© 2015, Springer-Verlag Berlin Heidelberg.Genetic studies have identified single nucleotide polymorphisms associated with the risk of prostate cancer. It remains unclear whether such genetic variants are associated with disease aggressiveness. The NCI-SPORE Genetics Working Group retrospectively collected clinicopathologic information and genotype data for 36 SNPs which at the time had been validated to be associated with PC risk from 25,674 cases with PC. Cases were grouped according to race, Gleason score and aggressiveness. Statistical analyses were used to compare the frequency (...) of the SNPs between different disease cohorts. After adjusting for multiple testing, only PC-risk SNP rs2735839 was significantly and inversely associated with aggressive and high-grade disease in European men. Similar associations with aggressive and high-grade disease were documented in African-American subjects. The G allele of rs2735839 was associated with disease aggressiveness even at low PSA levels in both European and African-American men. Our results provide further support that a PC-risk SNP rs2735839 near the KLK3 gene on chromosome 19q13 may be associated with aggressive and high-grade PC. Future prospectively designed, case-case GWAS are needed to identify additional SNPs associated with PC aggressiveness. (shrink)

This book explores aspects of William H. Poteat’s philosophical anthropology, which proposes a post-critical alternative to the prevailing dualistic conception of the person and opens a path to recovery of the pre-reflective ontological ground of the person where our personhood can be recovered and re-appropriated.

n this paper I venture to bring out and disclose an element of faith at the heart of the kind of critical inquiry that we encourage and foster in philosophy with children. It is clearly distinct from doubt, the kind of doubt we customarily associate with what makes critical thinking critical, but, properly understood, it grants to doubt and critical reflection essential roles in the process. What I mean by “faith” in this connection may be understood as trust and confidence (...) in the process of thoughtful inquiry. Our coming to recognize the centrality of faith in this sense within philosophy with children may entail some changes in our thinking about where philosophy with children fits into the larger cultural movements of our time and as well about how involvement in philosophy with children bears upon the beliefs and traditions of the sub-cultural backgrounds of children who participate. I should make clear that my perspective is informed by the philosophical insights of Michael Polanyi into what he calls the tacit dimension of all kinds of knowing, even the most rigorous and formal, especially considering knowing as an ongoing process. Polanyi focuses a great deal on what he speaks of as “the fiduciary [i.e., faith] coefficient of our knowing” – indeed, of all explicit propositions we may happen to entertain or hold. He takes as his paradigm of knowing the anticipation of an approaching discovery, whether in the natural sciences or in other areas. I will also relate my discussion to the well-known controversy between W. K. Clifford’s “The Ethics of Belief” and William James’ “The Will to Believe.” I contend that James’ most important point in that controversy has much more to do with general epistemology than philosophy of religion. (shrink)

This book explores aspects of William H. Poteat's philosophical anthropology, which proposes a post-critical alternative to the prevailing dualistic conception of the person and opens a path to recovery of the pre-reflective ontological ground of the person where our personhood can be recovered and re-appropriated.

This paper essays an account of William H. Poteat's teaching--both what he taught and how he taught--as an effort to bring his students to a realization of the bankruptcy of the modern critical sensibility and help them negotiate a transition to a post-critical intellectual sensibility. Enigmatic aspects of his teaching become intelligible through considering them in light of traditional disciplines of spiritual formation.

This paper essays an account of William H. Poteat's teaching--both what he taught and how he taught--as an effort to bring his students to a realization of the bankruptcy of the modern critical sensibility and help them negotiate a transition to a post-critical intellectual sensibility. Enigmatic aspects of his teaching become intelligible through considering them in light of traditional disciplines of spiritual formation.

Like the cracking of the genetic code and the creation of the atomic bomb, the discovery of how the brain's neurons work is one of the fundamental scientific developments of the twentieth century. The discovery of neurotransmitters revolutionized the way we think about the brain and what it means to be human yet few people know how they were discovered, the scientists involved, or the fierce controversy about whether they even existed. The War of the Soups and the Sparks tells (...) the saga of the dispute between the pharmacologists, who had uncovered the first evidence that nerves communicate by releasing chemicals, and the neurophysiologists, experts on the nervous system, who dismissed the evidence and remained committed to electrical explanations. The protagonists of this story are Otto Loewi and Henry Dale, who received Nobel Prizes for their work, and Walter Cannon, who would have shared the prize with them if he had not been persuaded to adopt a controversial theory (how that happened is an important part of this history). Valenstein sets his story of scientific discovery against the backdrop of two world wars and examines the fascinating lives of several scientists whose work was affected by the social and political events of their time. He recounts such stories as Loewi's arrest by Nazi storm troopers and Dale's efforts at helping key scientists escape Germany. The War of the Soups and the Sparks reveals how science and scientists work. Valenstein describes the observations and experiments that led to the discovery of neurotransmitters and sheds light on what determines whether a novel concept will gain acceptance among the scientific community. His work also explains the immense importance of Loewi, Dale, and Cannon's achievements in our understanding of the human brain and the way mental illnesses are conceptualized and treated. (shrink)

Abstract Galileo Then and Now (Draft of paper to be discussed at the Conference, HPD1, to be held at the Center for Philosophy of Science, University of Pittsburgh, 11-14 October 2007) William R. Shea, University of Padua The aim of this paper is to stimulate discussion on how shifts in philosophical fashion and societal moods tell us not only what to read but how to go about it, and how history and philosophy of science can jointly deepen our grasp (...) of the issues at stake. The first part highlights some of the things that have occurred in the field of Galileo studies between the monumental edition of Galileo Opere in twenty volumes, edited by Antonio Favaro between 1890 and 1909, and the new enlarged edition that will be published from 2009 onwards by a team of scholars working under Paolo Galluzzi. Part One. From Favaro to Galluzzi "Publish or perish" is an injunction that resonated as clearly in the ears of assistant professors at the end of the 19th century as it does in the first decade of the 21st. But publishing can also mean perishing when what is being edited is the work of an eminent scientist of the past. It simply does not do to offer material that is not what readers expect even if it was written by someone as famous as Galileo, and well authenticated sources were sometimes disregarded when they appeared to be of no interest. It is largely for this reason that a new national edition of Galileo's works is required. Of course, over the last hundred years, a number of letters from and to Galileo as well as a few laudatory or damning comments about his personality or his work have been uncovered, but this would not have been enough to drum up financial and scholarly support for a major editorial project. But the interesting material is Favaro had left out. Before mentioning what this material is, allow me a disclaimer. I'm not focusing on Favaro because he is a singularity, but because he illustrates how a conscientious historian can ride slipshod over evidence because of a philosophical commitment that he is only vaguely aware of, in this case naïve positivism. So what did Favaro to leave out? The answer is large chunks of three collections of manuscript notes that are bound in some of the 347 volumes of the Galilean material in the National Library in Florence. The first of these collections deals with logical treatises and related essays on Aristotelian philosophy, the second with Galileo's laboratory notes on the experiments that he carried out on the pendulum and inclined planes; and the third with astrological computations. Favaro rejected the first collection because they were "pre-Galilean" and hence could only have been trite scholastic exercises that "poor" young Galileo had to undergo in high school. He neglected the second because he had trouble making sense of them The third, astrological collection, he set aside with more trepidation since Galileo cast horoscopes for himself (at least twice), his children and his friends. But the fact that they were also, epistemologically speaking, "pre-Galilean", was enough to cast them into the outer darkness (in this case a dimly lit corridor of the National Library in Florence). The Aristotelian notes that Favaro had neglected were made available by William Wallace, who showed that Galileo culled long passages from professors at the Roman College. Galileo attacked several of Aristotle's ideas, but he never queried Aristotle's scientific realism–namely, the view that there is a uniquely true physical theory, discovered by human powers of reason and observation, and that alternative theories are consequently falls. Wallace made this the basis of his claim that Galileo created, in the heaven above and here on earth, a new science of motion by following the Aristotelian cannons laid down in the Posterior Analytics. On this view, Galileo used Aristotle's logic to subvert Aristotelian physics. It is interesting to contrast Wallace's thesis with that of philosophers of different allegiance, who offer a reconstruction of Galileo's methodology along lines that are much more modern and in which the epistemological core is no longer Aristotelian logic, but common sense instrumentalism. This is not to deny that experiments sometimes speak with a forked tongue, but to stress that methodological rules have also been known to be no more than clashing cymbals. Recent writers have also stressed that Galileo aimed his arguments at a specific audience, and that we must take cognizance of the values and whims of the society in which he operated. The sociology of science can help us understand the background against which Galileo's arguments were assessed and the reasons why he favored some rhetorical strategies over other ones. Mario Biagoli's Galileo Courtier sheds light on the Tuscan court and the Roman famiglia (as the popes styled their entourage), where Galileo found many of his readers and most of his critics. But Galileo was much more than a courtier, and I shall argue that we should use our enhanced knowledge of Galileo's education, his language, his style, and his emoluments to understand his science, not to supplant it. History and philosophy of science can combine their insights to achieve a more critical and balanced view of what actually occurred and why. (shrink)

In this contribution, I examine several key publications on the physiology of emotions from the 1860s to the 1930s. I focus on physiologists who studied the emotions prior to and following William James’s 1884 Mind article, by critically reflecting on the conceptual and practical origins and constituents of the Cannon–Bard thalamic theory of emotions. I offer a historical corrective to several major assumptions in our histories of the scientific study of emotions.

This response to review essays (covering all of my major scholarly writing) by David Rutledge and Dale Cannon appreciatively affirms most points emphasized in their respective analyses. I acknowledge that my scholarship has served my teaching, as Rutledge notes; I frequently use diagrams because I believe they usually are pedagogically very effective. My writing has strong interdisciplinary overtones and I have special interest in religion, art and education. Slowly, I have worked to integrate the ideas of Polanyi and other (...) important thinkers emphasized by my teacher William Poteat, and, as Cannon recognizes, this is not an easy task. I frequently use the term “postmodern” rather than Polanyi’s “post-critical” because the term engages the current philosophical dialogue outside of Polanyi circles. I believe that metaphorical thinking and speaking is the heart of our embodied, everyday discourse and it liberates our language and thought from the restrictions imposed by the “pseudo-objectivism” of the standard way of carrying on philosophical endeavor. I have focused on the epistemological rather than the existential aspects of Polanyi’s thought. (shrink)

William James’s theory of emotion has been controversial since its inception, and a basic analysis of Cannon’s critique is provided. Research on the impact of facial expressions, expressive behaviors, and visceral responses on emotional feelings are each reviewed. A good deal of evidence supports James’s theory that these types of bodily feedback, along with perceptions of situational cues, are each important parts of emotional feelings. Extensions to James’s theory are also reviewed, including evidence of individual differences in the (...) effect of bodily responses on emotional experience. (shrink)

The effects of grandparent survival on child survival and mean interbirth interval, both independent of and relative to parent survival, were investigated in a historical population. Families for the data set were reconstituted from the parish and census records of Cambridgeshire, 1770–1861. In a logistic regression analysis, only the mother’s and the maternal grandmother’s survival were found to be significant predictors of child survival. Maternal grandmother’s survival was found to influence child survival both via maternal survival and independent of maternal (...) survival. Grandparent survival was not found to influence mean interbirth interval. These findings are reviewed with respect to other studies of grandmothering, the Grandmother Hypothesis, and the evolutionary significance of human female postreproductive lifespan. (shrink)

We tend to suppose that the ancient Greeks had primitive ideas of the self, of responsibility, freedom, and shame, and that now humanity has advanced from these to a more refined moral consciousness. Bernard Williams's original and radical book questions this picture of Western history. While we are in many ways different from the Greeks, Williams claims that the differences are not to be traced to a shift in these basic conceptions of ethical life. We are more like the ancients (...) than we are prepared to acknowledge, and only when this is understood can we properly grasp our most important differences from them, such as our rejection of slavery. The author is a philosopher, but much of his book is directed to writers such as Homer and the tragedians, whom he discusses as poets and not just as materials for philosophy. At the center of his study is the question of how we can understand Greek tragedy at all, when its world is so far from ours. Williams explains how it is that when the ancients speak, they do not merely tell us about themselves, but about ourselves. _Shame and Necessity_ gives a new account of our relations to the Greeks, and helps us to see what ethical ideas we need in order to live in the modern world. (shrink)

Former Google advertising strategist, now Oxford-trained philosopher James Williams launches a plea to society and to the tech industry to help ensure that the technology we all carry with us every day does not distract us from pursuing our true goals in life. As information becomes ever more plentiful, the resource that is becoming more scarce is our attention. In this 'attention economy', we need to recognise the fundamental impacts of our new information environment on our lives in order to (...) take back control. Drawing on insights ranging from Diogenes to contemporary tech leaders, Williams's thoughtful and impassioned analysis is sure to provoke discussion and debate. Williams is the inaugural winner of the Nine Dots Prize, a new Prize for creative thinking that tackles contemporary social issues. This title is also available as Open Access. (shrink)

An analysis of two heuristic strategies for the development of mechanistic models, illustrated with historical examples from the life sciences. In Discovering Complexity, William Bechtel and Robert Richardson examine two heuristics that guided the development of mechanistic models in the life sciences: decomposition and localization. Drawing on historical cases from disciplines including cell biology, cognitive neuroscience, and genetics, they identify a number of "choice points" that life scientists confront in developing mechanistic explanations and show how different choices result in (...) divergent explanatory models. Describing decomposition as the attempt to differentiate functional and structural components of a system and localization as the assignment of responsibility for specific functions to specific structures, Bechtel and Richardson examine the usefulness of these heuristics as well as their fallibility—the sometimes false assumption underlying them that nature is significantly decomposable and hierarchically organized. When Discovering Complexity was originally published in 1993, few philosophers of science perceived the centrality of seeking mechanisms to explain phenomena in biology, relying instead on the model of nomological explanation advanced by the logical positivists (a model Bechtel and Richardson found to be utterly inapplicable to the examples from the life sciences in their study). Since then, mechanism and mechanistic explanation have become widely discussed. In a substantive new introduction to this MIT Press edition of their book, Bechtel and Richardson examine both philosophical and scientific developments in research on mechanistic models since 1993. (shrink)

In the Critique of Judgment, Kant claims that genius is a talent for art, but not for science. Despite his restriction of genius to the domain of fine art, several recent interpreters have suggested that genius has a role to play in Kant’s account of cognition in general and scientific practice in particular. In this paper, I explore Kant’s reasons for excluding genius from science as well as the reasons that one might nevertheless be tempted to think that his account (...) allows room for the scientific genius. I then argue that Kant’s concerns are not only epistemic, but also moral, and together, they give us good reason for resisting the veneration of genius. (shrink)

Epigenetics impacts gene–culture coevolution by amplifying phenotypic variation, including clustering, and bridging the difference in timescales between genetic and cultural evolution. The dual inheritance model described by Uchiyama et al. could be modified to provide greater explanatory power by incorporating epigenetic effects.

Summary The task of this article is to review the principle of relational determination, as described by Solomon Asch (1952) which expands over Karl Duncker’s (1939) critique of ethical relativism. Relational determination has much to offer to the therapeutic community first with regard to interpersonal relations and social relations. My main goal is to extend this relational analysis to intrapsychic life, which may expose new potentialities for internal conflict resolution and personal integration, predicated on the cultivation of relational understanding (i.e., (...) recognition of relational determination in organization of conscious experience). But this approach is best illustrated in its application to value differences and conflict across societies, which are typically viewed from the absolutist or relativist perspective. The principle of relationality casts doubt on elementaristic assumptions common to both (e.g., meaning constancy). Such assumptions lead to some ill-considered conclusions: of irreconcilable moral differences dividing both individuals and groups, deprived of any basis in understanding. Those views fail to consider the contexts underlying the meanings and valuations we impute. When these are taken into account, Duncker’s hypothesis of an invariant relation between meaning and value finds support. Value differences (or changes) need not represent fundamental differences in morality, but instead (factual) differences in understanding of the situation. If so, then value differences may indeed be both understandable and reconcilable. Relational determination reveals this same potentiality with regard to intrapsychic conflict, where the same presumption of irreconcilable differences must be overcome. Work by Erich Neumann provides a valuable depth psychological perspective on this inner conflict, which accords surprisingly well with the relationality principle in particular and field theory in general. From that vantage point, psychological defenses may be recognized as structural properties of yet unreconciled psychical fields. Gestalt theory’s relational view, which aligns well with Neumann’s account of a “new ethic” helps to reveal the processes by which these defensive postures might abate, as value realms that earlier dwelt in hostile opposition develop more of a conscious and respectful relation with each other, as the individual inches toward greater wholeness. (shrink)

The standard argument to the conclusion that artificial intelligence (AI) constitutes an existential risk for the human species uses two premises: (1) AI may reach superintelligent levels, at which point we humans lose control (the ‘singularity claim’); (2) Any level of intelligence can go along with any goal (the ‘orthogonality thesis’). We find that the singularity claim requires a notion of ‘general intelligence’, while the orthogonality thesis requires a notion of ‘instrumental intelligence’. If this interpretation is correct, they cannot be (...) joined as premises and the argument for the existential risk of AI turns out invalid. If the interpretation is incorrect and both premises use the same notion of intelligence, then at least one of the premises is false and the orthogonality thesis remains itself orthogonal to the argument to existential risk from AI. In either case, the standard argument for existential risk from AI is not sound.—Having said that, there remains a risk of instrumental AI to cause very significant damage if designed or used badly, though this is not due to superintelligence or a singularity. (shrink)

Bernard Williams's remarkable essay on morality confronts the problems of writing moral philosophy, and offers a stimulating alternative to more systematic accounts which seem nevertheless to have left all the important issues somewhere off the page. Williams explains, analyses and distinguishes a number of key positions, from the purely amoral to notions of subjective or relative morality, testing their coherence before going on to explore the nature of 'goodness' in relation to responsibilities and choice, roles, standards, and human nature. The (...) final chapters make a fascinating enquiry into what morality is about, looking beyond happiness to other human aims and ideals. This re-issue of a classic in moral philosophy includes a new foreword by the author. (shrink)

One of the great American pragmatic philosophers alongside Peirce and Dewey, William James (1842–1910) delivered these eight lectures in Boston and New York in the winter of 1906–7. Though he credits Peirce with coining the term 'pragmatism', James highlights in his subtitle that this 'new name' describes a philosophical temperament as old as Socrates. The pragmatic approach, he says, takes a middle way between rationalism's airy principles and empiricism's hard facts. James' pragmatism is both a method of interpreting ideas (...) by their practical consequences and an epistemology which identifies truths according to their useful outcomes. Furnished with many examples, the lectures illustrate pragmatism's response to classic problems such as the question of free will versus determinism. Published in 1907, this work further develops James's approach to religion and morality, introduced in The Will to Believe (1897) and The Varieties of Religious Experience (1902), both reissued in this series. (shrink)

A pioneer in early studies of the human mind and founder of that peculiarly American philosophy called Pragmatism, William James remains America's most widely read philosopher. Generations of students have been drawn to his lucid presentations of philosophical problems. His works, now being made available for the first time in a definitive edition, have a permanent place in American letters and a continuing influence in philosophy and psychology. The essays gathered in the posthumously published Essays in Radical Empiricism formulate (...) ideas that had brewed in James's mind for thirty years as he sought a way out of the philosophical dilemmas generated by the new psychology of the late nineteenth century. They constitute the explanatory core of his doctrine of radical empiricism, a doctrine that charts his course between the absolute idealism he could not accept and, at the other extreme, the law of associationism, which reduces knowledge to sheer contiguity of ideas. In his introduction John J. McDermott describes the historical background and the genesis of James's theory and considers the objections raised by its opponents. (shrink)

This is the first critical study of The Logic of Sense, Gilles Deleuze's most important work on language and ethics, as well as the main source of his vital philosophy of the event.James Williams explains the originality of Deleuze's work with careful definitions of all his innovative terms and a detailed description of the complex structure he constructs. This reading makes connections to his ground-breaking work on literature, to his critical but also progressive relation to the sciences, and to his (...) controversial denial of the priority of standard logics, human values and 'meaning' in thinking.This book will open new debates and develop current ones around Deleuze's work in philosophy, politics, literature, linguistics, cultural studies and sociology. (shrink)

Information can be public among a group. Whether or not information is public matters, for example, for accounts of interdependent rational choice, of communication, and of joint intention. A standard analysis of public information identifies it with (some variant of) common belief. The latter notion is stipulatively defined as an infinite conjunction: for p to be commonly believed is for it to believed by all members of a group, for all members to believe that all members believe it, and so (...) forth. This analysis is often presupposed without much argument in philosophy. Theoretical entrenchment or intuitions about cases might give some traction on the question, but give little insight about why the identification holds, if it does. The strategy of this paper is to characterize a practical-normative role for information being public, and show that the only things that play that role are (variants of) common belief as stipulatively characterized. In more detail: a functional role for “taking a proposition for granted” in non-isolated decision making is characterized. I then present some minimal conditions under which such an attitude is correctly held. The key assumption links this attitude to beliefs about what is public. From minimal a priori principles, we can argue that a proposition being public among a group entails common commitment to believe among that group. Later sections explore partial converses to this result, the factivity of publicity and publicity from the perspective of outsiders to the group, and objections to the aprioricity of the result deriving from a posteriori existential presuppositions. (shrink)

The debate over the existence of a “public sphere” in China’s Late Qing/Early Republican era began nearly three decades ago, but it has yet to generate a special socio-cultural review on the “Confucian social imaginary” of the Chinese people. The article builds on existing “economic-political approach” and “idea-communication approach” to argue decisive factors hindering the development of a Habermasian “public sphere.” These includes (1) people’s traditional-collectivist lifestyle, (2) lack of understanding of “universal equality,” (3) conservative self-positioning during social transition, (4) (...) regionalist attitude toward outsiders, (5) lack of access to Enlightenment ideas, (6) disregard for parliamentary systems, and (7) ignorance of the rule of law. (shrink)

This new volume of philosophical papers by Bernard Williams is divided into three sections: the first Action, Freedom, Responsibility, the second Philosophy, Evolution and the Human Sciences; in which appears the essay which gives the collection its title; and the third Ethics, which contains essays closely related to his 1983 book Ethics and the Limits of Philosophy. Like the two earlier volumes of Williams's papers published by Cambridge University Press, Problems of the Self and Moral Luck, this volume will be (...) welcomed by all readers with a serious interest in philosophy. It is published alongside a volume of essays on Williams's work, World, Mind, and Ethics: Essays on the Ethical Philosophy of Bernard Williams, edited by J. E. J. Altham and Ross Harrison, which provides a reappraisal of his work by other distinguished thinkers in the field. (shrink)

Introduction: the advance of governmentality -- Foucault, power, and governmentality: introduction; what is governmentality?; beyond the microphysics of power?; from theory of the state to genealogy of the state; history of the art of government; pastoral power; raison d'état; liberal governmentality; five propositions on foucault and governmentality -- Governmentality 3.4.7.: introduction; governmentality after Foucault; governmentality and the political sciences; some problems in governmentality -- Foucault effect redux? some notes on international governmentality studies: constellation; a few preliminary observations; problems and debates (...) in international governmentality studies -- Reconnecting governmentality and genealogy: introduction; genealogy and governmentality; pluralizing genealogy; practicing genealogy; lines of descent: the family tree of power?; counter-memory and re-serialization; the retrieval of forgotten struggles and subjugated knowledges -- Conclusion: encountering governmentality: governmentality as a new cartography of power; from mapping to encountering; governmentality and politics. (shrink)

As humans, we want to live meaningfully, yet we are often driven by impulse. In Religion and the Meaning of Life, Williams investigates this paradox – one with profound implications. Delving into felt realities pertinent to meaning, such as boredom, trauma, suicide, denial of death, and indifference, Williams describes ways to acquire meaning and potential obstacles to its acquisition. This book is unique in its willingness to transcend a more secular stance and explore how one's belief in God may be (...) relevant to life's meaning. Religion and the Meaning of Life's interdisciplinary approach makes it useful to philosophers, religious studies scholars, psychologists, students, and general readers alike. The insights from this book have profound real-world applications – they can transform how readers search for meaning and, consequently, how readers see and exist in the world. (shrink)

This is a theoretical paper. A little theory goes a long way in history, for me; but it is good to collect as much as is feasible in one paper, so that gaps and inconsistencies can be noticed. I use ‘theory’ in the definite sense of a set of hypothetical statements such that deductions can be made and compared with data, facts, or generalizations obtained in some other way than as derivation from theory. Deductions need not always be rigorous, and (...) there may be two or more ‘solutions’ obtainable, of which the scientist may choose one and discard the rest . I am ignoring the differences between propositions, demonstrations, problems, and the like. Actually there must always be several statements, including rules of procedure, in the set; but often many are assumed and only the new or controversial one is stated as ‘the’ hypothesis of Mr X. (shrink)

Bernard Williams; XIV*—The Truth in Relativism, Proceedings of the Aristotelian Society, Volume 75, Issue 1, 1 June 1975, Pages 215–228, https://doi.org/10.1093.