The identification of Smad proteins as molecular components of the transforming growth factor-β (TGF-β) signaling cascade has enhanced our understanding of how ligand-mediated activation of TGF-β receptors leads to modulation of target gene transcription. Recent studies have identified a distinct, structurally related class of Smads which inhibits, rather than transduces, TGF-β family signals. The molecular mechanism of action and the exact signaling pathways that are targeted by antagonistic Smads are not completely understood. These proteins appear to participate in autoregulatory negative (...) feedback loops in which signaling initiated by specific TGF-β family ligands induces the expression of an inhibitory Smad that then functions to modulate the amplitude or duration of signaling. Negative feedback circuits such as these play important roles in fine-tuning the activity of multifunctional signaling molecules during embryonic patterning and in response to pathologic stimuli in adults. BioEssays 21:382–390, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

This article analyses domestic and foreign reactions to a 2008 report in the British Medical Journal on the complementary and, as argued, synergistic relationship between palliative care and euthanasia in Belgium. The earliest initiators of palliative care in Belgium in the late 1970s held the view that access to proper palliative care was a precondition for euthanasia to be acceptable and that euthanasia and palliative care could, and should, develop together. Advocates of euthanasia including author Jan Bernheim, independent from but (...) together with British expatriates, were among the founders of what was probably the first palliative care service in Europe outside of the United Kingdom. In what has become known as the Belgian model of integral end-of-life care, euthanasia is an available option, also at the end of a palliative care pathway. This approach became the majority view among the wider Belgian public, palliative care workers, other health professionals, and legislators. The legal regulation of euthanasia in 2002 was preceded and followed by a considerable expansion of palliative care services. It is argued that this synergistic development was made possible by public confidence in the health care system and widespread progressive social attitudes that gave rise to a high level of community support for both palliative care and euthanasia. The Belgian model of so-called integral end-of-life care is continuing to evolve, with constant scrutiny of practice and improvements to procedures. It still exhibits several imperfections, for which some solutions are being developed. This article analyses this model by way of answers to a series of questions posed by Journal of Bioethical Inquiry consulting editor Michael Ashby to the Belgian authors. (shrink)

Medical, scientific and societal progress has been such that, in a universalist humanist perspective such as the WHO’s, it has become an ethical imperative for the primary endpoints in evidence based health care research to be expressed in e.g. Quality Adjusted Life Years (QALYs). The classical endpoints of discrete health‐related functions and duration of survival are increasingly perceived as unacceptably reductionistic. The major problem in ‘felicitometrics’ is the measurement of the ‘quality’ term in QALYs. That the mental, physical and social (...) domains, each containing many dimensions and items, all contribute to QOL is uncontroversial. What is controversial, is the weight of the different dimensions in overall QOL. It has been shown to be very different between different patient populations. In human individuals, assuredly complex systems, the many dimensions and items of QOL observably interact, probably sometimes also in chaotic ways. In these conditions, the weights of isolated items in individuals become for all practical purposes meaningless. Therefore, the much used multi‐item questionnaires at best describe, but do not evaluate QOL, neither in individuals, nor in populations. For example, allergic patients treated with cetirizine scored better than those a placebo on all dimensions of the SF‐36, a standard QOL questionnaire. Here there is no serious doubt that the treatment improved QOL, because it is highly unlikely that any important dimension on which the patient groups would have scored otherwise is missing in the SF‐36. However, whether piracetam treatment of acute stroke, which improved the surrogate endpoints neurological and functional scores, also improved QOL is plausible, but will be proven only when comprehensive QOL measurement will have been done. And suppose in randomised populations of end‐stage metastatic solid cancer patients, one would compare palliative last‐line chemotherapy with only palliative care, and one would, as can be expected, find no significant differences in average survival, and chemotherapy superior for the mental domain, but inferior for the physical comfort domain: we would not know which treatment, on aggregate, would be the better. The problem is that QOL is an individual and emergent construct, the resultant of a great many intractions, and of a different order than its contributing components. Overall QOL can therefore best be captured only as the Gestalt of a global self‐assessment. Just as people in everyday life, while acting under uncertainty, make global assessments all the time, so they can seriously answer the serious question: ‘How have you been?’ A solemn, practical, non peer‐relativistic, non‐cultural, experiential, and well tolerated way to obtain such responses is Anamnestic Comparative Self Assessment (ACSA), in which the subjects' memories of the best and the worst times in their life experience define their individual scale of QOL. ACSA is thus both exquisitely idiosyncratic, and yet can in a universalist humanistic perspective be considered generic. Using both a multi‐item questionnaire and a global assessment allows by one logistic regression, to estimate the weights of the dimensions and items in populations, and thus identify those whose improvement would most contribute to the QOL of the greatest number. A combined approach to measurement of QOL is necessary to maximise the utility of QOL interventions. (shrink)

Recently, heated discussions about artificial intelligence, creativity, and work have re-emerged. Despite the dominant focus on the novelty of this entanglement, it is rich with history. In this paper, I will first introduce creativity as a historical and socio-culturally embedded concept, looking at how and why we have invented creativity in the guises we have. The focus will mostly be on the political and ideological backdrop of these historical processes–for instance how creativity was repeatedly cast as the positive counterimage of (...) (industrial and bureaucratic) alienated labour, and hence stood in a complex relationship to automation, robotization, and so on. Based on this I will then discuss a series of scenarios that are related to the (perhaps) forthcoming automation of creativity, more specifically four ways in which automation might in different ways impact (the fields of) creative practices and labour. (shrink)

During the 1980s many communities turned to grassroots activities to promote economic development, rather than relying on industrial recruitment strategies. We evaluate the characteristics of these projects, their benefits and costs, and obstacles they face in the development process. The data are drawn from a survey of more than one hundred communities in the United States. Self-development efforts do not appear to replace traditional rural economic development activities, but may complement them. Self-development activities produce a wide variety of jobs that (...) are taken primarily by local residents. The cost and availability of credit are major obstacles for self-development projects. Although self-development strategies should not be considered the primary economic development strategy for most rural communities, they do enable communities to build a more viable local economy. (shrink)

The use of quality of life (QOL) outcomes in clinical trials is increasing as a number of practical, ethical, methodological, and regulatory reasons for their use have become apparent. It is important, then, that QOL measurements and differences between QOL scores be readily interpretable. We study interpretation in two contexts: when determining QOL and when basing decisions on QOL differences. We consider both clinical situations involving individual patients and research contexts, e.g., randomized clinical trials, involving groups of patients. We note (...) the ethical importance of such understanding: proper interpretation and communication facilitate health care decision making. Communication that facilitates interpretation is of moral significance since better communication can attenuate ethical problems and inform choices. Much of what is communication worthy about QOL assessments is determined by the particular QOL instrument used in the assessment and how it is administered. In practice, these choices will be driven by the purpose of the assessment, but, it is argued, to maximize understanding, we should combine the information garnered from traditional standardized QOL instruments, from individualized QOL assessments, and from a recently proposed dialogic paradigm, where QOL is determined by shared conversation regarding the interpretation of texts. And, while some studies can surely succeed using abbreviated methods of administration (e.g., postal surveys may suffice for certain purposes), we will focus on methods of administration involving interviewer–respondent interaction. We suggest that during the QOL elicitation process, interviewer and respondent should engage in a two-way conversation in order to achieve a shared understanding of the “answers” to QOL “questions” and, finally, to reach a shared interpretation of the individual’s QOL. (shrink)

Data Safety and Monitoring Boards have been referred to as a “growth industry,” and this trend continues to be fueled by recent FDA guidance and the NIH's requirement that DSMBs be employed in virtually all phase III clinical trials. The widening role of DSMBs has been sporadically questioned on ethical grounds, but growth has continued, despite the fact that many of the questions endure, unanswered, save for repeated references to safeguarding the scientific integrity of trials. This may be about to (...) change. The recently appointed director of the Office for Human Research Protections , Jerry Menikoff, is on record as regarding current practices — where consent forms often promise what the DSMB has been assembled to specifically not provide — as constituting fraudulent behavior. That is, a subject may inherently rely on, to their detriment, information that has been misrepresented in the consent document. In this paper, we assemble some of the enduring questions and top them off with Menikoff's tour de force to present what we hope will be a compelling argument to require that consent forms fairly represent what the DSMB will do — and not do — with trial data as they accumulate. We argue that DSMBs should be used only in rare circumstances, and question the practice of precluding principal investigators from DSMB membership, but our main thrust is to ensure that DSMBs, when used at all, are properly described in trial consent forms. (shrink)

Data Safety and Monitoring Boards were introduced in the 1960s to monitor data in clinical trials to ensure subject safety. It was thought important that DSMB members be experts in the field of interest, but not otherwise involved in the study in order to maximize objectivity. Since then, the use of DSMBs has increased dramatically, and their scope has expanded to include scientific issues — in particular, to avoid bias that can result when trials are stopped early because of evidence (...) that one treatment has greater efficacy or causes greater harm than another; or that no treatment is likely to do better than any other. (shrink)

The study of biodiversity spans many disciplines and includes data pertaining to species distributions and abundances, genetic sequences, trait measurements, and ecological niches, complemented by information on collection and measurement protocols. A review of the current landscape of metadata standards and ontologies in biodiversity science suggests that existing standards such as the Darwin Core terminology are inadequate for describing biodiversity data in a semantically meaningful and computationally useful way. Existing ontologies, such as the Gene Ontology and others in the Open (...) Biological and Biomedical Ontologies (OBO) Foundry library, provide a semantic structure but lack many of the necessary terms to describe biodiversity data in all its dimensions. In this paper, we describe the motivation for and ongoing development of a new Biological Collections Ontology, the Environment Ontology, and the Population and Community Ontology. These ontologies share the aim of improving data aggregation and integration across the biodiversity domain and can be used to describe physical samples and sampling processes (for example, collection, extraction, and preservation techniques), as well as biodiversity observations that involve no physical sampling. Together they encompass studies of: 1) individual organisms, including voucher specimens from ecological studies and museum specimens, 2) bulk or environmental samples (e.g., gut contents, soil, water) that include DNA, other molecules, and potentially many organisms, especially microbes, and 3) survey-based ecological observations. We discuss how these ontologies can be applied to biodiversity use cases that span genetic, organismal, and ecosystem levels of organization. We argue that if adopted as a standard and rigorously applied and enriched by the biodiversity community, these ontologies would significantly reduce barriers to data discovery, integration, and exchange among biodiversity resources and researchers. (shrink)

This book is the first to trace the origins and significance of positivism on a global scale. Taking their cues from Auguste Comte and John Stuart Mill, positivists pioneered a universal, experience-based culture of scientific inquiry for studying nature and society—a new science that would enlighten all of humankind. Positivists envisaged one world united by science, but their efforts spawned many. Uncovering these worlds of positivism, the volume ranges from India, the Ottoman Empire, and the Iberian Peninsula to Central Europe, (...) Russia, and Brazil, examining positivism’s impact as one of the most far-reaching intellectual movements of the modern world. Positivists reinvented science, claiming it to be distinct from and superior to the humanities. They predicated political governance on their refashioned science of society, and as political activists, they sought and often failed to reconcile their universalism with the values of multiculturalism. Providing a genealogy of scientific governance that is sorely needed in an age of post-truth politics, this volume breaks new ground in the fields of intellectual and global history, the history of science, and philosophy. (shrink)

Agriculture in Western Europe has become efficient and productive but at a cost. The quality of biodiversity, soil, air, and water has been compromised. In the search for ways to ensure food security and meet the challenges of climate change, new production systems have been proposed. One of these is the transition to circular agriculture: closing the cycles of nutrients and other resources to minimise losses and end the impact on climate change. This development aims to address existing problems in (...) food production but also raises questions about animal health and welfare. Although the role animals can play in this development is not ignored, the animal welfare dimension of circular agriculture seems to be overlooked. We argue that this is a problem both for the success of circular agriculture and for the animals involved. To substantiate this claim, we analyse the background to this lack of attention, which we find in (a) the way circular agriculture is conceptualised; (b) the institutional hurdles related to the legal, political and economic context; and (c) the concept of animal welfare, which requires further innovation. By analysing these aspects, we develop stepping stones for an animal-welfare inclusive concept of circular agriculture. These stepping stones include: recognising the animal as a participant with its own interests in the innovation towards circular agriculture; using a dynamic concept of animal welfare; a concept of circularity that provides space for social values, including animal welfare; and attention to institutional innovation by improving public engagement and building trust. (shrink)

Most models of response time (RT) in elementary cognitive tasks implicitly assume that the speed-accuracy trade-off is continuous: When payoffs or instructions gradually increase the level of speed stress, people are assumed to gradually sacrifice response accuracy in exchange for gradual increases in response speed. This trade-off presumably operates over the entire range from accurate but slow responding to fast but chance-level responding (i.e., guessing). In this article, we challenge the assumption of continuity and propose a phase transition model for (...) RTs and accuracy. Analogous to the fast guess model (Ollman, 1966), our model postulates two modes of processing: a guess mode and a stimulus-controlled mode. From catastrophe theory, we derive two important predictions that allow us to test our model against the fast guess model and against the popular class of sequential sampling models. The first prediction—hysteresis in the transitions between guessing and stimulus-controlled behavior—was confirmed in an experiment that gradually changed the reward for speed versus accuracy. The second prediction—bimodal RT distributions—was confirmed in an experiment that required participants to respond in a way that is intermediate between guessing and accurate responding. (shrink)

In a recent issue of Philosophy East and West Douglas Berger defends a new reading of Mūlamadhyamakakārikā XXIV : 18, arguing that most contemporary translators mistranslate the important term prajñaptir upādāya, misreading it as a compound indicating "dependent designation" or something of the sort, instead of taking it simply to mean "this notion, once acquired." He attributes this alleged error, pervasive in modern scholarship, to Candrakīrti, who, Berger correctly notes, argues for the interpretation he rejects.Berger's analysis, and the reading of (...) the text he suggests is grounded on that analysis, is insightful and fascinating, and certainly generates an understanding of Nāgārjuna's enterprise that is welcome .. (shrink)

This Editorial reports an exchange in form of a comment and reply on the article “History and Nature of the Jeffreys–Lindley Paradox” (Arch Hist Exact Sci 77:25, 2023) by Eric-Jan Wagenmakers and Alexander Ly.

Kazimierz Twardowski is most commonly known as the teacher of great philosophers and the founder of the Lvov-Warsaw School. As a philosopher however, he is primarily remembered for his famous comparison of the contents and objects of various kinds of representations, a comparison that remains enshrined in European thought.In fact, he attained important results in many other branches of philosophy as well. For instance, in ontology, he laid the foundations for the modern theory of formal structure of objects, and he (...) introduced the theoretically fruitful pair of terms, action-product. In epistemology, he developed a profound analysis of the notion and criteria of truth; and he provided a forceful account of the errors underlying relativist theories of truth. In methodology, he drew an explicit distinction between the processes of discovering, systematising, and grounding in science, and he offered accurate descriptions of the nature of psychology and other humanities. In logic, he offered decisive arguments on behalf of the idiogenetic conception of judgement, and he improved the traditional typology of adjectives.These achievements are of significance that is not only historical. Kazimierz Twardowski's work, formulated in plain, precise language, are instructive and inspiring for contemporary students of philosophy. (shrink)