genético alternativo para levar a cabo a diferenciação gonodal para o ovário. Finalmente, devemos ter presente que é necessária uma correlação entre mudanças morfológicas e expressão de genes durante o desenvolvimento para entender os mecanismos relacionados com a diferenciação. -/- Apoio -/- Realização -/- REFERÊNCIAS BIBLIOGRÁFICAS ANDERSON, Robert et al. The onset of germ cell migration in the mouse embryo. Mechanisms of development, v. 91, n. 1-2, p. 61-68, 2000. AUSTIN, Colin Russell; SHORT, R. V. Reproduction in Mammals: Volume 1, Germ Cells and Fertilization. Londres: Cambridge University Press, 1972. BRONSON, Franklin H. Mammalian reproductive biology. Chicago: University of Chicago Press, 1989. BUEHR, Mia. The primordial germ cells of mammals: some current perspectives. Experimental cell research, v. 232, n. 2, p. 194-207, 1997. BYSKOV, Anne G. Differentiation of mammalian embryonic gonad. Physiological reviews, v. 66, n. 1, p. 71-117, 1986. CAPEL, Blanche et al. Migration of mesonephric cells into the mammalian gonad depends on Sry. Mechanisms of development, v. 84, n. 1-2, p. 127-131, 1999. CAPEL, Blanche. The battle of the sexes. Mechanisms of development, v. 92, n. 1, p. 89-103, 2000. DERIVAUX, Jules; BARNABÉ, Renato Campanarut. Reprodução dos animais domésticos. Zaragoza: Acribia, 1980. DOMENICE, Sorahia et al. Aspectos moleculares da determinação e diferenciação sexual. Arquivos Brasileiros de Endocrinologia & Metabologia, v. 46, n. 4, p. 433-443, 2002. DONAHOE, Patricia K. et al. Mullerian inhibiting substance activity in bovine fetal, newborn and prepubertal testes. Biology of reproduction, v. 16, n. 2, p. 238-243, 1977. HAFEZ, Elsayed Saad Eldin; HAFEZ, B. Reprodução animal. São Paulo: Manole, 2004. HANLEY, Neil A. et al. Steroidogenic factor 1 (SF-1) is essential for ovarian development and function. Molecular and cellular endocrinology, v. 163, n. 1-2, p. 27-32, 2000. HIORT, Olaf; PAUL-MARTIN, H. The molecular basis of male sexual differentiation. European journal of endocrinology, v. 142, n. 2, p. 101-110, 2000. HOLY, Lubos; MARTÍNEZ JÚSTIZ, G. Colab. Biología de la reproducción bovina. Havana: Revolucionária, 1975. JOSSO, Nathalie et al. The role of anti-Müllerian hormone in gonadal development. Molecular and cellular endocrinology, v. 145, n. 1-2, p. 3-7, 1998. JOST, Alfred et al. Studies on sex differentiation in mammals. In: Proceedings of the 1972 Laurentian Hormone Conference. Londres: Academic Press, 1973. p. 1-41. KNOBIL, Ernst. Knobil and Neill's physiology of reproduction. EUA: Gulf Professional Publishing, 2006. KOFMAN ALFARO, S.; MERCHANT LARIOS, H.; PEREZ PALACIOS, G. Diferenciacion sexual. I. Bases biologicas del dimorfismo sexual. Rev. invest. clín, p. 349-59, 1982. KOOPMAN, Peter. Sry and Sox9: mammalian testis-determining genes. Cellular and Molecular Life Sciences CMLS, v. 55, n. 6-7, p. 839-856, 1999. MCDONALD, L. E. Veterinary endocrinology. Lea & Febiger, Philadelphia, Pa, 1969. MEIZEL, S.; JOHNSON, M. H. Development in mammals. MH Johnson, Ed, v. 3, p. 1-64, 1978. MELLO, Maricilda Palandi de; ASSUMPÇÃO, Juliana de G.; HACKEL, Christine. Genes envolvidos na determinação e diferenciação do sexo. Arquivos Brasileiros de Endocrinologia & Metabologia, v. 49, n. 1, p. 14-25, 2005. -/- REFERÊNCIAS BIBLIOGRÁFICAS MERCHANT-LARIOS, H. Ovarian differentiation. The Vertebrate Ovary, p. 47-81, 1978. MIES FILHO, Antonio. Reprodução dos animais. Porto Alegre: Sulina, 1987. NEF, Serge; PARADA, Luis F. Hormones in male sexual development. Genes & Development, v. 14, n. 24, p. 3075-3086, 2000. PARKER, Keith L.; SCHEDL, Andreas; SCHIMMER, Bernard P. Gene interactions in gonadal development. Annual review of physiology, v. 61, n. 1, p. 417-433, 1999. SWAIN, Amanda; LOVELL-BADGE, Robin. Mammalian sex determination: a molecular drama. Genes & development, v. 13, n. 7, p. 755-767, 1999. WILHELM, Dagmar; PALMER, Stephen; KOOPMAN, Peter. Sex determination and gonadal development in mammals. Physiological reviews, v. 87, n. 1, p. 1-28, 2007. WILSON, Jean D.; GRIFFIN, James E.; GEORGE, Fredrick W. Sexual differentiation: early hormone synthesis and action. Biology of reproduction, v. 22, n. 1, p. 9-17, 1980. -/- Emanuel Isaque Cordeiro da Silva Belo Jardim, 07 de Maio de 2020. (shrink)

Default positions, predetermined starting points that aid in complex decision-making, are common in clinical medicine. In this article, we identify and critically examine common default positions in clinical ethics practice. Whether default positions ought to be held is an important normative question, but here we are primarily interested in the descriptive, rather than normative, properties of default positions. We argue that default positions in clinical ethics function to protect and promote important values in medicine—respect for persons, utility, and justice. Further, (...) default positions in clinical ethics may also guard against harm. Where default positions exist, there are epistemic burdens to overturn them. The person wishing to reject the default position, rather than the person endorsing it, bears this burden. The person who bears the burden of meeting the epistemic requirements must provide evidence proportional to the degree of harm the default position protects against. Default positions that protect against significant harm impose significant epistemic requirements to overturn. This asymmetry not only makes medical decision-making more economical but also serves to promote and protect certain values. The identification and analysis of common and recognizable default positions can help to identify other default positions and the conditions under which their associated epistemic requirements are met. The article concludes with considerations of potential problems with the use of default positions in clinical ethics. (shrink)

The practice of medicine frequently involves the unconsented restriction of liberty. The reasons for unilateral liberty restrictions are typically that being confined, strapped down, or sedated are necessary to prevent the person from harming themselves or others. In this paper, we target the ethics of chemical restraints, which are medications that are used to intentionally restrict the mental states associated with the unwanted behaviors, and are typically not specifically indicated for the condition for which the patient is being treated. Specifically, (...) we aim to identify the conditions under which chemical restraints are ethically permissible. It is wrong to assume that what is morally true of physical restraints is also true of chemical restraints. Our aim is thus to identify the conditions under which chemical restraints are permissible while distinguishing these conditions from those of the application of physical restraints. (shrink)

It has recently been argued that a person’s moral judgments (about both their own and others’ actions) are constrained by the nature and extent of their relevant ignorance and, thus, that such judgments are determined in the first instance by the person’s epistemic circumstances. It has been argued, in other words, that the epistemic is logically prior to other normative (e.g., ethical, prudential, pecuniary) considerations in human decision-making, that these other normative considerations figure in decision-making only after (logically and temporally) (...) relevant ignorance has constrained the decision-maker’s menu of options. If this is right, then a person’s moral judgments in some set of circumstances should vary with their knowledge and ignorance of these circumstances. In this study, we test the hypothesis of the logical priority of the epistemic. We describe two experiments in which subjects’ knowledge and ignorance of relevant consequences were manipulated. In the second experiment, we also compared the effect of ignorance on moral judgments with that of personal force, a factor previously shown to influence moral judgments. We found broad empirical support for the armchair arguments that epistemic considerations are logically prior to normative considerations. (shrink)

In this paper, I will attempt to develop and defend a common form of intuitive resistance to the companions in guilt argument. I will argue that one can reasonably believe there are promising solutions to the access problem for mathematical realism that don’t translate to moral realism. In particular, I will suggest that the structuralist project of accounting for mathematical knowledge in terms of some form of logical knowledge offers significant hope of success while no analogous approach offers such hope (...) for moral realism. (shrink)

In this article, I discuss a trivialization worry for Hartry Field’s official formulation of the access problem for mathematical realists, which was pointed out by Øystein Linnebo. I argue that various attempted reformulations of the Benacerraf problem fail to block trivialization, but that access worriers can better defend themselves by sticking closer to Hartry Field’s initial informal characterization of the access problem in terms of general epistemic norms of coincidence avoidance.

Berger (forthcoming) states that moral intimacy is important in applying the best interests standard. But what he calls moral intimacy requires that someone has overcome epistemic burdens needed to represent the patient. We argue elsewhere that good surrogate decision-making is first and foremost a matter of overcoming epistemic burdens, or those obstacles that stand in the way of a surrogate decision-maker knowing what a patient wants and how to satisfy those preferences. Berger’s notion of moral intimacy depends on epistemic intimacy: (...) the fact that a surrogate's epistemic burdens with respect to the best interests of the incapacitated patient have been adequately surmounted, plus some other feature. Thus, where a particular patient-surrogate relationship fails to be morally intimate, what is lacking is either epistemic intimacy or this second feature. Furthermore, Berger uses the notion of moral intimacy as an explanans for the application of the best interests standard. We argue that the notions of epistemic intimacy and epistemic burdens not only help to explain the notion of moral intimacy, but also better explain the application of the best interests standard. Given the role of epistemic burdens and the epistemic intimacy that overcoming them enables, bioethicists and physicians should consider a surrogate’s epistemic standing relative to the patient’s best interests before pronouncing on the former’s ethical probity. (shrink)

As the science and technology of the brain and mind develop, so do the ways in which brains and minds may be surveilled and manipulated. Some cognitive libertarians worry that these developments undermine cognitive liberty, or “freedom of thought.” I argue that protecting an individual’s cognitive liberty undermines others’ ability to use their own cognitive liberty. Given that the threatening devices and processes are not relevantly different from ordinary and frequent intrusions upon one’s brain and mind, strong protections of cognitive (...) liberty may proscribe neurotechnological intrusions, but also ordinary intrusions. Thus, the cognitive libertarian position “hog-ties” others’ use of their own liberties. This problem for the cognitive libertarian is the same problem that ordinary libertarianism faces in protecting individual rights to property and person. But the libertarian strategies for resolving the problem don’t work for the cognitive libertarian. I conclude that the right to mental privacy is weaker than what cognitive libertarians want it to be. (shrink)

Some theorists argue that moral bioenhancement ought to be compulsory. I take this argument one step further, arguing that if moral bioenhancement ought to be compulsory, then its administration ought to be covert rather than overt. This is to say that it is morally preferable for compulsory moral bioenhancement to be administered without the recipients knowing that they are receiving the enhancement. My argument for this is that if moral bioenhancement ought to be compulsory, then its administration is a matter (...) of public health, and for this reason should be governed by public health ethics. I argue that the covert administration of a compulsory moral bioenhancement program better conforms to public health ethics than does an overt compulsory program. In particular, a covert compulsory program promotes values such as liberty, utility, equality, and autonomy better than an overt program does. Thus, a covert compulsory moral bioenhancement program is morally preferable to an overt moral bioenhancement program. (shrink)

Epistemic burdens – the nature and extent of our ignorance (that and how) with respect to various courses of action – serve to determine our incentive structures. Courses of action that seem to bear impossibly heavy epistemic burdens are typically not counted as options in an actor’s menu, while courses of action that seem to bear comparatively heavy epistemic burdens are systematically discounted in an actor’s menu relative to options that appear less epistemically burdensome. That ignorance serves to determine what (...) counts as an option means that epistemic considerations are logically prior to moral, prudential, and economic considerations: in order to have moral, prudential, or economic obligations, one must have options, and epistemic burdens serve to determine our options. One cannot have obligations without doing some epistemic work. We defend this claim on introspective grounds. We also consider how epistemic burdens distort surrogate decision-making. The unique epistemology of surrogate cases makes the priority of the epistemic readily apparent. We then argue that anyone who accepts a principle similar to ought implies can is committed to the logical priority of the epistemic. We also consider and reject several possible counterarguments. -/- . (shrink)

Contemporary scholarship is divided over whether Anselm maintains a version of Eudaemonism. The debate centers on the question of whether the will for justice only moderates the will for happiness or, instead, provides a distinct end for which to act. Because of two key passages, various scholars hold that Anselm maintained elements of medieval Eudaemonism. In this article, I argue that Anselm separates morality from happiness, and I provide a sketch of his alternative view. First, I argue against some recent (...) perspectives that Anselm maintained Eudaemonism. To do so, I provide a non-Eudaemonist reading of the two key passages and show how Eudaemonist readings are lacking in different respects. Second, I examine what this argument means for Anselm’s understanding of happiness and moral obligation. While there are some Eudaemonist themes in Anselm’s thinking, he flatly denies and revises aspects of the system. (shrink)

Since Benacerraf’s ‘What Numbers Could Not Be, ’ there has been a growing interest in mathematical structuralism. An influential form of mathematical structuralism, modal structuralism, uses logical possibility and second order logic to provide paraphrases of mathematical statements which don’t quantify over mathematical objects. These modal structuralist paraphrases are a useful tool for nominalists and realists alike. But their use of second order logic and quantification into the logical possibility operator raises concerns. In this paper, I show that the work (...) of both these elements can be done by a single natural generalization of the logical possibility operator. (shrink)

There is recent empirical evidence that personal identity is constituted by one’s moral traits. If true, this poses a problem for those who advocate for moral enhancement, or the manipulation of a person’s moral traits through pharmaceutical or other biological means. Specifically, if moral enhancement manipulates a person’s moral traits, and those moral traits constitute personal identity, then it is possible that moral enhancement could alter a person’s identity. I go a step further and argue that under the right conditions, (...) moral enhancement can constitute murder. I then argue that these conditions are not remote. (shrink)

In biomedical ethics, there is widespread acceptance of moral realism, the view that moral claims express a proposition and that at least some of these propositions are true. Biomedical ethics is also in the business of attributing moral obligations, such as “S should do X.” The problem, as we argue, is that against the background of moral realism, most of these attributions are erroneous or inaccurate. The typical obligation attribution issued by a biomedical ethicist fails to truly capture the person's (...) actual obligations. We offer a novel argument for rife error in obligation attribution. The argument starts with the idea of an epistemic burden. Epistemic burdens are all of those epistemic obstacles one must surmount in order to achieve some aim. Epistemic burdens shape decision-making such that given two otherwise equal options, a person will choose the option that has the lesser of epistemic burdens. Epistemic burdens determine one's potential obligations and, conversely, their non-obligations. The problem for biomedical ethics is that ethicists have little to no access to others' epistemic burdens. Given this lack of access and the fact that epistemic burdens determine potential obligations, biomedical ethicists often can only attribute accurate obligations out of luck. This suggests that the practice of attributing obligations in biomedical ethics is rife with error. To resolve this widespread error, we argue that this practice should be abolished from the discourse of biomedical ethics. (shrink)

Mathematical knowledge and moral knowledge (or normative knowledge more generally) can seem intuitively puzzling in similar ways. For example, taking apparent human knowledge of either domain at face value can seem to require accepting that we benefited from some massive and mysterious coincidence. In the mathematical case, a pluralist partial response to access worries has been widely popular. In this paper, I will develop and address a worry, suggested by some works in the recent literature like (Clarke-Doane, 2020 ), that (...) connections between ought facts and action prevent us from giving a similarly pluralist response to moral access worries. (shrink)

We thank all the thoughtful authors for their insightful comments. In this response, we try to address some of themes that emerged from the commentaries. We leave aside some of those comments that...

In this paper I’ll examine whether we could be justified in attributing consciousness to artificial intelligent systems. First, I’ll give a brief history of the concept of artificial intelligence (AI) and get clear on the terms I’ll be using. Second, I’ll briefly review the kinds of AI programs on offer today, identifying which research program I think provides the best candidate for machine consciousness. Lastly, I’ll consider the three most plausible ways of knowing whether a machine is conscious: (1) an (...) AI demonstrates a sufficient level of organizational similarity to that of a human thinker, (2) an inference to the best explanation, and (3) what I call “punting to panpsychism”, i.e., the idea that if everything is conscious, then we get machine consciousness in AI for free. However, I argue that all three of these methods for attributing machine consciousness are inadequate since they each face serious philosophical problems which I will survey and specifically tailor to each method. (shrink)

Augustine’s privation theory of evil maintains that something is evil in virtue of a privation, a lack of something which ought to be present in a particular nature. While it is not evil for a human to lack wings, it is indeed evil for a human to lack rationality according to the end of a rational nature. Much of the literature on the privation theory focuses on whether it can successfully defend against counterexamples of positive evils, such as pain. This (...) focus of the discussion is not surprising, given that the privation theory is a theory about the nature of evil. But it is also a theory that protects venerable theological concerns, namely, that God is the good creator of everything, and that everything is good. It is the purpose of this article to further this discussion on both fronts. I argue that the counterexample of pain still defeats the privation theory despite the most recent defense. What is more, I suggest, this is not theologically disastrous. The individual who rejects the privation theory is not obligated to reject the theological theses which motivate it. To show how a rejection of the privation theory is a live option, I offer an alternative view of evil that also maintains these theological theses and encompasses both privative and positive evils. (shrink)

Moral bioenhancement is the potential practice of manipulating individuals’ moral behaviors by biological means in order to help resolve pressing moral issues such as climate change and terrorism. This practice has obvious ethical implications, and these implications have been and continue to be discussed in the bioethics literature. What have not been discussed are the epistemological implications of moral bioenhancement. This article details some of these implications of engaging in moral bioenhancement. The argument begins by making the distinction between moral (...) bioenhancement that manipulates the contents of mental states and that which manipulates other, non-representational states. Either way, I argue, the enhanced moral psychology will fail to conform to epistemic norms, and the only way to resolve this failure and allow the moral bioenhancement to be effective in addressing the targeted moral issues is to make the moral bioenhancement covert. (shrink)

Despite the lack of evidence for their effectiveness, the use of physical restraints for patients is widespread. The best ethical justification for restraining patients is that it prevents them from harming themselves. We argue that even if the empirical evidence supported their effectiveness in achieving this aim, their use would nevertheless be unethical, so long as well known exceptions to informed consent fail to apply. Specifically, we argue that ethically justifiable restraint use demands certain necessary and sufficient conditions. These conditions (...) are that the physician obtain informed consent for their application, that their application be medically appropriate, and that restraints be the least liberty-restricting way of achieving the intended benefit. It is a further question whether their application is ever medically appropriate, given the dearth of evidence for their effectiveness. (shrink)

Abstract In his discourses on ‘the lily of the field and the bird of the air,’ Kierkegaard presents faith as the best possible response to our precarious and uncertain condition, and as the ideal way to cope with the insecurities and concerns that his readers will recognize as common features of human existence. Reading these discourses together, we are introduced to the portrait of a potential believer who, like the ‘divinely appointed teachers’—the lily and the bird—succeeds in leading a life (...) that is full of care, but free of worry. Such a portrait, we claim, echoes Kierkegaard’s portrait of the knight of faith in Fear and Trembling . In this essay we suggest that faith, as characterized in the ‘lily and bird’ discourses, is a kind of existential trust that would allow us to overcome worry, while remaining wholeheartedly engaged in the finite realm of our cares and concerns. We claim that Kierkegaard’s goal in these discourses is not to belittle our earthly cares, but to invite us to develop a modified attitude toward all that we are susceptible to worry about. Content Type Journal Article Category Article Pages 1-19 DOI 10.1007/s11153-011-9322-5 Authors Sharon Krishek, Department of Philosophy, The Hebrew University of Jerusalem, Jerusalem, Israel Rick Anthony Furtak, Department of Philosophy, Colorado College, Colorado Springs, CO, USA Journal International Journal for Philosophy of Religion Online ISSN 1572-8684 Print ISSN 0020-7047. (shrink)

In this paper I will draw attention to an important route to external world skepticism, which I will call confidence skepticism. I will argue that we can defang confidence skepticism (though not a meeker ‘argument from might’ which has got some attention in the 20th century literature on external world skepticism) by adopting a partially psychologistic answer to the problem of priors. And I will argue that certain recent work in the epistemology of mathematics and logic provides independent support for (...) such psychologism. (shrink)

We aim to establish the following claim: other factors held constant, the relative weights of the epistemic burdens of competing treatment options serve to determine the options that patient surrogates pursue. Simply put, surrogates confront an incentive, ceteris paribus, to pursue treatment options with respect to which their knowledge is most adequate to the requirements of the case. Regardless of what the patient would choose, options that require more knowledge than the surrogate possesses (or is likely to learn) will either (...) be neglected altogether or deeply discounted in the surrogate’s incentive structure. We establish this claim by arguing that the relation between epistemic burdens and incentives in decision-making is a general feature of surrogate decision-making. After establishing the claim, we draw out some of the implications for surrogate decision-making in medicine and offer philosophical and psychological explanations of the phenomenon. (shrink)

Various thinkers are concerned that the Orthodox view of Ancestral Sin does not avoid the age-old Augustinian concern of Pelagianism. After all, the doctrine of Ancestral Sin maintains that fallen human beings do not necessarily or inevitably commit actual sins. In contemporary literature, this claim could be articulated as a denial of the ‘inevitability thesis.’ A denial of the inevitability thesis, so contemporary thinkers maintain, seems to imply both that human beings can place themselves in right relation to God as (...) well as the Pelagian denial that all require Christ's work to attain this right relation to God. This article demonstrates that the Ancestral Sin, along with a denial of the inevitability thesis, is neither Pelagian nor Semi-Pelagian. I show that the doctrine of Ancestral Sin denies (Semi-) Pelagianism in various ways. I show that, for Ancestral Sin to entail (Semi-) Pelagianism, one must commit to several assumptions, each of which is plausibly deniable and none of which Orthodox thinkers affirm. (shrink)

Interventions aiming to slow, stop, or reverse the aging process are starting to enter clinical trials. Though this line of research is nascent, it has the potential to not only prevent prolonged human suffering, but also to extend human well-being. As this line of research develops, it is important to understand the ethical constraints of conducting such research. This paper discusses some of these constraints. In particular, it discusses the ethical difficulties of conducting this research in a way that would (...) produce reliable data regarding the effectiveness of an anti-aging intervention. Clinical trials of such interventions, I argue, will be faced with a dilemma between two confounding variables. Eliminating the variables requires introducing ethically problematic research practices. Thus, researchers must either perform research in ethically problematic ways, or forego the conduct of high-impact clinical research on anti-aging interventions. (shrink)

The paper argues that knowledge is not closed under logical inference. The argument proceeds from the openness of evidential support and the dependence of empirical knowledge on evidence, to the conclusion that knowledge is open. Without attempting to provide a full-fledged theory of evidence, we show that on the modest assumption that evidence cannot support both a proposition and its negation, or, alternatively, that information that reduces the probability of a proposition cannot constitute evidence for its truth, the relation of (...) evidential support is not closed under known entailment. Therefore the evidence-for relation is deductively open regardless of whether evidence is probabilistic or not. Given even a weak dependence of empirical knowledge on evidence, we argue that empirical knowledge is also open. On this basis, we also respond to the strongest argument in support of knowledge closure. Finally, we present a number of significant benefits of our position, namely, offering a unified explanation for a range of epistemological puzzles. (shrink)

Most contemporary political science researchers are advocates of multimethod research, however, the value and proper role of qualitative methodologies, like case study analysis, is disputed. A pluralistic philosophy of science can shed light on this debate. Methodological pluralism is indeed valuable, but does not entail causal pluralism. Pluralism about the goals of science is relevant to the debate and suggests a focus on the difference between evidence for warrant and evidence for use. I propose that case study research provides evidence (...) for use through providing information that bears on the applicability of causal generalizations and risk assessment. (shrink)

In a recent issue of Bioethics, I argued that compulsory moral bioenhancement should be administered covertly. Alexander Zambrano has criticized this argument on two fronts. First, contrary to my claim, Zambrano claims that the prevention of ultimate harm by covert moral bioenhancement fails to meet conditions for permissible liberty‐restricting public health interventions. Second, contrary to my claim, Zambrano claims that covert moral bioenhancement undermines autonomy to a greater degree than does overt moral bioenhancement. In this paper, I rebut both of (...) these arguments, then finish by noting important avenues of research that Zambrano’s arguments motivate. (shrink)

The idea that knowledge can be extended by inference from what is known seems highly plausible. Yet, as shown by familiar preface paradox and lottery-type cases, the possibility of aggregating uncertainty casts doubt on its tenability. We show that these considerations go much further than previously recognized and significantly restrict the kinds of closure ordinary theories of knowledge can endorse. Meeting the challenge of uncertainty aggregation requires either the restriction of knowledge-extending inferences to single premises, or eliminating epistemic uncertainty in (...) known premises. The first strategy, while effective, retains little of the original idea—conclusions even of modus ponens inferences from known premises are not always known. We then look at the second strategy, inspecting the most elaborate and promising attempt to secure the epistemic role of basic inferences, namely Timothy Williamson’s safety theory of knowledge. We argue that while it indeed has the merit of allowing basic inferences such as modus ponens to extend knowledge, Williamson’s theory faces formidable difficulties. These difficulties, moreover, arise from the very feature responsible for its virtue- the infallibilism of knowledge. (shrink)

It has recently been argued that a person’s moral judgments (about both their own and others’ actions) are constrained by the nature and extent of their relevant ignorance and, thus, that such judgments are determined in the first instance by the person’s epistemic circumstances. It has been argued, in other words, that the epistemic is logically prior to other normative (e.g., ethical, prudential, pecuniary) considerations in human decision-making, that these other normative considerations figure in decision-making only after (logically and temporally) (...) relevant ignorance has constrained the decision-maker’s menu of options. If this is right, then a person’s moral judgments in some set of circumstances should vary with their knowledge and ignorance of these circumstances. In this study, we test the hypothesis of the logical priority of the epistemic. We describe two experiments in which subjects’ knowledge and ignorance of relevant consequences were manipulated. In the second experiment, we also compared the effect of ignorance on moral judgments with that of personal force, a factor previously shown to influence moral judgments. We found broad empirical support for the armchair arguments that epistemic considerations are logically prior to normative considerations. (shrink)

It’s sometimes suggested that we can (in a sense) settle the truth-value of some statements in the language of number theory by stipulation, adopting either φ or ¬φ as an additional axiom. For example, in Clarke-Doane (2020b) and a series of recent APA presentations, Clarke-Doane suggests that any Σ01 sound expansion of our current arithmetical practice would express a truth. In this paper, I’ll argue that (given a certain popular assumption about the model-theoretic representability of languages like ours) we can’t (...) know ourselves to have any such freedom. (shrink)

Humans are morally deficient in a variety of ways. Some of these deficiencies threaten the continued existence of our species. For example, we appear to be incapable of responding to climate change in ways that are likely to prevent the consequent suffering. Some people are morally better than others, but we could all be better. The price of not becoming morally better is that when those events that threaten us occur, we will suffer from them. If we can prevent this (...) suffering from occurring, then we ought to do so. That we ought to make ourselves morally better in order to prevent very bad things from happening justifies, according to some, the development and administration of moral enhancement. I address in this paper the idea that moral enhancement could give rise to moral transhumans, or moral post-persons. Contrary to recent arguments that we shouldn’t engender moral post-persons, I argue that we should. Roughly, the reasons for this conclusion are that we can expect moral post-persons to resemble the morally best of us, our moral exemplars. Since moral exemplars promote their interests by promoting the interests of others (or they promote others’ interests at the expense of their own) we can expect moral post-persons to pursue our interests. Since we should also pursue our own interests, we should bring about moral post-persons. (shrink)

Harman and Lewis credit Kripke with having formulated a puzzle that seems to show that knowledge entails dogmatism. The puzzle is widely regarded as having been solved. In this paper we argue that this standard solution, in its various versions, addresses only a limited aspect of the puzzle and holds no promise of fully resolving it. Analyzing this failure and the proper rendering of the puzzle, it is suggested that it poses a significant challenge for the defense of epistemic closure.

As the federal government distributed remdesivir to some of the states COVID-19 hit hardest, policymakers scrambled to develop criteria to allocate the drug to their hospitals. Our state, Michigan, was among those states to receive an initial quantity of the drug from the U.S. government. The disparities in burden of disease in Michigan are striking. Detroit has a death rate more than three times the state average. Our recommendation to the state was that it should prioritize the communities that bear (...) a disproportionate burden of suffering in the allocation of the new potential treatment. This recommendation is justified not only for new drugs with uncertain effects, but also for drugs of certain benefit or vaccines. For states with significant health disparities, such as Michigan, this allocation priority may help to repair them. In fact, any other allocation strategy may make them worse. (shrink)

Most current dental ethics curricula use a deontological approach to biomedical and dental ethics that emphasizes adherence to duties and principles as properties that determine whether an act is ethical. But the actual ethical orientation of students is typically unknown. The purpose of the current study was to determine the ethical orientation of dental students in resolving clinical ethical dilemmas. First-year students from one school were invited to participate in an electronic survey that included eight vignettes featuring ethical conflicts common (...) to the health care setting. The Multidimensional Ethics Scale was used to evaluate the students’ ethical judgments of these conflicts. Students rated each vignette along 13 ethically relevant items using a 7-point scale. Nine of the thirteen items were analyzed because they represent the dominant ethical theories, including deontology. One hundred sixteen dental students successfully completed the survey. Of the analyzed items, those associated with deontology had comparatively weak associations with whether students judged the action to be ethical and whether students judged themselves likely to perform the action. Whether an action was judged to be caring had the strongest association with whether the action was judged to be ethical and whether students judged themselves likely to perform the action. These results suggest that adherence to duties or principles has weaker association with students’ ethical judgments and behavior compared to caring, which was found to be more influential in their ethical judgments and behavior. Current dental school curricula with a primary focus on deontology may no. (shrink)

Brummett and Salter propose a useful and timely taxonomy of clinical ethics expertise (2019). As the field becomes further “professionalized” this taxonomy is important, and the core of it is right. It needs some refinement around the edges, however. In their conclusion, Brummett and Salter rightly point out that there is a significant difference between the ethicist whose recommendations are procedure- and process-heavy, consensus-driven, and dialogical and the authoritarian ethicist whose recommendations flow from “private moral views” (Brummett and Salter, 2019). (...) This admission doesn’t go far enough. Brummett and Salter’s taxonomy fails to capture the notion that offering recommendations whose normative force is moral is different in kind from recommendations whose normative force is non-moral, such as those recommendations that are free of moral content or justified by convention. The difference is in kind, not scale. I argue further that clinical ethics expertise, if possible, consists at least in offering recommendations whose normative force is moral. These two claims imply that the taxonomy fails to cut clinical ethics expertise at the joints: the ethicist who offers justified non-moral normative recommendations is a different kind of ethicist from the one who offers justified moral normative recommendations, yet both are categorized as clinical ethics experts. I finish by offering a refinement of the taxonomy that more precisely categorizes clinical ethicists. (shrink)

The ‘Ordinary Language’ philosophy of the early 20th century is widely thought to have failed. It is identified with the broader so-called ‘linguistic turn’, a common criticism of which is captured by Devitt and Sterelny (1999), who quip: “When the naturalistic philosopher points his finger at reality, the linguistic philosopher discusses the finger.” (p 280) The implication is that according to ‘linguistic’ philosophy, we are not to study reality or truth or morality etc, but the meaning of the words ‘reality’, (...) ‘truth’, ‘morality’ etc. Ordinary Language philosophy has fallen so thoroughly into disrepute because it is supposed to advocate that not only are we to study words and meanings rather than the phenomena themselves (which is apparently bad enough), but we must restrict that study to words and meanings as they occur in the language used by the ordinary speaker. A number of preposterous corollaries have been taken to follow from this view. Most seriously, perhaps, and irritatingly, is that any theory which contains ‘non-ordinary’ uses of expressions is thereby ‘meaningless’ or simply false – which is clearly absurd. In this paper I show that this is a completely inaccurate picture of Ordinary Language philosophy. My aim is to correct these persistent misinterpretations, and make possible a more sensible reassessment of the philosophy. (shrink)

We critically engage two traditional views of scientific data and outline a novel philosophical view that we call the pragmatic-representational view of data. On the PR view, data are representations that are the product of a process of inquiry, and they should be evaluated in terms of their adequacy or fitness for particular purposes. Some important implications of the PR view for data assessment, related to misrepresentation, context-sensitivity, and complementary use, are highlighted. The PR view provides insight into the common (...) but little-discussed practices of iteratively reusing and repurposing data, which result in many datasets’ having a phylogeny—an origin and complex evolutionary history—that is relevant to their evaluation and future use. We relate these insights to the open-data and data-rescue movements, and highlight several future avenues of research that build on the PR view of data. (shrink)

It is plausible that current generations owe something to future generations. One possibility is that we have a duty to not harm them. Another possibility is that we have a duty to protect them. In either case, however, to satisfy the duties to future generations from environmental or political degradation, we need to engage in widespread collective action. But, as we are, we have a limited ability to do so, in part because we lack the self-discipline necessary for successful collective (...) action. Given that having an obligation hinges on being able to satisfy it, the apparent duty to future generations is at odds with our apparent inability to satisfy it. Thus, we either need to rethink our duties to future generations or rethink the nature of our abilities. I argue in this chapter that we should rethink the nature of our abilities. Specifically, we should enhance our self-discipline, which is distinct from enhancements of motivation, judgment, or emotion. Even the most intelligent, motivated, and empathetic actor is likely to slip up, which encourages others to withdraw their cooperation. Without the necessary self-discipline to sustain our public cooperative behavior, collective action is likely to fail, leaving us with one alternative: to abandon our duties to future generations. (shrink)

There are few indulgences academics can crave more than to have their work considered and addressed by leading researchers in their field. We have been fortunate to have two outstanding philosophers from whose work we have learned a great deal give ours their thoughtful attention. Grappling with Stephen Yablo’s, and Juan Comesaña’s comments and criticisms has helped us gain a better understanding of our ideas as well as their shortcomings. We are extremely grateful to them for the attentiveness and seriousness (...) with which they have considered our arguments and to philosophical studies for giving us this opportunity. Given the substantive difference between the two response papers, there is not much beyond sincere gratitude that we can covey to them jointly. We will therefore address them in turn. (shrink)

Timothy Williamson has famously argued that the principle should be rejected. We analyze Williamson's argument and show that its key premise is ambiguous, and that when it is properly stated this premise no longer supports the argument against. After canvassing possible objections to our argument, we reflect upon some conclusions that suggest significant epistemological ramifications pertaining to the acquisition of knowledge from prior knowledge by deduction.

In this article, we reflect on our experiences teaching a PWOL course called Philosophy for Living. The course uses modules focused on different historical philosophical ways of life (Epicureanism, Stoicism, Confucianism, Existentialism, etc.) to engage students in exploring how philosophy can be a way of life and how its methods, virtues, and ideas can improve their own lives. We describe and compare our experiences with two central aspects of our approach: engagement with diversity and the use of immersive experiences and (...) assignments. In particular, we discuss how we recognize and center various forms of diversity in philosophy—cultural and gender diversity, but also diversity in how and in what forms philosophy can be done and what “philosophy as a way of life” can be. We also examine how the experimental and experiential aspects of immersive assignments promote deeper understanding and create possibilities for personal transformation. (shrink)

I argue that current discussions of the epistemological significance of reflection have entangled concerns about reflection with agential concerns. I begin by showing that a central strand of internalist criticism finds externalism unsatisfactory because it fails to provide a particular kind of self-knowledge, knowledge about the epistemic status of one’s own beliefs. Identifying this internalist motivation as the desire for a kind of self-knowledge opens up new possibilities and suggests new conceptual resources. I employ one of these resources—Richard Moran’s distinction (...) between the theoretical stance and the deliberative stance—to locate two types of reflection: mere reflective awareness of one’s attitudes and agent-awareness of one’s attitudes. I then examine Ernest Sosa’s account of the importance of reflection, showing how Moran’s distinction brings out the centrality of agential concerns in Sosa’s argument for reflective knowledge. I also consider briefly its relevance to fully apt knowledge. While I focus on Sosa’s epistemology, the point extends to internalism more generally. (shrink)