What is narrative possibility?

In this paper I offer a new account of narrative possibility that I call the “ecological approach.” I situate it relative to alternative “metaphysical” and “epistemological” approaches, and argue that it has advantages in comparison. It saves some of the important insights from each, but serves the purposes of narrative explanation better than either, specifically because it delimits the explanatory modal space of narrative explanation correctly, whereas the others do not.     

What is a text?

This paper argues that textuality—the property of being a text—is assigned by the reader, rather than constituting an inherent property, and that the being of texts was both captured and mystified by the figure of ‘the text’ as this developed from the 1970s onwards. Textuality consists in the abstraction of verbal content from its origins, entailing the apprehension of that content as copresent with the reader; and it is given a material embodiment in the process of publication, especially in the production of canonical works, which together comprise the locus classicus of the textual apprehension. Whole disciplines—here termed the hermeneutico-canonical disciplines—are based upon that apprehension, and the discipline or approach known as hermeneutics consists of its theoretical elaboration. In contrast, the discipline of history rests upon the apprehension of the verbal under the sign of the document or its cognates, and this difference renders intelligible the longstanding relationship of mutual suspicion between hermeneutics and history. The historiography of science, remarkably enough, manages to combine these approaches; the paper concludes by suggesting that these can be brought into a more fruitful synthesis by investigating historically the construction of scientific canons.     

What is ontic structural realism?

In recent years a doctrine known as ontic structural realism (OSR) has achieved a degree of notoriety, but many people remain confused as to what exactly the doctrine amounts. In this paper three main variants of OSR are defined and discussed: (i) OSR1, which is the view that relations are ontologically primitive but objects and properties are not; (ii) OSR2, which is the view that objects and relations are ontologically primitive but properties are not; (iii) OSR3, which is the view that properties and relations are ontologically primitive but objects are not. Proponents of OSR claim that it is a “naturalistic” metaphysics, arguing that metaphysical views that take objects and/or properties as ontologically primitive are undermined by contemporary physics. In this paper it is argued that OSR1 and OSR2 are themselves undermined by contemporary physics. On the other hand, it is also argued that considerations about the objects of quantum mechanics and general relativity do seem to suggest that we should abandon some of our “common-sense” metaphysical intuitions, and that OSR3 is one of the metaphysical views that is compatible with what these theories seem to tell us about fundamental ontology.     

No-go theorems: What are they good for?

No-go theorems have played an important role in the development and assessment of scientific theories. They have stopped whole research programmes and have given rise to strong ontological commitments. Given the importance they obviously have had in physics and philosophy of physics and the huge amount of literature on the consequences of specific no-go theorems, there has been relatively little attention to the more abstract assessment of no-go theorems as a tool in theory development. We will here provide this abstract assessment of no-go theorems and conclude that the methodological implications one may draw from no-go theorems are in disagreement with the implications that have often been drawn from them in the history of science.     

What is mechanistic evidence,and why do we need it for evidence-based policy?

It has recently been argued that successful evidence-based policy should rely on two kinds of evidence: statistical and mechanistic. The former is held to be evidence that a policy brings about the desired outcome, and the latter concerns how it does so. Although agreeing with the spirit of this proposal, we argue that the underlying conception of mechanistic evidence as evidence that is different in kind from correlational, difference-making or statistical evidence, does not correctly capture the role that information about mechanisms should play in evidence-based policy. We offer an alternative account of mechanistic evidence as information concerning the causal pathway connecting the policy intervention to its outcome. Not only can this be analyzed as evidence of difference-making, it is also to be found at any level and is obtainable by a broad range of methods, both experimental and observational. Using behavioral policy as an illustration, we draw the implications of this revised understanding of mechanistic evidence for debates concerning policy extrapolation, evidence hierarchies, and evidence integration.     

What is the environment in environmental health research? Perspectives from the ethics of science

Environmental health research produces scientific knowledge about environmental hazards crucial for public health and environmental justice movements that seek to prevent or reduce exposure to these hazards. The environment in environmental health research is conceptualized as the range of possible social, biological, chemical, and/or physical hazards or risks to human health, some of which merit study due to factors such as their probability and severity, the feasibility of their remediation, and injustice in their distribution. This paper explores the ethics of identifying the relevant environment for environmental health research, as judgments involved in defining an environmental hazard or risk, judgments of that hazard or risk's probability, severity, and/or injustice, as well as the feasibility of its remediation, all ought to appeal to non-epistemic as well as epistemic values. I illustrate by discussing the case of environmental lead, a housing-related hazard that remains unjustly distributed by race and class and is particularly dangerous to children. Examining a controversy in environmental health research ethics where researchers tested multiple levels of lead abatement in lead-contaminated households, I argue that the broader perspective on the ethics of environmental health research provided in the first part of this paper may have helped prevent this controversy.     

Protein kinases: which one is the memory molecule?

Encoding of new experiences is likely to induce activity-dependent modifications in the brain. Studies in organisms far apart on the phylogenetic scale have shown that similar, sometimes identical, signal transduction pathways subserve plasticity in neuronal systems, and they may play pivotal roles in the formation of long-term memories. It has become evident that phosphorylation/dephosphorylation reactions are critical for the initiation of cellular mechanisms that embody, retain and modify information in neural circuits. Although physiological investigations on synaptic plasticity have had a major impact, we have concentrated our review on behavioural studies that provide direct or indirect evidence for a role of kinases in mechanisms underlying memory formation. From these, it appears that the learning event induces activation of a variety of kinases with specific time courses. For instance, the calcium/calmodulin-dependent protein kinase II seems to participate in an early phase of memory formation. Apparently, activation of both protein tyrosine kinases and mitogen-activated protein kinases is required for much longer and may thus have a particular function during transformation from short-term into long-term memory. Quite different time courses appear for protein kinase C (PKC) and protein kinase A (PKA), which may function at two different time points, shortly after training and again much later. This suggests that PKC and PKA might play a role at early and late stages of memory formation. However, we have considered some examples showing that these signalling pathways do not function in isolation but rather interact in an intricate intracellular network. This is indicative of a more complex contribution of each kinase to the fine tuning of encoding and information processing. To decipher this complexity, pharmacological, biochemical and genetic investigations are more than ever necessary to unravel the role of each kinase in the syntax of learning and memory formation.     

Inflammatory bowel disease: is it a primary immunodeficiency?

Inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn’s disease are chronic and relapsing conditions, characterized by abdominal pain, diarrhea, bleeding and malabsorption. IBD has been considered a hyperinflammatory state due to disturbed interactions between the immune system and the commensal bacterial flora of the gut. However, there is evidence that Crohn’s disease might be the consequence of a reduced release of pro-inflammatory cytokines and an impaired acute inflammatory response, thereby suggesting that IBD might be an immunodeficiency rather than an excessive inflammatory reaction. This theory has been supported by observations in patients with primary immunodeficiencies such as the Wiskott–Aldrich syndrome and IPEX (immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome). In contrary, defects in the anti-inflammatory down-regulation of the immune response as they are seen in patients with Mendelian defects in the IL10 signaling pathway support the hyper-inflammatory theory. In this review, we describe and discuss primary immunodeficiencies associated with IBD and show that the bowel is a highly sensitive indicator of dysregulations, making IBD a model disease to study and identify key regulators required to balance the human mucosal immune system.     

What was classical genetics?

I present an account of classical genetics to challenge theory-biased approaches in the philosophy of science. Philosophers typically assume that scientific knowledge is ultimately structured by explanatory reasoning and that research programs in well-established sciences are organized around efforts to fill out a central theory and extend its explanatory range. In the case of classical genetics, philosophers assume that the knowledge was structured by T. H. Morgan’s theory of transmission and that research throughout the later 1920s, 30s, and 40s was organized around efforts to further validate, develop, and extend this theory. I show that classical genetics was structured by an integration of explanatory reasoning (associated with the transmission theory) and investigative strategies (such as the ‘genetic approach’). The investigative strategies, which have been overlooked in historical and philosophical accounts, were as important as the so-called laws of Mendelian genetics. By the later 1920s, geneticists of the Morgan school were no longer organizing research around the goal of explaining inheritance patterns; rather, they were using genetics to investigate a range of biological phenomena that extended well beyond the explanatory domain of transmission theories. Theory-biased approaches in history and philosophy of science fail to reveal the overall structure of scientific knowledge and obscure the way it functions.     

How specific is immunity?

Zusammenfassung Der vorstehende Artikel enthält eine allgemeine Diskussion über die Grenzen der Spezifität, die der erworbenen Resistenz gegen Infektionskrankheiten zugrunde liegt. Es wird die These vertreten, dass spezifische Mechanismen von grösserer Bedeutung sind als häufig angenommen wird und dass sog. unspezifische Abwehrkräfte in vielen Fällen sich nicht von echten Antikörpern unterscheiden lassen.     

Understanding algorithm aversion: When is advice from automation discounted?

Forecasting advice from human advisors is often utilized more than advice from automation. There is little understanding of why “algorithm aversion” occurs, or specific conditions that may exaggerate it. This paper first reviews literature from two fields—interpersonal advice and human–automation trust—that can inform our understanding of the underlying causes of the phenomenon. Then, an experiment is conducted to search for these underlying causes. We do not replicate the finding that human advice is generally utilized more than automated advice. However, after receiving bad advice, utilization of automated advice decreased significantly more than advice from humans. We also find that decision makers describe themselves as having much more in common with human than automated advisors despite there being no interpersonal relationship in our study. Results are discussed in relation to other findings from the forecasting and human–automation trust fields and provide a new perspective on what causes and exaggerates algorithm aversion.     

Molecular mimicry in neurological disease: what is the evidence?

Autoimmune diseases are a leading cause of disability and are increasing in incidence in industrialized countries. How people develop autoimmune diseases is not completely understood, but is related to an interaction between genetic background, environmental agents, autoantigens and the immune response. Molecular mimicry continues to be an important hypothesis that explains how an infection with an environmental agent results in autoimmune disease of the nervous system and other target organs. Although molecular mimicry has yet to be unequivocally proven, in the past several years there has been a sharpening of its definition with better experimental data implicating it as a cause of neurological disease in humans. Received 9 July 2007; received after revision 15 November 2007; accepted 27 November 2007     

Liver cell therapy: is this the end of the beginning?

The prevalence of liver diseases is increasing globally. Orthotopic liver transplantation is widely used to treat liver disease upon organ failure. The complexity of this procedure and finite numbers of healthy organ donors have prompted research into alternative therapeutic options to treat liver disease. This includes the transplantation of liver cells to promote regeneration. While successful, the routine supply of good quality human liver cells is limited. Therefore, renewable and scalable sources of these cells are sought. Liver progenitor and pluripotent stem cells offer potential cell sources that could be used clinically. This review discusses recent approaches in liver cell transplantation and requirements to improve the process, with the ultimate goal being efficient organ regeneration. We also discuss the potential off-target effects of cell-based therapies, and the advantages and drawbacks of current pre-clinical animal models used to study organ senescence, repopulation and regeneration.     

RhoA/Rho-kinase and vascular diseases: what is the link?

RhoA/Rho-kinase pathway plays an important role in many pathological conditions. RhoA participates in the regulation of smooth muscle tone and activates many downstream kinases. The best characterized are the serine/threonine kinase isoforms (Rho-kinase or ROCK), ROCKα/ROCK2 and ROCKβ/ROCK1. ROCK is necessary for diverse functions such as local blood flow, arterial/pulmonary blood pressure, airway resistance and intestinal peristalsis. ROCK activation permits actin/myosin interactions and smooth muscle cells contraction by maintaining the activity of myosin light-chain kinase, independently of the free cytosolic calcium level. The sensitization of smooth muscle myofilaments to calcium has been implicated in many pathological states, such as hypertension, diabetes, heart attack, stroke, pulmonary hypertension, erectile dysfunction, and cancer. The focus of this review is on the involvement of RhoA/Rho-kinase in diseases. We will briefly describe the ROCK isoforms and the role of RhoA/Rho-kinase in the vasculature, before exploring the most recent findings regarding this pathway and various diseases.     

Exogenous or endogenous Toll-like receptor ligands: which is the MVP in tumorigenesis?

Toll-like receptors (TLRs) are a class of pattern recognition receptors sensing microbial components and triggering an immune response against pathogens. In addition to their role in anti-infection immunity, increasing evidence indicates that engagement of TLRs can promote cancer cell survival and proliferation, induce tumor immune evasion, and enhance tumor metastasis and chemoresistance. Recent studies have demonstrated that endogenous molecules or damage-associated molecular patterns released from damaged/necrotic tissues are capable of activating TLRs and that the endogenous ligands-mediated TLR signaling is implicated in the tumor development and affects the therapeutic efficacy of tumors. Since both exogenous and endogenous TLR ligands can initiate TLR signaling, which is the most valuable player in tumor development becomes an interesting question. Here, we summarize the effect of TLR signaling on the development and progression of tumors, and discuss the role of exogenous and endogenous TLR ligands in the tumorigenesis.