We propose a novel paradigmatic approach to sentient reality as a whole, with specific application to Information-guided DNA dynamics, leading to a triadic genomic configuration , which accommodates besides the parental hereditar legacy, a transcendental originating highly complex guiding matrix able to control the specific way the protein-synthesis is performed. The Self’s own “Soul Genome”, transcending the zero point energy interdimensional barrier, couples to the zygote’s quantum-governed energetic configuration by way of resonant bands of subtle energy superposition effects at the (...) instance of fertilization, triggered by a Zinc-spark related biophotonic bridge. Thus, unique secondary torsion parameters in the DNA strands determine the way the basic protein-generating template is read, supplying the new entity’s psycho-cognitive particularities along purposeful developmental vectors. (shrink)

Critics of commodification often claim that the buying and selling of some good communicates disrespect or some other inappropriate attitude. Such semiotic critiques have been leveled against markets in sex, pornography, kidneys, surrogacy, blood, and many other things. Brennan and Jaworski (2015a) have recently argued that all such objections fail. They claim that the meaning of a market transaction is a highly contingent, socially constructed fact. If allowing a market for one of these goods can improve the supply, access or (...) quality of the good, then instead of banning the market on semiotic grounds, they urge that we should revise our semiotics. In this reply, I isolate a part of the meaning of a market transaction that is not socially constructed: our market exchanges always express preferences. I then show how cogent semiotic critiques of some markets can be constructed on the basis of this fact. (shrink)

Many take the claim that you cannot ‘get’ an ‘ought’ from an ‘is’ to imply that non- moral beliefs are by themselves incapable of justifying moral beliefs. I argue that this is a mistake and that the position that moral beliefs are justified exclusively by non-moral beliefs—a view that I call moral inferentialism—presents an attractive non-sceptical moral epistemology.

As we build increasingly intelligent machines, we confront difficult questions about how to specify their objectives. One approach, which we call human-centered, tasks the machine with the objective of learning and satisfying human objectives by observing our behavior. This paper considers how human-centered AI should conceive the humans it is trying to help. We argue that an Aristotelian model of human agency has certain advantages over the currently dominant theory drawn from economics.

Ethical beliefs are not justified by familiar methods. We do not directly sense ethical properties, at least not in the straightforward way we sense colors or shapes. Nor is it plausible to think – despite a tradition claiming otherwise – that there are self-evident ethical truths that we can know in the way we know conceptual or mathematical truths. Yet, if we are justified in believing anything, we are justified in believing various ethical propositions e.g., that slavery is wrong. If (...) ethical beliefs are not justified in these familiar ways, how are they justified? -/- In her widely read, “Modern Moral Philosophy,” and in her short complimentary paper, “On Brute Facts,” G.E.M. Anscombe answers this question with a compelling and unorthodox account of justification in ethics. Because of her polemical tone and because “Modern Moral Philosophy” does so much else besides, this contribution is easy to overlook. But her account is worth taking seriously, since (a) it is an underappreciated yet plausible account that sidesteps traditional controversies, (b) it offers rich conceptual tools for interpreting and critiquing ethical theories, (c) it suggests an appealing account of the place of ethical theory in ethical knowledge and, (d) it provides useful guidance for doing applied ethics. (shrink)

This chapter develops Moral Occasionalism, according to which moral facts are grounded in certain natural facts, which are called sub-moral grounds, and these sub-moral grounds influence us in such a way as to induce largely correct moral beliefs. Moral Occasionalism is designed to explain the correlation of moral beliefs with the moral facts—and to do so in a way that is consistent with non-interactionist views, according to which moral facts neither influence nor are influenced by moral beliefs. It is argued (...) that moral non-naturalists and others who are committed to non-interactionist views ought to be in the business of defending Moral Occasionalism. The chapter shows that Moral Occasionalism has major advantages over its chief non-interactionist rival, namely David Enoch’s “godless pre-established harmony” view. The chapter anticipates and responds to several objections. (shrink)

In the beginning of the COVID pandemic, researchers and bioethicists called for human challenge trials to hasten the development of a vaccine for COVID. However, the fact that we lacked a specific, highly effective treatment for COVID led many to argue that a COVID challenge trial would be unethical and we ought to pursue traditional phase III testing instead. These ethical objections to challenge trials may have slowed the progress of a COVID vaccine, so it is important to evaluate their (...) merit. One common way of doing so is to make an analogy to other social practices that are relevantly similar and which we currently sanction. We submit that non-directed live organ donation (NDLOD) is a promising analogy. After arguing that the risks to volunteers for each activity appear similar, we explore potential disanalogies that would undermine the comparison. We note that there are differences in both the kind and certainty of benefit secured by NDLOD compared to challenge trials. We conclude these differences are insufficient to make NDLOD permissible and challenge trials impermissible. Ultimately, if we think the risks associated with NDLOD are ethically permissible, then we should think the same of the risks associated with COVID challenge trials. (shrink)

Using automated systems to avoid the need for human discretion in government contexts – a scenario we call ‘rule by automation’ – can help us achieve the ideal of a free and equal society. Drawing on relational theories of freedom and equality, we explain how rule by automation is a more complete realization of the rule of law and why thinkers in these traditions have strong reasons to support it. Relational theories are based on the absence of human domination and (...) hierarchy, which automation helps us achieve. Nevertheless, there is another understanding of relational theories where what matters is the presence of valuable relationships with those in power. Exploring this further might help us see when and why we should accept human discretion. (shrink)

Previous studies have shown that zinc deficiency leads to apoptosis of neuronal precursor cells in vivo and in vitro. In addition to the role of p53 as a nuclear transcription factor in zinc deficient cultured human neuronal precursors (NT-2), we have now identified the translocation of phosphorylated p53 to the mitochondria and p53-dependent increases in the pro-apoptotic mitochondrial protein BAX leading to a loss of mitochondrial membrane potential as demonstrated by a 25% decrease in JC-1 red:green fluorescence ratio. (...) Disruption of mitochondrial membrane integrity was accompanied by efflux of the apoptosis inducing factor (AIF) from the mitochondria and translocation to the nucleus with a significant increase in reactive oxygen species (ROS) after 24 h of zinc deficiency. Measurement of caspase cleavage, mRNA, and treatment with caspase inhibitors revealed the involvement of caspases 2, 3, 6, and 7 in zinc deficiency-mediated apoptosis. Down-stream targets of caspase activation, including the nuclear structure protein lamin and polyADP ribose polymerase (PARP), which participates in DNA repair, were also cleaved. Transfection with a dominant-negative p53 construct and use of the p53 inhibitor, pifithrin- ␮, established that these alterations were largely dependent on p53. Together these data identify a cascade of events involving mitochondrial p53 as well as p53-dependent caspase-mediated mechanisms leading to apoptosis during zinc deficiency. (shrink)

Collected essays consider points of affinity and friction between Walter Benjamin and Martin Heidegger. Despite being contemporaries, Walter Benjamin and Martin Heidegger never directly engaged with one another. Yet, Hannah Arendt, who knew both men, pointed out common ground between the two. Both were concerned with the destruction of metaphysics, the development of a new way of reading and understanding literature and art, and the formulation of radical theories about time and history. On the other hand, their life trajectories and (...) political commitments were radically different. In a 1930 letter, Benjamin told a friend that he had been reading Heidegger and that if the two were to engage with one another, “sparks will fly.” Acknowledging both their affinities and points of conflict, this volume stages that confrontation, focusing in particular on temporality, Romanticism, and politics in their work. (shrink)

Abstract: Background: Tuberculosis is a major public health problem world-wide, it is contagious disease caused by organism mycobacterium tuberculosis. The aim of this study was to assess the level of zinc and albumin in newly diagnosed patients with pulmonary tuberculosis in Khartoum state. Methods: Fifty blood samples were collected from newly diagnosed pulmonary tuberculosis patients during the period between April to May 2017, chosen randomly from Abu Anga Teaching Hospital and fifty blood samples from apparently healthy individuals serve as (...) control group. Estimation of serum albumin level was performed using spectrophotometer and estimation of serum zinc by using flame atomic absorption spectrophotometer. The results were analyzed by using (SPSS) computer program. Results: The study showed that, serum level of zinc and albumin were significantly decrease in patients compared to control group (mean± SD for cases versus control). For zinc :( 0.16±0.05 versus 0.58± 0.13 mg/l, P. value= 0.000). For albumin: (2.5±0.58 versus 4.1±0.31g/dl, P. value= 0.000). The result of this study showed that, there was statically significant decrease in the mean of BMI in patients compared to control group. Mean ±SD for case versus control (18.7±0.17 versus 21.5±1.7). The result of this study showed that, pulmonary tuberculosis most common among age between (20-39) years (52%) and (48%) of patients between age (40-58) years and this disease most abundant in males (78%) than females (22%). Persons correlation showed that there was no correlation between serum zinc level and age (r =-0.128, p. value=0.374) also there was no correlation between the level of serum albumin and age (r=0.137, p. value =0.344). Conclusion: The serum levels of zinc and albumin were significantly decreased in newly diagnosed patients with pulmonary tuberculosis in Khartoum state. (shrink)

The present paper looks at one of the most thorough articles on the intelligence of GPT, research conducted by engineers at Microsoft. Although there is a great deal of value in their work, I will argue that, for familiar philosophical reasons, their methodology, ‘Black-box Interpretability’ is wrongheaded. But there is a better way. There is an exciting and emerging discipline of ‘Inner Interpretability’ (also sometimes called ‘White-box Interpretability’) that aims to uncover the internal activations and weights of models in order (...) to understand what they represent and the algorithms they implement. In my view, a crucial mistake in Black-box Interpretability is the failure to appreciate that how processes are carried out matters when it comes to intelligence and understanding. I can’t pretend to have a full story that provides both necessary and sufficient conditions for being intelligent, but I do think that Inner Interpretability dovetails nicely with plausible philosophical views of what intelligence requires. So the conclusion is modest, but the important point in my view is seeing how to get the research on the right track. Towards the end of the paper, I will show how some of the philosophical concepts can be used to further refine how Inner Interpretability is approached, so the paper helps draw out a profitable, future two-way exchange between Philosophers and Computer Scientists. (shrink)

In his new book, Knowledge: The Philosophical Quest in History, Steve Fuller returns to core themes of his program of social epistemology that he first outlined in his 1988 book, Social Epistemology. He develops a new, unorthodox theology and philosophy building upon his testimony in Kitzmiller v. Dover Area School District in defense of intelligent design, leading to a call for maximal human experimentation. Beginning from the theological premise rooted in the Abrahamic religious tradition that we are created in the (...) image of God, Fuller argues that the spark of the divine within us distinguishes us from animals. I argue that Fuller’s recent work takes us away from key insights of his original work. In contrast, I advocate for a program of social epistemology rooted in evolutionary science rather than intelligent design, emphasize a precautionary and ecological approach rather than a proactionary approach that favors risky human experimentation, and attend to our material and sociological embeddedness rather than a transhumanist repudiation of the body. (shrink)

In the ancient world, the Greeks believed that all great insights came from one of nine muses, divine sisters who brought inspiration to mere mortals. In the modern world, few people still believe in the muses, but we all still love to hear stories of sudden inspiration. Like Newton and the apple, or Archimedes and the bathtub (both another type of myth), we’re eager to hear and to share stories about flashes of insight. But what does it take to be (...) actually creative? How to have such a flash insight? Turns out, there is real science behind "aha moments." We prefer to call it “intuilytics.”. (shrink)

During the past decades, our image ofHomo neanderthalensishas changed dramatically. Initially, Neanderthals were seen as primitive brutes. Increasingly, however, Neanderthals are regarded as basically human. New discoveries and technologies have led to an avalanche of data, and as a result of that it becomes increasingly difficult to pinpoint what the difference between modern humans and Neanderthals really is. And yet, the persistent quest for a minimal difference which separates them from us is still noticeable in Neanderthal research. Neanderthal discourse is (...) a vantage point from which the logic of ‘us’ versus ‘other’ is critically reconsidered. Studying contemporary academic literature and science autobiographies from an oblique perspective, focusing not on Neanderthals as objects, but on the dynamics of interaction between Neanderthal researchers and their finds, basic convictions at work in this type of research are retrieved. What is at issue is not the actual distinction between modern humans and Neanderthals, but rather the dualistic construction of human and nonhuman. Neanderthal understanding is affected by the desire to safeguard human uniqueness. The overall trend is to identify the human mark or spark, which defines us as favoured ‘winners’. The paradoxes emerging in contemporary Neanderthal discourse are symptomatic of the fact that a dualistic style of thinking is no longer tenable. (shrink)

He claims he wants it to bring moments of calmness. Maybe, but I found it to be more of a fun way to spark some creativity… and thinking.

For me, it’s more of an inspiration to observe widely, think about what I’ve seen in a little deeper manner, and enjoy a laugh or two.

For long time, especially in the West, there is old paradigm that is strong separation between science and theology/religion matters. Especially, such a diverging path started from Galileo persecution, and also other patterns where religious authority seem to hold the last word on scientific issues. Other area of this World, seems to not hold such a diverging path, for instance it can be read in the works of physicist turned to religious philosopher, for instance Pavel Florensky and Nesteruk. That is (...) why we also discuss shortly about those scientists in this book. In the last chapter, we discuss about eureka, an experience which for a long time was attributed to divine spark or “God’s favor to an artist or to a scientist, such luminaries like Newton, Pascal, Leibniz etc.” Nonetheless, new methodology appears to be able to be generated once we accept balanced brain approach, where left brain and right brain hemispheres of humans can work together. (shrink)

Though the vegetarian movement sparked by Peter Singer’s book Animal Liberation has achieved some success, there is more animal suffering caused today due to factory farming than there was when the book was originally written. In this paper, I argue that there may be a technological solution to the problem of animal suffering in intensive factory farming operations. In particular, I suggest that recent research indicates that we may be very close to, if not already at, the point where we (...) can genetically engineer factory-farmed livestock with a reduced or completely eliminated capacity to suffer. In as much as animal suffering is the principal concern that motivates the animal welfare movement, this development should be of central interest to its adherents. Moreover, I will argue that all people concerned with animal welfare should agree that we ought to replace the animals currently used in factory farming with animals whose ability to suffer is diminished if we are able to do so. (shrink)

The accumulation of potentially toxic elements (PTEs) has raised public awareness due to harmful contamination to both human and marine creatures. This study was designed to determine the concentration of copper (Cu), zinc (Zn), cadmium (Cd), and nickel (Ni) in the intestine, kidney, muscle, gill, and liver tissues of local commercial edible fish, fourfinger threadfin (Eleutheronema tetradactylum), and black pomfret (Parastromateus niger) collected from Morib (M) and Kuala Selangor (KS). Among the studied PTEs, Cu and Zn were essential elements (...) to regulate body metabolism with certain dosages required while Cd and Ni were considered as non-essential elements that posed chronic and carcinogenic risk. The concentration of PTEs in fish tissue samples was analyzed using flame atomic absorption spectrometry (F-AAS). By comparing the concentration of PTEs in fish tissues as a bioindicator, the environmental risk of Morib was more serious than Kuala Selangor because both fish species collected from Morib resulted in a higher PTEs concentration. For an average 62 kg adult with a fish ingestion rate (FIR) of 0.16 kg/person/day in Malaysia, the estimated weekly intake (EWI) of Cd from the consumption of E. tetradactylum (M: 0.0135 mg/kg; KS: 0.0134 mg/kg) and P. niger (M: 0.0140 mg/kg; KS: 0.0132 mg/kg) had exceeded the provisional tolerable weekly intake (Cd: 0.007 mg/kg) established by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and oral reference dose (ORD) values of Cd (0.001 mg/kg/day) as provided by the United States Environmental Protection Agency (USEPA) regional screening level, thus it posed chronic risks for daily basis consumption. Besides, the value of the carcinogenic risk of Cd (0.7−3 to 0.8−3) and Ni (0.5−3 to 0.6−3) were in between the acceptable range (10−6 to 10−4) of the health index that indicates a relatively low possibility cancer occurrence to the consumers in both Morib and Kuala Selangor. This study recommended FIR to be 0.80 kg/person/day to reduce the possibility of posing chronic and carcinogenic risks while at the same time obtaining the essential nutrients from the fish. (shrink)

Tropical grasses are fast growing and often used for phytoremediation. Three different types of tropical grasses: Vetiver (V. zizanoides), Imperata (I. cylindrical) and Pennisetum (P. purpureum) tested in different growth media of spiked heavy metal contents under the glasshouse environment of RimbaIlmu for 60-day. The growth performance, metals tolerance and phyto-assessment of cadmium (Cd), lead (Pb), zinc (Zn) and copper (Cu) in shoots and roots were assessed using flame atomic absorption spectrometry (FAAS).Tolerance index (TI), translocation factor (TF), biological accumulation (...) coefficient (BAC), biological concentration factor (BCF), and uptake efficacy was applied to evaluate the metal translocation ability among all three grasses. All three grasses showed significantly higher (p<0.05) accumulation of the total heavy metals in the spiked metal treatment compared with other tested treatments. Vetiver accumulated remarkably higher total concentration of Cd (93.08 ± 3.81 mg/kg) and Zn (1284.00 ± 234.83 mg/kg) than both Imperata and Pennisetum. The overall trend of heavy metals accumulation for all three grasses followed the order of Zn>Pb>Cd>Cu. The results of study suggested that both Imperata and Pennisetum are commendable and potential phytoextractors for Zn as well as phytostabilizers for Cd, Pb and Cu, respectively. (shrink)

The mental health crisis and loneliness epidemic have sparked a growing interest in leveraging artificial intelligence (AI) and chatbots as a potential solution. This report examines the benefits and risks of incorporating chatbots in mental health treatment. AI is used for mental health diagnosis and treatment decision-making and to train therapists on virtual patients. Chatbots are employed as always-available intermediaries with therapists, flagging symptoms for human intervention. But chatbots are also sold as stand-alone virtual therapists or as friends and lovers. (...) There is evidence that these uses of AI and chatbots can provide better quality service, improve accessibility, and lower costs. The systems can reduce the stigma and shame of sharing their problems and leverage a mass of biometric and behavioral data to supplement self-reports. As the systems' intelligence rapidly improves, they will need to be rigorously tested for the accuracy and precision of their diagnoses and the quality of their interactions with patients. As chatbots become indistinguishable from humans and leverage their superhuman capacity to detect affect and draw on knowledge of a patient’s life, patients will be drawn to attribute personality to and relationship with the chatbot. Consequently, it will be essential to study what the “therapeutic alliance” with an actual human counselor provides and the risks of patients attributing such a relationship to a one-sided or “parasocial” relationship. (shrink)

Synthetic cells spark intriguing questions about the nature of life. Projects such as BaSyC (‘Building a Synthetic Cell’) aim to build an entity that mimics how living cells work from basic components. But what kind of entity would a synthetic cell really be? I assess this question from a philosophical perspective, and show how early fictional narratives of artificial life – such as the laboratory scene in Goethe’s Faust – can help us to understand the challenges faced by synthetic (...) biology researchers. (shrink)

RESUMO A alimentação é o fator que mais onera um sistema de produção animal. Assim, a utilização de diferentes estratégias de alimentação dos animais ainda é o grande desafio da nutrição animal, principalmente, levando em consideração as exigências nutricionais de diferentes categorias de ruminantes, em especial bovinos em regiões tropicais, haja vista que a sazonalidade na produção de forragens afeta diretamente a produção bovina, promovendo inadequação no atendimento das exigências nutricionais dos animais principalmente em minerais e vitaminas. Uma alimentação que (...) não atenda as exigências nutricionais dos ruminantes gera prejuízos no sistema de produção, além de, em casos mais graves, ocasionar a perda do animal. Estudos que abordam o efeito e a importância de vitaminas e minerais na nutrição bovina são escassos e necessários. Recentemente a National Research Council (NRC) apresentou novos registros das exigências nutricionais das vitaminas e minerais. Essas alterações proporcionam um impacto econômico significativo em relação à nutrição animal. Nesse sentido, objetivou-se com esta revisão trazer informações acerca de vitaminas e minerais na nutrição de bovinos em pastejo. -/- Palavras-chave: Alimentação animal; forragem; pastagem; requerimentos nutricionais; ruminantes; vitaminas lipossolúveis (Source: AGROVOC). -/- ABSTRACT Animal feed is the factor that most burdens a production system. Thus, the use of different animal feeding strategies is still the great challenge of animal nutrition, taking into account the nutritional requirements of different categories of ruminants, especially cattle in tropical regions, given that seasonality in forage production directly affects cattle production, promoting inadequacy in meeting the nutritional requirements of animals, mainly in minerals and vitamins. A diet that does not meet the nutritional requirements of ruminants generates losses in the production system, in addition to, in more serious cases, causing the loss of the animal. Studies that address the effect and importance of vitamins and minerals in bovine nutrition are scarce and necessary. Recently the National Research Council (NRC) presented new records of the nutritional requirements of vitamins and minerals. These changes provide a significant economic impact on animal nutrition. In this sense, the objective of this review was to bring information about vitamins and minerals in the nutrition of grazing cattle. -/- Keywords: Animal feeding; fat soluble vitamins; forage; nutritional requirements; pasture feeding; ruminants (Source: AGROVOC). -/- REFERÊNCIAS BIBLIOGRÁFICAS -/- 1. Cavalcanti CPL, Silva e Macedo TJ, Gois GC, Menezes VG, Monte APO, Silva AD, Silva DJM, Silva EO, Araújo GGL, Rodrigues RTS, Wischral A, Matos MHT, Queiroz MAA. 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Coronavirus is a viral irresistible sickness brought about by SARS- COV2. Its clinical signs and side effects are on an expansive range going from asymptomatic to serious confusions like multi-organ disappointment, thromboembolism, and extreme pneumonia with respiratory disappointment. More awful results and higher death rates have been accounted for in the old, individuals with co-morbidities, and malnourished people. Sustenance is central to acceptable wellbeing and safe capacity. It frames an essential segment of therapy modalities for different intense and persistent infections, (...) particularly where a causative therapy isn't yet perceived. Despite the fact that reviews tending to the part of explicit supplements in COVID-19 are still at a beginning phase, accessible proof recommends that addressing the necessities of a variety of large scale and miniature supplements (energy, proteins, fats, nutrients A, D, E, C, B nutrients, iron, selenium, zinc, and so forth) Additionally, supplements are Immune System Might Promote Recovery for Mild COVID-19 Patients Impact of Coronavirus on Education in India Review 466 determinants of the sythesis of the gut microbiota that thusly impacts the attributes of safe reactions in the body. (shrink)

Digital technology has prompted philosophers to rethink some of the fundamental categories we use to make sense of the world and ourselves. Particularly, the concept of ‘identity’ and its reconfiguration in the digital age has sparked much debate in this regard. While many studies have addressed the impact of the digital on personal and social identities, the concept of ‘collective identity’ has been remarkably absent in such inquiries. In this article, I take the context of social movements as an entry (...) point to discuss the reconfiguration of collective identity in social media environments. I do so by introducing a narrative approach to collective identity. I argue that Twitter’s affordances invite new ways of constructing collective identities and imply a shifting relationship between the individual and the collective. (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)

This paper adopts two modeling tools, namely, multiple linear regression (MLR) and artificial neural networks (ANNs), to predict the concentrations of heavy metals (zinc, boron, and manganese) in surface waters of the Oued Inaouen watershed flowing towards Inaouen, using a set of physical-chemical parameters. XLStat was employed to perform multiple linear and nonlinear regressions, and Statista 10 was chosen to construct neural networks for modeling and prediction. The effectiveness of the ANN- and MLR-based stochastic models was assessed by the (...) determination coefficient (R²), the sum squared error (SSE) and a review of fit graphs. The results demonstrate the value of ANNs for prediction modeling. Drawing on supervised learning and back propagation, the ANN-based prediction models adopt an architecture of [18-15-1] for zinc, [18-11-1] for manganese, and [18-8-1] for boron, and perform effectively with a single cached layer. It was found that the MLR-based prediction models are substantially less accurate than those based on the ANNs. In addition, the physical-chemical parameters being investigated are nonlinearly correlated with the levels of heavy metals in the surface waters of the Oued Inaouen watershed flowing towards Inaouen. (shrink)

Building on Kant’s text, I develop and defend an account of a specific kind of anger, which Kant calls “aesthetically sublime rage”. Unlike other kinds of anger, aesthetically sublime rage does not play a motivational function for the subject throughout the time she is feeling rage. Because of this, aesthetically sublime rage escapes the problems that anger has when it motivates one to act. Despite not playing such a direct motivational function, aesthetically sublime rage can have an indirect motivational role (...) that is future-directed. As such, it can help the subject achieve and realize moral ends in the future, when the rage subsides and proper reflection is more likely to be achieved. Indeed, the experience of aesthetically sublime rage a) can help the subject realize that she cares about pursuing moral progress; b) can spark in her critical inquiry about what such progress should entail; c) can prepare her to value something against her self-centered interest. (shrink)

An alliance of established experts on critical care, Front Line COVID-19 Critical Care Alliance (FLCCC), has published two protocols for treatment of COVID-19. The first one, methylprednisolone, ascorbic acid, thiamine, and heparin (MATH+), is intended for hospital and intensive care unit treatment of pulmonary phases of the disease. It is based on affordable, commonly available components: anti-inflammatory corticosteroids (methylprednisolone, "M"), high-dose vitamin C infusion (ascorbic acid, "A"), vitamin B1 (thiamine, "T"), anticoagulant heparin ("H"), antiparasitic agent ivermectin, and supplemental components ("+") (...) including melatonin, vitamin D, elemental zinc, and magnesium. -/- The MATH+ protocol has received scarce attention due to the World Health Organization (WHO) advising against the use of corticosteroids in the beginning of the pandemic. In addition, randomized controlled clinical trials were required as a condition for adoption of the protocol. As the hospital mortality rate of MATH+ treated patients was approximately a quarter of the rate of patients receiving a standard of care, the authors of the protocol considered performing such trials unethical. Other parties have later performed clinical trials with corticosteroids and anticoagulants, which has led to a more widespread adoption of these components. -/- In October 2020, ivermectin was upgraded from an optional component to an essential component of the protocol. According to the authors, ivermectin is considered the first agent effective for both prophylaxis (prevention) of COVID-19 and for treatment of all phases of COVID-19 including outpatient treatment of the early symptomatic phase. Therefore, at the end of October 2020, a separate ivermectin-based I-MASK+ protocol for prophylaxis and early outpatient treatment of COVID-19 was published. (shrink)

In the realm of pixels and virtual spaces, the art of placemaking transcends physical confines, weaving a digital mosaic of voices and visions. Feminist digital placemaking emerges as a vibrant brushstroke on this canvas, painting online environments with the hues of inclusion, safety, and empowerment. The "Woman, Life, Freedom" movement in Iran, mirrored in the "Year of Hope" digital exhibition, showcases the transformative power of feminist digital placemaking in amplifying voices, knitting solidarity, and challenging oppressive narratives. The "Woman, Life, Freedom" (...) movement, sparked by the tragic demise of Mahsa (Jina) Amini, unfolds like a poignant narrative, with women scripting the chapters of resistance. This movement, a collage of courage and defiance, has found a digital stage in the "Year of Hope" exhibition, where each artwork tells a story, each pixel a testament to the unyielding spirit of Iranian women. (shrink)

This paper argues that public statues of persons typically express a positive evaluative attitude towards the subject. It also argues that states have duties to repudiate their own historical wrongdoing, and to condemn other people’s serious wrongdoing. Both duties are incompatible with retaining public statues of people who perpetrated serious rights violations. Hence, a person’s being a serious rights violator is a sufficient condition for a state’s having a duty to remove a public statue of that person. I argue that (...) this applies no less in the case of the ‘morally ambiguous’ wrongdoer, who both accomplishes significant goods and perpetrates serious rights violations. The duty to remove a statue is a defeasible duty: like most duties, it can be defeated by lesser-evil considerations. If removing a statue would, for example, spark a violent riot that would risk unjust harm to lots of people, the duty to remove could be outweighed by the duty not to foreseeably cause unjust harm. This would provide a lesser-evil justification for keeping the statue. But it matters that the duty to remove is outweighed, rather than negated, by these consequences. Unlike when a duty is negated, one still owes something in cases of outweighing. And it especially matters that it is outweighed by the predicted consequences of wrongful behaviour by others. (shrink)

In December 2015, Wales became the first country in the UK to move away from an opt-in system in organ procurement. The new legislation introduces the concept of deemed consent whereby a person who neither opt in nor opt out is deemed to have consented to donation. The data released by the National Health Service in July 2017 provide an excellent opportunity to assess this legislation in light of concerns that it would decrease procurement rates for living and deceased donation, (...) as well as sparking an increase in family refusals. None of these concerns have come to pass, with Wales experiencing more registered donors, fewer family refusals and more living donations. However, as the number of actual donors has dropped slightly from a high level, the situation must be monitored closely in the years to come. (shrink)

The Ganga is one of the most sacred and worshipped river of India, is regarded as the cradle of Indian civilization. Uttar Pradesh the largest state of India is blessed with the most holy and important river in its region but due to increased urbanization and industrialization this river is under intimidation of high water pollution. The major objectives of the present study were to investigate heavy metal's concentration in water and sediments of the River Ganga. Water and sediments collected (...) from different locations were analyzed for Iron (Fe), Chromium (Cr), Lead (Pb),Nickel(Ni) and Zinc(Zn). The concentration of these heavy metals in the study area indicates that the river is highly polluted. The possible sources of these heavy metal pollutants are diverse, originated from natural or anthropogenic sources and point sources. The concentrations determined were more than the maximum admissible and desirable limit when compared with the National and International organizations like WHO, USEPA. Exposure to heavy metals has been linked to chronic and acute toxicity developing retardation, neurotoxicity, kidney damage, various cancers, liver damage, lung damage, and fragile bones and even death in instances of very high exposure. (shrink)

The potential of memory modification techniques (MMTs) has raised concerns and sparked a debate in neuroethics, particularly in the context of identity and authenticity. This paper addresses the question whether and how MMTs influence authenticity. I proceed by drawing two distinctions within the received views on authenticity. From this, I conclude that an analysis of MMTs based on a dual-basis, process view of authenticity is warranted, which implies that the influence of MMTs on authenticity crucially depends on the specifics of (...) how memory modification would eventually work. Therefore, I continue with a systematic analysis of possible properties of MMTs in which I distinguish between the dimensions of memories and the kinds of experiences that can be modified as well as the properties of the process of memory modification. The impact of MMTs on authenticity is analyzed regarding the possible properties of MMTs and based on a narrative approach to authenticity which fulfills the requirements of a dual-basis, process view of authenticity. Lastly, I explore the potential of MMTs to shift the balance between self-discovery and self-creation within authenticity and thereby alter the concept itself as well as the value of authenticity. (shrink)

Tropical grasses are fast growing and often used for phytoremediation. Three different types of tropical grasses: Vetiver (V. zizanoides), Imperata (I. cylindrical) and Pennisetum (P. purpureum) tested in different growth media of spiked heavy metal contents under the glasshouse environment of RimbaIlmu for 60-day. The growth performance, metals tolerance and phyto-assessment of cadmium (Cd), lead (Pb), zinc (Zn) and copper (Cu) in shoots and roots were assessed using flame atomic absorption spectrometry (FAAS).Tolerance index (TI), translocation factor (TF), biological accumulation (...) coefficient (BAC), biological concentration factor (BCF), and uptake efficacy was applied to evaluate the metal translocation ability among all three grasses. All three grasses showed significantly higher (pPb> Cd >Cu. The results of study suggested that both Imperata and Pennisetum are commendable and potential phytoextractors for Zn as well as phytostabilizers for Cd, Pb and Cu, respectively. (shrink)

In this chapter I give an account of how our judgments of anger often play out in certain political instances. While contemporary philosophers of emotion have provided us with check box guides like “fittingness” and “size” for evaluating anger, I will argue that these guides do not by themselves help us escape the tendency to mark or unmark the boxes selectively, inconsistently, and erroneously. If anger—particularly anger in a political context—can provide information and spark positive change or political destruction, (...) then we have moral reasons to evaluate it properly. But can we? And what are the limitations and errors we often face when evaluating anger? -/- I will begin by laying out the ways in which we evaluate emotions and the moral and epistemic errors we attribute to the angry agent in judgments of disapproval. Then I attempt to answer the question: How do we judge political anger improperly? An improper evaluation, in my view, does not take into account relevant information that is needed to evaluate the anger. An overly generous, uninformed, biased, or selfish process of evaluation produces an improper evaluation. We see this occur when we immediately evaluate anger. I will also identify two social discursive practices of improper evaluation as well as the moral and epistemic errors committed when anger evaluators participate in these practices. (shrink)

A term expresses a thick concept if it expresses a specific evaluative concept that is also substantially descriptive. It is a matter of debate how this rough account should be unpacked, but examples can help to convey the basic idea. Thick concepts are often illustrated with virtue concepts like courageous and generous, action concepts like murder and betray, epistemic concepts like dogmatic and wise, and aesthetic concepts like gaudy and brilliant. These concepts seem to be evaluative, unlike purely descriptive concepts (...) such as red and water. But they also seem different from general evaluative concepts. In particular, thick concepts are typically contrasted with thin concepts like good, wrong, permissible, and ought, which are general evaluative concepts that do not seem substantially descriptive. When Jane says that Max is good, she appears to be evaluating him without providing much description, if any. Thick concepts, on the other hand, are evaluative and substantially descriptive at the same time. For instance, when Max says that Jane is courageous, he seems to be doing two things: evaluating her positively and describing her as willing to face risk. Because of their descriptiveness, thick concepts are especially good candidates for evaluative concepts that pick out properties in the world. Thus they provide an avenue for thinking about ethical claims as being about the world in the same way as descriptive claims. -/- Thick concepts became a focal point in ethics during the second half of the twentieth century. At that time, discussions of thick concepts began to emerge in response to certain disagreements about thin concepts. For example, in twentieth-century ethics, consequentialists and deontologists hotly debated various accounts of good and right. It was also claimed by non-cognitivists and error-theorists that these thin concepts do not correspond to any properties in the world. Dissatisfaction with these viewpoints prompted many ethicists to consider the implications of thick concepts. The notion of a thick concept was thought to provide insight into meta-ethical questions such as whether there is a fact-value distinction, whether there are ethical truths, and, if there are such truths, whether these truths are objective. Some ethicists also theorized about the role that thick concepts can play in normative ethics, such as in virtue theory. By the beginning of the twenty-first century, the interest in thick concepts had spread to other philosophical disciplines such as epistemology, aesthetics, metaphysics, moral psychology, and the philosophy of law. -/- Nevertheless, the emerging interest in thick concepts has sparked debates over many questions: How exactly are thick concepts evaluative? How do they combine evaluation and description? How are thick concepts related to thin concepts? And do thick concepts have the sort of significance commonly attributed to them? This article surveys various attempts at answering these questions. (shrink)

The summer of 2020 witnessed perhaps the largest protests in American history in response to police and vigilante brutality against the black community. New protests are still erupting every time another suppressed video, such as of Daniel Prude, surfaces, or another killing, such as Breonna Taylor’s, goes unpunished. As communities demand meaningful reform, the point – or pointlessness – of “implicit bias training” takes on renewed urgency. Implicit bias trainings aim to raise awareness about the unwitting or unwilling prejudices and (...) stereotypes that shape our habits of thinking, feeling, and navigating through the social world. These trainings have been widely adopted by businesses, schools, and law enforcement agencies. Do they make any difference? -/- Although I conduct implicit bias trainings myself (including for courts, judges, police, and attorneys), I share many critics’ concerns. Many trainings are too brief and oversimple, and too often their real function is to permit organisations to “check a box” to protect against litigation, rather than to spark real change. But “implicit bias training” is just another way of saying “education about implicit bias,” and, like all kinds of education, it can be done well or poorly. If implicit bias is one important piece of a large and complex puzzle, then education about it – when done right – should have a meaningful role to play in helping us understand ongoing inequities and enact reforms. (shrink)

Derek Parfit’s early work on the metaphysics of persons has had a vast influence on Western philosophical debates about the nature of personal identity and moral theory. Within the study of Buddhism, it also has sparked a continuous comparative discourse, which seeks to explicate Buddhist philosophical principles in light of Parfit’s conceptual framework. Examining important Parfitian-inspired studies of Buddhist philosophy, this article points out various ways in which a Parfitian lens shaped, often implicitly, contemporary understandings of the anātman doctrine and (...) its relation to Buddhist ethics. I discuss in particular three dominant elements appropriated by Parfitian-inspired scholarship: Parfit’s theoretical categories; philosophical problems raised by his reductionist theory of persons; and Parfit’s argumentative style. I argue that the three elements used in this scholarship constitute different facets of one methodological approach to cross-cultural philosophy, which relies on Western terminology and conceptual schemes to establish a conversation with non-Western philosophy. I suggest that while this methodology is fruitful in many ways, philosophy as a cosmopolitan space may benefit significantly from approaching Buddhist philosophy using its own categories and terminology. (shrink)

This past decade has seen a great resurgence of interest in the perception of change. Change has, of course, long been recognized as a phenomenon worthy of study, and vision scientists have given their attention to it at various times in the past (for a review, see Rensink, 2002a). But things seem different this time around. This time, there is an emerging belief that instead of being just another visual ability, the perception of change may be something central to our (...) ‘visual life’, and that the mechanisms that underlie it may provide considerable insight into the operation of much of our visual system. This development may have been sparked by a number of factors: technology that allowed the easy creation of dynamic displays, a feeling in the air that it was time for something new, or it may have simply been a matter of chance. But once underway, this development was fueled by results, results that included both novel behavioral effects and new theoretical insights. Many of these centered around change blindness, the failure of observers to see large changes that are made contingent upon.. (shrink)

In the aftermath of the financial crisis, heightened awareness of ethical issues has sparked increased efforts toward moral education within universities and businesses. In many cases, psychological tests are used to measure whether moral development occurs. As long as we understand moral development as synonymous with moral progress, this may seem like a good sign: it would appear that such tests give us a handle on moral progress. Alas, moral development and moral progress are two very different things. And although (...) we know a lot about moral development, what we know has little to do with moral progress. Let’s untangle both concepts. (shrink)

Could a Nazi soldier or terrorist be courageous? The Courage Problem asks us to answer this sort of question, and then to explain why people are reluctant to give this answer. The present paper sheds new light on the Courage Problem by examining a controversy sparked by Bill Maher, who claimed that the 9/11 terrorists’ acts were ‘not cowardly.’ It is shown that Maher's controversy is fundamentally related to the Courage Problem. Then, a unified solution to both problems is provided. (...) This solution entails that gutsy people who lack good ends are not courageous. (shrink)

Population obesity and associated morbidities pose significant public health and economic burdens in the United Kingdom, United States, and globally. As a response, public health initiatives often seek to change individuals’ unhealthy behavior, with the dual aims of improving their health and conserving health care resources. One such initiative—taxes on sugar‐sweetened beverages (SSB)—has sparked considerable ethical debate. Prominent in the debate are arguments seeking to demonstrate the supposed impermissibility of SSB taxes and similar policies on the grounds that they interfere (...) with individuals’ freedom and autonomy. Commentators have often assumed that a policy intended to restrict or change private individuals’ consumption behavior will necessarily curtail freedom and, as a corollary, will undermine individuals’ autonomy with respect to their consumption choices. Yet this assumption involves a conceptual mistake. To address the misunderstanding, it’s necessary to attend to the differences between negative liberty, freedom of options, and autonomy. Ultimately, concerns about negative liberty, freedom, and autonomy do not provide strong grounds for opposing SSB taxes. (shrink)

(Part of a symposium on an OUP collection of Paul Russell's papers on free will and moral responsibility). Paul Russell’s The Limits of Free Will is more than the sum of its parts. Among other things, Limits offers readers a comprehensive look at Russell’s attack on the problematically idealized assumptions of the contemporary free will debate. This idealization, he argues, distorts the reality of our human predicament. Herein I pose a dilemma for Russell’s position, critical compatibilism. The dilemma illuminates the (...) tension between Russell’s critical and compatibilist commitments. The problem is not obviously insurmountable, and as a compatibilist who is sympathetic to the view, my aim is to spark further discussion. (shrink)

In this paper we discuss James Buchanan’s contribution in the narrow domain of understanding committee voting under majority rule. We then go on to discuss Charles Plott’s seminal experimental work on the topic that sparked a wave of public choice experimental work. However, given Plott’s claims that Buchanan influenced him significantly, it is puzzling that his work with Morris Fiorina explores a question outside of those which Buchanan and Tullock found interesting. We suggest several ways to resolve this tension. Our (...) chapter concludes by discussing a lacuna in the experimental public choice literature in which Buchanan was particularly interested—logrolling, or vote trading. (shrink)

Background independence begins life as an informal property that a physical theory might have, often glossed as 'doesn't posit a fixed spacetime background'. Interest in trying to offer a precise account of background independence has been sparked by the pronouncements of several theorists working on quantum gravity that background independence embodies in some sense an essential discovery of the General Theory of Relativity, and a feature we should strive to carry forward to future physical theories. This paper has two goals. (...) The first is to investigate what a world must be like in order to be truly described by a background independent theory given extant accounts of background independence. The second is to argue that there are no non-empirical reasons to be more confident in theories that satisfy extant accounts of background independence than in theories that don't. The paper concludes by drawing a general moral about a way in which focussing primarily on mathematical formulations of our physical theories can adversely affect debates in the metaphysics of physics. (shrink)

Some collateral harms affecting enemy civilians during a war are agentially mediated – for example, the US-led invasion of Iraq in 2003 sparked an insurgency which killed thousands of Iraqi civilians. I call these ‘collaterally enabled harms.’ Intuitively, we ought to discount the weight that these harms receive in the ‘costs’ column of our ad bellum proportionality calculation. But I argue that an occupying military force with de facto political authority has a special obligation to provide minimal protection to the (...) civilian population. As a result, when an occupying military force collaterally enables a harm affecting the civilian population, the weight that the harm ought to receive in the ad bellum proportionality calculation is unaffected by the fact that the harm is agentially mediated – it ought to be weighed at least as heavily as those harms that the occupying force collaterally commits directly. As a result, satisfying the ad bellum proportionality constraint in wars of territorial occupation is more difficult than it has been thought. (shrink)

Case reports about patients undergoing Deep Brain Stimulation (DBS) for various motor and psychiatric disorders - including Parkinson’s Disease, Obsessive Compulsive Disorder, and Treatment Resistant Depression - have sparked a vast literature in neuroethics. Questions about whether and how DBS changes the self have been at the fore. The present chapter brings these neuroethical debates into conversation with recent research in moral psychology. We begin in Section 1 by reviewing the recent clinical literature on DBS. In Section 2, we consider (...) whether DBS poses a threat to personal identity. In Section 3 we argue for engagement with recent empirical work examining judgements of when identity changes. We conclude in Section 4 by highlighting a range of ethical issues raised by DBS, including various cross-cultural considerations. (shrink)

Over four decades, research and policy have created layers of understandings in the quest for "good" corporate governance. The corporate excesses of the 1970s sparked a search for market mechanisms and disclosure to empower shareholders. The UK-focused problems of the 1990s prompted board-centric, structural approaches, while the fall of Enron and many other companies in the early 2000s heightened emphasis on director independence and professionalism. With the financial crisis of 2007–09, however, came a turn in some policy approaches and in (...) academic literature seeking a different way forward. This paper explores those four phases and the discourse each develops and then links each to assumptions about accountability and cognition. After the financial crisis came pointers in policy and practice away from narrow, rationalist prescriptions and toward what the philosopher Stephen Toulmin calls "reasonableness". Acknowledging that heightens awareness of complexity and interdependence in corporate governance practice. The paper then articulates a research agenda concerning what "reasonably" good corporate governance might entail. (shrink)