We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 controls and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls. Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents. Probands were more likely to carry an additional large copy-number variant when compared to matched controls. The clinical (...) features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity indicates that this two-hit model might be more generally applicable to neuropsychiatric disease. © 2010 Nature America, Inc. All rights reserved. (shrink)

We still ask the question ‘What is Enlightenment?’ Every generation seems to offer new and contradictory answers to the question. In the last thirty or so years, the most interesting characterisations of Enlightenment have been by historians. They have told us that there is one Enlightenment, that there are two Enlightenments, that there are many Enlightenments. This has thrown up a second question, ‘How Many Enlightenments?’ In the spirit of collaboration and criticism, I answer both questions by arguing in this (...) article that there are in fact three Enlightenments: Radical, Sceptical and Liberal. These are abstracted from the rival theories of Enlightenment found in the writings of the historians Jonathan Israel, John Robertson and J.G.A. Pocock. Each form of Enlightenment is political; each involves an attitude to history; each takes a view of religion. They are arranged in a sequence of increasing sensitivity to history, as it is this which makes it possible to relate them to each other and indeed propose a composite definition of Enlightenment. The argument should be of interest to anyone concerned with ‘the Enlightenment’ as a historical phenomenon or with ‘Enlightenment’ as a philosophical abstraction. (shrink)

For over half a century there have been concerns about increases in the occurrence of academic misconduct by higher education students and this is now claimed to have reached crisis proportions (e.g. Mostrous & Kenber, 2016a ). This study explores the extent to which multi-national faculty judge the effectiveness of higher education institutions in dealing with such misconduct. A survey of multi-national higher education faculty was conducted to explore the perceived barriers to the implementation of academic integrity processes. It asked (...) faculty how likely some hypothetical scenarios of failures of such processes were to occur in the real world of higher education institutions. 63% of our participants perceived there to be institutional and/or faculty barriers to effectively dealing with academic misconduct. Mostly, they blamed the higher education model for this which, in the interests of mass education, has come to prioritise the need for institutions to focus more on their quantity of output as corporate business enterprises than on the integrity of their output as educators. In discussing participants’ comments, about the relationship of faculty to their employing institutions, Schein and Scheins’ ( 2016 ) theory of three levels of organisational culture was used. Participants’ comments suggested that, at the deepest level of organisational culture i.e. basic underlying taken-for-granted assumptions about beliefs and values, inadequate integrity measures have tended to become normalised. Despite the often considerable, efforts of the institutions, organisational barriers were noted which mitigate against faculty behaving professionally i.e. from doing a ‘good job’ in respect of student academic misconduct. Some blame was also placed on faculty. We argue that apparent institutional inability to effectively manage the integrity process, has potentially significant consequences for wider society. We discuss ways in which this situation might be improved including a recommendation that governments regulate this aspect of the corporate social responsibility of higher education institutions as they do other aspects, requiring that it be managed effectively. (shrink)

We have been oversold on the base rate fallacy in probabilistic judgment from an empirical, normative, and methodological standpoint. At the empirical level, a thorough examination of the base rate literature (including the famous lawyer–engineer problem) does not support the conventional wisdom that people routinely ignore base rates. Quite the contrary, the literature shows that base rates are almost always used and that their degree of use depends on task structure and representation. Specifically, base rates play a relatively larger role (...) in tasks where base rates are implicitly learned or can be represented in frequentist terms. Base rates are also used more when they are reliable and relatively more diagnostic than available individuating information. At the normative level, the base rate fallacy should be rejected because few tasks map unambiguously into the narrow framework that is held up as the standard of good decision making. Mechanical applications of Bayes's theorem to identify performance errors are inappropriate when (1) key assumptions of the model are either unchecked or grossly violated, and (2) no attempt is made to identify the decision maker's goals, values, and task assumptions. Methodologically, the current approach is criticized for its failure to consider how the ambiguous, unreliable, and unstable base rates of the real world are and should be used. Where decision makers' assumptions and goals vary, and where performance criteria are complex, the traditional Bayesian standard is insufficient. Even where predictive accuracy is the goal in commonly defined problems, there may be situations (e.g., informationally redundant environments) in which base rates can be ignored with impunity. A more ecologically valid research program is called for. This program should emphasize the development of prescriptive theory in rich, realistic decision environments. (shrink)

Despite promising early work into the role of immune cells such as eosinophils in adipose tissue (AT) homeostasis, recent findings revealed that elevating the number of eosinophils in AT alone is insufficient for improving metabolic impairments in obese mice. Eosinophils are primarily recognized for their role in allergic immunity and defence against parasitic worms. They have also been detected in AT and appear to contribute to adipose homeostasis and drive energy expenditure, but the underlying mechanisms remain elusive. It has long (...) been recognized that immune cells such as macrophages respond to external signals to regulate adipose homeostasis and energy balance, however, less is known about the relevance of eosinophil activity in AT. As the authors propose in this review, given recent debate over the relative importance of their tissue‐specific abundance, the stage is now set for exploring the functionality and activation states of AT eosinophils. (shrink)

This book assesses how Vatican II opened up the Catholic Church to encounter, dialogue, and engagement with other world religions. Opening with a contribution from the President of the Pontifical Council for Interreligious Dialogue, Cardinal Jean-Louis Tauran, it next explores the impact, relevance, and promise of the Declaration Nostra Aetate before turning to consider how Vatican II in general has influenced interfaith dialogue and the intellectual and comparative study of world religions in the postconciliar decades, as well as the contribution (...) of particular past and present thinkers to the formation of current interreligious and comparative theological methods. Additionally, chapters consider interreligious dialogue vis-à-vis theological anthropology in conciliar documents; openness to the spiritual practices of other faith traditions as a way of encouraging positive interreligious encounter; the role of lay and new ecclesial movements in interreligious dialogue; and the development of Monastic Interreligious Dialogue. Finally, it includes a range of perspectives on the fruits and future of Vatican’s II’s opening to particular faiths such as Judaism, Islam, Hinduism, and Buddhism. (shrink)

Most donated organs in the United States come from brain dead donors, while a small percentage come from patients who die in “controlled,” or expected, circumstances, typically after the family or surrogate makes a decision to withdraw life support. The number of organs available for transplant could be substantially if donations were permitted in “uncontrolled” circumstances–that is, from people who die unexpectedly, often outside the hospital. According to projections from the Institute of Medicine, establishing programs permitting “uncontrolled donation after circulatory (...) determination of death,” or uDCDD, throughout the United States has the potential to provide 22,000 more donation opportunities annually. In contrast, U.S. controlled donation after circulatory determination of death, or cDCDD, cases have increased progressively over the past decade from 87 to 848 donors, but currently account for only 10.6 percent of all deceased donors. Following the IOM recommendations, several projects exploring the feasibility of uDCDD were funded by the federal government, including a grant from the Health Resources and Services Administration that supported a pilot project in New York City in which the authors of this article participated.A key feature of our protocol, and indeed of many uDCDD protocols, is the initiation of preservation methods such as chest compressions and extracorporeal membrane oxygenation shortly after death in order to perfuse and preserve the donor's organs. Critics of uDCDD argue that the means of determining death deviates from generally ascribed principles. They assert that reinstituting circulation in order to preserve organs has the effect of “undoing” the prior determination of death. The result is that cDCDD is widely accepted and practiced routinely even though it only marginally increases the number of organs available for transplantation, and uDCDD is widely considered unacceptable despite being ethically embraced and proven to significantly increase organ donation opportunities in other countries. This article explores the evolution of this counterintuitive state of affairs and calls for a policy that, in line with the IOM report, allows for both cDCDD and uDCDD protocols. (shrink)

This new edition of Alexander Miller’s highly readable introduction to contemporary metaethics provides a critical overview of the main arguments and themes in twentieth- and twenty-first-century contemporary metaethics. Miller traces the development of contemporary debates in metaethics from their beginnings in the work of G. E. Moore up to the most recent arguments between naturalism and non-naturalism, cognitivism and non-cognitivism. From Moore’s attack on ethical naturalism, A. J. Ayer’s emotivism and Simon Blackburn’s quasi-realism to anti-realist and best opinion accounts (...) of moral truth and the non-reductionist naturalism of the ‘Cornell realists’, this book addresses all the key theories and ideas in this field. As well as revisiting the whole terrain with revised and updated guides to further reading, Miller also introduces major new sections on the revolutionary fictionalism of Richard Joyce and the hermeneutic fictionalism of Mark Kalderon. The new edition will continue to be essential reading for students, teachers and professional philosophers with an interest in contemporary metaethics. (shrink)

Intracellular NLR (Nucleotide‐binding domain and Leucine‐rich Repeat‐containing) receptors are sensitive monitors that detect pathogen invasion of both plant and animal cells. NLRs confer recognition of diverse molecules associated with pathogen invasion. NLRs must exhibit strict intramolecular controls to avoid harmful ectopic activation in the absence of pathogens. Recent discoveries have elucidated the assembly and structure of oligomeric NLR signalling complexes in animals, and provided insights into how these complexes act as scaffolds for signal transduction. In plants, recent advances have provided (...) novel insights into signalling‐competent NLRs, and into the myriad strategies that diverse plant NLRs use to recognise pathogens. Here, we review recent insights into the NLR biology of both animals and plants. By assessing commonalities and differences between kingdoms, we are able to develop a more complete understanding of NLR function. (shrink)

We give a novel approach to proving soundness and completeness for a logic (henceforth: the object-logic) that bypasses truth-in-a-model to work directly with validity. Instead of working with specific worlds in specific models, we reason with eigenworlds (i.e., generic representatives of worlds) in an arbitrary model. This reasoning is captured by a sequent calculus for a _meta_-logic (in this case, first-order classical logic) expressive enough to capture the semantics of the object-logic. Essentially, one has a calculus of validity for the (...) object-logic. The method proceeds through the perspective of reductive logic (as opposed to the more traditional paradigm of deductive logic), using the space of reductions as a medium for showing the behavioural equivalence of reduction in the sequent calculus for the object-logic and in the validity calculus. Rather than study the technique in general, we illustrate it for the logic of Bunched Implications (BI), thus IPL and MILL (without negation) are also treated. Intuitively, BI is the free combination of intuitionistic propositional logic and multiplicative intuitionistic linear logic, which renders its meta-theory is quite complex. The literature on BI contains many similar, but ultimately different, algebraic structures and satisfaction relations that either capture only fragments of the logic (albeit large ones) or have complex clauses for certain connectives (e.g., Beth’s clause for disjunction instead of Kripke’s). It is this complexity that motivates us to use BI as a case-study for this approach to semantics. (shrink)

Ecological developmental biology (eco‐devo) explores the mechanistic relationships between the processes of individual development and environmental factors. Recent studies imply that some of these relationships have deep evolutionary origins, and may even pre‐date the divergences of the simplest extant animals, including cnidarians and sponges. Development of these early diverging metazoans is often sensitive to environmental factors, and these interactions occur in the context of conserved signaling pathways and mechanisms of tissue homeostasis whose detailed molecular logic remain elusive. Efficient methods for (...) transgenesis in cnidarians together with the ease of experimental manipulation in cnidarians and sponges make them ideal models for understanding causal relationships between environmental factors and developmental mechanisms. Here, we identify major questions at the interface between animal evolution and development and outline a road map for research aimed at identifying the mechanisms that link environmental factors to developmental mechanisms in early diverging metazoans.Also watch the Video Abstract. (shrink)

This paper is a reconstruction of Walter Benjamin's philosophy of language, especially as it expressed in 1916's “On Language as Such and the Language of Man”. I read Benjamin's theory as a contribution to what Charles Taylor has called the “expressivist” tradition that includes eighteenth century thinkers like J.G. Herder and J.G. Hamann. Hamann's work and his interpretation of the theological concept of condescension are of particular importance. Although Benjamin's views are often regarded as impenetrable or mystical, they are relevant (...) to and, in part, motivated by concerns of more mainstream twentieth century philosophy of language, in particular Russell's paradox. His “metaphysics of language” understands reference or designation, central to analytic theories of meaning, as derived from a more fundamental, aesthetic meaning. (shrink)

Societal problems are not solved by individualistic interventions, but nor are systemic approaches optimal given their neglect of the social psychology underpinning group dynamics. This impasse can be addressed through agroup-level analysis (a “g-frame”) that social identity theorizing affords. Using a g-frame can make policy interventions more adaptive, inclusive, and engaging.

Spiel und Arbeit gelten oft als Gegensätze: Das Spiel als freie Betätigung menschlicher Vermögen, die Arbeit als deren Subordination unter einen äußeren Zweck. Die Festlegung des Spiels auf konsequenzlose Wiederholbarkeit hat ihm den Ruf des Unernsten eingetragen, während das Abzwecken der Arbeit auf die Nützlichkeit ihres Resultats im Bund mit der Sorge ums Dasein steht. Auf einen zweiten Blick scheint dieser Gegensatz jedoch, gerade in den hochentwickeltsten Ausprägungen beider Tätigkeitsformen, zu verschwinden. So kann eine hochgradige Rationalisierung von Spielpraktiken in Arbeit (...) umschlagen, wie etwa im Leistungssport, oder ein komplexer Arbeitsvorgang selbstzweckhafte Momente und Eigendynamiken gewinnen, die ihm Spielcharakter verleihen. Auch andere technologische Entwicklungen geben Anlass dazu, das Verhältnis von Spiel und Arbeit noch einmal grundsätzlich zu bedenken, etwa im Hinblick auf: adaptive Systeme in der Robotik, serious games, Kreativitätstechniken in Unternehmenskulturen, wissenschaftliche Experimentalanordnungen, Online-Rollenspiele oder die Kommodifizierung nicht-zweckrationaler Lebensvollzüge, die traditionell vom Begriff produktiver Arbeit ausgeschlossen waren – einschließlich der Spielräume, die durch neue Umwelt- und Biotechniken erschlossen werden. Die Beschaffenheit der jeweils zum Einsatz kommenden Mittel und Verfahren sowie die Setzung, Variation oder Preisgabe von Zwecken können den Charakter von Spiel und Arbeit sowie ihr Verhältnis zueinander bestimmen oder verändern. Mit Beiträgen von Francesco Amigoni, Andreas Brenneis, Petra Gehring, Armin Grunwald, Florian Heßdörfer, Wolfram Ette, Christoph Hubig, Andreas Kaminski, Nicole C. Karafyllis, Christian Klager, Alexander Kluge, Uwe Küster, Oliver Laas, Hildrun Lampe, Pieter Lemmens, Stefan Meißner, Alfred Nordmann, Felix Raczkowski, Markus Rautzenberg, Michael Resch, Nicole J. Saam, Viola Schiaffonati, Alexander Schmidl, Jan C. Schmidt und G. Günter Voß. (shrink)

There are two ways in which Symbol and Myth are related to each other. Firstly, a certain class of symbols represents the remnant of myths. Such figures as, e.g. the Dragon, Leviathan, etc., which we find in Biblical literature, are not used in the full sense of the underlying mythological conception, but in a metaphorical sense. They are chosen by the author because of their mythical associations, but not in their mythical meaning. Ametaphor of this kind is, as H. J. (...) D. Astley put it, “broken-down mythology.” There are a great many symbols both in poetry and mysticism which must be understood as the relics of mythical thought. We owe a great deal to ethnology for having thrown light on this relation. The microcosm-macrocosm symbolism, for instance, becomes more intelligible if we consider that in primitive mythology the world emerged from the body of primordial man. The gifts to the dead appear in later forms of sacrificial cults as purely symbolical, but there is no doubt that originally they were intended for the real use of the dead. In these and in numerous other cases the symbol has only a reduced value as compared with the original-myth from which it is borrowed. It is not self-evident, but relies on the mythical conception, without, however, taking it seriously. It is “merely” a symbol, and has no truth of its own. (shrink)

Somatic mutations arising in human skin cancers are heterogeneously distributed across the genome, meaning that certain genomic regions (e.g., heterochromatin or transcription factor binding sites) have much higher mutation densities than others. Regional variations in mutation rates are typically not a consequence of selection, as the vast majority of somatic mutations in skin cancers are passenger mutations that do not promote cell growth or transformation. Instead, variations in DNA repair activity, due to chromatin organization and transcription factor binding, have been (...) proposed to be a primary driver of mutational heterogeneity in melanoma. However, as discussed in this review here, recent studies indicate that chromatin organization and transcription factor binding also significantly modulate the rate at which UV lesions form in DNA. The authors propose that local variations in lesion susceptibility may be an important driver of mutational hotspots in melanoma and other skin cancers, particularly at binding sites for ETS transcription factors. (shrink)

The dorsal anterior cingulate cortex is a key node in the human salience network. It has been ascribed motor, pain-processing and affective functions. However, the dynamics of information flow in this complex region and how it responds to inputs remain unclear and are difficult to study using non-invasive electrophysiology. The area is targeted by neurosurgery to treat neuropathic pain. During deep brain stimulation surgery, we recorded local field potentials from this region in humans during a decision-making task requiring motor output. (...) We investigated the spatial and temporal distribution of information flow within the dACC. We demonstrate the existence of a distributed network within the anterior cingulate cortex where discrete nodes demonstrate directed communication following inputs. We show that this network anticipates and responds to the valence of feedback to actions. We further show that these network dynamics adapt following learning. Our results provide evidence for the integration of learning and the response to feedback in a key cognitive region. (shrink)