The precise orchestration of two opposing protein complexes – one in the cytoplasm (β‐catenin destruction complex) and the other at the plasma membrane (LRP6 signaling complex) – is critical for controlling levels of the transcriptional co‐factor β‐catenin, and subsequent activation of the Wnt/β‐catenin signal transduction pathway. The Wnt pathway component Axin acts as an essential scaffold for the assembly of both complexes. How the β‐catenin destruction and LRP6 signaling complexes are modulated following Wnt stimulation remains controversial. A recent study in (...) Science by He and coworkers reveals an underlying logic for Wnt pathway control in which Axin phosphorylation toggles a switch between the active and inactive states. This mini‐review focuses on this and two other recent studies that provide insight into the initial signaling events triggered by Wnt exposure. We emphasize regulation of the β‐catenin destruction and LRP6 signaling complexes and propose a framework for future work in this area. (shrink)

Synthetic biology is a research field that has grown rapidly and attracted considerable attention. Most prominently, it has been labelled the ‘engineering of biology’. While other attempts to label the field have been also pursued, the program of engineering can be considered the core of the field’s disciplinary program, of its identity. This article addresses the success of the ‘engineering program’ in synthetic biology and argues that its success can partly be explained by distinct practices of persuasion that aim at (...) persuading scientific, but also non-scientific audiences. The article explores two different modes of persuasion:, building tools as heuristic models and posing visionary claims. Objects such as the toggle switch or the synthetic oscillator in synthetic biology can more adequately be described as heuristic models of engineering instead of simply as prototypes of ‘tools’. Posing visionary claims can be also understood as a persuasion practice, since the claims are used to construct the societal relevance of the field. Drawing upon Michel Callon’s ‘sociology of translation’, I argue that both practices of persuasion aim at ‘enrolling’ entities into the disciplinary identity. The article is based on the textual analysis of rhetorical practices in three synthetic biology review articles which are considered seminal for the history of the field. (shrink)

Permissivism is the view that there are evidential situations that rationally permit more than one attitude toward a proposition. In this paper, I argue for Intrapersonal Belief Permissivism (IaBP): that there are evidential situations in which a single agent can rationally adopt more than one belief-attitude toward a proposition. I give two positive arguments for IaBP; the first involves epistemic supererogation and the second involves doubt. Then, I should how these arguments give intrapersonal permissivists a distinct response to the (...) class='Hi'>toggling objection. I conclude that IaBP is a view that philosophers should take seriously. (shrink)

The “Slicing Problem” is a thought experiment that raises questions for substrate-neutral computational theories of consciousness, including those that specify a certain causal structure for the computation like Integrated Information Theory. The thought experiment uses water-based logic gates to construct a computer in a way that permits cleanly slicing each gate and connection in half, creating two identical computers each instantiating the same computation. The slicing can be reversed and repeated via an on/off switch, without changing the amount of matter (...) in the system. The question is what do different computational theories of consciousness believe is happening to the number and nature of individual conscious units as this switch is toggled. Under a token interpretation, there are now two discrete conscious entities; under a type interpretation, there may remain only one. Both interpretations lead to different implications depending on the adopted theoretical stance. Any route taken either allows mechanisms for “consciousness-multiplying exploits” or requires ambiguous boundaries between conscious entities, raising philosophical and ethical questions for theorists to consider. We discuss resolutions under different theories of consciousness for those unwilling to accept consciousness-multiplying exploits. In particular, we specify three features that may help promising physicalist theories to navigate such thought experiments. (shrink)

Over the course of the past few decades, comparative political theory has acquired a measure of institutional legitimacy and intellectual recognition as part of the ongoing, interdisciplinary challenge to prevailing academic categories, coordinates, and borders. This arrival has been accompanied by a conspicuous focus on methodology both by those who claim the mantle of comparative political theory and those who reject it. The following reflections read this focus symptomatically, as revealing intellectual, institutional, and professional exigencies rather than as distinct to (...) any particular scholar, argument, or publication. Neither a “state of the field” nor a proprietary defense of what comparative political theory is or should be, these observations toggle back and forth between reflections on my own engagement and disengagement with the topic of comparative political theory on the one hand and, on the other, concerns about how this preoccupation with method simultaneously expresses and exacerbates the displacement of politics in the very field that aims to understand it. Among the questions I raise are: What might be driving this disproportionate focus on methodological arguments in and about comparative political theory? What are the stakes of such a focus, particularly for younger scholars in political science departments decreasingly hospitable to political theory? Finally, what does this augur for the future of the study of politics broadly understood within disciplines dedicated to the scientific study of human behavior? (shrink)

A central feature of our waking mental experience is that our attention naturally toggles back and forth between “external” and “internal” stimuli. In the midst of an externally demanding task, attention can involuntarily shift internally with no clear reason how or why thoughts momentarily shifted inward. In the case of external attention, we are typically exploring and encoding aspects of our external world, whereas internal attention often involves searching for and retrieving potentially relevant information from our memory networks. Cognitive science (...) has traditionally focused on understanding forms of internal and external attention separately, leaving a mystery about what sparks the seemingly automatic shifts between the two. Specifically, what shifts attentional focus from being outward‐directed to being inward‐directed? We present a candidate mechanism: Familiarity‐detection. (shrink)

Arnold Berleant shares much in common with John Dewey. His notion of aesthetic engagement, which is central to his philosophy of art, is, like Dewey’s concept of “an experience,” an attack on dualistic notions of aesthetic experience. To the extent that Berleant and I are both Deweyans, we agree that we need to turn from the art object to art experience. Art is what it does in experience. Yet appreciative experience of art cannot happen without, at some point, focusing on (...) the art object as such, and this means bracketing context. Engagement is important, but so too are contemplation, disinterestedness and distance. Contemplation, for example, is a moment both in the creative process and in the process of appreciation. Moreover, following Brand and Gracyk, it will be argued in the present paper that only through toggling between contemplation and engagement can we obtain a full experience of art, nature, or of the everyday. (shrink)

On a ‘comparative’ conception of practical reasons, reasons are like ‘weights’ that can make an action more or less rational. Bernard Gert adopts instead a ‘toggle’ conception of practical reasons: something counts as a reason just in case it alone can make some or other otherwise irrational action rational. I suggest that Gert’s conception suffers from various defects, and that his motivation for adopting this conception – his central claim that actions can be rational without there being reasons for them (...) – does not require adoption of the toggle conception. The more intuitive comparative conception of reasons for action can accommodate the insight. (shrink)

Fragmented regions face a range of collective action problems on issues ranging from transportation to affordable housing. Specifically, within regions, free-rider and race-to-the-bottom problems both abound. This Article offers theoretical lenses to clarify the sources of, and barriers to solving, these problems. First, it introduces the concept of concentricity to better understand the region. The municipality and the region represent coexisting, concentric communities and nodes of competition. The geographically based identity that one espouses may toggle between the local and the (...) regional across different contexts. Second, this Article describes a community-competitor feedback loop. Drawing on social science literature, the Article shows how encouraging deep identification with a community can inspire competition with other communities. And encouraging competition between communities can deepen community identity. The Article then applies these theories to practical considerations. Given the persistent nature of hyperlocal identity, intraregional competition, and the resultant feedback loop, mandatory regional solutions may often be politically unattainable, even when they are the optimal solution. Accordingly, this Article presents two voluntary, cooperative regionalist solutions that embrace and potentially exploit regions’ concentric identities, instead of doing the more costly work of dislodging local identity. (shrink)

This paper argues for the specific pedagogical and philosophical value of toggling between places, as experienced in service or community-based learning. Regular shifting of student perspectives by traveling from a classroom to a community service site alienates students from their assumptions about beliefs, and opens up more diverse perspectives within the classroom.

Abstract:Christian Bendayán (Iquitos, Peru 1973 -) is one of a cadre of visual artists from Iquitos, Peru that has cultivated an Amazonian pop aesthetic over the last decade. Bendayán creates an alternative, counter-dominant viewpoint to seemingly intractable archival versions of the Amazon and its peoples. The place, its habitants, and its flora and fauna have been documented in published texts and drawings by sixteenth-century missionaries, eighteenth-century botanists, nineteenth-century rubber barons, and countless adventurers. I argue that Bendayán queers some of these (...) archival documents through his incorporation of gender non-conforming and homoerotic figures into his depiction of Iquitos. Additionally, he reconfigures images and texts from previous eras via his transformation of historical facts into open-ended narratives that reflect a queer temporality that toggles back and forth between the past, the present and the future. Through his transformation of archival materials, and his incorporation of local myths and pop culture, he presents physical desire not as a means to procreation, but as an end in and of itself. In sum, through his paintings, Bendayán perceives from and with Iquitos. He turns his city into a distinct viewpoint instead of a fantastical destination for the projections of outsiders. (shrink)

By coincidence, it seems, the critical vocabulary and concerns that came to be known as postcolonial theory and methodology rose to be a dominant school of inquiry in the Anglo-American academy in the same years that the Soviet Union collapsed (notwithstanding that key theoretical texts by Frantz Fanon and others predated this moment by decades). Yet, oddly, postcolonialist terms were seldom applied to postsocialist and post-Soviet cases until the 2000s, and they have become more broadly utilized in these territories only (...) in the past decade. Further, it must be admitted that few results of these applications of postcolonial tools to postsocialist cases have made much of a mark among broader circles of postcolonial scholars and thinkers. Djagalov's book may help to correct this situation. Rather than work in the mode of “application”—applying a postcolonial framework to yet one more case—Djagalov reconstructs the history of a century of socialist anti-imperialism, as it was expressed in global cultural institutions and networks, and in so doing discovers the ignored or forgotten genealogy that links contemporary postcolonial thought to writers, activists, and theoreticians of the socialist world.Djagalov's book toggles between, on the one hand, chapters of institutional history that chronicle the global cultural institutions (such as the Afro-Asian Writers Association, the Tashkent Film Festival, and the Lotus Prize) that connected the Soviet Union with decolonizing countries and, on the other hand, chapters of synthetic cultural criticism that articulate typological analyses of common narrative forms that circulated in the fiction and film of the socialist world—recurring varieties of “solidarity narratives,” as Djagalov calls them. His work reveals how central the state-socialist political imaginary was for writers and filmmakers ranging from Nâzım Hikmet to Ngūgī wa Thiong'o, and how prominent their itineraries through Soviet institutions and networks were in their biographies. Ngūgī, for instance, finished his 1977 novel Petals of Blood during a residency in the Soviet Writers House in Yalta.In recovering the lost continent of anti-imperial socialist globality that bridged the “second” and “third worlds,” Djagalov has demonstrated not how postcolonial terms can be applied to postsocialist cases but how postcolonial theory and method are themselves postsocialist phenomena. Djagalov does not attempt to rectify the state-socialist prehistory of postcolonial thought with a critique of Soviet imperial habits or of the postcolonial contexts of contemporary Eastern Europe, the Caucasus, and Central Asia. At least, though, the challenges of thinking “postcolonial” and “postsocialist” together have now become clearer. From Internationalism to Postcolonialism leaves us with new research problems: what, for example, does it mean to be a postcolony of an anti-imperial empire? (shrink)

The cognitive and evolutionary sciences of religion offer a standard model of religious representations, but no equivalent paradigm for investigating religiously interpreted altered states of consciousness (religious ASCs). Here, I describe a neo‐Durkheimian framework for studying religious ASCs that centralizes social predictive cognition. Within a processual model of ritual, ritual behaviors toggle between reinforcing normative social structures and downplaying them. Specifically, antistructural ritual shifts cognitive focus away from conventional affordances, collective intentionality, and social prediction, and toward physical affordances and behavioral (...) motivations that make few references to others’ intentional states. Using synchrony and dance as paradigmatic examples of antistructural ritual that stimulate religious ASCs, I assemble literature from anthropology, cognitive neuroscience, and philosophy of language to offer fruitful empirical predictions and opportunities for testing based on this framework. Among the empirical predictions is that antistructural ritual may provide for cultural change in religions when religions are construed as complex adaptive systems. (shrink)

The Garden of Leaders explores two related questions: What is leadership? And what sort of education could prepare young people to be leaders? Paul Woodruff argues that higher education--particularly but not exclusively in the liberal arts--should set its main focus on cultivating leadership in students. Woodruff advances a new view of liberal arts education that places leadership at the root of everything it does, so that students will be prepared to lead in their lives and careers--and not necessarily in management (...) roles. Woodruff views the contemporary university as sorely lacking an emphasis on leadership, and presents three core sets of recommendations for how they can and should foster it. First, Woodruff posits co-curricular groups, activities, and projects as essential activities for students to gain confidence and leadership skills. Administrations should encourage students to engage in activities outside the classroom, convert coached sports teams into student-led clubs as far as possible, and discourage social organizations that are segregated by race or sex. Second, Woodruff advocates for a different curriculum for all undergraduates, no matter their major-arguing that they need to be taught leadership in the forms of key skills including communication, as well as exposure to key material in history literature, social science, and ethics. Students should be asked to consider the hardest ethical dilemmas that leaders face, toggling between Machiavelli and great ethical thinkers such as Confucius and Socrates. Third, Woodruff calls for the teaching methods used by instructors to re-orient themselves around the question of leadership, particularly by emphasizing teamwork. Professors should respect their students' independence, avoid tyrannical teaching, and remember that all teachers teach ethics simply by the examples they set in dealing with students. Whether in engineering, music, or classics, The Garden of Leaders advances leadership as a core value that should be at the heart of the educational enterprise-contending that while a college campus can be many things, it should at the very least be a ground upon which new leaders can grow. (shrink)

Co‐expression of two or more genes at the single‐cell level is usually associated with functional co‐regulation. While mRNA co‐expression—measured as the correlation in mRNA levels—can be influenced by both transcriptional and post‐transcriptional events, transcriptional regulation is typically considered dominant. We review and connect the literature describing transcriptional and post‐transcriptional regulation of co‐expression. To enhance our understanding, we integrate four datasets spanning single‐cell gene expression data, single‐cell promoter activity data and individual transcript half‐lives. Confirming expectations, we find that positive co‐expression necessitates (...) promoter coordination and similar mRNA half‐lives. Surprisingly, negative co‐expression is favored by differences in mRNA half‐lives, contrary to initial predictions from stochastic simulations. Notably, this association manifests specifically within clusters of genes. We further observe a striking compensation between promoter coordination and mRNA half‐lives, which additional stochastic simulations suggest might give rise to the observed co‐expression patterns. These findings raise intriguing questions about the functional advantages conferred by this compensation between distal kinetic steps. (shrink)

X‐chromosome inactivation ensures dosage compensation between the sexes in mammals by randomly choosing one out of the two X chromosomes in females for inactivation. This process imposes a plethora of questions: How do cells count their X chromosome number and ensure that exactly one stays active? How do they randomly choose one of two identical X chromosomes for inactivation? And how do they stably maintain this state of monoallelic expression? Here, different regulatory concepts and their plausibility are evaluated in the (...) context of theoretical studies that have investigated threshold behavior, ultrasensitivity, and bistability through mathematical modeling. It is discussed how a twofold difference between a single and a double dose of X‐linked genes might be converted to an all‐or‐nothing response and how mutually exclusive expression can be initiated and maintained. Finally, candidate factors that might mediate the proposed regulatory principles are reviewed. (shrink)

Mammalian synthetic biology holds the promise of providing novel therapeutic strategies, and the first success stories are beginning to be reported. Here we focus on the latest generation of mammalian transgene control devices, highlight state‐of‐the‐art synthetic gene network design, and cover prototype therapeutic circuits. These will have an impact on future gene‐ and cell‐based therapies and help bring drug discovery into a new era. The inventory of biological parts that are essential for life on this planet is becoming increasingly complete. (...) The postgenomic era has provided encyclopedic information on gene‐function correlations and systems biology is now delivering comprehensive details on the dynamics of biochemical reaction networks in living organisms. The time has come to reassemble these catalogued items and design new biological devices and systems with novel and useful functionality in a rational and systematic manner. This is the premise of synthetic biology, a constructive systems biology discipline likely to become the life science revolution of the 21st century. (shrink)