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)

Moral emotions are evolved mechanisms that function in part to optimize social relationships. We discuss two moral emotions— disgust and the “cuteness response”—which modulate social-engagement motives in opposite directions, changing the degree to which the eliciting entity is imbued with mental states (i.e., mentalized). Disgust-inducing entities are hypo-mentalized (i.e., dehumanized); cute entities are hyper-mentalized (i.e., “humanized”). This view of cuteness—which challenges the prevailing view that cuteness is a releaser of parental instincts (Lorenz, 1950/1971)—explains (a) the broad range of affiliative behaviors (...) elicited by cuteness, (b) the marketing of cuteness to children (by toy makers and animators) to elicit play, and (c) the apparent ease and frequency with which cute things are anthropomorphized. (shrink)

This is a field-based disguised case which describes a dilemma faced by the protagonists; do they continue to do business with a land developer who has assisted them in the past when now the developer chooses to, against their recommendations, also do business with their ex-business partner? The problem for the characters in question is whether or not to work on a project that will yield them a net profit of $4 million dollars given the fact it would require them (...) to work in the same development as their former business associate. The central characters are afraid that their ex-partner will be a destabilizing factor in the development of the project and that their work sites will be in jeopardy of being vandalized. Several factors complicate this situation including: the developer’s desire for a quick land purchase, the developer’s changing the discount rate from 20% to 10% perhaps based upon difficulties that surrounded the first land deal, the protagonists’ plans to build their own homes in this new development, and the negative relationship between the protagonists and the ex-business partner. The case has a difficulty level appropriate for a sophomore or junior level course. The case is designed to be taught in one class period and is expected to require between three to five hours of outside preparation by students. (shrink)

Analysis of sites of newly integrated DNA in cellular genomes is important to several fields, but methods for analyzing and visualizing these datasets are still under development. Here, we describe tools for data analysis and visualization that take as input integration site data from our INSPIIRED pipeline. Paired-end sequencing allows inference of the numbers of transduced cells as well as the distributions of integration sites in target genomes. We present interactive heatmaps that allow comparison of distributions of integration sites to (...) genomic features and that support numerous user-defined statistical tests. To summarize integration site data from human gene therapy samples, we developed a reproducible report format that catalogs sample population structure, longitudinal dynamics, and integration frequency near cancer-associated genes. We also introduce a novel summary statistic, the UC50, which provides a single number summarizing possible clonal expansion. Using these tools, we characterize ongoing longitudinal characterization of a patient from the first trial to treat severe combined immunodeficiency-X1, showing successful reconstitution for 15 years accompanied by persistence of a cell clone with an integration site near the cancer-associated gene CCND2. Software is available at https://github.com/BushmanLab/INSPIIRED. (shrink)

RésuméL'authenticité et la diversité font aujourd'hui figure de slogans dans les sociétés contemporaines de part et d'autre de l'Atlantique nord. En revanche, on a peu exploré les liens entre ces deux idées. À cette fin, cet article aborde les écrits tantôt convergents, tantôt divergents de Charles Taylor et Martin Heidegger pour prolonger leurs réflexions respectives sur l'authenticité et montrer en quoi elles peuvent servir defondement à une nouvelle forme de diversité culturelle. Pour tous deux, l'être-au-monde authentique nous permet d'accider au (...) tréfonds du matériel culturel dont nous devons disposer pour que se nouent des rapports fructueux avec les autres cultures. (shrink)

John McDowell’s ethical writings interpret ethical experience as intentional, socially-conditioned, virtuous responsiveness to situations and develop a modest account of practical rationality. His work converges with investigations of ethical experience by recent Kant scholars (Sherman, Brewer, Herman) and Emmanuel Levinas. The Kantian interpreters and Levinas locate the categorical demands of ethical experience in rational agents’ demands for respect, while McDowell finds it in noble adherence to the demands of virtuous living. For McDowell, moral-practical rational efforts to justify ethics cannot (...) transcend one’s form of life and are motivated by desires to coerce others under a veneer of rationality or an unnecessary modern anxiety to protect community beliefs. He overlooks how such justifications can be motivated by a desire to give an account of one’s beliefs out of responsibility to others different from oneself, a responsibility elicited by others in ethical experience as depicted by the Kantian interpreters and Levinas. (shrink)

If there is to be any progress in the debate about what sort of positive moral status Kant can give the emotions, we need a taxonomy of the terms Kant uses for these concepts. It used to be thought that Kant had little room for emotions in his ethics. In the past three decades, Marcia Baron, Paul Guyer, Barbara Herman, Nancy Sherman, Allen Wood and others have argued otherwise. Contrary to what a cursory reading of the Groundwork may indicate, (...) Kant thinks the emotions play an important role in the moral life. I want to extend the work of Baron, Guyer, Herman, Sherman and Wood in three ways. First, I will set out in a diagram Kant's taxonomy of feelings and emotions. Agreement on such a taxonomy should make it easier to evaluate debates about Kant and the emotions. Second, I will focus on a certain subclass of emotions – reason-caused affects – that have previously received little attention, even from these Kant scholars. Third, these scholars base much of their defence of Kant on his later works – especially the Metaphysics of Morals and the Anthropology – but Kant's fairly rich taxonomy of the emotions, including reason-caused affects, is clearly in place at least as early as the Critique of Judgment . I believe that the Critique of Judgment is an importantly ignored resource for understanding the moral role of the emotions for Kant. The third Critique makes positive, philosophically interesting claims about the emotions and morality. Kant emphasizes certain roles for emotions in this work that he develops to the same extent nowhere else. Nevertheless, the Critique of Judgment goes all but unmentioned by many who write on these issues. In what follows, I will defend as many of my claims as possible using the third Critique. (shrink)

We present a population density and moment-based description of the stochastic dynamics of domain $${\text{Ca}}^{2+}$$ -mediated inactivation of L-type $${\text{Ca}}^{2+}$$ channels. Our approach accounts for the effect of heterogeneity of local $${\text{Ca}}^{2+}$$ signals on whole cell $${\text{Ca}}^{2+}$$ currents; however, in contrast with prior work, e.g., Sherman et al. :985–995, 1990), we do not assume that $${\text{Ca}}^{2+}$$ domain formation and collapse are fast compared to channel gating. We demonstrate the population density and moment-based modeling approaches using a 12-state Markov chain (...) model of an L-type $${\text{Ca}}^{2+}$$ channel introduced by Greenstein and Winslow :2918–2945, 2002). Simulated whole cell voltage clamp responses yield an inactivation function for the whole cell $${\text{Ca}}^{2+}$$ current that agrees with the traditional approach when domain dynamics are fast. We analyze the voltage-dependence of $${\text{Ca}}^{2+}$$ inactivation that may occur via slow heterogeneous domain [ $${\text{Ca}}^{2+}$$ ]. Next, we find that when channel permeability is held constant, $${\text{Ca}}^{2+}$$ -mediated inactivation of L-type channels increases as the domain time constant increases, because a slow domain collapse rate leads to increased mean domain [ $${\text{Ca}}^{2+}$$ ] near open channels; conversely, when the maximum domain [ $${\text{Ca}}^{2+}$$ ] is held constant, inactivation decreases as the domain time constant increases. Comparison of simulation results using population densities and moment equations confirms the computational efficiency of the moment-based approach, and enables the validation of two distinct methods of truncating and closing the open system of moment equations. In general, a slow domain time constant requires higher order moment truncation for agreement between moment-based and population density simulations. (shrink)

The Equal Weight View holds that, when we discover we disagree with an epistemic peer, we should give our peer’s judgment as much weight as our own. But how should we respond when we cannot tell whether those who disagree with us are our epistemic peers? I argue for a position I will call the Earn-a-Spine View. According to this view, parties to a disagreement can remain confdent, at least in some situations, by fnding justifable reasons to think their opponents (...) are less credible than themselves, even if those reasons are justifable only because they lack information about their opponents. (shrink)

Journal Name: Cognitive Linguistics Issue: Ahead of print.

Although Adorno criticizes the existential tradition, it is frequently argued that he and Heidegger share a number of theoretical interests. Adorno does come into direct contact with existential thought at certain points, but it is Kierkegaard, not Heidegger, who more closely approaches his concerns. I begin by reviewing Adorno's Kierkegaard: Construction of the Aesthetic. I then argue that, unlike Hegel, who is also criticized by Adorno on various grounds, Kierkegaard has had an influence on Adorno that has been underappreciated. While (...) Adorno criticizes Kierkegaard for breaking off the subject-object dialectic, they converge in their attacks on identity-thinking, the retention of a negative utopian standpoint of critique, and a deliberately provocative style of writing, all of which are marshaled in defense of the individual, who is besieged by modern society. Unlike Kierkegaard, however, and despite the generally accepted view, I conclude by arguing that because Adorno does not break off the subject-object dialectic, he has the necessary theoretical resources to deal with the theory-practice problem. Key Words: Adorno • communication • dialectic • individual • Kierkegaard • subject-object • subjectivity • theory-practice. (shrink)

Sarah McGrath (2008; 2011) argues that, when it comes to our controversial moral views, we have no reason to think we are less likely to be in error than those who disagree with us. I refer to this position as the Moral Peer View (MPV). Under pressure from Nathan King (2011a; 2011b), McGrath admits that the Moral Peer View need not always have been true, though she maintains it is true now. Although King seems to think there should be current (...) counterexamples to the Moral Peer View, he holds back from actually proposing any. I argue that those of us who favor marriage equality and gender equality are currently in a position to reject the Moral Peer View with regard to these issues, and I propose conditions under which people can reasonably take their moral beliefs to be epistemically advantaged. King and McGrath agree that opponents of slavery like William Wilberforce could reasonably believe they enjoyed an epistemic advantage over proponents of slavery, and I suggest that proponents of marriage equality and gender equality might make similar claims. I propose that we can make additional claims to epistemic advantages if we believe that (1) almost everyone that considers the matter admits they are advantages, (2) those who disagree with use would admit they are advantages, and (3) we can give a plausible explanation as to why those that we think are epistemically disadvantaged have not noticed that they are disadvantaged. Finally, I argue that it reasonable to think our controversial beliefs are justified if we can find reasons to think our opponents are mistaken, and do not see similar reasons to think ourselves mistaken. This is a better policy than supposing we are just as prone to make mistakes as our opponents, as the latter is both less defensible in theory, and more likely to stifle intellectual progress. (shrink)

Ever since Max Weber started an argument about the role of Protestantism in jump-starting northern Europe's economic development, scholars have clashed over the influence of religion and culture on a society's economic prospects. Today, many wonder whether the "explosion" of Protestantism in Latin America will effect a similar wave of growth and democratization. In this book, Sherman compiles the results of her field study and national survey of 1000 rural Guatemalan households. She offers persuasive evidence that, in Guatemala and (...) throughout the region, religious world-views significantly influence economic life. Sherman explains how the change in attitude and behavior that accompanies conversion from animism to a Biblically orthodox world-view has improved the domestic welfare and economic status of many families. Further, she asserts that this new attitude, sympathetic to democratic-capitalism, has created a "moral cultural soil" in which freedom, personal empowerment, an enhanced status for women, and a desire to get ahead can be nurtured. (shrink)

While Aristotle in the Nicomachean Ethics does not provide a guide for action in the form of rules for a decision process as deontological or consequentialistethical theories purport to do, he does present a description of the virtuous agent and the virtues that this agent exercises in his choices of action. In this paper Iargue that Aristotle’s mature virtuous agent characteristically exercises the virtue of wisdom (sophia) as well as the practical virtues of character and intelligence in his choices of (...) action and that students of virtue (those sincerely interested in becoming virtuous by acting as the virtuous agent does) can derive certain action-guiding rules from a description of these three virtues and how they are exercised by the mature virtuous agent in any given choice of action. (shrink)