Rare copy number variants have a prominent role in the aetiology of schizophrenia and other neuropsychiatric disorders. Substantial risk for schizophrenia is conferred by large CNVs at several loci, including microdeletions at 1q21.1, 3q29, 15q13.3 and 22q11.2 and microduplication at 16p11.2. However, these CNVs collectively account for a small fraction of cases, and the relevant genes and neurobiological mechanisms are not well understood. Here we performed a large two-stage genome-wide scan of rare CNVs and report the significant association of copy (...) number gains at chromosome 7q36.3 with schizophrenia. Microduplications with variable breakpoints occurred within a 362-kilobase region and were detected in 29 of 8,290 patients versus 2 of 7,431 controls in the combined sample. All duplications overlapped or were located within 89 kilobases upstream of the vasoactive intestinal peptide receptor gene VIPR2. VIPR2 transcription and cyclic-AMP signalling were significantly increased in cultured lymphocytes from patients with microduplications of 7q36.3. These findings implicate altered vasoactive intestinal peptide signalling in the pathogenesis of schizophrenia and indicate the VPAC2 receptor as a potential target for the development of new antipsychotic drugs. © 2011 Macmillan Publishers Limited. All rights reserved. (shrink)

© Copyright 2015, Mary Ann Liebert, Inc..Signal transducer and activator of transcription factor 3 is hyperactivated in head and neck squamous cell carcinomas. Cumulative evidence indicates that IL-6 production by HNSCC cells and/or stromal cells in the tumor microenvironment activates STAT3 and contributes to tumor progression and drug resistance. A library of 94,491 compounds from the Molecular Library Screening Center Network was screened for the ability to inhibit interleukin-6 -induced pSTAT3 activation. For contractual reasons, the primary high-content screening campaign was (...) conducted over several months in 3 distinct phases; 1,068 primary HCS actives remained after cytotoxic or fluorescent outliers were eliminated. One thousand one hundred eighty-seven compounds were cherry-picked for confirmation; actives identified in the primary HCS and compounds selected by a structural similarity search of the remaining MLSCN library using hits identified in phases I and II of the screen. Actives were confirmed in pSTAT3 IC50 assays, and an IFNγ-induced pSTAT1 activation assay was used to prioritize selective inhibitors of STAT3 activation that would not inhibit STAT1 tumor suppressor functions. Two hundred three concentration-dependent inhibitors of IL-6-induced pSTAT3 activation were identified and 89 of these also produced IC50s against IFN-γ-induced pSTAT1 activation. Forty-nine compounds met our hit criteria: they reproducibly inhibited IL-6-induced pSTAT3 activation by ≥70% at 20 μM; their pSTAT3 activation IC50s were ≤25 μM; they were ≥2-fold selective for pSTAT3 inhibition over pSTAT1 inhibition; a cross target query of PubChem indicated that they were not biologically promiscuous; and they were ≥90% pure. Twenty-six chemically tractable hits that passed filters for nuisance compounds and had acceptable drug-like and ADME-Tox properties by computational evaluation were purchased for characterization. The hit structures were distributed among 5 clusters and 8 singletons. Twenty-four compounds inhibited IL-6-induced pSTAT3 activation with IC50s ≤20 μM and 13 were ≥3-fold selective versus inhibition of pSTAT1 activation. Eighteen hits inhibited the growth of HNSCC cell lines with average IC50s ≤ 20 μM. Four chemical series were progressed into lead optimization: the guanidinoquinazolines, the triazolothiadiazines, the amino alcohols, and an oxazole-piperazine singleton. (shrink)

When healthcare professionals feel constrained from acting in a patient’s best interests, moral distress ensues. The resulting negative sequelae of burnout, poor retention rates, and ultimately poor patient care are well recognized across healthcare providers. Yet an appreciation of how particular disciplines, including physicians, come to be “constrained” in their actions is still lacking. This paper will examine how the application of shared decision-making may contribute to the experience of moral distress for physicians and why such distress may go under-recognized. (...) Appreciation of these dynamics may assist in cross-discipline sensitivity, enabling more constructive dialogue and collaboration. (shrink)

“Recognizing that prisons disproportionately confine sick people, with mental illness, substance abuse, HIV disease among other illnesses; and that prisoners are subject to further morbidity and mortality in these institutions, due to lack of access and/or resources for health care, overcrowding, violence, emotional deprivation, and suicide.… condemns the social practice of mass imprisonment.”After decades of steady decline, tuberculosis has emerged as a significant public health threat in the United States. The rising rates of tuberculosis cases, an increasing proportion of which (...) are resistant to standard chemotherapies, are linked to the many scourges threatening our communities: the explosion of poverty, drug use, violence, the HIV epidemic, and the concomitant rise in congregate housing including homeless shelters, residential drug treatment programs and incarceration facilities. Jails and prisons have disproportionately high rates of tuberculosis infection and have been implicated as points of tuberculosis spread and, as such, are a critical point for tuberculosis control interventions. (shrink)

John Stuart Mill worked for the East India Company in London for thirty-five years (1823-58), drafting many hundreds of dispatches for the guidance of British administrators in India. Historians have long been aware of Mill's involvement in British Indian government. This comprehensive effort brings together different strands of scholarship on Mill to determine the character of his role based on analyses of his draft despatches and comparisons of their practical and theoretical concerns with the broad themes of Mill's major writings (...) on political philosophy and economics. The essays in this collection explore specific aspects of Mill's approach to Indian issues, including religion, law, education, and security, and also place him within the broader currents of utilitarianism. The contributors present different perspectives on the ideology in Mill's pragmatic work for the Company and his personal philosophy. (shrink)

The upcoming U.S. Supreme Court decision in Dobbs v. Jackson Women’s Health Organization has the potential to eliminate or severely restrict access to legal abortion care in the United States. We a...

The ideal introduction for students of semantics, Lexical Meaning fills the gap left by more general semantics textbooks, providing the teacher and the student with insights into word meaning beyond the traditional overviews of lexical relations. The book explores the relationship between word meanings and syntax and semantics more generally. It provides a balanced overview of the main theoretical approaches, along with a lucid explanation of their relative strengths and weaknesses. After covering the main topics in lexical meaning, such as (...) polysemy and sense relations, the textbook surveys the types of meanings represented by different word classes. It explains abstract concepts in clear language, using a wide range of examples, and includes linguistic puzzles in each chapter to encourage the student to practise using the concepts. 'Adopt-a-Word' exercises give students the chance to research a particular word, building a portfolio of specialist work on a single word. (shrink)

A longitudinal study of 308 white -collar U.S. employees revealed that feelings of hope and gratitude increase concern for corporate social responsibility. In particular, employees with stronger hope and gratitude were found to have a greater sense of responsibility toward employee and societal issues; interestingly, employee hope and gratitude did not affect sense of responsibility toward economic and safety/quality issues. These findings offer an extension of research by Giacalone, Paul, and Jurkiewicz.

The editor of this volume takes it to mean that a prior experience affects behavior without the individual's appreciation (ability to report) of this...

This book explores how some word meanings are paradigmatically related to each other, for example, as opposites or synonyms, and how they relate to the mental organization of our vocabularies. Traditional approaches claim that such relationships are part of our lexical knowledge (our "dictionary" of mentally stored words) but Lynne Murphy argues that lexical relationships actually constitute our "metalinguistic" knowledge. The book draws on a century of previous research, including word association experiments, child language, and the use of synonyms and (...) antonyms in text. (shrink)

One cue that may facilitate children's word learning is iconicity, or the correspondence between a word's form and meaning. Some have even proposed that iconicity in the early lexicon may serve to help children learn how to learn words, supporting the acquisition of even noniconic, or arbitrary, word–referent associations. However, this proposal remains untested. Here, we investigate the iconicity of caregivers’ speech to young children during a naturalistic free‐play session with novel stimuli and ask whether the iconicity of caregivers’ speech (...) facilitates children's learning of the noniconic novel names of those stimuli. Thirty‐four 1.5‐2‐year‐olds (19 girls; half monolingual English learners and half bilingual English‐Spanish learners) participated in a naturalistic free‐play task with their caregivers followed by a test of word‐referent retention. We found that caregivers’ use of iconicity, particularly in utterances in which they named the novel stimuli, was associated with the likelihood that children learned that novel name. This result held even when controlling for other factors associated with word learning, such as the concreteness and frequency of words in caregiver speech. Together, the results demonstrate that iconicity not only can serve to help children identify the referent of novel words (as in previous research) but can also support their ability to retain even noniconic word‐referent mappings. (shrink)

Democratically inspired critics identify a number of problems with the contemporaryidentification of survey research and public opinion. Surveys are said tonormalize or rationalize opinion, to promote state or corporate rather thandemocratic interests, to constrain authentic forms of participation, and to forcean individualized conception of public opinion. Some of these criticisms arerelatively easily answered by survey researchers. But the criticisms contain acomplaint that survey researchers have largely failed to address: that surveyresearch discourages the public, visible, and face-to-face generation of opinion.Public opinion (...) researchers who use surveys paradoxically seek the opinions ofcitizens in private, nonpolitical situations. But nothing inherent in the methodsof survey research requires this private focus. The author argues that by reframingthe survey's unit of analysis and considering alternatives to standard,national samples in political surveys, new democratic possibilities within surveyresearch may be found. (shrink)

Recent judicial rulings and changes in federal and state legislation have given for-profit corporations a growing list of rights and constitutional protections, including the right to practice religion free from many types of federal or state restriction. In this paper, we highlight the implications of these developments using Rawls’ Theory of Justice to explore the consequences of for-profit corporate religious freedom for consumers and employees. We identify preliminary principles to spark a discussion as to how expanding religious freedom for businesses (...) and fair access to goods and services can coexist in the for-profit marketplace. (shrink)

The idea of “postponed withholding,” proposed by Syltern et al. (2022), is a provocative one, and like all good provocative ideas, provokes deeper thinking from fresh perspectives. Our attention wa...

A friend once told me I was wasting my time writing about cross-cultural perspectives on the beginnings of life. “Your work is interesting for its curiosity value,” he said, “but fundamentally worthless. What happens in other cultures is totally irrelevant to what is happening here.” Those were discouraging words, but as I followed the American debates about the beginnings and ends of life, it seemed he was right. Anthropologists have written a great deal about birth and death rites in other (...) societies and about non-western notions of personhood, but to date our findings have had little impact on American policy, ethics, or law. The recognized experts on contentious topics such as abortion and euthanasia tend to come from the fields of philosophy, bioethics, theology, law, and biology, but rarely from the social sciences. I was a bit surprised, therefore, to be invited to address the Thomas A. Pitts Memorial Lectureship on “Defining the Beginning and the End of Human Life.”. (shrink)

SummaryQuine uses the notion of ‘quality space’ in Word and Object and in ‘Natural Kinds' as a means of characterizing similarity recognition, which in turn is seen as basic to induction and to language acquisition. In this paper it is argued that ‘quality space’ is too simplistic a notion to bear the explanatory weight given to ‘similarity’. Similarity is explanatorily plausible only because it contains much covert complexity and is essentially mentalistic. The attempt to expunge this mentalism by the behavioural (...) mapping of quality spaces simply loses the explanatory force of similarity.RésuméQuine utilise dans ≤Word and Object≥ et dans ≤Natural Kinds≥ la notion ?on; ≤espace des qualityés≥ comme une façon de caractériser la reconnaissance de la similitude, qui est à son tour considérée comme fondamentale pour ľinduction ct pour ľacquisition du langage. auteur montre que la notion ?on; ≤cspace des qualityés≥ est trop simpliste pour fournir une base suffisante à la valeur explicative attendue de la ≤similitude≥. La similitude ňest plausible comme explication que parce qu'elle cache une grande complexité et čest une notion essentiellement mentale. La tentative de remplacer ce mentalisme par une projection behavioriste sur ľespace des qualites fait perdre à la similitude sa valeur explicative.ZusammenfassungIn ≤Word and Object≥ und in ≤Natural Kinds≥ benutzt Quine den Begriff ≤Eigenschafts‐raum≥ als Mittel um die Wahrnehmung der Ähnlichkeit zu charakterisieren, welche ihrerseits als grundlegend für Induktion und Aneignung der Sprache betrachtet wird. In der vorliegenden Arbeit wird argumentiert, dass dieser ≤Eigenschaftsraum≥ zu arm ist, um den Erklärungsgehalt des Begriffs ≤Ähnlichkeit≥ zu tragen. Die Erklärung durch Ähnlichkeit ist nur deshalb plausibel, weil sie versteckte Komplexität enthält und wesentlich mentalistisch ist. Bei dem Versuch, diesem Men‐talismus mithilfe der behavioristischen Abbildung der Eigenschäftsraume auszuweichen, geht die Erklärungskraft des Begriffs der Ähnlichkeit einfach verloren. (shrink)

The matrix‐degrading metalloproteinases are an intriguing family of enzymes that have evolved to digest specific extracellular matrix components. The expression of these enzymes is very highly regulated and can be controlled transcriptionally by a number of growth factors, tumor promoters, oncogenes, and hormones. It is suggested that the coordinated regulation of matrix metalloproteinases and their inhibitors by these agents modify the integrity of the extracellular matrix. These modifications may, at least in part, be responsible for mediating the effects of these (...) factors on complex physiological processes. (shrink)

We review here the data indicating a role for epidermal growth factor receptor (EGF receptor) signalling in early mouse development. Embryonic development of the metazoan embryo generally begins with the formation of a cystic structure and epithelial layers that subsequently form anlagen of the definitive body parts and organs. For the mammalian embryo, this cystic structure is a blastocyst whose wall consists of trophectoderm, the first epithelium to develop during mammalian embryogenesis. The onset of expression and function of EGF receptors (...) is coincident with the onset of trophectoderm development. Modulating EGF receptor expression and function modulates trophectoderm differentiation, leading to the hypothesis that functional EGF receptors participate in the induction of trophectoderm development and perhaps of other embryonic epithelial derivatives such as nervous tissues. (shrink)

This essay critiques feminist treatments of maternal-fetal "relationality" that unwittingly replicate features of Western individualism (for example, the Cartesian division between the asocial body and the social-cognitive person, or the conflation of social and biological birth). I argue for a more reflexive perspective on relationality that would acknowledge how we produce persons through our actions and rhetoric. Personhood and relationality can be better analyzed as dynamic, negotiated qualities realized through social practice.

Perhaps I am wrong to take this article personally, but when the authors refer to Cassandras “voicing concern about a post-Roe degradation of pregnant persons’ right to chart their own medical cour...

The historical analysis of the complex and often contradictory views of Florence Nightingale regarding the rights of women is explored in this paper. Feminism and nursing are often viewed as contradictory and antithetical. The relationship between the two is examined through the link between Florence Nightingale and her contemporary, Barbara Leigh‐Smith Bodichon. Leigh‐Smith was founder and primary financier of The English Women's Journal that provided a public platform for the major feminist writings of the period. Its offices in Langham Place (...) formed the administrative centre of the Society for Promoting the Employment of Women. Bodichon and her colleagues were often referred to as the ‘Langham Place Group’. Unexplored prior to this study was the fact that Leigh‐Smith and Nightingale were first cousins. Utilizing techniques of internal and external criticism, primary and secondary sources were surveyed relating to Nightingale and Leigh‐Smith. The views of both women on the subjects of the rights of women, women's suffrage, the employment status of women, and the societal place of women are compared and contrasted. The legacy of both Leigh‐Smith and Nightingale to twentieth century feminism, the status of women, and the profession of nursing is then elaborated. The exploration of the views of both Nightingale and Leigh‐Smith is important to gain a clearer understanding of the existing relationship between nursing and feminism. In keeping with the aims of feminist inquiry, women's experiences, specifically those of Nightingale and Leigh‐Smith, are the major ‘objects’ of investigation. The concluding interpretation provides a synthesis that is emancipatory as well as knowledge generative. (shrink)

A hallmark of skilled motor performance is behavioral flexibility – i.e., experts can not only produce a movement pattern to reliably achieve a given task goal, but also possess the ability to change that movement pattern to fit a new context. In this perspective article, we briefly highlight the factors that are critical to understanding behavioral flexibility, and its connection to movement variability, stability, and learning. We then address how practice strategies should be developed from a motor learning standpoint to (...) enhance behavioral flexibility. Finally, we highlight some important future avenues of work that are needed to advance our understanding of behavioral flexibility. We use examples from sport as a context to highlight these issues, especially in regard to elite performance and development. (shrink)

Purpose Recent research has found unrealistic optimism among patient-subjects in early-phase oncology trials. Our aim was to investigate the cognitive and motivational factors that evoke this bias in this context. We expected perceptions of control to be a strong correlate of unrealistic optimism. Methods A study of patient-subjects enrolled in early-phase oncology trials was conducted at two sites in the USA. Respondents completed questionnaires designed to assess unrealistic optimism and several risk attribute variables that have been found to evoke the (...) bias in other contexts. Results One hundred and seventy-one patient-subjects agreed to be interviewed for our study. Significant levels of perceived controllability were found with respect to all nine research-related questions. Perceptions of control were found to predict unrealistic optimism. Two other risk attribute variables, awareness of indicators and mental image, were correlated with unrealistic optimism. However, in multivariate regression analysis, awareness and mental image dropped out of the model and perceived controllability was the only factor independently associated with unrealistic optimism. Conclusion Patient-subjects reported that they can, at least partially, control the benefits they receive from participating in an early-phase oncology trial. This sense of control may underlie unrealistic optimism about benefiting personally from trial participation. Effective interventions to counteract unrealistic optimism may need to address the psychological factors that give rise to distorted risk/benefit processing. (shrink)