Cofactor squelching is the term used to describe competition between transcription factors (TFs) for a limited amount of cofactors in a cell with the functional consequence that TFs in a given cell interfere with the activity of each other. Since cofactor squelching was proposed based primarily on reporter assays some 30 years ago, it has remained controversial, and the idea that it could be a physiologically relevant mechanism for transcriptional repression has not received much support. However, recent genome‐wide studies have (...) demonstrated that signal‐dependent TFs are very often absent from the enhancers that are acutely repressed by those signals, which is consistent with an indirect mechanism of repression such as squelching. Here we review these recent studies in the light of the classical studies of cofactor squelching, and we discuss how TF cooperativity in so‐called hotspots and super‐enhancers may sensitize these to cofactor squelching. (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)

Die Aufsätze des Bandes leisten einen Beitrag zur Debatte über die Relevanz des Hegelschen Sittlichkeitsbegriffs. Sie nehmen verschiedene Begriffe, Argumentationsmuster und Lösungsvorschläge von Hegels Rechtsphilosophie auf, testen deren Gegenwartstauglichkeit und zeichnen Rezeptionslinien nach. Im Zentrum stehen dabei neben dem Gehalt des Sittlichkeitstheorems und der Geschichtlichkeit sittlicher Lebensformen sowohl Personenbegriff, Bildungsidee wie Komplexität des zentralen Freiheitgedankens bei Hegel, aber auch die Perspektive der bürgerlichen Gesellschaft und die Reichweite und Aktualität der Sittlichkeitssemantik. Mit Beiträgen von Christiane Bender, Thomas Sören Hoffmann, Christian Hofmann, (...) Christian Krijnen, Wolfgang Schild, Christian Schmidt, Steffen Schmidt, Sebastian Schwenzfeuer, Michael Spieker, Pirmin Stekeler-Weithofer und Benno Zabel. (shrink)

Although thought experiments were first discovered as a sui generis methodological tool by philosophers of science (most prominently by Ernst Mach), the tool can also be found – even more frequently – in contemporary philosophy. Thought experiments in philosophy and science have a lot in common. However, in this chapter we will concentrate on thought experiments in philosophy only. Their use has been the centre of attention of metaphilosophical discussion in the past decade, and this chapter will provide an overview (...) of the results this discussion has achieved and point out which issues are still open. (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)

During gestation, fetomaternal exchange occurs in the villous tree (labyrinth) of the placenta. Development of this structure depends on tightly coordinated cellular processes of branching morphogenesis and differentiation of specialized trophoblast cells. The basal chorionic trophoblast (BCT) cell layer that localizes next to the chorioallantoic interface is of critical importance for labyrinth morphogenesis in rodents. Gcm1‐positive cell clusters within this layer initiate branching morphogenesis thereby guiding allantoic fetal blood vessels towards maternal blood sinuses. Later these cells differentiate and contribute to (...) the syncytiotrophoblast of the fetomaternal barrier. Additional cells within the BCT layer sustain continued morphogenesis, possibly through a repopulating progenitor population. Several mouse mutants highlight the importance of a structurally intact BCT epithelium, and a growing number of studies addresses its patterning and epithelial architecture. Here, we review and discuss emerging concepts in labyrinth development focussing on the biology of the BCT cell layer. (shrink)

A wide-ranging attempt to develop a theory of ethical life from a hermeneutic understanding of language.

:War has broken out in the technological global economy, principally in battles over intellectual property. A particularly fierce aspect of this battle sets people who guard proprietary software against hackers, who want information to be free. The key challenge today is to produce an adequate conceptual lens for seeing what ethically is at stake in this battle. Toward this end, this paper uses the just war tradition to analyze differences between proponents of Free Software and proponents of Open Source Software. (...) This paper’s use of three just war criteria—Just Cause, Right Intention, and Discrimination—illustrates how the just war tradition can raise the level of ethical awareness about the intellectual property wars that continue to rage in the technological global economy.The division between the two [open source and free software] is often bitterly contested, both from inside and outside the communities. The holiest of holy wars are not fought over word processors, operating systems, or compilers. They are all about software licenses.—Joe Barr. (shrink)

Semantic memory encompasses one's knowledge about the world. Distributional semantic models, which construct vector spaces with embedded words, are a proposed framework for understanding the representational structure of human semantic knowledge. Unlike some classic semantic models, distributional semantic models lack a mechanism for specifying the properties of concepts, which raises questions regarding their utility for a general theory of semantic knowledge. Here, we develop a computational model of a binary semantic classification task, in which participants judged target words for the (...) referent's size or animacy. We created a family of models, evaluating multiple distributional semantic models, and mechanisms for performing the classification. The most successful model constructed two composite representations for each extreme of the decision axis (e.g., one averaging together representations of characteristically big things and another of characteristically small things). Next, the target item was compared to each composite representation, allowing the model to classify more than 1,500 words with human‐range performance and to predict response times. We propose that when making a decision on a binary semantic classification task, humans use task prompts to retrieve instances representative of the extremes on that semantic dimension and compare the probe to those instances. This proposal is consistent with the principles of the instance theory of semantic memory. (shrink)