The Wnt family of developmental regulators were named after the Drosophila segmentation gene wingless and the murine proto‐oncogene int‐1. Homology between these two genes connected oncogenesis to cell‐cell signals in development. I review how wingless was initially characterized, and cloned, as part of the quest to identify developmental cell‐to‐cell signals, based on predictions of the Positional Information Model, and on the properties of homeotic and segmentation gene mutants. The requirements and cell‐nonautonomy of wingless in patterning multiple embryonic and adult structures (...) solidified its status as a candidate signaling molecule. The physical location of wingless mutations and transcription unit defined the gene and its developmental transcription pattern. When the Drosophila homolog of int‐1 was then isolated, and predicted to encode a secreted proto‐oncogene homolog, it's identity to the wingless gene confirmed that a developmental cell‐cell signal had been identified and connected cancer to development. (shrink)

In 1995, the eyeless (ey) gene was dubbed the “master‐regulator” of eye development in Drosophila. Not only is ey required for eye development, but its misexpression can convert many other tissues into eye, including legs, wings and antennae.(1) ey is remarkable for its ability to drive coordinate differentiation of the multiple cell types that have to differentiate in a very precise pattern to construct the fly eye, and for its power to override the previous differentiation programs of many other diverse (...) tissues. Even more remarkable, the ey homolog Pax6 and homologs of other eye determination genes from Drosophila are also required for eye development in vertebrates,(2,3) prompting reassessment of the evolution of vision throughout the animal kingdom.(4,5) Now Kumar and Moses have published a study that throws a new light on ey function in Drosophila.(6) According to their work, ey becomes a master regulator of eye development much later than previously thought, and is regulated by signalling through the Notch and EGFR signaling pathways. BioEssays 23:763–766, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Much progress has been made recently towards uncovering the mechanisms that control the size to which organisms and their organs grow, and identifying some of the genes responsible. Size control, however, is only half of the equation. In growing to the right size, tissues must also grow to the right shape. A recent paper1 suggests that a hitherto overlooked cellular behaviour governs the size and shape of a growing tissue, and issues a challenge to developmental biologists to identify the molecular (...) mechanisms involved. BioEssays 25:5–8, 2003. © 2002 Wiley Periodicals, Inc. (shrink)

Claims about what justice “requires” and the “requirements” of justice are pervasive in political philosophy. However, there is a highly significant ambiguity in such claims that appears to have gone unnoticed. Such claims may pick out either one of two categorically distinct and noncoextensive kinds of requirement that we call 1) requirements-as-necessary-conditions for justice and 2) requirements-as-demands of justice. This is an especially compelling instance of an ambiguity that John Broome has famously observed in the context of claims about other (...) requirements (notably the requirements of rationality and morality). But it appears to have been overlooked by political philosophers in the case of claims about the requirements of justice. The ambiguity is highly significant inasmuch as failing to notice it is liable to distort our normative thinking about politics and make us vulnerable to certain kinds of normatively consequential errors: both mistakenly drawing inferences about what justice demands of us from claims that certain states or societies are not just; and mistakenly drawing inferences about what states or societies are or would be just from claims that justice does not demand of states or societies that they do certain things. Paying greater attention to the distinction between these two different kinds of requirements and the ways in which they come apart is helpful, not merely in avoiding these distortions and errors, but also in resolving, or at least clarifying, a number of other notoriously murky meta-normative debates, especially various important debates about realism and idealism in political philosophy. (shrink)

Over the last 30 years, colleges of education across the nation have examined and deliberated how best to educate pre-service history teachers for the challenges of the modern classroom. Specifically, they sought to create and refine teacher preparation programs that foster within the pre-service history teacher the propensity to use authentic teaching practices once they are licensed and instructing independently in the classroom. Using a situated learning theoretical framework, this research study adds to the literature on this topic by examining (...) how a semester-long pre-service residency at a historic site, archive, library, or museum influences in-service history teacher pedagogy. Utilizing an ex post facto qualitative research methodology with a questionnaire, interviews, and analysis of lesson plans, this study pursued the objective of evaluating the nuances of a residency and how those experiences influence in-service pedagogical dispositions. The findings of the study conclude pre-service history teacher residencies offer valuable and unique learning spaces for the pedagogical development of pre-service history teachers by promoting authentic-based teaching models that participants carry into their in-service teaching. (shrink)

Background To describe the preferences for disclosure of individual biomarker results among mothers participating in a longitudinal birth cohort. Methods We surveyed 343 mothers that participated in the Health Outcomes and Measures of the Environment Study about their biomarker disclosure preferences. Participants were told that the study was measuring pesticide metabolites in their biological specimens, and that the health effects of these low levels of exposure are unknown. Participants were asked whether they wanted to receive their results and their child's (...) results. In addition, they were asked about their preferred method (letter vs in person) and format (more complex vs less complex) for disclosure of results. Results Almost all of the study participants wanted to receive their individual results (340/343) as well as their child's results (342/343). However, preferences for receiving results differed by education level. Mothers with less than a college degree preferred in-person disclosure of results more often than mothers with some college education or a college degree (34.3% vs 17.4% vs 7.9%, p<0.001). Similarly, mothers with less than a college education preferred a less complex disclosure format than mothers with some college education or a college degree (59.7% vs 79.1% vs 86.3%, p<0.0001). Conclusion While almost all study participants preferred to receive results of their individual biomarker tests, level of education was a key factor in predicting preferences for disclosure of biomarker results. To ensure effective communication of this information, disclosure of biomarker results should be tailored to the education level of the study participants. (shrink)

Beginning in 2002, Wells Fargo began opening fraudulent accounts for unsuspecting customers. Stakeholders at every level either participated in, ignored, or tolerated the bank’s behavior that defrauded consumers on a massive scale. These unethical and well-documented schemes spanned more than a decade. Using public sources, this case recounts the events and ethical lapses that unfolded over the multiyear investigation of the Wells Fargo fraudulent accounts scandal and illuminates the general systemic failures of corporate culture and governance, public regulation, and market (...) responses to promote ethical business practices. This case provides the opportunity to consider what means for fostering ethical conduct might exist if a corporation can be big enough and rich enough that civil, criminal, regulatory, and market forces cannot deter unethical corporate practices, and if the market does not punish the corporation for a culture that promotes fraud. (shrink)

Abstract:Sustainable development and built heritage are oft-naturalized hegemonic discourses of the dominant social class. However, under the lens of critical sociomateriality, these categories destabilize—and in Brexit-era London, epicenter of a financial and technological capitalist circulatory space, “all that is solid melts” into the scopal regime of London's View Management Framework (LVMF). Analyzing multiple discourses of Southwark's Strata SE1— billed London's first “sustainable tower”—and adaptive reuse of the historically preserved Lambeth Water Tower, I argue that these structures constitute ‘interface objects’ in (...) a broader relational geography imbricating physical material, social objects, gentrification and the naturalized epistemologies of hegemonic development within London's skyline itself. I offer a reading of critical sociomateriality which illuminates rhythms of daily life within spatial-technological systems of energy provision, urban metabolic processes, as well as “hegemonic premiums,” what Richard Barras terms expected return on symbolic capital vis-à-vis the dominant panopticism of the LVMF. This paper contributes a theorization of critical sociomateriality, operating across a diversity of scales, tactics, and disciplines, analyzing discourses and practices which insinuate politics, artifacts, and technologies across contested issues. Critical sociomateriality is presented as a methodology for deconstructing tactics for inhabiting and interfacing with ‘sustainability’ through London's skyline in an unequal capitalist system marked by dissensus over runaway development, social precarity, and inequality in lived experiences of the urban environment. (shrink)

Nonsense‐mediated RNA decay (NMD) represents an established quality control checkpoint for gene expression that protects cells from consequences of gene mutations and errors during RNA biogenesis that lead to premature termination during translation. Characterization of NMD‐sensitive transcriptomes has revealed, however, that NMD targets not only aberrant transcripts but also a broad array of mRNA isoforms expressed from many endogenous genes. NMD is thus emerging as a master regulator that drives both fine and coarse adjustments in steady‐state RNA levels in the (...) cell. Importantly, while NMD activity is subject to autoregulation as a means to maintain homeostasis, modulation of the pathway by external cues provides a means to reprogram gene expression and drive important biological processes. Finally, the unanticipated observation that transcripts predicted to lack protein‐coding capacity are also sensitive to this translation‐dependent surveillance mechanism implicates NMD in regulating RNA function in new and diverse ways. (shrink)

Bacteria have evolved advanced strategies for surviving during nutritional stress, including expression of specialized enzyme systems that allow them to grow on unusual nutrient sources. Inorganic phosphate (Pi) is limiting in most ecosystems, hence organisms have developed a sophisticated, enzymatic machinery known as carbon‐phosphorus (C‐P) lyase, allowing them to extract phosphate from a wide range of phosphonate compounds. These are characterized by a stable covalent bond between carbon and phosphorus making them very hard to break down. Despite the challenges involved (...) in both synthesizing and catabolizing phosphonates, they are widespread in nature. The enzymes required for the bacterial C‐P lyase pathway have been identified and for the most part structurally characterized. Nevertheless, the mechanistic principles governing breakdown of phosphonate compounds remain enigmatic. In this review, an overview of the C‐P lyase pathway is provided and structural aspects of the involved enzyme complexes are discussed with a special emphasis on the role of ATP‐binding cassette (ABC) proteins. (shrink)

Bacteria have evolved advanced strategies for surviving during nutritional stress, including expression of specialized enzyme systems that allow them to grow on unusual nutrient sources. Inorganic phosphate (Pi) is limiting in most ecosystems, hence organisms have developed a sophisticated, enzymatic machinery known as carbon‐phosphorus (C‐P) lyase, allowing them to extract phosphate from a wide range of phosphonate compounds. These are characterized by a stable covalent bond between carbon and phosphorus making them very hard to break down. Despite the challenges involved (...) in both synthesizing and catabolizing phosphonates, they are widespread in nature. The enzymes required for the bacterial C‐P lyase pathway have been identified and for the most part structurally characterized. Nevertheless, the mechanistic principles governing breakdown of phosphonate compounds remain enigmatic. In this review, an overview of the C‐P lyase pathway is provided and structural aspects of the involved enzyme complexes are discussed with a special emphasis on the role of ATP‐binding cassette (ABC) proteins. (shrink)

A community's abilities to promote health and maximize its response to public health threats require fulfillment of one of the four elements of public health legal preparedness, the capacity to effectively coordinate law-based efforts across different governmental jurisdictions, as well as across multiple sectors and disciplines. Government jurisdictions can be viewed “vertically” in that response efforts may entail coordination in the application of laws across multiple levels, including local, state, tribal, and federal governments, and even with international organizations. Coordination of (...) legal responses to public health emergencies also may involve a horizontal dimension comprising numerous and diverse sectors, such as public health, public and private health care, emergency management, education, law enforcement, the judiciary, and the military.Although responses to many acute health threats can implicate multiple jurisdictions and sectors, the jurisdictional and sectoral dimensions of legal preparedness are complex and may vary substantially by the nature of a threat, its geographic and geopolitical extent, and the operational response demanded. (shrink)

A community's abilities to promote health and maximize its response to public health threats require fulfillment of one of the four elements of public health legal preparedness, the capacity to effectively coordinate law-based efforts across different governmental jurisdictions, as well as across multiple sectors and disciplines. Government jurisdictions can be viewed “vertically” in that response efforts may entail coordination in the application of laws across multiple levels, including local, state, tribal, and federal governments, and even with international organizations. Coordination of (...) legal responses to public health emergencies also may involve a horizontal dimension comprising numerous and diverse sectors, such as public health, public and private health care, emergency management, education, law enforcement, the judiciary, and the military.Although responses to many acute health threats can implicate multiple jurisdictions and sectors, the jurisdictional and sectoral dimensions of legal preparedness are complex and may vary substantially by the nature of a threat, its geographic and geopolitical extent, and the operational response demanded. (shrink)

We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 controls and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls. Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents. Probands were more likely to carry an additional large copy-number variant when compared to matched controls. The clinical (...) features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity indicates that this two-hit model might be more generally applicable to neuropsychiatric disease. © 2010 Nature America, Inc. All rights reserved. (shrink)

We report evidence further supporting homology between proteins in the F1FO‐ATP synthetase and the bacterial flagellar motor (BFM). BFM proteins FliH, FliI, and FliJ have been hypothesized to be homologous to FO‐b + F1‐δ, F1‐α/β, and F1‐γ, with similar structure and interactions. We conduct a further test by constructing a gene order dataset, examining the order offliH,fliI, andfliJgenes across the phylogenetic breadth of flagellar and nonflagellar type 3 secretion systems, and comparing this to published surveys of gene order in the (...) F1FO‐ATP synthetase, its N‐ATPase relatives, and the bacterial/archaeal V‐ and A‐type ATPases. Strikingly, thefliHIJgene order was deeply conserved, with the few exceptions appearing derived, and exactly matching the widely conserved F‐ATPase gene orderatpFHAG, coding for subunits b‐δ‐α‐γ. The V/A‐type ATPases have a similar conserved gene order. Our results confirm homology between these systems, and suggest a rare case of synteny conserved over billions of years, predating the Last Universal Common Ancestor (LUCA). (shrink)

Peter Abelard (1079–1142 ce) was the most wide‐ranging philosopher of the twelfth century. He quickly established himself as a leading teacher of logic in and near Paris shortly after 1100. After his affair with Heloise, and his subsequent castration, Abelard became a monk, but he returned to teaching in the Paris schools until 1140, when his work was condemned by a Church Council at Sens. His logical writings were based around discussion of the “Old Logic”: Porphyry's Isagoge, aristotle'S Categories and (...) On Interpretation and boethius'S textbook on topical inference. They comprise a freestanding Dialectica (“Logic”; probably c.1116), a set of commentaries (known as the Logica [Ingredientibus], c. 1119) and a later (c. 1125) commentary on the Isagoge (Logica Nostrorum Petititoni Sociorum or Glossulae). In a work Abelard called his Theologia, issued in three main versions (between 1120 and c.1134), he attempted a logical analysis of trinitarian relations and explored the philosophical problems surrounding God's claims to omnipotence and omniscience. The Collationes (“Debates,” also known as “Dialogue between a Christian, a Philosopher and a Jew”; probably c.1130) present a rational investigation into the nature of the highest good, in which the Christian and the Philosopher (who seems to be modeled on a philosopher of pagan antiquity) are remarkably in agreement. The unfinished Scito teipsum (“Know thyself,” also known as the “Ethics”; c.1138) analyses moral action. (shrink)

Clark and Fischer (C&F) claim that trait attribution has major limitations in explaining human–robot interactions. We argue that the trait attribution approach can explain the three issues posited by C&F. We also argue that the trait attribution approach is parsimonious, as it assumes that the same mechanisms of social cognition apply to human–robot interaction.

This article uses computerized analysis of text, along with a close reading of text, to trace change and development in Burkitt's lymphoma research. While past researchers have focused on the way a text enters the literature, we wish to learn what happens to knowledge claims after they arrive in the published literature. In order to explain why some claims are successfully solidified into facts while others remain as isolated, unsupported claims, we rely upon the notion of the material and social (...) technology required to do successful work in a research area. (shrink)

Deep convolutional networks exceed humans in sensitivity to local image properties, but unlike biological vision systems, do not discover and encode abstract relations that capture important properties of objects and events in the world. Coupling network architectures with additional machinery for encoding abstract relations will make deep networks better models of human abilities and more versatile and capable artificial devices.

Production and comprehension have long been viewed as inseparable components of language. The study of vision, by contrast, has centered almost exclusively on comprehension. Here we investigate drawing—the most basic form of visual production. How do we convey concepts in visual form, and how does refining this skill, in turn, affect recognition? We developed an online platform for collecting large amounts of drawing and recognition data, and applied a deep convolutional neural network model of visual cortex trained only on natural (...) images to explore the hypothesis that drawing recruits the same abstract feature representations that support natural visual object recognition. Consistent with this hypothesis, higher layers of this model captured the abstract features of both drawings and natural images most important for recognition, and people learning to produce more recognizable drawings of objects exhibited enhanced recognition of those objects. These findings could explain why drawing is so effective for communicating visual concepts, they suggest novel approaches for evaluating and refining conceptual knowledge, and they highlight the potential of deep networks for understanding human learning. (shrink)

This article focuses on the accuracy of satellite data, which may then be used in wave power applications. The satellite data are compared to data from wave buoys, which are currently considered to be the most accurate of the devices available for measuring wave characteristics. This article presents an analysis of satellite- (Topex/poseidon) and buoy-measured significant wave heights for a 1-year period at Cape Sorell and Rottnest Island, off the Australian coast. The analysis found that the satellite-measured wave heights showed (...) a slight positive bias. This is contrary to the findings of most other authors, who have analyzed data from the Northern Hemisphere and generally found a negative bias in the satellite-measured wave heights. The implication is that calibration functions to improve the correlation between the buoy and satellite data may vary for different hemispheres or even regions within these. (shrink)

In the course of an immune response, antibodies undergo affinity maturation in order to increase their efficiency in neutralizing foreign invaders. Affinity maturation occurs by the introduction of multiple point mutations in the variable region gene that encodes the antigen binding site. This somatic hypermutation is restricted to immunoglobulin genes and occurs at very high rates. The precise molecular basis of this process remains obscure. However, recent studies using a variety of in vivo and in vitro systems have revealed important (...) regulatory regions, base motifs that are preferred targets of mutation and evidence that transcription may play an active role in hypermutation. BioEssays 20:227–234, 1998. © 1998 John Wiley & Sons, Inc. (shrink)

The open borders view is frequently dismissed for making infeasible demands. This is a potent strategy. Unlike normative arguments regarding open borders, which tend to be relatively intractable, the charge of infeasibility is supposed to operate as what we call a "normative argument-stopper." Nonetheless, we argue that the strategy fails. Bringing about open borders is perfectly feasible on the most plausible account of feasibility. We consider and reject what we take to be the only three credible ways to save the (...) charge of infeasibility: by proposing an alternative account of feasibility; by proposing an alternative, more circumscribed interpretation of the subject-matter of feasibility claims; and by proposing a more expansive account of the addressees of the demand for open borders. The first fails to vindicate the claim that infeasibility is a normative argument-stopper. The second does not provide an argument against open borders at all. The third underestimates the power of at least some non-state actors. We conclude by drawing some lessons for the open borders view and the use of feasibility in politics more generally. (shrink)

We investigated people's ability to infer others’ mental states from their emotional reactions, manipulating whether agents wanted, expected, and caused an outcome. Participants recovered agents’ desires throughout. When the agent observed, but did not cause the outcome, participants’ ability to recover the agent's beliefs depended on the evidence they got. When the agent caused the event, participants’ judgments also depended on the probability of the action ; when actions were improbable given the mental states, people failed to recover the agent's (...) beliefs even when they saw her react to both the anticipated and actual outcomes. A Bayesian model captured human performance throughout, consistent with the proposal that people rationally integrate information about others’ actions and emotional reactions to infer their unobservable mental states. (shrink)

When Journeys Through Philosophy first appeared in 1977, it quickly established a reputation as one of the most complete and versatile introductory philosophy textbooks for the beginning student. Combining carefully chosen selections from the original works of many eminent philosophers with invaluable commentaries designed to illuminate the ideas of these great minds, and an extensive section on how one should read philosophy, the editors have answered the instructional needs of students and teachers alike. The revised edition contains selections by Denis (...) Diderot, Kierkegaard, Irving Kristol, Paul Kurtz, George Moore, William Paley, Jean-Paul Sarte, and John Wisdom, in addition to many of the excerpts from classical and contemporary thinkers found in the earlier edition. The highly acclaimed section on how to read philosophy is complemented by the addition of new introductions. Journeys Through Philosophy is surely destined to become the introductory philosophy textbook for our times. (shrink)

The organization of the genome into topologically associated domains (TADs) appears to be a fundamental process occurring across a wide range of eukaryote organisms, and it likely plays an important role in providing an architectural foundation for gene regulation. Initial studies emphasized the remarkable parallels between TAD organization in organisms as diverse as Drosophila and mammals. However, whereas CCCTC‐binding factor (CTCF)/cohesin loop extrusion is emerging as a key mechanism for the formation of mammalian topological domains, the genome organization in Drosophila (...) appears to depend primarily on the partitioning of chromatin state domains. Recent work suggesting a fundamental conserved role of chromatin state in building domain architecture is discussed and insights into genome organization from recent studies in Drosophila are considered. (shrink)

Direct-to-consumer genetic testing is a growing phenomenon, fuelled by the notion that knowledge equals control. One ethical question that arises concerns the proband’s duty to share information indicating genetic risks in their relatives. However, such duties are unenforceable and may result in the realisation of anticipated harm to relatives. We argue for a shift in responsibility from proband to provider, placing a duty on test providers in the event of identified actionable risks to relatives. Starting from Parker and Lucassen’s 'joint (...) account model', we adapt Kilbride’s application of the rule of rescue and balance it against the relative’s right not to know, placing responsibility on the providers of direct-to-consumer genetic testing. Where the risk of disease to a relative is actionable, we argue providers ought to share results even in the face of the proband’s objections. Confidentiality issues are navigated by a pre-emptive consent model, whereby consumers agree to the sharing of certain information with their relatives ahead of testing and as a condition of testing. When a relative is informed, the proband’s privacy is protected by maximal deidentification, and the rights of the relative are met by a stepwise approach to informing that allows them to decide how much information they receive. (shrink)