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)

The neural basis of progress monitoring has received relatively little attention compared to other sub-processes that are involved in goal directed behavior such as motor control and response inhibition. Studies of error-monitoring have identified the dorsal anterior cingulate cortex (dACC) as a structure that is sensitive to conflict detection, and triggers corrective action. However, monitoring goal progress involves monitoring correct as well as erroneous events over a period of time. In the present research, 20 healthy participants underwent fMRI while playing (...) a game that involved monitoring progress towards either a numerical or a visuo-spatial target. The findings confirmed the role of the dACC in detecting situations in which the current state may conflict with the desired state, but also revealed activations in the frontal and parietal regions, pointing to the involvement of processes such as attention and working memory in monitoring progress over time. In addition, activation of the cuneus was associated with monitoring progress towards a specific target presented in the visual modality. This is the first time that activation in this region has been linked to higher-order processing of goal-relevant information, rather than low-level anticipation of visual stimuli. Taken together, these findings identify the neural substrates involved in monitoring progress over time, and how these extend beyond activations observed in conflict and error monitoring. (shrink)

Literacy is an essential skill. Learning to read is a requirement for becoming a self-providing human being. However, while spoken language is acquired naturally with exposure to language without explicit instruction, reading and writing need to be taught explicitly. Decades of research have shown that well-structured teaching of phonological awareness, letter knowledge, and letter-to-sound mapping is crucial in building solid foundations for the acquisition of reading. During the COVID-19 pandemic, children worldwide did not have access to consistent and structured teaching (...) and are, as a consequence, predicted to be behind in the development of their reading skills. Subsequent evidence confirms this prediction. With the best evidence-based practice in mind, we developed an online version of a well-structured early literacy training program for 5-year-old children. This 2-week online Reading Camp program is designed for pre-K children. It incorporates critical components of the fundamental skills essential to learning to read and is taught online in an interactive, multi-sensory, and peer-learning environment. We measure the participants’ literacy skills and other related skills before and after participating in the online Reading Camp and compare the results to no-treatment controls. Results show that children who participated in the online Reading Camp improved significantly on all parameters in relation to controls. Our results demonstrate that a well-structured evidence-based reading instruction program, even if online and short-term, benefits 5-year-old children in learning to read. With the potential to scale up this online program, the evidence presented here, alongside previous evidence for the efficacy of the in-person program, indicates that the online Reading Camp program is effective and can be used to tackle a variety of questions regarding structural and functional plasticity in the early stages of reading acquisition. (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)

The COVID-19 pandemic laid bare systemic inequities shaped by social determinants of health (SDoH). Public health agencies, legislators, health systems, and community organizations took notice, and there is currently unprecedented interest in identifying and implementing programs to address SDoH. This special issue focuses on the role of medical-legal partnerships (MLPs) in addressing SDoH and racial and social inequities, as well as the need to support these efforts with evidence-based research, data, and meaningful partnerships and funding.

ABSTRACTFeelings and cognitions influence judgment through attribution. For instance, the attribution of positive feelings and cognitions to a stimulus leads to a positive judgment of that stimulus. We examined whether misattribution is moderated by the applicability of a distractor to the judgment question. For instance, when are people more likely to attribute to a target person the affective and cognitive experiences triggered by a kitten – when trying to judge the person’s cuteness or trustworthiness? The kitten triggers experiences specifically relevant (...) to cuteness, but people might more easily suspect the kitten’s potential influence when judging cuteness rather than trustworthiness. Using the Affect Misattribution Procedure, we found that applicability increases the effect of misattribution on valenced judgments. The results emphasise the importance of specific information in attribution and suggest that high applicability of distractors to the judgment question d... (shrink)

La monnaie symbolise la valeur, le souverain, ou le Peuple, bref la Totalité. Mais quelle fonction a cette symbolisation? Au plus strict, la fonction symbolique de la monnaie c’est de quantifier. Or la quantification est déjà épaisse de nombreux problèmes philosophiques. Alors, le propos tentera ici de montrer une problématisation foucaldienne de la fonction symbolique de la monnaie, en termes de pouvoir-savoir. Car la considération de la fonction symbolique de la monnaie ouvre, au niveau théorique, le problème de l’articulation de (...) la valeur (intensive) à sa manifestation (extensive), et au niveau épistémologique, un problème d’objectivation de l’objectivation, un problème réflexif de valeur de vérité des jugements de valeurs (bulle spéculative). (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)

La question de l'identité personnelle, sous ses deux formes : " Qui suis-je? " et " Qu'est-ce que le moi? ", a souvent été traitée par des philosophes qui ont entrepris de la résoudre en empruntant la voie du raisonnement pur. Elle est ici abordée par un autre biais, à partir de trois protocoles expérimentaux qui permettent de la saisir à vif, en situation, et non dans l'abstrait : l'ouvrage que Marc Parmentier a consacré à " la philosophie des sites (...) de rencontre ", le récit fait par Jean Genet d'un étrange épisode vécu au cours d'un chemin de fer, dont les enseignements s'étaient raccordés dans son esprit à la fréquentation de deux peintres, Rembrandt et Giacometti, la série de clichés photographiques réalisés par Cindy Sherman où, en vue de mettre en scène la mythologie de la femme américaine, elle s'est prise elle-même pour modèle. L'examen de ces expériences concrètes illustre la possibilité de faire de la philosophie autrement ; s'en dégage, non une réponse inédite à la question de l'identité personnelle, mais la confirmation du caractère définitivement aporétique des interrogations auxquelles celle-ci renvoie. (shrink)

A textbook for undergraduates. Some 70 selections (more than half are new to this edition) follow an introductory essay. Current controversies (surrogacy, genetic engineering, proxy consent) are thoroughly covered. Annotation copyrighted by Book News, Inc., Portland, OR.

D. H. Mellor; VI*—Conscious Belief, Proceedings of the Aristotelian Society, Volume 78, Issue 1, 1 June 1978, Pages 87–102, https://doi.org/10.1093/aristotelian.

Recently, the Israel National Bioethics Council (INBC) issued recommendations permitting egg freezing to prevent both disease- and age-related fertility decline. The INBC report forms the basis of Israel's new policy, being one of the first countries to regulate and authorise egg freezing for what it considers to be non-medical (ie, social) uses. The ethical discussion in the INBC report is reviewed and compared with the scant ethical discourse in the academic literature on egg freezing as a means of preventing age-related (...) loss of fertility. We argue that both the INBC recommendations and the bioethical academic discourse on egg freezing are grounded in liberal ideology, which views technology as primarily enabling. Accordingly, they promote ‘individual autonomy’ as exercised through informed consent. Our study suggests that a relational approach to autonomy may be a more suitable model for considering women's choices about egg freezing. (shrink)

D. H. Mellor; VI*—Conscious Belief, Proceedings of the Aristotelian Society, Volume 78, Issue 1, 1 June 1978, Pages 87–102, https://doi.org/10.1093/aristotelian.

This paper argues that the concept and role of ‘institutional racism’ in contemporary discussions of race should be reconsidered. It starts by distinguishing between ‘intrinsic institutional racism’, which holds that institutions are racist in virtue of their constitutive features, and ‘extrinsic institutional racism’, which holds that institutions are racist in virtue of their negative effects. It accepts intrinsic institutional racism, but argues that a ‘disparate impact’ conception of extrinsic conception faces a number of objections, the most serious being that it (...) has no plausible account of what it is that makes extrinsically racist institutions racist. It also argues that claims about the explanatory indispensability of institutional racism are overstated (individual racism is at least as important), critiques structural approaches to racial inequality, and suggests that there is reason to doubt whether institutional reform can provide us with all that morality may require in the racial domain. (shrink)

Cho and Martinez-Martin (2023) provide a compelling critique of the profound influence that data sourcing for artificial intelligence (AI) has on the healthcare sector. They emphasize the need for...