Diderot is widely praised as a master of lively, dramatic and original dialogue. This book studies the developing role of dialogue in his early writings (1745 to 1754). Diderot's earlier experiments with the dialogue form, meticulously charted and analysed by D. J. Adams, opened the way to the exploration of human communication and cooperation which lies at the heart of the Encyclopédie. At first for Diderot dialogue ended in the triumph of monologue, with one speaker reducing another to silence. (...) But one of his central problems was precisely that of solipsism. Is it possible for people to communicate effectively with each other? By engaging with this problem in his early writings Diderot gradually came to realise the epistemological importance of true dialogue as an escape from the solipsistic trap; and, slowly and hesitantly, he developed the form of communicative dialogue which was to flourish in the masterpieces of his later years. (shrink)

In this review, we discuss the application of mouse models to the identification and pre‐clinical validation of novel therapeutic targets in colorectal cancer, and to the search for early disease biomarkers. Large‐scale genomic, transcriptomic and epigenomic profiling of colorectal carcinomas has led to the identification of many candidate genes whose direct contribution to tumourigenesis is yet to be defined; we discuss the utility of cross‐species comparative ‘omics‐based approaches to this problem. We highlight recent progress in modelling late‐stage disease using mice, (...) and discuss ways in which mouse models could better recapitulate the complexity of human cancers to tackle the problem of therapeutic resistance and recurrence after surgical resection. (shrink)

It was, until recently, accepted that the two classes of acetylcholine (ACh) receptors are distinct in an important sense: muscarinic ACh receptors signal via heterotrimeric GTP binding proteins (G proteins), whereas nicotinic ACh receptors (nAChRs) open to allow flux of Na+, Ca2+, and K+ ions into the cell after activation. Here we present evidence of direct coupling between G proteins and nAChRs in neurons. Based on proteomic, biophysical, and functional evidence, we hypothesize that binding to G proteins modulates the activity (...) and signaling of nAChRs in cells. It is important to note that while this hypothesis is new for the nAChR, it is consistent with known interactions between G proteins and structurally related ligand‐gated ion channels. Therefore, it underscores an evolutionarily conserved metabotropic mechanism of G protein signaling via nAChR channels.Also watch the Video Abstract. (shrink)

It was, until recently, accepted that the two classes of acetylcholine (ACh) receptors are distinct in an important sense: muscarinic ACh receptors signal via heterotrimeric GTP binding proteins (G proteins), whereas nicotinic ACh receptors (nAChRs) open to allow flux of Na+, Ca2+, and K+ ions into the cell after activation. Here we present evidence of direct coupling between G proteins and nAChRs in neurons. Based on proteomic, biophysical, and functional evidence, we hypothesize that binding to G proteins modulates the activity (...) and signaling of nAChRs in cells. It is important to note that while this hypothesis is new for the nAChR, it is consistent with known interactions between G proteins and structurally related ligand‐gated ion channels. Therefore, it underscores an evolutionarily conserved metabotropic mechanism of G protein signaling via nAChR channels.Also watch the Video Abstract. (shrink)

This paper presents methods to visualize the structure of trees that occur in genetic programming. These methods allow for the inspection of structure of entire trees even though several thousands of nodes may be involved. The methods also scale to allow for the inspection of structure for entire populations and for complete trials even though millions of nodes may be involved. Examples are given that demonstrate how this new way of “seeing” can afford a potentially rich way of understanding dynamics (...) that underpin genetic programming. The examples indicate further studies that might be enabled by visualizing structure at these scales. (shrink)

We present a one per cent measurement of the cosmic distance scale from the detections of the baryon acoustic oscillations in the clustering of galaxies from the Baryon Oscillation Spectroscopic Survey, which is part of the Sloan Digital Sky Survey III. Our results come from the Data Release 11 sample, containing nearly one million galaxies and covering approximately 8500 square degrees and the redshift range 0.2 < z < 0.7. We also compare these results with those from the publicly released (...) DR9 and DR10 samples. Assuming a concordance Λ cold dark matter cosmological model, the DR11 sample covers a volume of 13 Gpc3 and is the largest region of the Universe ever surveyed at this density. We measure the correlation function and power spectrum, including density-field reconstruction of the BAO feature. The acoustic features are detected at a significance of over 7σ in both the correlation function and power spectrum. Fitting for the position of the acoustic features measures the distance relative to the sound horizon at the drag epoch, rd, which has a value of rd,fid = 149.28 Mpc in our fiducial cosmology. We find DV = at z = 0.32 and DV = at z = 0.57. At 1.0 per cent, this latter measure is the most precise distance constraint ever obtained from a galaxy survey. Separating the clustering along and transverse to the line of sight yields measurements at z = 0.57 of DA = and H =. Our measurements of the distance scale are in good agreement with previous BAO measurements and with the predictions from cosmic microwave background data for a spatially flat CDM model with a cosmological constant. © 2014 The Author Published by Oxford University Press on behalf of the Royal Astronomical Society. (shrink)

Using fMRI, we investigated how right temporal lobe gliomas affecting the posterior superior temporal sulcus alter neural processing observed during speech perception and production tasks. Behavioural language testing showed that three pre-operative neurosurgical patients with grade 2, grade 3 or grade 4 tumours had the same pattern of mild language impairment in the domains of object naming and written word comprehension. When matching heard words for semantic relatedness (a speech perception task), these patients showed under-activation in the tumour infiltrated right (...) superior temporal lobe compared to 61 neurotypical participants and 16 patients with tumours that preserved the right postero-superior temporal lobe, with enhanced activation within the (tumour-free) contralateral left superior temporal lobe. In contrast, when correctly naming objects (a speech production task), the patients with right postero-superior temporal lobe tumours showed higher activation than both control groups in the same right postero-superior temporal lobe region that was under-activated during auditory semantic matching. The task dependent pattern of under-activation during the auditory speech task and over-activation during object naming was also observed in eight stroke patients with right hemisphere infarcts that affected the right postero-superior temporal lobe compared to eight stroke patients with right hemisphere infarcts that spared it. These task-specific and site-specific cross-pathology effects highlight the importance of the right temporal lobe for language processing and motivate further study of how right temporal lobe tumours affect language performance and neural reorganisation. These findings may have important implications for surgical management of these patients, as knowledge of the regions showing functional reorganisation may help to avoid their inadvertent damage during neurosurgery. (shrink)

The model of clinical ethics consultation (CEC) defended in the ASBH Core Competencies report has gained significant traction among scholars and healthcare providers. On this model, the aim of CEC is to facilitate deliberative reflection and thereby resolve conflicts and clarify value uncertainty by invoking and pursuing a process of consensus building. It is central to the model that the facilitated consensus falls within a range of allowable options, defined by societal values: prevailing legal requirements, widely endorsed organizational policies, and (...) professional standards of practice and codes of conduct. Moreover, the model stipulates that ethics consultants must refrain from giving substantive recommendations regarding how parties to a moral disagreement in the clinic should evaluate their options. We argue that this model of CEC is incomplete, because it wrongly assumes that what counts as the proper set of allowable options among which the parties are to deliberate will itself always be clearly discernible. We illustrate this problem with a recent case on which one of us consulted—a neonate born with trisomy 18 (T18). We try to show that law, policy, and standards of practice reveal no clear answer to the question posed by the case: namely, whether forgoing gastrostomy tube feedings for a baby with T18 is allowable. We suggest there may be other kinds of cases in which it may simply be unsettled whether a given choice falls within the set of allowable options within which consensus is to be facilitated. What should an ethicist do when confronting such unsettled cases? We agree with the facilitation model that an ethicist should remain neutral among the allowable options, when it is clear what the allowable options are. But, in unsettled cases, the role of a consultant should be expanded to include a process of moral inquiry into what the allowable options should be. We end by raising the issue of whether this means an ethicist should share his or her own conclusions or views about the allowability of a given clinical option. (shrink)

We argued in our joint article that the facilitated consensus model of clinical ethics consultation is incomplete because it does not address the problem of what we have called “unsettled cases.” Sabrina Derrington and April Dworetz, Mark Aulisio, and Al Jonsen have each usefully challenged our claims and conclusions. In this brief article we respond to some of their arguments.

The arts of rule cover the exercise of power by princes and popular sovereigns, but they range beyond the domain of government itself, extending to civil associations, political parties, and religious institutions. Making full use of political philosophy from a range of backgrounds, this festschrift for Harvey Mansfield recognizes that although the arts of rule are comprehensive, the best government is a limited one.

Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR and SPINK1 variants were associated with pancreatitis risk. We now report two associations at genome-wide significance identified and replicated at PRSS1-PRSS2 and X-linked CLDN2 through a two-stage genome-wide study. The PRSS1 variant likely affects disease susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is (...) associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men. © 2012 Nature America, Inc. All rights reserved. (shrink)

In real-time, Twitter strongly imprints world events, popular culture, and the day-to-day; Twitter records an ever growing compendium of language use and change; and Twitter has been shown to enable certain kinds of prediction. Vitally, and absent from many standard corpora such as books and news archives, Twitter also encodes popularity and spreading through retweets. Here, we describe Storywrangler, an ongoing, day-scale curation of over 100 billion tweets containing around 1 trillion 1-grams from 2008 to 2020. For each day, we (...) break tweets into 1-, 2-, and 3-grams across 150+ languages, record usage frequencies, and generate Zipf distributions. We make the data set available through an interactive time series viewer, and as downloadable time series and daily distributions. We showcase a few examples of the many possible avenues of study we aim to enable including how social amplification can be visualized through ‘contagiograms’. (shrink)

Advancements in novel neurotechnologies, such as brain computer interfaces and neuromodulatory devices such as deep brain stimulators, will have profound implications for society and human rights. While these technologies are improving the diagnosis and treatment of mental and neurological diseases, they can also alter individual agency and estrange those using neurotechnologies from their sense of self, challenging basic notions of what it means to be human. As an international coalition of interdisciplinary scholars and practitioners, we examine these challenges and make (...) recommendations to mitigate negative consequences that could arise from the unregulated development or application of novel neurotechnologies. We explore potential ethical challenges in four key areas: identity and agency, privacy, bias, and enhancement. To address them, we propose democratic and inclusive summits to establish globally-coordinated ethical and societal guidelines for neurotechnology development and application, new measures, including “Neurorights,” for data privacy, security, and consent to empower neurotechnology users’ control over their data, new methods of identifying and preventing bias, and the adoption of public guidelines for safe and equitable distribution of neurotechnological devices. (shrink)

fusion theory challenges efforts to see theory as inhibiting by presenting an approach that is innovative, eclectic, and subtle in order to draw out competing and constellating ideas and opinions. This collected volume of essays examines fusion theory and demonstrates how the theory can be applied to the reading of various works of Indian English novelists.

Psychology's tendency to focus on confirmatory analyses before ensuring constructs are clearly defined and accurately measured is exacerbating the generalizability crisis. Our growing use of digital behaviors as predictors has revealed the fragility of subjective measures and the latent constructs they scaffold. However, new technologies can provide opportunities to improve conceptualizations, theories, and measurement practices.

Psychiatry is rapidly adopting digital phenotyping and artificial intelligence/machine learning tools to study mental illness based on tracking participants’ locations, online activity, phone and text message usage, heart rate, sleep, physical activity, and more. Existing ethical frameworks for return of individual research results (IRRs) are inadequate to guide researchers for when, if, and how to return this unprecedented number of potentially sensitive results about each participant’s real-world behavior. To address this gap, we convened an interdisciplinary expert working group, supported by (...) a National Institute of Mental Health grant. Building on established guidelines and the emerging norm of returning results in participant-centered research, we present a novel framework specific to the ethical, legal, and social implications of returning IRRs in digital phenotyping research. Our framework offers researchers, clinicians, and Institutional Review Boards (IRBs) urgently needed guidance, and the principles developed here in the context of psychiatry will be readily adaptable to other therapeutic areas. (shrink)

Communitarian social philosophy was born in opposition to some tenets of liberalism. Liberal individualism has been among its most strongly contested claims. In their criticisms, the communitarians point to the Enlightenment’s sources of the individualist vision of society and morality. The aim of this paper is to demonstrate that, even if the communitarian line of argument has been justified in more than one way, it is at the same time important to remember that the greatest figure of the Scottish Enlightenment, (...) that of of David Hume, does not fit the individualistic picture too well. I shall begin with a contemporary definition of individualism, as defined by John Watkins, then I shall proceed to argue that methodological individualism is rarely an innocent philosophical position, i.e. that it is very often a preliminary step in attempts to find a solution to many other, much more important and more practically relevant issues. For methodological individualism is usually associated with ontological, as well as moral and political individualistic doctrines, and they usually go hand in hand, influencing and strengthening each other. (shrink)

© 2017. The American Astronomical Society. All rights reserved.We present new observations of the low-mass companion to HD 984 taken with the Gemini Planet Imager as a part of the GPI Exoplanet Survey campaign. Images of HD 984 B were obtained in the J and H bands. Combined with archival epochs from 2012 and 2014, we fit the first orbit to the companion to find an 18 au orbit with a 68% confidence interval between 14 and 28 au, an eccentricity (...) of 0.18 with a 68% confidence interval between 0.05 and 0.47, and an inclination of 119°with a 68% confidence interval between 114°and 125°. To address the considerable spectral covariance in both spectra, we present a method of splitting the spectra into low and high frequencies to analyze the spectral structure at different spatial frequencies with the proper spectral noise correlation. Using the split spectra, we compare them to known spectral types using field brown dwarf and low-mass star spectra and find a best-fit match of a field gravity M6.5 ±1.5 spectral type with a corresponding temperature of K. Photometry of the companion yields a luminosity of log=2.88 ± 0.07 dex with DUSTY models. Mass estimates, again from DUSTY models, find an age-dependent mass of 34 ±1 to 95 ±4 M Jup. These results are consistent with previous measurements of the object. (shrink)

Misinformation is a serious concern for societies across the globe. To design effective interventions to combat the belief in and spread of misinformation, we must understand which psychological processes influence susceptibility to misinformation. This paper tests the widely assumed – but largely untested – claim that emotionally provocative headlines are associated with worse ability to identify true versus false headlines. Consistent with this proposal, we found correlational evidence that overall emotional response at the headline level is associated with diminished truth (...) discernment, except for experienced anger which was associated with increased truth discernment. The second set of studies tested a popular emotion regulation intervention where people were asked to apply either emotional suppression or emotion reappraisal techniques when considering the veracity of several headlines. In contrast to the correlation results, we found no evidence that emotion regulation helped people distinguish false from true news headlines. (shrink)

David Hume's sympathetic principle applies to physical equals. In his account, we sympathize with those like us. By contrast, Adam Smith's sympathetic principle induces equality. We consider Hume's “other rational species” problem to see whether Smith's wider sympathetic principle would alter Hume's conclusion that “superior” beings will enslave “inferior” beings. We show that Smith introduces the notion of “generosity,” which functions as if it were Hume's justice even when there is no possibility of contract.

In part one of our analysis of the unpublished lecture materials of thomas reid relating to adam smith, The authors touched on issues of provenance, Of manuscript description and arrangement, As well as of substance concerning reid's actual comments on smith. We have now provided as authentic a reproduction as possible of the relevant manuscript materials in the birkwood collection, Aberdeen, Arguing that there is a perceptible and studied order to reid's forceful objections.

The meta-problem of consciousness is the problem of explaining why we have problem intuitions about consciousness, why we intuitively think that conscious experience cannot be scientifically explained. In his discussion of this problem, David Chalmers briefly considers the possibility of giving a 'genealogical' solution, according to which problem intuitions are 'accidents of cultural history' (2018, p. 33). Chalmers' response to this solution is largely dismissive. In this paper, we defend the viability of a genealogical solution. Our strategy is to (...) focus on a particular problem intuition: the thought that the phenomenal character of colour experience is irreducibly subjective. We use the history of the inverted spectrum thought experiment as a window into how various philosophers have thought about colour experience. Our genealogy reveals that problem intuitions about colour are not timeless, but instead arise in a specific historical context, one that, in large part, explains why we have these intuitions. (shrink)

James Buchanan often argued that fairness is an obligation toward our equals. If Adam Smith is our equal, then we are under obligation to try to understand him. We see this in Buchanan’s attempts to reformat political economy on the basis of natural equals, a world in which Smith’s street porter does indeed have the same capacity as the philosopher. This shows in Buchanan’s excitement over increasing returns models as well as John Rawls’ Theory of Justice both of which he (...) saw a way to make this view operational. (shrink)

In 2001, Betty Dukes, then a 54‐year‐old African American, filed suit against her employer, Wal‐Mart, alleging that she had been the victim of gender discrimination. Ms. Dukes alleged that Wal‐Mart, the nation's largest private employer, routinely paid women less than men for comparable work and arbitrarily favored men over women in promotion decisions. In 2004, a U.S. District Court entered an order granting class certification, potentially extending the retailer's financial liability to thousands of current and past Wal‐Mart employees. At that (...) time, the Wal‐Mart suit was the largest class action lawsuit ever approved in the United States. In 2011, the U.S. Supreme Court reversed the lower court's ruling. Writing for the majority, Justice Scalia cited Wal‐Mart's long‐standing explicit gender‐neutral employment policy and the decentralized manner in which local managers have discretion to adjust salaries and recommend applicants for promotion—factors that led the majority to question “the glue” binding the class together. Proponents of the Court's decision hailed the ruling as a victory for business and a step in the direction of needed legal reform. Critics viewed the decision as another in a series of defeats for minority interests by a pro‐business, ideologically divided Court. Did the Court get it right, or is this yet another example of might defeating right? (shrink)