The recent discovery and structure determination of a novel ubiquitin‐like dimerization domain in protein kinase D (PKD) has significant implications for its activation. PKD is a serine/threonine kinase activated by the lipid second messenger diacylglycerol (DAG). It is an essential and highly conserved protein that is implicated in plasma membrane directed trafficking processes from the trans‐Golgi network. However, many open questions surround its mechanism of activation, its localization, and its role in the biogenesis of cargo transport carriers. In reviewing this (...) field, the focus is primarily on the mechanisms that control the activation of PKD at precise locations in the cell. In light of the new structural findings, the understanding of the mechanisms underlying PKD activation is critically evaluated, with particular emphasis on the role of dimerization in PKD autophosphorylation, and the provenance and recognition of the DAG that activates PKD. (shrink)

Religionskritik wird gerade in der jungeren Vergangenheit bevorzugt als Kritik an der vermeintlichen Irrationalitat religiosen Glaubens artikuliert. Die Autoren der im vorliegenden Konferenzband versammelten Beitrage fragen zunachst anhand exemplarischer Studien zu Hamann, Hegel, Schelling, Nietzsche und Rudolf Otto nach der Bedeutung und Funktion des Irrationalen in rezeptionsgeschichtlich massgeblichen religionsphilosophischen Entwurfen der (Nach-)Aufklarung. Erganzt und zugespitzt wird der historische Abschnitt des Bandes durch Analysen zu Werk und Wirkung Soren Kierkegaards, dem neuzeitlichen Irrationalitatstheoretiker par excellence. Daruber hinaus wird aus systematischer Perspektive nach (...) der kritischen und/oder konstruktiven Funktion des Irrationalitatsthemas fur Religionsphilosophie und Theologie gefragt, wobei nicht nur semantische, sondern auch fundamentaltheologische und ethische Aspekte Berucksichtigung finden. Mit Beitragen von: Daniel Conway, Istvan Czako, Dario Gonzalez, Todd Gooch, Zoltan Gyenge, Gesche Linde, William McDonald, Peter Sajda, Jochen Schmidt, Heiko Schulz, Harald Steffes, Jon Stewart, Curtis Thompson, Knut Wenzel, Oliver Wiertz. (shrink)

Cancer is a complex disease, necessitating research on many different levels; at the subcellular level to identify genes, proteins and signaling pathways associated with the disease; at the cellular level to identify, for example, cell-cell adhesion and communication mechanisms; at the tissue level to investigate disruption of homeostasis and interaction with the tissue of origin or settlement of metastasis; and finally at the systems level to explore its global impact, e.g. through the mechanism of cachexia. Mathematical models have been proposed (...) to identify key mechanisms that underlie dynamics and events at every scale of interest, and increasing effort is now being paid to multi-scale models that bridge the different scales. With more biological data becoming available and with increased interdisciplinary efforts, theoretical models are rendering suitable tools to predict the origin and course of the disease. The ultimate aims of cancer models, however, are to enlighten our concept of the carcinogenesis process and to assist in the designing of treatment protocols that can reduce mortality and improve patient quality of life. Conventional treatment of cancer is surgery combined with radiotherapy or chemotherapy for localized tumors or systemic treatment of advanced cancers, respectively. Although radiation is widely used as treatment, most scheduling is based on empirical knowledge and less on the predictions of sophisticated growth dynamical models of treatment response. Part of the failure to translate modeling research to the clinic may stem from language barriers, exacerbated by often esoteric model renderings with inaccessible parameterization. Here we discuss some ideas for combining tractable dynamical tumor growth models with radiation response models using biologically accessible parameters to provide a more intuitive and exploitable framework for understanding the complexity of radiotherapy treatment and failure. (shrink)

The detection and categorization of animate motions is a crucial task underlying social interaction and perceptual decision making. Neural representations of perceived animate objects are partially located in the primate cortical region STS, which is a region that receives convergent input from intermediate-level form and motion representations. Populations of STS cells exist which are selectively responsive to specific animated motion sequences, such as walkers. It is still unclear how and to what extent form and motion information contribute to the generation (...) of such representations and what kind of mechanisms are involved in the learning processes. The article develops a cortical model architecture for the unsupervised learning of animated motion sequence representations. We demonstrate how the model automatically selects significant motion patterns as well as meaningful static form prototypes characterized by a high degree of articulation. Such key poses are selectively reinforced during learning through a cross talk between the motion and form processing streams. Furthermore, we show how sequence-selective representations are learned in STS by fusing static form and motion input from the segregated bottom-up driving input streams. Cells in STS, in turn, feed their activities recurrently to their input sites along top-down signal pathways. We show how such learned feedback connections enable predictions about future input as anticipation generated by sequence-selective STS cells. Network simulations demonstrate the computational capacity of the proposed model by reproducing several experimental findings from neurosciences and by accounting for recent behavioral data. (shrink)

We give an overview of the practice of developing and using complex climate models, as seen from experiences in a major climate modelling center and through participation in the Coupled Model Intercomparison Project. We discuss the construction and calibration of models; their evaluation, especially through use of out-of-sample tests; and their exploitation in multi-model ensembles to identify biases and make predictions. We stress that adequacy or utility of climate models is best assessed via their skill against more naïve predictions. The (...) framework we use for making inferences about reality using simulations is naturally Bayesian, and has many points of contact with more familiar examples of scientific epistemology. While the use of complex simulations in science is a development that changes much in how science is done in practice, we argue that the concepts being applied fit very much into traditional practices of the scientific method, albeit those more often associated with laboratory work. (shrink)

Many of our attitudes are non-culpable: there was nothing that we should have done to avoid holding them. I argue that we can still be blameworthy for non-culpable attitudes: they can impair our relationships in ways that make our full practice of apology and forgiveness intelligible. My argument poses a new challenge to indirect voluntarists, who attempt to reduce all responsibility for attitudes to responsibility for prior actions and omissions. Rationalists, who instead explain attitudinal responsibility by appeal to reasons-responsiveness, can (...) make sense of blameworthiness for non-culpable attitudes. In response, voluntarists could propose a revision of our actual practices. This would lead us into a quite different debate. (shrink)

As synthetic biology develops into a promising science and engineering field, we need to have clear ideas and priorities regarding its safety, security, ethical and public dialogue implications. Based on an extensive literature search, interviews with scientists, social scientists, a 4 week long public e-forum, and consultation with several stakeholders from science, industry and civil society organisations, we compiled a list of priority topics regarding societal issues of synthetic biology for the years ahead. The points presented here are intended to (...) encourage all stakeholders to engage in the prioritisation of these issues and to participate in a continuous dialogue, with the ultimate goal of providing a basis for a multi-stakeholder governance in synthetic biology. Here we show possible ways to solve the challenges to synthetic biology in the field of safety, security, ethics and the science-public interface. (shrink)

The present study evaluates the cognitive representation of a kicking movement performed by a human and a humanoid robot, and how they are represented in experts and novices of soccer and robotics, respectively. To learn about the expertise-dependent development of memory structures, we compared the representation structures of soccer experts and robot experts concerning a human and humanoid robot kicking movement. We found different cognitive representation structures for both expertise groups under two different motor performance conditions . In general, the (...) expertise relies on the perceptual-motor knowledge of the human motor system. Thus, the soccer experts’ cognitive representation of the humanoid robot movement is dominated by their representation of the corresponding human movement. Additionally, our results suggest that robot experts, in contrast to soccer experts, access functional features of the technical system of the humanoid robot in addition to their perceptual-motor knowledge about the human motor system. Thus, their perceptual-motor and neuro-functional machine representation are integrated into a cognitive representation of the humanoid robot movement. (shrink)

This note proposes to emend the problematic preserved reading ad cuius mensae sacra (Val. Max. 4.2.3) to ad Iouis mensae sacra.

This study presents a contrastive corpus linguistic analysis of language use before and after Stonewall. It uses theoretical insights on normativity from the field of language and sexuality to investigate how the shifting normativities associated with the Stonewall Riots – widely considered the central event of gay liberation in the Western world – have shaped our conceptualization of sexuality as it surfaces in language use. Drawing on two corpora of gay men’s pre-Stonewall narratives dating from two time periods, the analysis (...) combines quantitative and qualitative corpus linguistic methods to examine discursive shifts as evident from narrators’ language use. The study identifies the terms homosexual and normal as central contrastive labels in PRE, and gay and straight as corresponding terms in POST. Other discursive shifts detected are from sexual desire/practices to identity, from an individualistic to a community-based conceptualization of sexuality, and from unquestioned heteronormativity and gender binarism to a weakening of such dominant discourses. The findings are discussed in relation to the desire-identity shift, which is traditionally assumed to have taken place at the end of the 19th century, and shed new light on Stonewall as a central event for the development of an identity-based conceptualization of sexuality as we know it today. (shrink)

Proteoglycan 4 (PRG4), first identified in synovial fluid, is an extracellular matrix structural protein in the joint implicated in reducing shear at the cartilage surface as well as controlling adhesion‐dependent synovial growth and regulating bulk protein deposition onto the cartilage. However, recent evidence suggests that it can bind to and effect downstream signaling of a number of cell surface receptors implicated in regulating the inflammatory response. Therefore, we pose the hypothesis: Does PRG4 regulate the inflammatory response and maintain tissue homeostasis? (...) Based on these novel findings implicating PRG4 as an inflammatory signaling molecule, we will present and discuss several hypotheses regarding potential mechanisms by which PRG4 may be able to regulate inflammation. If future studies can demonstrate that PRG4 is a potent inflammatory mediator, this will change current paradigms in the musculoskeletal and ophthalmological fields regarding the how the inflammatory microenvironment is regulated in these tissues and potentially others. (shrink)

This paper has two goals. The first is to develop a cross-linguistically valid model of modality and mood that captures the most important dimensions along which modal expressions vary. I posit a model with two such dimensions, one of volitivity, and one of event-orientation vs. speaker-orientation, mood being placed at the speaker-oriented end relative to modality proper. The second goal is to provide a new perspective on semantic change of modal expressions on the basis of the proposed model. I argue (...) that unidirectional change along the event-oriented / speaker-oriented dimension is the one overarching tendency of semantic change in modals. This stands in contrast to the widespread perception that change from deontic to epistemic is the dominant tendency. The directionality suggested in this new model is also more comprehensive than previously proposed tendencies of change, such as ‘‘from agent-oriented to epistemic’’, ‘‘from agent-oriented to speaker-oriented’’, and ‘‘from participant-internal to participant-external’’, as it better accounts for various kinds of change that have been previously neglected, including change from epistemic to deontic. (shrink)

What is the purpose of our economic system? What would a more life-serving economy look like? There are many books about business and society, yet very few of them question the primacy of GDP growth, profit maximization and individual utility maximization. Even developments with a humanistic touch like stakeholder participation, corporate social responsibility or corporate philanthropy serve the same goal: to foster long-term growth and profitability. Humanism in Business questions these assumptions and investigates the possibility of creating a human-centered, value-oriented (...) society based on humanistic principles. An international team of academics and practitioners present philosophical, spiritual, economic, psychological and organizational arguments that show how humanism can be used to understand, and possibly transform, business at three different levels: the systems level, the organizational level and the individual level. This groundbreaking book will be of interest to academics, practitioners and policymakers concerned with business ethics and the relationship between business and society. (shrink)

IntroductionThe objectives of this study are to assess and compare differences in the intensity, frequency, and overall severity of moral distress among a diverse group of healthcare professionals.MethodsParticipants from within Baylor Health Care System completed an online seven-point Likert scale (range, 0 to 6) moral distress survey containing nine core clinical scenarios and additional scenarios specific to each participant’s discipline. Higher scores reflected greater intensity and/or frequency of moral distress.ResultsMore than 2,700 healthcare professionals responded to the survey (response rate 18.14 (...) percent); survey respondents represented multiple healthcare disciplines across a variety of settings in a single healthcare system. Intensity of moral distress was high in all disciplines, although the causes of highest intensity varied by discipline. Mean moral distress intensity for the nine core scenarios was higher among physicians than nurses, but the mean moral distress frequency was higher among nurses. Taking into account both intensity and frequency, the difference in mean moral distress score was statistically significant among the various disciplines. Using post hoc analysis, differences were greatest between nurses and therapists.ConclusionsMoral distress has previously been described as a phenomenon predominantly among nursing professionals. This first-of-its-kind multidisciplinary study of moral distress suggests the phenomenon is significant across multiple professional healthcare disciplines. Healthcare professionals should be sensitive to situations that create moral distress for colleagues from other disciplines. Policy makers and administrators should explore options to lessen moral distress and professional burnout that frequently accompanies it. (shrink)

Name der Zeitschrift: Cognitive Linguistics Jahrgang: 27 Heft: 1 Seiten: 101-136.

Humans are normative beings through and through. This capacity for normativity lies at the core of uniquely human forms of understanding and regulating socio-cultural group life. Plausibly, therefore, the hominin lineage evolved specialized social-cognitive, motivational, and affective abilities that helped create, transmit, preserve, and amend shared social practices. In turn, these shared normative attitudes and practices shaped subsequent human phylogeny, constituted new forms of group life, and hence structured human ontogeny, too. An essential aspect of human ontogeny is therefore its (...) reciprocal nature regarding normativity. This chapter reviews recent evidence from developmental psychology suggesting that, from early on, human children take a normative attitude toward others’ conduct in social interactions, and thus a collectivistic and impersonal perspective on norms. We discuss to what extent our closest living primate relatives lack normative attitudes and therefore live in a non-normative socio-causal world structured by individual preferences, power relationships, and regularities. (shrink)