While outcomes for children with T-cell acute lymphoblastic leukemia have improved dramatically, survival rates for patients with relapsed/refractory disease remain dismal. Prior studies indicate that glucocorticoid resistance is more common than resistance to other chemotherapies at relapse. In addition, failure to clear peripheral blasts during a prednisone prophase correlates with an elevated risk of relapse in newly diagnosed patients. Here we show that intrinsic GC resistance is present at diagnosis in early thymic precursor T-ALLs as well as in a subset (...) of non-ETP T-ALLs. GC-resistant non-ETP T-ALLs are characterized by strong induction of JAK/STAT signaling in response to interleukin-7 stimulation. Removing IL7 or inhibiting JAK/STAT signaling sensitizes these T-ALLs, and a subset of ETP T-ALLs, to GCs. The combination of the GC dexamethasone and the JAK1/2 inhibitor ruxolitinib altered the balance between pro- and anti-apoptotic factors in samples with IL7-dependent GC resistance, but not in samples with IL7-independent GC resistance. Together, these data suggest that the addition of ruxolitinib or other inhibitors of IL7 receptor/JAK/STAT signaling may enhance the efficacy of GCs in a biologically defined subset of T-ALL.Leukemia advance online publication, 30 May 2017; doi:10.1038/leu.2017.136. (shrink)

> Wealthy nations must do much more, much faster. The United Nations General Assembly in September 2021 will bring countries together at a critical time for marshalling collective action to tackle the global environmental crisis. They will meet again at the biodiversity summit in Kunming, China, and the climate conference 26) in Glasgow, UK. Ahead of these pivotal meetings, we—the editors of health journals worldwide—call for urgent action to keep average global temperature increases below 1.5°C, halt the destruction of nature (...) and protect health. Health is already being harmed by global temperature increases and the destruction of the natural world, a state of affairs health professionals have been bringing attention to for decades.1 The science is unequivocal; a global increase of 1.5°C above the preindustrial average and the continued loss of biodiversity risk catastrophic harm to health that will be impossible to reverse.2 3 Despite the world’s necessary preoccupation with COVID-19, we cannot wait for the pandemic to pass to rapidly reduce emissions. Reflecting the severity of the moment, this editorial appears in health journals across the world. We are united in recognising that only fundamental and equitable changes to societies will reverse our current trajectory. The risks to health of increases above 1.5°C are now well established.2 Indeed, no temperature rise is ‘safe’. In the past 20 years, heat-related mortality among people aged over 65 has increased by more than 50%.4 Higher temperatures have brought increased dehydration and renal function loss, dermatological malignancies, tropical infections, adverse mental health outcomes, pregnancy complications, allergies, and cardiovascular and pulmonary morbidity and mortality.5 6 Harms disproportionately affect the most vulnerable, including children, older populations, ethnic minorities, poorer communities and those with underlying health problems.2 4 Global heating is also contributing to the decline in …. (shrink)

The COVID-19 pandemic revealed numerous weaknesses in pandemic preparedness and response, including underfunding, inadequate surveillance, and inequitable distribution of countermeasures. To overcome these weaknesses for future pandemics, WHO released a zero draft of a pandemic treaty in February, 2023, and subsequently a revised bureau's text in May, 2023. COVID-19 made clear that pandemic prevention, preparedness, and response reflect choices and value judgements. These decisions are therefore not a purely scientific or technical exercise, but are fundamentally grounded in ethics. The latest (...) treaty draft reflects these ethical considerations by including a section entitled Guiding Principles and Approaches. Most of these principles are ethical—they establish core values that undergird the treaty. Unfortunately, the treaty draft's set of principles are numerous, overlapping, and show inadequate coherence and consistency. We propose two improvements to this section of the draft pandemic treaty. First, key guiding ethical principles should be clearer and more precise than they currently are. Second, the link between ethical principles and policy implementation should be clearly established and define boundaries on acceptable interpretation, ensuring that signatories abide by these principles. (shrink)

The Infectious Disease Ontology (IDO) is a suite of interoperable ontology modules that aims to provide coverage of all aspects of the infectious disease domain, including biomedical research, clinical care, and public health. IDO Core is designed to be a disease and pathogen neutral ontology, covering just those types of entities and relations that are relevant to infectious diseases generally. IDO Core is then extended by a collection of ontology modules focusing on specific diseases and pathogens. In this paper we (...) present applications of IDO Core within various areas of infectious disease research, together with an overview of all IDO extension ontologies and the methodology on the basis of which they are built. We also survey recent developments involving IDO, including the creation of IDO Virus; the Coronaviruses Infectious Disease Ontology (CIDO); and an extension of CIDO focused on COVID-19 (IDO-CovID-19).We also discuss how these ontologies might assist in information-driven efforts to deal with the ongoing COVID-19 pandemic, to accelerate data discovery in the early stages of future pandemics, and to promote reproducibility of infectious disease research. (shrink)

The paper discusses regularisation of dualities. A given duality between (concrete) categories, e.g. a variety of algebras and a category of representation spaces, is lifted to a duality between the respective categories of semilattice representations in the category of algebras and the category of spaces. In particular, this gives duality for the regularisation of an irregular variety that has a duality. If the type of the variety includes constants, then the regularisation depends critically on the location or absence of constants (...) within the defining identities. The role of schizophrenic objects is discussed, and a number of applications are given. Among these applications are different forms of regularisation of Priestley, Stone and Pontryagin dualities. (shrink)

A substantial body of evidence suggests that autobiographical recollection and simulation of future happenings activate a shared neural network. Many of the neural regions implicated in this network are affected in patients with bipolar disorder , showing altered metabolic functioning and/or structural volume abnormalities. Studies of autobiographical recall in BD reveal overgeneralization, where autobiographical memory comprises primarily factual or repeated information as opposed to details specific in time and in place and definitive of re-experiencing. To date, no study has examined (...) whether these deficits extend to future event simulation. We examined the ability of patients with BD and controls to imagine positive, negative and neutral future events using a modified version of the Autobiographical Interview that allowed for separation of episodic and non-episodic details. Patients were selectively impaired in imagining future positive, negative, and neutral episodic details; simulation of non-episodic details was equivalent across groups. (shrink)

How can we take history seriously as real and relevant? Despite the hazards of politically dangerous or misleading accounts of the past, we live our lives in a great network of cooperation with other actors; past, present, and future. We study and reflect on the past as a way of exercising a responsibility for shared action. In each of the chapters of Full History Smith poses a key question about history as a concern for conscious participants in the sharing (...) of action, starting with “What Is Historical Meaningfulness?” and ending with “How Can History Have an Aim?” Constructing new models of historical meaning while engaging critically with perspectives offered by Ranke, Dilthey, Rickert, Heidegger, Eliade, Sartre, Foucault, and Arendt, Smith develops a philosophical account of thinking about history that moves beyond postmodernist skepticism. Full History seeks to expand the cast of significant actors, establishing an inclusive version of the historical that recognizes large-scale cumulative actions but also encourages critical revision and expansion of any paradigm of shared action. (shrink)

Evolving the Mind has two main themes: how ideas about the mind evolved in science; and how the mind itself evolved in nature. The mind came into physical science when it was realised, first, that it is the activity of a physical object, a brain, which makes a mind; and secondly, that our theories of nature are largely mental constructions, artificial extensions of an inner model of the world which we inherited from our distant ancestors. From both of these perspectives, (...) consciousness is the great enigma. If consciousness evolved, however, it is in some sense a material thing whatever else may be said of it. Physics, chemistry, molecular biology, brain function and evolutionary biology - almost the whole of science - is involved, and there can be no expert in all these fields. So the style of the book is simple, almost conversational. The excitement is that we seem to be close to a scientific theory of consciousness. (shrink)

Both the theory that traumatic childhood memories can be repressed, and the reliability of the techniques used to retrieve these memories are challenged in this paper. Questions are raised about the robustness of the theory and the literature that purports to provide scientific evidence for it. Evidence to this end is provided by the demographic and qualitative results of a research study conducted by the authors which surveyed New Zealand families in which one member had accused another (or others) of (...) sexual abuse on the basis of recovered memories. It is shown that a number of these allegations involve very low probability events. Since memory repression theory is not currently scientifically substantiated it is argued that care needs to be taken in the mental health, legal and insurance compensation arenas. Memories recalled during therapy may be treated as metaphorical but, in the absence of corroborative evidence, should not be considered factually true. Clinicians who wish to use memory recovery techniques should inform patients of their experimental and controversial nature, point out potential adverse effects, and obtain consent before proceeding. (shrink)

To the French critics who originally labelled certain films noir it seemed that a class of Hollywood products had gone darker during the war years – as though a dark filter had been placed over the lens. Films were not designed or marketed as noir, and retrospectively noir's status as a genre is still unsettled. Yet there is widespread interest today in experiencing diverse films as noir, and even in using a Noir Filter in Instagram and video games. Pursuing the (...) filter clue, the noir experience can be thought of as subjection to a dark filtering of narrative. Image filtering styles can help to resolve not only the puzzle of noir's quasi-genre status but also an issue of general interest in aesthetic experience. The use of image filters makes a distinctively powerful contribution to the experience of a work or genre, or to the cultural dominance of an aesthetic regime, due to the unobtrusive formative role it plays in the economy of experience. (shrink)

Both the theory that traumatic childhood memories can be repressed, and the reliability of the techniques used to retrieve these memories are challenged in this paper. Questions are raised about the robustness of the theory and the literature that purports to provide scientific evidence for it. Evidence to this end is provided by the demographic and qualitative results of a research study conducted by the authors which surveyed New Zealand families in which one member had accused another of sexual abuse (...) on the basis of recovered memories. It is shown that a number of these allegations involve very low probability events. Since memory repression theory is not currently scientifically substantiated it is argued that care needs to be taken in the mental health, legal and insurance compensation arenas. Memories recalled during therapy may be treated as metaphorical but, in the absence of corroborative evidence, should not be considered factually true. Clinicians who wish to use memory recovery techniques should inform patients of their experimental and controversial nature, point out potential adverse effects, and obtain consent before proceeding. (shrink)

v. 1. Nicomachean ethics. Politics. The Athenian Constitution. Rhetoric. On Poetics.--v. 2. Logic.--v. 3. Physics. Metaphysics. On the soul. Short physical treaties.--v. 4. On the heavens. On generation and corruption. Meteorology. Biological treatises.

This article maps the components of telephone tutorial conferences used for distance learning in higher education. Using conversation analysis we identified four common sequences of TTCs as `calling in'; `agenda-setting'; `tutorial proper'; and `closing down'. Patterns of student participation look similar to those in face-to-face tutorials and the degree of interaction during `calling-in' and agenda setting does not foretell student participation in the `tutorial proper'. Student participation was related to differences in `communicative formats' adopted by tutors and students for different (...) purposes. These findings have helped us reflect on our communicative practices as university teachers and indicate that TTCs are functionally comparable with face-to-face tutorials in higher education settings. (shrink)

We have synthesized a 582,970-base pair Mycoplasma genitalium genome. This synthetic genome, named M. genitalium JCVI-1.0, contains all the genes of wild-type M. genitalium G37 except MG408, which was disrupted by an antibiotic marker to block pathogenicity and to allow for selection. To identify the genome as synthetic, we inserted "watermarks" at intergenic sites known to tolerate transposon insertions. Overlapping "cassettes" of 5 to 7 kilobases (kb), assembled from chemically synthesized oligonucleotides, were joined by in vitro recombination to produce intermediate (...) assemblies of approximately 24 kb, 72 kb ("1/8 genome"), and 144 kb ("1/4 genome"), which were all cloned as bacterial artificial chromosomes in Escherichia coli. Most of these intermediate clones were sequenced, and clones of all four 1/4 genomes with the correct sequence were identified. The complete synthetic genome was assembled by transformation-associated recombination cloning in the yeast Saccharomyces cerevisiae, then isolated and sequenced. A clone with the correct sequence was identified. The methods described here will be generally useful for constructing large DNA molecules from chemically synthesized pieces and also from combinations of natural and synthetic DNA segments. 10.1126/science.1151721. (shrink)

A medical information commons is a networked data environment utilized for research and clinical applications. At three deliberations across the U.S., we engaged 75 adults in two-day facilitated discussions on the ethical and social issues inherent to sharing data with an MIC. Deliberants made recommendations regarding opt-in consent, transparent data policies, public representation on MIC governing boards, and strict data security and privacy protection. Community engagement is critical to earning the public's trust.

Plato's Republic has proven to be of astounding influence and importance. Justly celebrated as Plato's central text, it brings together all of his prior works, unifying them into a comprehensive vision that is at once theological, philosophical, political and moral. The essays in this volume provide a picture of the most interesting aspects of the Republic, and address questions that continue to puzzle and provoke, such as: Does Plato succeed in his argument that the life of justice is the most (...) attractive one? Is his tripartite analysis of the soul coherent and plausible? Why does Plato seem to have to force his philosopher-guardians to rule when they know this is something that they ought to do? What is the point of the strange and complicated closing Myth of Er? This volume will be essential to those looking for thoughtful and detailed excursions into the problems posed by Plato's text and ideas. (shrink)

Are contemporary philosophers to follow Pyrrho of Elis in adopting his skeptic craft or at least core aspects of it as a reaction to the fact that, since immemorial times, persons have been engaged in disputes in metaphysics? Over the last 2500 years or so, most Western philosophers have not done so in being more influenced by Aristotle’s dogmatic craft than by Pyrrho’s skeptic one. Over the last fifty years or so, a few Brazilian neo-Pyrrhonist philosophers, such as Oswald Porchat, (...) Otávio Bueno and Plínio Junqueira Smith, have done the opposite in aiming to spell out the pertinence of Ancient Pyrrhonism to contemporary philosophy. On its part, this essay makes a case for the claim that one is to react to the stated fact by adopting a conflictual craft that promotes a synthesis of Pyrrho’s skeptic craft and the dogmatic craft. This synthesis: brings to light the core features of the skeptic and of the dogmatic craft; problematizes the dogmatic craft by means of the skeptic one and vice-versa so that the shortcomings of these crafts are avoided; and aims to keep certain positive aspects both of the skeptic craft and of the dogmatic one. (shrink)

A theoretical framework Is presented that distinguishes among three knowledge sources that form the basis for generative performance. The three knowledge sources, termed conceptual, procedural, and utilizational competence, were implemented as a computational model that derives plans for counting procedures. In a previous analysis, Greeno, Riley, and Gelman (1984) developed a characterization of the conceptual competence (implicit understanding of general concepts and principles) associated with the skill of counting and related conceptual competence to various models of performance. In the current (...) work all three knowledge sources are formalized in a computer program (COUNTPLAN) that generates planning nets of counting procedures. The sufficiency of COUNTPLAN's knowledge components is demonstrated through its capacity to generate new plans for counting in novel settings from a core of conceptual competence. The utility of COUNTPLAN to facilitate the distinction between hypotheses of competence and hypotheses of performance is discussed. (shrink)

This book offers 32 texts and case studies from across a wide range of business sectors around a managerial framework for Sustainable Business. The case studies are developed for and tested in executive education programmes at leading business schools. The book is based on the premise that the key for managing the sustainable business is finding the right balance over time between managing competitiveness and profitability AND managing the context of the business with its political, social and ecological risks and (...) opportunities. In that way, a sustainable business is highly responsive to the demands and challenges from both markets and societies and managers embrace the complexity, ambivalence and uncertainty that goes along with this approach. The book presents a framework that facilitates the adoption of best business practice. This framework leads executives through a systematic approach of strategic analysis and business planning in risk management, issues management, stakeholder management, sustainable business development and strategic differentiation, business model innovation and developing dynamic capabilities. The approach helps broaden the understanding of what sustainable performance means, by protecting business value against sustainability risks and creating business value from sustainability opportunities. (shrink)