In this paper, we apply the perspective of intra-organismal ecology by investigating a family of ecological models suitable to describe a gene therapy to a particular metabolic disorder, the adenosine deaminase deficiency (ADA-SCID). The gene therapy is modeled as the prospective ecological invasion of an organ (here, bone marrow) by genetically modified stem cells, which then operate niche construction in the cellular environment by releasing an enzyme they synthesize. We show that depending on the chosen order (a (...) choice that cannot be made on \textit{a priori} assumptions), different kinds of dynamics are expected, possibly leading to different therapeutic strategies. This drives us to discuss several features of the extension of ecology to intra-organismal ecology. (shrink)

Previous studies of Zika virus (ZIKV) pathogenesis have focused primarily on virus‐driven pathology and neurotoxicity, as well as host‐related changes in cell proliferation, autophagy, immunity, and uterine function. It is now hypothesized that ZIKV pathogenesis arises instead as an (unintended) consequence of host innate immunity, specifically, as the side effect of an otherwise well‐functioning machine. The hypothesis presented here suggests a new way of thinking about the role of host immune mechanisms in disease pathogenesis, focusing on dysregulation of post‐transcriptional RNA (...) editing as a candidate driver of a broad range of observed neurodevelopmental defects and neurodegenerative clinical symptoms in both infants and adults linked with ZIKV infections. The authors collect and synthesize existing evidence of ZIKV‐mediated changes in the expression of adenosine deaminases acting on RNA (ADARs), known links between abnormal RNA editing and pathogenesis, as well as ideas for future research directions, including potential treatment strategies. (shrink)

Graphical AbstractAdenosine Deaminases Acting on RNA (ADARs) enzymes are prominent regulators of neural transcriptome diversity and play a role in the innate immune response. In article number 1800239, Piontkivska et al. outline how neurodevelopmental and neurodegenerative pathogenesis of Zika virus (ZIKV), including congenital Zika and Guillain-Barré syndromes, can be attributed to ADAR editing dysregulation triggered by ZIKV, Explaining Pathogenicity of Congenital Zika and Guillain-Barré Syndromes: Does Dysregulation of RNA Editing Play a Role? DOI: 10.1002/bies.201800239.

The RNA editing enzyme ADAR1 seemingly has more functions besides RNA editing. Mouse models lacking ADAR1 and sensors of foreign RNA show that RNA editing by ADAR1 plays a crucial role in the innate immune response. Still, RNA editing alone cannot explain all observed phenotypes. Thus, additional roles for ADAR1 must exist. Binding of ADAR1 to RNA is independent of its RNA editing function. Thus, ADAR1 may compete with other RNA-binding proteins. A very recent manuscript elaborates on this and reports (...) competition of ADAR1 with STAUFEN1, thereby modulating RNA-degradation. ADAR1 is also known to recruit proteins such as DROSHA to nascent transcripts. Still, many open questions remain. For instance, the biological role of the Z-DNA binding domains in ADAR1 is not defined. Moreover, the impact of ADAR1 on the RNA-folding landscape is unclear. In sum, moonlighting functions of ADAR1 may be manifold and have a great impact on the transcriptome. Adenosine to inosine RNA editing by ADAR1 is mostly known for its role in the innate immune response to help discriminate self from non-self RNA. Here we discuss the other face of ADAR1 that impacts on cellular processes independent of its editing function. These include Staufen-mediated-decay, mRNA processing, or miRNA maturation. (shrink)

Deamination of adenosine in RNA to form inosine has wide ranging consequences on RNA function including amino acid substitution to give proteins not encoded in the genome. What determines which adenosines in an mRNA are subject to this modification reaction? The answer lies in an understanding of the mechanism and substrate recognition properties of adenosine deaminases that act on RNA (ADARs). Our recent publication of X‐ray crystal structures of the human ADAR2 deaminase domain bound to RNA editing (...) substrates shed considerable light on how the catalytic domains of these enzymes bind RNA and promote adenosine deamination. Here we review in detail the deaminase domain‐RNA contact surfaces and present models of how full length ADARs, bearing double stranded RNA‐binding domains (dsRBDs) and deaminase domains, could process naturally occurring substrate RNAs. (shrink)

One of the distinctive features of the primate genome is the Alu element, a repetitive short interspersed element, over a million highly similar copies of which account for >10% of the genome. A direct consequence of this feature is that primates' transcriptome is highly enriched in long stable dsRNA structures, the preferred target of adenosine deaminases acting on RNAs (ADARs), which are the enzymes catalyzing A‐to‐I RNA editing. Indeed, A‐to‐I editing by ADARs is extremely abundant in primates: over a (...) hundred million editing sites exist in their genomes. However, there are few essential editing sites conserved across mammals that have maintained their editing level despite the radical change in ADAR target landscape. Here, we review and discuss the cost of having an unusual amount of dsRNA and editing in the transcriptome, as well as the opportunities it presents, which might have contributed to the accelerated evolution of the primates. (shrink)

Adenosine transport in cultured human umbilical vein endothelial cells (HUVEC) was characterized and shown to be mediated by a single facilitated diffusion mechanism. Initial rates of adenosine influx at 22 degrees C were saturable [apparent Michaelis constant, 69 +/- 10 mu M; maximum velocity (V-max), 600 +/- 70 pmol.10(6) cells(-1).s(-1)] and inhibited by nitrobenzylthioinosine (NBMPR). Formycin B had an unusually high affinity [inhibitory constant K-i), 18 +/- 4.3 mu M], whereas inosine had a low affinity (K-i, 440 +/- (...) 68 mu M) and nucleobases were without effect on adenosine influx. The number of transporters (1.2 x 10(6) sites/cell) was estimated by NBMPR equilibrium binding (apparent dissociation constant, 0.11 +/- 0.01 nM; maximum binding, 2.0 +/- 0.15 pmol/10(6) cells). In addition, we compared these endothelial cells with those obtained from cords from pregnancies complicated by diabetes (HUVEC-D), since embriopathy may occur in these conditions. HUVEC-D exhibited a 2.3-fold reduction in both the V-max for adenosine influx and the maximum number of NBMPR binding sites (260 +/- 40 pmol.10(6) cells(-1).s(-1) and 0.86 +/- 0.08 pmol/10(6) cells, respectively). However, the turnover number for each nucleoside transporter in normal and diabetic HUVEC was similar (approximate to 300 adenosine molecules/s). Adenosine metabolism at 10 mu M in HUVEC-D was modified compared with normal cells. Intracellular phosphorylation (> 90%) was the predominant pathway in normal HUVEC, whereas in HUVEC-D, substantial levels of adenine and adenosine were detected. The present results demonstrate therefore the downregulation of the NBMPR-sensitive nucleoside transporter and changes in adenosine metabolism in HUVEC from diabetic pregnancies. (shrink)

Theories of distributive justice are often criticised for either excluding people with disabilities from the domain of justice altogether, or casting them as deficient in personal attributes. I argue that the capabilities approach to justice is largely immune to these flaws. It has the conceptual resources to locate most of the causes of disadvantage in the interaction between a person and her environment and in doing so can characterise the disadvantages of disability in a way that avoids the imputation of (...) natural deficiency. However, I also argue that the capabilities approach cannot accommodate some of the stronger claims advanced by some disability scholars. No plausible capabilities approach can guarantee that social change will always be the just or fair remedy for disadvantage, and there is a small number of severe cases of disability where capability shortfalls will be attributed to the person’s ‘deficient’ physical and mental impairments. (shrink)

The most recent work toward compiling a comprehensive database of adenosine‐to‐inosine RNA editing events suggests that the potential for RNA editing is much more pervasive than previously thought; indeed, it is manifest in more than 100 million potential editing events located primarily within Alu repeat elements of the human transcriptome. Pairs of inverted Alu repeats are found in a substantial number of human genes, and when transcribed, they form long double‐stranded RNA structures that serve as optimal substrates for RNA (...) editing enzymes. A small subset of edited Alu elements has been shown to exhibit diverse functional roles in the regulation of alternative splicing, miRNA repression, and cis‐regulation of distant RNA editing sites. The low level of editing for the remaining majority may be non‐functional, yet their persistence in the primate genome provides enhanced genomic flexibility that may be required for adaptive evolution. (shrink)

Jennifer Lackey presents a puzzle to which she argues there is no current solution. Lackey's claim is that testimonial knowledge can have something conspicuously wrong with it and still be knowledge. Testimonial knowledge can be ‘deficient’. Given that knowledge is a normative category, that it describes what it is for a belief to go right, there is a puzzle that comes with accounting for how a testimonial belief could be knowledge and yet go wrong in the ways Lackey has in (...) mind. In this paper, I argue that the deficiency is one of teamwork, and that Lackey's puzzle offers one a window into the respect in which testimony is a kind of team achievement. (shrink)

Here we review concepts related to an ensemble description of G-protein-coupled receptors. The ensemble is characterized by both inactive and active states, whose equilibrium populations and exchange rates depend sensitively on ligand, environment, and allosteric factors. This review focuses on the adenosine A2 receptor, a prototypical class A GPCR. 19F Nuclear Magnetic Resonance studies show that apo A2AR is characterized by a broad ensemble of conformers, spanning inactive to active states, and resembling states defined earlier for rhodopsin. In keeping (...) with ideas associated with a conformational selection mechanism, addition of agonist serves to allosterically restrict the overall degrees of freedom at the G protein binding interface and bias both states and functional dynamics to facilitate G protein binding and subsequent activation. While the ligand does not necessarily “induce” activation, it does bias sampling of states, increase the cooperativity of the activation process and thus, the lifetimes of functional activation intermediates, while restricting conformational dynamics to that needed for activation. GPCRs represent a ubiquitous class of transmembrane receptors, responsible for cell signaling and cell homeostasis. Their activation gives rise to conformational changes that allow the receptor to engage downstream partners. Activation can be thought of in terms of a free energy landscape associated with distinct conformers, responsible for the process. Here, the action of ligands is seen to alter this landscape by enabling transitions between key intermediates. (shrink)

Plato seems to have been pessimistic about how most people stand with regard to virtue. However, unlike the Stoics, he did not conclude that most people are vicious. Rather, as we know from discussions across several dialogues, he countenanced decent ethical conditions that fall short of genuine virtue, which he limited to the philosopher. Despite Plato's obvious interest in this issue, commentators rarely follow his lead by investigating in detail such conditions in the dialogues. When scholars do investigate what kind (...) of virtue, if any, Plato thinks is open to non-philosophers, they typically look to the Republic. But in the Republic Plato sets out an ideal city; therefore, the virtue available to non-philosophers there is likely different from what he thinks is available to them in the real world. If we want to determine Plato's thoughts about the virtue of actual non-philosophers, we must look elsewhere. In this paper, I set my sights on the Phaedo. (shrink)

Scientific research is supposed to acquire or generate knowledge, but such a purpose would be severely undermined by instances of research misconduct (RM) and questionable research practices (QRP). RM and QRP are often framed in terms of moral transgressions by individuals (bad apples) whose aberrant acts could be made conducive by shortcomings in regulatory measures of organizations or institutions (bad barrels). This notion presupposes, to an extent, that the erring parties know exactly what they are doing is wrong and morally (...) culpable, but had nonetheless proceeded to commit wrongful acts. However, a confession of intent to deceived is often not readily admitted by perpetrators of RM. I posit that beyond the simplistic notion of conscious moral transgression, deficits in epistemic virtues and/or the prevalence of epistemic vices have important roles to play in initiating and driving RM/QRP. For the individual perpetrator, deficits in epistemic virtues could lead to or amplify errors in one’s desperate attempt to be accomplished or to excel, and pushes one across the ethical line or down the slippery slope of misconduct. Likewise, a lack of epistemic virtue within perpetrators’ institution or organization could make it conducive for deceitful acts and suppress indications and warning signs for the former. Furthermore, epistemic vices exhibited by reviewers, editors and journals could also promote RM/QRP. In this view, epistemic failings, rather than widespread moral deficiencies of individuals within the research ecosystem, may underlie the prevalence of RM/QRP. (shrink)

Although higher education understands the need to develop critical thinkers, it has not lived up to the task consistently. Students are graduating deficient in these skills, unprepared to think critically once in the workforce. Limited development of cognitive processing skills leads to less effective leaders. Various definitions of critical thinking are examined to develop a general construct to guide the discussion as critical thinking is linked to constructivism, leadership, and education. Most pedagogy is content-based built on deep knowledge. Successful critical (...) thinking pedagogy is moving away from this paradigm, teaching students to think complexly. Some of the challenges faced by higher education moving to a critical thinking curricula are discussed, and recommendations are offered for improving outcomes. (shrink)

I give a brief overview of Albert Casullo’s Essays on A Priori Knowledge and Justification, followed by a summary of his diagnostic framework for evaluating accounts of a priori knowledge and a priori justification. I then discuss Casullo’s strategy for countering deficiency arguments against empiricism. A deficiency argument against empiricism can be countered by mounting a parallel argument against moderate rationalism that shows moderate rationalism to be defective in a similar way. I argue that a particular deficiency (...) argument put forth by George Bealer in “The Incoherence of Empiricism” can withstand a parallel challenge mounted by Casullo.I then consider Casullo’s preferred analysis of the concept of a priori justification, which identifies a belief’s being justified by some nonexperiential source as the feature by virtue of which it is justified a priori. On the analysis, an apriori-justfied belief that is justified to a degree that is sufficient for knowledge is not taken to be empirically indefeasible. I argue that Casullo could avail himself of an empirical indefeasibility requirement that is consistent with his minimal and fallibilist conception of a priori knowledge. Doing so would capture a feature of the concept of a priori knowledge that is of particular interest and significance. (shrink)

As the world's literary, religious, and philosophical traditions attest, deficiency in the world is a matter of perennial human concern. Ontologically speaking deficient existence is a problem that has occupied metaphysical thinking from Heraclitus to Heidegger. What is it to exist deficiently? ;This dissertation addresses the question, first, through a survey of answers given by six ancient philosophers. Parmenides describes deficient existence as changing multiplicity; Plato, as being in an inferior world; Plotinus, as mis-seeing; Augustine, as disorderedness; Gregory of (...) Nyssa, as "nothingification" &parl0;`h e ,xoud e&d12;nwsi v&parr0; ; Dionysius, as failed participation. The dissertation then gives a more systematic answer through close study of the metaphysics of John Scotus Eriugena , who builds on the foundation established by these thinkers. ;The Eriugenian cosmos is a "theophanic" one. To be is to be the showing or expression of God. What exists, then, is divine and good. Furthermore, all deficiencies, such as they are, must be characterized as privations or impoverishments. ;What can deficient existence be in such a world? Eriugena's first answer is that it is existence on an inferior level of reality. This dualistic view must be rejected, however, because it is not consistent with the fundamental metaphysical principles that reality is an ontological unity and every being is divine. ;Two better descriptions of deficient existence can be found in his metaphysics. First, to be deficiently is to see the world deficiently; that is, deficient existence is a misunderstanding of reality. Second, deficient existence is metaphysically incomplete existence. Being as a whole is an ontological work in progress, a creatio ex nihilo that is a creatio ex nihilo hic et illuc et ubique ---here, there, and everywhere. ;Such a creation depends in part on human choice and is subject to the destructive influences of non-being. But rather than a fall from some primordial perfection, creation is a movement towards perfection. Hence the existence that it constitutes is an existence in the theophanic world. Moreover, creation is theophanic to the extent that it does exist, even though, as deficient, it does not yet fully exist. (shrink)

This paper is a critique of NIH guidelines for the care and protection of laboratory animals. It exposes four serious deficiencies in these guidelines: (1) failure to make it dear that the mere pursuit of knowledge does not justify using animals; (2) failure to give any guidance concerning what constitutes human benefit or well-being; (3) failure to countenance trade-offs between human benefit or well-being and animal well-being; (4) failure to clearly specify what constitutes keeping animals in an ‘environment appropriate to (...) the species and its life history.’ It concludes with the suggestion that the construction and revision of these guidelines is too important to be left to the professionals. Keywords: animals, benefit, NIH, research, trade-offs, well-being CiteULike Connotea Del.icio.us What's this? (shrink)

I give a brief overview of Albert Casullo’s Essays on A Priori Knowledge and Justification (2012), followed by a summary of his diagnostic framework for evaluating accounts of a priori knowledge and a priori justification. I then discuss Casullo’s strategy for countering deficiency arguments against empiricism. A deficiency argument against empiricism can be countered by mounting a parallel argument against moderate rationalism that shows moderate rationalism to be defective in a similar way. I argue that a particular (...) class='Hi'>deficiency argument put forth by George Bealer in “The Incoherence of Empiricism” (1992) can withstand a parallel challenge mounted by Casullo (2012, Ch.6). -/- I then consider Casullo’s preferred analysis of the concept of a priori justification, which identifies a belief’s being justified by some nonexperiential source as the feature by virtue of which it is justified a priori. On the analysis, an apriori-justfied belief that is justified to a degree that is sufficient for knowledge is not taken to be empirically indefeasible. I argue that Casullo could avail himself of an empirical indefeasibility requirement that is consistent with his minimal and fallibilist conception of a priori knowledge. Doing so would capture a feature of the concept of a priori knowledge that is of particular interest and significance. (shrink)

This paper examines the few, but important legal and coronial cases concerning withdrawing or withholding life-sustaining treatment from severely disabled or critically impaired infants in Australia. Although sparse in number, the judgements should influence common clinical practices based on assessment of “best interests” but these have not yet been adopted. In particular, although courts have discounted assessment of “quality of life” as a legitimate component of determination of “best interests,” this remains a prominent component of clinical guidelines. In addition, this (...) paper highlights the lack of uniform clinical guidelines available to medical professionals and parents in Australia when making end-of-life decisions for severely ill infants. Thus, it is argued here that there is a need for an overarching prescriptive uniform framework or set of guidelines in end-of-life decision-making for impaired infants. This would encourage greater transparency, consistency, and some degree of objectivity in an area that often appears subjective. (shrink)

The contemporary debate on justice is understandably dominated by theories and arguments addressing the problems of justice pertinent to nearly just societies, as virtually all the theorists participating in this debate live in such societies. They are obviously, and rightly so, first and foremost concerned with the philosophical problems of their own societies. Although almost all the contemporary theories of justice were formulated in the context of nearly just societies, why can we not apply them to the issues and problems (...) of radically unjust societies? The view that such a move is permissible and wise is at present no more than an unexamined assumption, an unargued view. Such an unargued view leads to the suspicion that a strong case may be made that radically unjust societies generate problems of social and political justice that should be considered in their own right. This does not imply that theories of justice developed in the context of, and aimed at, those issues current in nearly just societies should be disregarded or discarded. What is required are arguments to indicate to what extent the theoretical insights and wisdom contained in these theories can be utilized in a discussion of the social and political problems of radically unjust societies. I argue for the view that the contemporary debate on justice contains a major deficiency. In this article, I attempt to specify this major deficiency, namely that exclusive attention is given to the problems of nearly just societies while the problems of radically unjust societies are mostly ignored. The strategy will be to raise issues pertinent to radically unjust societies and note the extent to which clear and unambiguous solutions could be provided by participants in the contemporary debate on justice. (shrink)

This paper delves into crucial issues surrounding attempts to make flawless Qur’anic recitation, in Nigeria, a permanent tradition. The paper identifies major militating factors against an error-free recitation of the holy Qur’an in Nigeria as a basis for locating appropriate remedial programmes. The study discovered that factors such as acquisition of deficient typologies, language interference, complexity of the rules, lack of awareness dearth of specialists , dearth of relevant texts , underutilization of orthographic symbols and methodology used in imparting the (...) knowledge constitute major impediments towards achieving ideal recital of the Qur’an. In proffering relevant remedial measures like the teaching of the ideal typologies of Qur’anic recitation supported by a well planned curriculum, the paper concludes that the rectification of diagnosed deficiencies in reciting the Qur’an is feasible, in the long run, provided the intervention strategies proposed are effectively implemented. (shrink)

This paper delves into crucial issues surrounding attempts to make flawless Qur’anic recitation, in Nigeria, a permanent tradition. The paper identifies major militating factors against an error-free recitation of the holy Qur’an in Nigeria as a basis for locating appropriate remedial programmes. The study discovered that factors such as acquisition of deficient typologies, language interference, complexity of the rules, lack of awareness dearth of specialists, dearth of relevant texts, underutilization of orthographic symbols and methodology used in imparting the knowledge constitute (...) major impediments towards achieving ideal recital of the Qur’an. In proffering relevant remedial measures like the teaching of the ideal typologies of Qur’anic recitation supported by a well planned curriculum, the paper concludes that the rectification of diagnosed deficiencies in reciting the Qur’an is feasible, in the long run, provided the intervention strategies proposed are effectively implemented. (shrink)

A natural heme deficiency that exists in cells outside of the circulation broadly compromises the heme contents and functions of heme proteins in cells and tissues. Recently, we found that the signaling molecule, nitric oxide (NO), can trigger or repress the deployment of intracellular heme in a concentration‐dependent hormetic manner. This uncovers a new role for NO and sets the stage for it to shape numerous biological processes by controlling heme deployment and consequent heme protein functions in biology.

Paul Ricœur says that our narrative identity depends on how others understand us. This claim, however, does not explicitly address the fact that not everyone receives the same recognition: it underexplains how certain groups are systemically not acknowledged, respected, or taken seriously. More recent work on narrative co-authoring starts to address this fact by examining how people’s vulnerability to co-authoring depends on the context in which they live. But I argue that this work should be extended to attend to the (...) kinds of vulnerabilities that result from what José Medina calls recognition deficiencies, which become more normalized due to structural oppression, specifically what Iris Marion Young calls cultural imperialism. I then illuminate the kinds of vulnerabilities that result from recognition deficiencies in cases of structural oppression by bringing in work in Black feminist thought and epistemic injustice, particularly that of Audre Lorde and Veronica Ivy, into conversation with narrative scholarship. (shrink)

This enlightening text analyses the origins of Western complaints, prevalent in the late nineteenth century, that Japan was characterised at the time by exceptionally low standards of ‘commercial morality’, despite a major political and economic transformation. As Britain industrialised during the nineteenth century the issue of ‘commercial morality’ was increasingly debated. Concerns about standards of business ethics extended to other industrialising economies, such as the United States. Hunter examines the Japanese response to the charges levelled against Japan in this context, (...) arguing that this was shaped by a pragmatic recognition that Japan had little choice but to adapt itself to Western expectations if it was to establish its position in the global economy. The controversy and criticisms, which were at least in part stimulated by fear of Japanese competition, are important in the history of thinking on business ethics, and are of relevance for today’s industrialising economies as they attempt to establish themselves in international markets. (shrink)