© 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)

This book follows postwar Germany's leading philosopher and social thinker, Jürgen Habermas, through four decades of political and constitutional struggle over the shape of liberal democracy in Germany. Habermas's most influential theories - of the public sphere, communicative action, and modernity - were decisively shaped by major West German political events: the failure to de-Nazify the judiciary, the rise of a powerful Constitutional Court, student rebellions in the late 1960s, the changing fortunes of the Social Democratic Party, NATO's decision to (...) station nuclear weapons, and the unexpected collapse of East Germany. In turn, Habermas's writings on state, law, and constitution played a critical role in reorienting German political thought and culture to a progressive liberal-democratic model. Matthew Specter uniquely illuminates the interrelationship between the thinker and his culture. (shrink)

This paper develops a model of individual decision-making under bounded rationality in which discretionary cognitive adjustment creates a durable stock that complements choice of action. While it increases utility, adjustment also entails a cost, because focusing attention optimally is effortful and mental resources are scarce. Associated behavioral phenomena are categorized based on whether the operative motivation in adjusting is forward-looking utility maximization or justification of prior action. The theory is in line with prior conceptions of cognitive dissonance, but also offers (...) a more empirically consistent explanation of the endowment effect, persuasive advertising, and sunk-cost effects than existing accounts. (shrink)

While the Deleuzo-Guattarian concept of ‘body without organs’ is developed alongside their critique of Freudian and Lacanian psychoanalysis, it is also developed alongside their critique of Christianity, most poignantly in the sixth plateau of A Thousand Plateaus. Here Deleuze and Guattari quote Antonin Artaud in order to show how ‘the judgment of God weighs upon and is exercised against the BwO’. In order to understand this relationship between judgement of God and the BwO, this essay explores Deleuze's critiques of Christianity (...) in his earlier works and concludes that the BwO, much like Artaud's own poetry, is developed in contrast to an internalised form of Christianity. (shrink)

Initially “meaningless” and randomly generated sounds can be learned over exposure. This is demonstrated by studies where repetitions of randomly determined sound patterns are detected better if they are the same sounds presented on previous trials than if they are novel. This experiment posed two novel questions about this learning. First, does familiarization with a sound outside of the repetition detection context facilitate later performance? Second, does familiarization enhance performance when repeats are interleaved with distracters? Listeners were first trained to (...) categorize a unique pattern of synchronous complex tone trains from other tone trains with similar qualities. They were then tasked to detect repeated pattern presentations interleaved with similar distracters in 4.2 s long excerpts. The familiarized pattern, an unfamiliar pattern that remained fixed throughout, or patterns that were uniquely determined on each trial could be presented as repeats. FF patterns were learned at a faster rate and achieved higher repetition detection sensitivity than UF and UU patterns. Similarly, FF patterns also showed steeper learning slopes in their response times than UF patterns. The data show that familiarity with a “meaningless” sound pattern on its own can facilitate repetition detection even in the presence of distracters. Familiarity effects become most apparent in the potential for learning. (shrink)

Anselm: I agreed that Pegasus is a flying horse according to the stories people tell, the paintings painters paint and so on . That is, Pegasus is a flying horse in the understanding of storytellers, their readers and the artists who depict Pegasus. You asked whether flying is not an unmediated causal power . Well, it could be an unmediated causal power if you or I had it, but not if a being with only mediated powers had it. And so (...) poor Pegasus, a being whose powers are only those given him by storytellers and artists, has only the mediated power of flying that they have given him. He flies in the thoughts and depictions of beings with unmediated powers. Still, Pegasus has not only the mediated power to fly but also the mediated power to entertain us, and perhaps even inspire us. Fool: But people could tell stories about you, too, about how you sprouted wings and flew onto the roof of Canterbury Cathedral. Anselm: Alas, if it were only in stories that I could do that, then flying would not be an unmediated causal power of mine. I would still have unmediated causal powers all right, and so would be greater than Pegasus. But flying is not one of my unmediated causal powers. However, something than which nothing greater can be conceived would, and does, as I have proved in my Proslogion, have unmediated causal powers – indeed, much greater unmediated causal powers than any poor mortals like you and me.1 •↵1 For …. (shrink)

Foucault’s lectures from early 1979 on the German Ordo-liberalen are typically taken to comprise his most comprehensive account of why Germany is important for understanding neo-liberal governmentality more broadly. This paper argues, to the contrary, that the 1979 lectures actually obscure a potentially more complete account of German, neo-liberal governmentality Foucault had begun to sketch in 1977. To support this reading and to offer an explanation of why Foucault would have decided to alter his presentation of West German neo-liberalism, the (...) paper undertakes a genealogy of Foucault’s involvement with West German political issues in 1977 and 1978. The core claims that structure the argument are as follows: (1) Key aspects of the “security state” that Foucault began to work out in 1977, must have been at least partly modeled on West German “militant” or “battle-ready” democracy; (2) Yet, in his 1979 lectures, there is no longer any trace of these repressive, extralegal dimensions; (3) This shift was motivated to a significant extent by his 1977 disagreement with Deleuze, Guattari, and others over whether the West German state of the late 1970s could be considered “fascist.” This concern to contest the accusation of fascism is carried forward in his 1979 lectures in a critique of “state phobia.”. (shrink)

Public access to the commons is often restricted, thus leading to implicit regulations. This is relevant toward spatial systems, as an important geographical issue is access to various sites over space, and this paper presents varying degrees of accessibility in different places. There is a dialectic struggle to enhance access to the commons as a fundamental right of the public, with the need to balance tourism and recreational uses of coastal resources with conservation and preservation eff orts. This paper will (...) aid policy makers and those concerned with beach access in Connecticut better understand the nature and complexity of how citizens and officials within coastal municipalities have come to perceive, in a collective sense, their beaches/ municipal parks as common property resources to be utilized for recreational purposes while balancing environmental conservation efforts simultaneously. Various legal frameworks, as well as federal and state efforts in coastal zones in key states, in addition to historically recent court cases in Connecticut resulting in legal enhancements toward increasing public access to nonresidents of specific municipalities, have shaped who can and who cannot access the commons. (shrink)

The Treatment Escalation Plan (TEP) was introduced into our trust in an attempt to improve patient involvement and experience of their treatment in hospital and to embrace and clarify a wider remit of treatment options than the Do Not Resuscitate (DNR) order currently offers. Our experience suggests that the patient and family are rarely engaged in DNR discussions. This is acutely relevant considering that the Mental Capacity Act (MCA) now obliges these discussions to take place. The TEP is a form (...) that the doctor completes, ideally with the competent patient or close relative, documenting what treatment options would be appropriate if that patient were to become acutely unwell. Ventilation of the lungs, cardiac resuscitation, renal replacement therapy, intravenous fluids and antibiotics are all discussed. The study evaluated patient and relative experiences with the TEP. 55 patients or their relatives were interviewed regarding their experience of the TEP and thoughts regarding the process. 96% of patients and relatives evaluated thought that the TEP was a good idea. Free text comments were all positive and only 34% of patients claimed to feel anxious when completing the form. Following this study, the TEP has been expanded hospital wide and into the community within our trust. Discussions are currently taking place in hospitals within our region to introduce the TEP form into other local trusts. (shrink)

The use of remember–know judgments to assess subjective experience associated with memory retrieval, or as measures of recollection and familiarity processes, has been controversial. In the current study we had participants think aloud during study and provide verbal reports at test for remember–know and confidence judgments. Results indicated that the vast majority of remember judgments for studied items were associated with recollection from study , but this correspondence was less likely for high-confidence judgments . Instead, high-confidence judgments were more likely (...) than remember judgments to be associated with incorrect recollection and a lack of recollection. Know judgments were typically associated with a lack of recollection , but still included recollection from the study context . Thus, although remember judgments provided fairly accurate assessments of retrieval including contextual details, know judgments did not provide accurate assessments of retrieval lacking contextual details. (shrink)

This study was designed to compare the natural free form communication that takes place when a person interacts with robotic entities versus live animals. One hundred and eleven participants interacted with one of four entities: an AIBO robotic dog, Legobot, Dog or Cat. It was found that participants tended to rate the Dog as more capable than the other entities, and often spoke to it more than the robotic entities. However, participants were not positively biased toward live entities, as the (...) Cat often was thought of and spoken to similarly to the AIBO robot. Results are consistent with a model in which both appearance and interactivity lead to the development of beliefs about a live or robotic entity in an interaction. Keywords: Human-robot interaction; human-animal interaction; AIBO; free form communication; attributions; human-entity interaction. (shrink)

This study was designed to compare the natural free form communication that takes place when a person interacts with robotic entities versus live animals. One hundred and eleven participants interacted with one of four entities: an AIBO robotic dog, Legobot, Dog or Cat. It was found that participants tended to rate the Dog as more capable than the other entities, and often spoke to it more than the robotic entities. However, participants were not positively biased toward live entities, as the (...) Cat often was thought of and spoken to similarly to the AIBO robot. Results are consistent with a model in which both appearance and interactivity lead to the development of beliefs about a live or robotic entity in an interaction. Keywords: Human-robot interaction; human-animal interaction; AIBO; free form communication; attributions; human-entity interaction. (shrink)

This study was designed to compare the natural free form communication that takes place when a person interacts with robotic entities versus live animals. One hundred and eleven participants interacted with one of four entities: an AIBO robotic dog, Legobot, Dog or Cat. It was found that participants tended to rate the Dog as more capable than the other entities, and often spoke to it more than the robotic entities. However, participants were not positively biased toward live entities, as the (...) Cat often was thought of and spoken to similarly to the AIBO robot. Results are consistent with a model in which both appearance and interactivity lead to the development of beliefs about a live or robotic entity in an interaction. Keywords: Human-robot interaction; human-animal interaction; AIBO; free form communication; attributions; human-entity interaction. (shrink)

At the same time that social justice concerns are on the rise on college campuses, empathy levels among US college students are falling. Social injustice resulting from organizational decisions and actions causes profound and unnecessary human suffering, and research to understand antecedents to these decisions and actions lacks attention. Empathy represents a potential tool and critical skill for organizational decision-makers, with empirical evidence linking empathy to moral recognition of ethical situations and greater breadth of understanding of stakeholder impact and improved (...) financial success. This study explores the potential relationship between empathy and social justice, using a multifaceted operationalization of social justice, which includes management actions and social sympathies. Results broadly support the positive empathy and social justice relationship and suggest higher education interventions to develop empathy in college business students. (shrink)

The Uniqueness Thesis holds, roughly speaking, that there is a unique rational response to any particular body of evidence. We first sketch some varieties of Uniqueness that appear in the literature. We then discuss some popular views that conflict with Uniqueness and others that require Uniqueness to be true. We then examine some arguments that have been presented in its favor and discuss why permissivists find them unconvincing. Last, we present some purported counterexamples that have been raised against Uniqueness and (...) discuss some possible reasons why proponents of Uniqueness might find these similarly unconvincing. (shrink)

In their forthcoming article, Shavelson and colleagues (2023) identify a key ethical concern associated with medical aid-in-dying (MAiD) laws in the eleven US jurisdictions where the practice is le...

Ageing causes progressive decline in metabolic, behavioural, and physiological functions, leading to a reduced health span. The extracellular matrix (ECM) is the three‐dimensional network of macromolecules that provides our tissues with structure and biomechanical resilience. Imbalance between damage and repair/regeneration causes the ECM to undergo structural deterioration with age, contributing to age‐associated pathology. The ECM ‘Ageing Across the Life Course’ interdisciplinary research network (ECMage) was established to bring together researchers in the United Kingdom, and internationally, working on the emerging field (...) of ECM ageing. Here we report on a consultation at a joint meeting of ECMage and the Medical Research Council / Versus Arthritis Centre for Integrated Research into Musculoskeletal Ageing, held in January 2023, in which delegates analysed the key questions and research opportunities in the field of ECM ageing. We examine fundamental biological questions, enabling technologies, systems of study and emerging in vitro and in silico models, alongside consideration of the broader challenges facing the field. (shrink)