The new class of anti-inflammatory drugs, the COX-2 inhibitors, have been commercially successful to the point of market dominance within a short time of their launch. They attract a price premium on the basis that they are associated with fewer adverse gastric events than traditional anti-inflammatory drugs. This marketing continues even though a pivotal safety study with one of the COX-2 inhibitors, rofecoxib, showed a significant increase in myocardial infarction with rofecoxib use compared with a traditional anti-inflammatory drug. (...) This finding has led to a series of publications containing pooled analyses of existing data that both support and refute the possibility of increased cardiovascular risk with COX-2 inhibitors.These medical journal publications have served to obfuscate rather than provide guidance for medical practitioners. Consideration of a research ethics committee approach to this issue suggests that it would deal with the controversy in a straightforward manner—namely, it would simply inform research participants of the trial results with rofecoxib. The certainty of this research ethics committee approach raises the issue of whether it should be applied in normal medical practice outside of the research environment. A consideration of the legal tests for disclosure of information suggests that therapeutic medical practice should mirror that within the research environment, in this case. (shrink)

Volume 32, Issue 6, August 2019, Page 992-999.

Given an ideal $I$ , let $\mathbb{P}_{I}$ denote the forcing with $I$ -positive sets. We consider models of forcing axioms $MA(\Gamma)$ which also have a normal ideal $I$ with completeness $\omega_{2}$ such that $\mathbb{P}_{I}\in \Gamma$ . Using a bit more than a superhuge cardinal, we produce a model of PFA (proper forcing axiom) which has many ideals on $\omega_{2}$ whose associated forcings are proper; a similar phenomenon is also observed in the standard model of $MA^{+\omega_{1}}(\sigma\mbox{-closed})$ obtained from a supercompact cardinal. (...) Our model of PFA also exhibits weaker versions of ideal properties, which were shown by Foreman and Magidor to be inconsistent with PFA. Along the way, we also show (1) the diagonal reflection principle for internally club sets ( $\mathit{DRP}(IC_{\omega_{1}})$ ) introduced by the author in earlier work is equivalent to a natural weakening of “there is an ideal $I$ such that $\mathbb{P}_{I}$ is proper”; and (2) for many natural classes $\Gamma$ of posets, $MA^{+\omega_{1}}(\Gamma)$ is equivalent to an apparently stronger version which we call $MA^{+\operatorname{Diag}}(\Gamma)$. (shrink)

Extract: Clearly, academic life takes place at the intersection of many social practices. If MacIntyre is right, the role-specific virtues of academic life should be understood in terms of these practices.2 Academic virtues are those excellences required to obtain the internal goods of the social practices constituting academic life. And the social practices of academic life are sustained, competitive and cooperative attempts to achieve a set of academic goals and realize academic forms of excellence. They are also sustained attempts to (...) expand and improve conceptions of these goals and forms of excellence. They emerge out of traditions—for instance the tradition of scientific argument— and must be understood in terms of these traditions. MacIntyre argues that this preliminary account of virtues in relation to social practices needs to be deepened in two ways: connecting it to the unity of an individual’s life on the one hand and to a coherent historical tradition on the other. Virtues are not just any set of traits delivering the internal goods of social practices, but those that serve to make coherent a person’s life and her place in an on-going tradition. They are crucial to lending meaning to one’s life and its struggles. (shrink)

We obtain lower bounds for the consistency strength of fully nonregular ultrafilters on ω₂.

It is well known that saturation of ideals is closely related to the “antichain-catching” phenomenon from Foreman–Magidor–Shelah [10]. We consider several antichain-catching properties that are weaker than saturation, and prove:If${\cal I}$is a normal ideal on$\omega _2 $which satisfiesstationary antichain catching, then there is an inner model with a Woodin cardinal;For any$n \in \omega $, it is consistent relative to large cardinals that there is a normal ideal${\cal I}$on$\omega _n $which satisfiesprojective antichain catching, yet${\cal I}$is not saturated. This provides a negative (...) answer to Open Question number 13 from Foreman’s chapter in the Handbook of Set Theory. (shrink)

The year 2020 is facing one of the worst public health situations in decades. The world is experiencing a pandemic that has triggered significant challenges to healthcare systems in both high and low‐middle income countries (LMICs). Government policymakers and healthcare personnel are experiencing real‐life ethical dilemmas and are pressed to respond to these situations. Many possible treatments are being investigated, one of which is the use of hydroxychloroquine or chloroquine. These drugs are approved for use by patients with systemic lupus (...) erythematosus (SLE), rheumatoid arthritis, and malaria. The demand for these products has increased, and the stocks are depleting for the patient population for whom the drugs are intended initially. Although both innovator and generic pharmaceutical manufacturers are making plans for increased production, there are challenges with global supply chains disruption and the retention of supplies for local markets. This may cause countries that rely on the importation of pharmaceuticals to be out of stock of supplies for an extended period. There are allegations of off‐label prescribing and hoarding. Pharmacists are the custodians and dispensers of medications and are faced with the task of assessing prescriptions and making decisions about the allocation of these products. This paper seeks to 1) highlight some of the ethical challenges of dispensing hydroxychloroquine by pharmacists during the COVID‐19 pandemic, 2) identify some of the responses to these issues from various regulatory authorities in the USA, and 3) recommend approaches to assist pharmacists in their decision‐making process, especially in LMICs. (shrink)

The human tumour suppressor protein p53 is critical for regulation of the cell cycle on genotoxic insult. When DNA is damaged by radiation, chemicals or viral infection, cells respond rapidly by arresting the cell cycle. A G1 arrest requires the activity of wild‐type p53, as it is not observed in cells lacking functionally wild‐type protein, and at least some component of S phase and G2/M arrests is also thought to be p53‐dependent. p53 functions as a transcription factor which binds specific (...) DNA sequences, and recently major downstream targets have been identified, including p21Cip1 an inhibitor of the cell cycle kinases that also blocks the replicative but not the repair function of DNA polymerase δ auxiliary factor, PCNA. Current interest focuses on developing novel cancer therapies based on our knowledge of the activity of p53 and p21Cip1 in the cell cycle. (shrink)

We develop the theory of layered posets and use the notion of layering to prove a new iteration theorem is κ-cc, as long as direct limits are used sufficiently often. This iteration theorem simplifies and generalizes the various chain condition arguments for universal Kunen iterations in the literature on saturated ideals, especially in situations where finite support iterations are not possible. We also provide two applications:1 For any n≥1, a wide variety of <ωn−1-closed, ωn+1-cc posets of size ωn+1 can consistently (...) be absorbed by quotients of saturated ideals on ωn.2 For any n∈ω, the tree property at ωn+3 is consistent with Chang’s conjecture ↠. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Reviewed by:Hamlet’s PerfectionJohn D. CoxHamlet’s Perfection, by William Kerrigan; xviii & 179pp. Baltimore: Johns Hopkins University Press, 1994, $29.95.While acknowledging that his reading of Hamlet is “idiosyncratic and unfashionable” (p. x), Kerrigan offers no apologies for it, asserting, instead, that tradition is worth vindicating, because “those who have been trained in a tradition may discard it, but those who come after, students of the discarders, will be simply oblivious” (...) (pp. 2–3). Putting all his cards on the table, Kerrigan acknowledges four influences in the tradition he defends: literary formalism, historical scholarship, intellectual history, and psychoanalysis (pp. xii–xiii).Hamlet criticism thus “begins with the Romantic Germans” (p. 1), and they eventually give rise to Freud, who “influences most of the criticism of our century” (p. 14), even when critics (like Eliot) disagree with him. Kerrigan’s reading of the tradition is illuminating, subtle, informed, and informative, and he uses it to establish his reading of the play, working within the tradition but extending it in hitherto unseen and insightful ways. Of course Hamlet delays for Kerrigan, but no one has ever explained his delay so carefully or with so many other factors taken into account. “This seems to me much the best reading yet of the delay,” Kerrigan asserts (p. 76), and one is inclined to assent, given the assumptions.But why make these assumptions? Kerrigan dismisses postmodern criticism: it is a symptom of “our current decadence” (p. 31) and has contributed “little to the elucidation of Hamlet” (p. xi). Since the elucidation of texts and characters is not the aim of postmodern critics, they unsurprisingly fail at what they do not attempt. Yet they follow a tradition established, for the most part, by Marx and Nietzsche, and Kerrigan does not explain why he venerates one of Paul Ricoeur’s “masters of suspicion,” namely Freud, and not the other two.In fact, many readers may feel that Kerrigan fails to avoid decadence himself. He relates his Oedipal explanation of Hamlet’s delay to the observation that Shakespeare never has anything good to say about cosmetics, even though he was a man of the theater. Kerrigan relates this “split,” in turn, to early traumas in Shakespeare’s life. The fact that Mary Shakespeare had lost two daughters before William’s birth means that she must have been overattentive to him as an infant, yet she must have weaned him nine months before birth of younger brother Gilbert, thus splitting William’s attitude toward her between resentment of her overattention and resentment of being displaced at the breast. Kerrigan finds evidence of the latter in Timon 4.3.114–20, where Timon inveighs against “milk-paps” as “horrible traitors” (p. 78). Never mind that these are virgin’s paps and that Timon’s emphasis is sexual, not maternal: breasts are traitors to Timon as sex objects, not as sources of nutrition. The critic’s confusion between virgin and maternal breasts perhaps explains why Kerrigan places Thaisa in a brothel in Pericles, rather than Marina (p. 80), but I am not sure what psychological explanation to offer for this particular split. [End Page 381]Kerrigan would do well to heed the postmodern insight that we all speak out of a specific tradition, with the attendant lesson that tolerance and mutual respect across traditions is imperative, since “ridiculous” and “mockable” are relative to context, as Corin points out to Touchstone.In privileging Freud, Kerrigan not only dismisses the heritage of Marx and Nietzsche but underestimates the importance of what lies behind all three. For the Romantic/Freudian tradition cannot claim to have originated either character analysis or individuality, which Kerrigan purports to value. “A man’s character is his fate,” Heraclitus says, perhaps generalizing from Homer, but the insight would eventually inform Aristotle’s notion of an ethics based on virtuous character, which in turn was Christianized by Thomas (where it complements the moral sense of individual worth that Hamlet acknowledges in the providential oversight of sparrows), and came to influence the Reformers in various ways. Kerrigan has good things to say about Stoicism in Hamlet, but to assert that “It all begins with the Romantic Germans... (shrink)

There is no satisfactory account for the general phenomenon of confabulation, for the following reasons: (1) confabulation occurs in a number of pathological and non-pathological conditions; (2) impairments giving rise to confabulation are likely to have different neural bases; and (3) there is no unique theory explaining the aetiology of confabulations. An epistemic approach to defining confabulation could solve all of these issues, by focusing on the surface features of the phenomenon. However, existing epistemic accounts are unable to offer sufficient (...) conditions for confabulation and tend to emphasise only its epistemic disadvantages. In this paper, we argue that a satisfactory epistemic account of confabulation should also acknowledge those features which are (potentially) epistemically advantageous. For example, confabulation may allow subjects to exercise some control over their own cognitive life which is instrumental to the construction or preservation of their sense of self. (shrink)

The year 2020 is facing one of the worst public health situations in decades. The world is experiencing a pandemic that has triggered significant challenges to healthcare systems in both high and low‐middle income countries (LMICs). Government policymakers and healthcare personnel are experiencing real‐life ethical dilemmas and are pressed to respond to these situations. Many possible treatments are being investigated, one of which is the use of hydroxychloroquine or chloroquine. These drugs are approved for use by patients with systemic lupus (...) erythematosus (SLE), rheumatoid arthritis, and malaria. The demand for these products has increased, and the stocks are depleting for the patient population for whom the drugs are intended initially. Although both innovator and generic pharmaceutical manufacturers are making plans for increased production, there are challenges with global supply chains disruption and the retention of supplies for local markets. This may cause countries that rely on the importation of pharmaceuticals to be out of stock of supplies for an extended period. There are allegations of off‐label prescribing and hoarding. Pharmacists are the custodians and dispensers of medications and are faced with the task of assessing prescriptions and making decisions about the allocation of these products. This paper seeks to 1) highlight some of the ethical challenges of dispensing hydroxychloroquine by pharmacists during the COVID‐19 pandemic, 2) identify some of the responses to these issues from various regulatory authorities in the USA, and 3) recommend approaches to assist pharmacists in their decision‐making process, especially in LMICs. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Philosophy and Literature 26.1 (2002) 107-124 [Access article in PDF] Shakespeare and Political Philosophy John D. Cox Though Shakespeare has been praised as one of the greatest thinkers who ever lived, he has no standing in the history of Western philosophy, being at best a footnote to the derivative neo-Platonists and skeptics of the late Renaissance. He died in 1616, more than twenty years before Descartes's Discourse on Method (...) heralded the autonomous rationalism of the Enlightenment, and Shakespeare did not achieve a reputation as a deep thinker until the nineteenth century, as a consequence of admiration for his characters. People seemed to think that a reflective and witty prince who could say to his friend, "There are more things in heaven and earth, Horatio, / Than are dreamt of in your philosophy" must be the product of a keenly philosophical intelligence—never mind that Hamlet is referring to the "antique Roman" philosophy he so admires in Horatio, i.e., Stoicism, which by 1599 was little more than an oft-repeated set of moral and social platitudes. 1 To assert that there are more things in heaven and earth than late Renaissance Stoicism is not to assert very much.But other ways of thinking about Shakespeare philosophically are more promising than character analysis. He was indeed a thoughtful playwright, and though he had no university education, he was a voracious and incisive reader, so the influences on his plays and poems include many writers who have some standing in the history of philosophy. More complex than discerning historical philosophical influences on Shakespeare is what might be called the hermeneutical approach, i.e., the interpretation of the plays and poems with particular philosophers and philosophies in mind, regardless of their possible historical influence in the sixteenth century. To survey the range of philosophical influences and hermeneutical approaches is impossible [End Page 107] in a single essay, but a manageable example of Shakespeare's thinking is his political philosophy, where both ways of understanding him can be discerned. The most influential interpreter of Shakespeare's history plays for the second half of the twentieth century, for example, was E. M. W. Tillyard, who purported to excavate the neo-Platonic assumptions of Shakespeare's political culture: order, degree, hierarchy, and obedience. 2 Though questions were increasingly raised concerning Tillyard's assumptions and documentation, the decisive challenge to his authority was issued in the 1980s by New Historicists and Cultural Materialists, whose allegiance was more or less explicitly Marxist, and who therefore interpreted Shakespeare in light of a particular nineteenth-century philosophy. 3 A clearer example of the difference between history and hermeneutics in understanding Shakespeare is hard to imagine.The clarity of the difference, however, does not mean that the two approaches are mutually exclusive. Tillyard construed Shakespeare's emphasis on hierarchical order as an advocacy of divine-right monarchy, and much in the plays of Shakespeare supports this construal. Despite his sympathetic portraits of particular characters, including commoners, remarks in his plays about commoners taken together ("the people") are always slighting and mistrustful—often indeed scornful—and the proportion of upper-class to lower-class characters reflects their perceived social importance, for the former invariably outnumber the latter, even in the comedies, whereas the aristocracy were a tiny fraction of the total population in Shakespeare's England. Shakespeare's portrayal of pre-imperial Rome, in Julius Caesar, Antony and Cleopatra, and Coriolanus, shows little understanding of, and less sympathy with, republican alternatives to one-person rule. Shakespeare was not responsive to Calvin's spirited defense of the "poor common people" against rapacious kings (even, or especially, under godly magistrates), and Shakespeare's plays offer no support to the nascent republicanism of those who took arms against the king of England in the mid-seventeenth century, largely inspired by Calvinism. 4 Shakespeare, in short, was no Milton.This is not to say, however, that he was an uncritically idealizing royalist, as we can see from his first venture into writing about English history: his four early plays on the civil unrest of the fifteenth century. Three of these plays... (shrink)

In “A Refutation of Environmental Ethics” Janna Thompson argues that by assigning intrinsic value to nonhuman elements of nature either our evaluations become (1) arbitrary, and therefore unjustified, or (2) impractical, or (3) justified and practical, but only by reflecting human interest, thus failing to be truly intrinsic to nonhuman nature. There are a number of possible responses to her argument, some of which have been made explicitly in reply to Thompson and others which are implicit in the literature. In (...) this discussion I describe still another response, one which takes Thompson’s concerns about value seriously, but does not assign nature intrinsic or nonanthropocentric value. I suggest a relational environmental ethic as the basis for a genuinely ethical stance toward nature in which our relations to nature are a principal object of ethical concern. (shrink)

(1983). The Educational Attitudes and Views about School of a Sample of Disadvantaged Fifteen‐year‐olds. Educational Studies: Vol. 9, No. 2, pp. 69-79.

The temporal structure of behavior contains a rich source of information about its dynamic organization, origins, and development. Today, advances in sensing and data storage allow researchers to collect multiple dimensions of behavioral data at a fine temporal scale both in and out of the laboratory, leading to the curation of massive multimodal corpora of behavior. However, along with these new opportunities come new challenges. Theories are often underspecified as to the exact nature of these unfolding interactions, and psychologists have (...) limited ready-to-use methods and training for quantifying structures and patterns in behavioral time series. In this paper, we will introduce four techniques to interpret and analyze high-density multi-modal behavior data, namely, to: (1) visualize the raw time series, (2) describe the overall distributional structure of temporal events (Burstiness calculation), (3) characterize the nonlinear dynamics over multiple timescales with Chromatic and Anisotropic Cross-Recurrence Quantification Analysis (CRQA), (4) and quantify the directional relations among a set of interdependent multimodal behavioral variables with Granger Causality. Each technique is introduced in a module with conceptual background, sample data drawn from empirical studies and ready-to-use Matlab scripts. The code modules showcase each technique’s application with detailed documentation to allow more advanced users to adapt them to their own datasets. Additionally, to make our modules more accessible to beginner programmers, we provide a “Programming Basics” module that introduces common functions for working with behavioral timeseries data in Matlab. Together, the materials provide a practical introduction to a range of analyses that psychologists can use to discover temporal structure in high-density behavioral data. (shrink)

We prove that \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${(\omega_3, \omega_2) \twoheadrightarrow (\omega_2, \omega_1)}$$\end{document} implies there is an inner model with a weak repeat measure.

There has been little previous research regarding the effectiveness of ethics education interventions for residential care‐givers. The Researching Interventions to Promote Ethics in social care project responded to the question: Which is the most effective ethics education intervention for care‐givers in residential social care? A pragmatic cluster trial explored the impact of three ethics education interventions for: (a) interactive face‐to‐face ethics teaching; (b) reflective ethics discussion groups; and (c) an immersive simulation experience. There was also a control arm (d). 144 (...) trial participants were recruited from 39 residential care homes for older people in southern England. Change scores compared across intervention arms showed a significant reduction in work‐related moral stress in the teaching arm compared with control group (p =.03); there were no significant differences between control and intervention arms in change scores for moral sensitivity, interpersonal reactivity (empathy) or ethical leadership. Qualitative data themes were as follows: ethical care; care challenges; and ethical care inhibitors. Overall findings stimulate reflection on the value of three different ethics education interventions and the most appropriate means to evaluate their impact. Findings suggest the complexity and diverse nature of ethical competence in care. We suggest a way forward for research evaluating ethics education. (shrink)

The focus on translational research in clinical trials has the potential to generate clinically relevant genetic data that could have importance to patients. This raises challenging questions about communicating relevant genetic research results to individual patients. An exploratory pharmacogenetic analysis was conducted in the international ovarian cancer phase III trial, AGO-OVAR 16, which found that patients with clinically important germ-line BRCA1/2 mutations had improved progression-free survival prognosis. Mechanisms to communicate BRCA results were evaluated, because these findings may be beneficial to (...) patients and their families. Communicating individual BRCA results was not anticipated during clinical trial design. Consequently, options were not available for patients to indicate their preference for receiving their individual results when they signed pharmacogenetic informed consent. Differences in local requirements, clinical practice, and opinion regarding the ethical aspects of how to convey genetic results to patients are all potential barriers to returning individual BRCA results to patients. Communicating the aggregate BRCA result from this study provided clinical investigators with a mechanism to disseminate the overall study finding to patients while taking individual circumstances, local guidelines and clinical practice into account. This study illustrates the importance of increasing the clarity and scope of informed consent and the need for patient engagement to ensure clinical trial participants can indicate their preference regarding receipt of potentially important individual pharmacogenetic results. This study was registered in the NCT Clinical Trial Registry under NCT00866697 on March 19, 2009, following approval from participating ethics committees. (shrink)

Purpose: The purpose of this mixed-methods study was to determine whether Facebook use affects biological response to stress and to characterize participants’ use of Facebook during a stressful event. Methods: College students completed a modified Trier Social Stress Test including video recording. Participants were randomly assigned to the Facebook group or control group (no preparatory materials). Pulse and salivary cortisol were measured and compared using t tests. Trained coders assessed videos for 13 common Facebook actions and categorized them as purposeful (...) (tool based) or nonpurposeful (distraction); pulse was compared between groups using Fisher’s exact test. Results: Of 41 participants, 14 (36%) were male and 36 (88%) were Caucasian, mean age was 19.6 ± 1.4 years; 19 participants were randomized to the Facebook group. Comparing Time 1 and Time 3, there were no significant differences in cortisol or pulse change between the Facebook group and the control group. However, males in the control group had a mean pulse reduction of −3.5 ± 0.2 bpm between baseline and Time 3; males in the Facebook group had a mean pulse increase of 10 ± 8.6 bmp (p =.01). Overall, 58.8% of videos were categorized as primarily tool based. Participants who primarily demonstrated distracted use of Facebook had higher than average pulse rates at Time 3 (mean 85.1 vs. 73.6 bpm, p =.03). Discussion: Male Facebook users and participants who demonstrated distracted Facebook use showed increased biologic signs of stress during a stressful event. Some college students may find Facebook use detrimental to performance in stressful situations, but this may vary by gender and type of use. (shrink)

Mirrored-self misidentification is the delusional belief that one's own reflection in the mirror is a stranger. In two experiments, we tested the ability of hypnotic suggestion to model this condition. In Experiment 1, we compared two suggestions based on either the delusion's surface features (seeing a stranger in the mirror) or underlying processes (impaired face processing). Fifty-two high hypnotisable participants received one of these suggestions either with hypnosis or without in a wake control. In Experiment 2, we examined the extent (...) to which social cues and role-playing could account for participants' behaviour by comparing the responses of 14 hypnotised participants to the suggestion for impaired face processing (reals) with those of 14 nonhypnotised participants instructed to fake their responses (simulators). Overall, results from both experiments confirm that we can use hypnotic suggestion to produce a compelling analogue of mirrored-self misidentification that cannot simply be attributed to social cues or role-playing. (shrink)

In eukaryotes, double‐stranded RNAs (dsRNAs) or short, interfering dsRNAs (siRNAs) can reduce the accumulation of a sequence‐related mRNA, often resulting in a loss‐of‐function phenotype—a process termed RNA interference (RNAi). Unfortunately, some mRNAs are resistant to the effects of dsRNA. Experiments designed to unravel RNAi mechanisms in Caenorhabditis elegans have led to the identification of two worm proteins, RRF‐31,2 and, now, ERI‐1,3 that can inhibit RNAi responses. Animals defective in either protein can display enhanced RNAi phenotypes for mRNAs that were previously (...) resistant to dsRNA. Since ERI‐1 is a conserved protein, development of procedures to enhance RNAi effectiveness in other systems may be possible. BioEssays 26:715–718, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Alzheimer's disease is characterized by formation of neuritic plaque primarily composed of a small filamentous protein called amyloid-beta peptide . The rate-limiting step in the production of Abeta is the processing of Abeta precursor protein by beta-site APP-cleaving enzyme . Hence, BACE1 activity plausibly plays a rate-limiting role in the generation of potentially toxic Abeta within brain and the development of AD, thereby making it an interesting drug target. A phase II trial of the promising LY2886721 inhibitor of BACE1 was (...) suspended in June 2013 by Eli Lilly and Co., due to possible liver toxicity. This outcome was apparently a surprise to the study's team, particularly since BACE1 knockout mice and mice treated with the drug did not show such liver toxicity. Lilly proposed that the problem was not due to LY2886721 anti-BACE1 activity. We offer an alternative hypothesis, whereby anti-BACE1 activity may induce apparent hepatotoxicity through inhibiting BACE1's processing of beta-galactoside alpha-2,6-sialyltransferase I . In knockout mice, paralogues, such as BACE2 or cathepsin D, could partially compensate. Furthermore, the short duration of animal studies and short lifespan of study animals could mask effects that would require several decades to accumulate in humans. Inhibition of hepatic BACE1 activity in middle-aged humans would produce effects not detectable in mice. We present a testable model to explain the off-target effects of LY2886721 and highlight more broadly that so-called off-target drug effects might actually represent off-site effects that are not necessarily off-target. Consideration of this concept in forthcoming drug design, screening, and testing programs may prevent such failures in the future. (shrink)

Protein synthesis inhibitors prolong the half‐lives of most mRNAs at least fourfold in the somatic cells of higher eukaryotes and in yeast cells. Some mRNAs are stabilized because the inhibitors affect mRNA‐specific regulatory factors; however, hundreds or thousands of other mRNAs are probably stabilized by a common mechanism. We propose that mRNA stabilization in cells treated with a translation inhibitor reflects a physiological process that occurs during each mitosis and is important for cell survival. Transcription and translation rates (...) decline drastically during a 1–2 hour interval of mitosis. We hypothesize that translational repression during this interval somehow inactivates a critical component of the mRNA degradation machinery. As a result, mRNA half‐lives are prolonged during the interval when transcription is repressed. If labile mRNAs were not stabilized during mitosis they, and perhaps also the labile proteins they encode, would be depleted as the cell entered G1 phase, with deleterious consequences. Stabilization during mitosis, or in response to translation inhibitors, thus preserves the capacity of the cell to synthesize essential proteins as it enters G1 or recovers from inhibitor treatment. mRNA stabilization might serve a similar purpose during starvation or any stress negatively affecting translation. (shrink)

Rationale In Belgium, several policies regulating reimbursement of acid suppressant drugs and evidence-based recommendations for clinical practice were issued in a short period of time, creating a unique opportunity to observe their effect on prescribing. Aims and objectives To describe the evolution of prescriptions for acid suppressants and explore the interaction of policies and practice recommendations with prescribing patterns. Method Monthly claims-based data for proton pump inhibitors (PPIs) and H-2-antihistamines by general practitioners, internists and "astroenterologists were obtained from the (...) Belgian national health insurance database (1997-2005). The evolution of reimbursed defined daily doses and expenses after introduction of reimbursement regulations and dissemination of practice recommendations was explored. Results Recommendations had no impact on prescribing. All changes can be related to concomitant policies. Lifting reimbursement restrictions for cheaper products did not control growth or save costs in the Iona term. Only restricting reimbursement of all PPIs managed to curb the growth. We observed an unintended increase of non-omeprazole PPIs by gastroenterologists. Conclusions Reimbursement policies influence prescribing, but their effect can be unintended. A dialogue between policymakers and guideline developers, and evidence-based policies that are linked to clinical guidelines, could be an effective way to pursue both cost-containment and quality of care. (shrink)

The bcl‐2 gene product, a 25 kDa membrane protein residing at mitochondrial, microsomal and nuclear membrane sites within many cell types, is a broad and potent inhibitor of cell death by apoptosis. A family of bcl‐2‐related genes with death‐inhibiting or ‐promoting activities has recently been described, indicating a potentially quite complex cell death regulatory network at the level of gene expression and protein‐protein interactions. The function of bcl‐2 may be to regulate a final common pathway in apoptosis. Current hypotheses suggest (...) that oxidative stress, specific proteolytic activity or cell cycle control may be common elements in apoptosis through which bcl‐2 exerts its survival function. Based on the extent to which elements of apoptotic pathways overlap with non‐apoptotic cellular functions, the physiological role of bcl‐2 may also extend to other cellular processes such as differentiation and proliferation. (shrink)

Beckwith‐Wiedemann syndrome is a human congenital disorder characterized by a wide variety of growth abnormalities, including developmental defects and predisposition to certain tumors. Genetic evidence has suggested a role for p57KIP2, a member of a family of cell cycle inhibitory genes, in Beckwith‐Wiedemann syndrome. Two independent groups(1,2) have reported the generation and characterization of mice lacking functional p57KIP2, These mice demonstrate a number of abnormal phenotypes which overlap with, although do not completely recapitulate, Beckwith‐Wiedemann syndrome. These findings advance the molecular (...) characterization of a human disorder, and provide insight into the interplay between regulation of cell division and development. (shrink)

Both W9 and OP3‐4 were known to bind the receptor activator of NF‐κB ligand (RANKL), inhibiting osteoclastogenesis. Recently, both peptides were shown to stimulate osteoblast differentiation; however, the mechanism underlying the activity of these peptides remains to be clarified. A primary osteoblast culture showed that rapamycin, an mTORC1 inhibitor, which was recently demonstrated to be an important serine/threonine kinase for bone formation, inhibited the peptide‐induced alkaline phosphatase activity. Furthermore, both peptides promoted the phosphorylation of Akt and S6K1, an upstream molecule (...) of mTORC1 and the effector molecule of mTORC1, respectively. In the in vivo calvarial defect model, W9 and OP3‐4 accelerated BMP‐2‐induced bone formation to a similar extent, which was confirmed by histomorphometric analyses using fluorescence images of undecalcified sections. Our data suggest that these RANKL‐binding peptides could stimulate the mTORC1 activity, which might play a role in the acceleration of BMP‐2‐induced bone regeneration by the RANKL‐binding peptides. (shrink)

Angiogenesis is a complex morphogenetic process regulated by growth factors, but also by the force balance between endothelial cells traction stresses and extracellular matrix viscoelastic resistance. Studies conducted with in vitro angiogenesis assays demonstrated that decreasing ECM stiffness triggers an angiogenic switch that promotes organization of EC into tubular cords or pseudo-capillaries. Thus, mechano-sensitivity of EC with regard to proteases secretion, and notably matrix metalloproteinases, should likely play a pivotal role in this switching mechanism. While most studies analysing strain regulation (...) of MMPs used cell cultured on stretched membranes, this work focuses on MMP expression during self-assembly of EC into capillary-like structures within fibrin gels, i.e. on conditions that mimics more closely the in vivo cellular mechanical microenvironment. The activity of MMP-2 and MMP-9, two MMPs that have a pivotal role in capillaries formation, has been monitored in pace with the progressive elongation of EAhy926 cells that takes place during the emergence of cellular cords. We found an increase of the zymogen proMMP-2 that correlates with the initial stages of EC cords formation. However, MMP-2 was not detected. ProMMP-9 secretion decreased, with levels of MMP-9 kept at a rather low value. In order to analyse more precisely the observed differences of EAhy926 response on fibrin and plastic substrates, we proposed a theoretical model of the mechano-regulation of proMMP-2 activation in the presence of type 2 tissue inhibitor of MMPs. Using association/dissociation rates experimentally reported for this enzymatic network, the model adequately describes the synergism of proMMP-2 and TIMP-2 strain activation during pseudo-capillary morphogenesis. All together, these results provide a first step toward a systems biology approach of angiogenesis mechano-regulation by cell-generated extracellular stresses and strains. (shrink)

Recent findings regarding the cellular biology and immunology of BST‐2 (also known as tetherin) indicate that its function could be exploited as a universal replication inhibitor of enveloped respiratory viruses (e.g., influenza, respiratory syncytial virus, etc.). BST‐2 inhibits viral replication by preventing virus budding from the plasma membrane and by inducing an antiviral state in cells adjacent to infection via unique inflammatory signaling mechanisms. This review presents the first comprehensive summary of what is currently known about BST‐2 anti‐viral function against (...) respiratory viruses, how these viruses construct countermeasures to antagonize BST‐2, and how BST‐2 function might be targeted to develop therapies to treat respiratory virus infections. The authors address the current gaps in knowledge, including the need for mechanistic understanding of BST‐2 antagonism by respiratory viruses, that should be bridged to achieve that goal. (shrink)

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)

Wansing’s extended intuitionistic linear logic with strong negation, called WILL, is regarded as a resource-conscious refinment of Nelson’s constructive logics with strong negation. In this paper, (1) the completeness theorem with respect to phase semantics is proved for WILL using a method that simultaneously derives the cut-elimination theorem, (2) a simple correspondence between the class of Petri nets with inhibitor arcs and a fragment of WILL is obtained using a Kripke semantics, (3) a cut-free sequent calculus for WILL, called twist (...) calculus, is presented, (4) a strongly normalizable typed λ-calculus is obtained for a fragment of WILL, and (5) new applications of WILL in medical diagnosis and electric circuit theory are proposed. Strong negation in WILL is found to be expressible as a resource-conscious refutability, and is shown to correspond to inhibitor arcs in Petri net theory. (shrink)

Mutations in the methyl‐CpG‐binding protein 2 (MeCP2) cause Rett syndrome, a severe neurodevelopmental disease associated with ataxia and other post‐natal symptoms similar to autism. Much research interest has focussed on the implications of MeCP2 in disease and neuron physiology. However, little or no attention has been paid to how MeCP2 turnover is regulated. The post‐translational control of MeCP2 is of critical importance, especially as subtle increases or decreases in MeCP2 amounts can affect neuron morphology and function. The latter point is (...) of particular importance for gene therapeutic approaches in which exogenous wild‐type MeCP2 is being introduced into diseased neurons. Further to this, we propose two hypotheses. The first hypothesis discusses the poly‐ubiquitin‐mediated post‐translational regulation of MeCP2 through its two PEST domains. The second hypothesis explores the use of histone deacetylase inhibitors to modulate the amounts of MeCP2 expressed in conjunction with the aforementioned therapeutic approaches. (shrink)

Protein–protein interactions are thought to be mediated by domains, which are autonomous folding units of proteins. Recently, a second type of interaction has been suggested, mediated by short segments termed linear motifs, which are related to recognition elements of intrinsically disordered regions. Here, we propose a third kind of protein–protein recognition mechanism, mediated by disordered regions longer than 20–30 residues. Bioinformatics predictions and well‐characterized examples, such as the kinase‐inhibitory domain of Cdk inhibitors and the Wiskott–Aldrich syndrome protein (WASP)‐homology domain (...) 2 of actin‐binding proteins, show that these disordered regions conform to the definition of domains rather than motifs, i.e., they represent functional, evolutionary, and structural units. Their functions are distinct from those of short motifs and ordered domains, and establish a third kind of interaction principle. With these points, we argue that these long disordered regions should be recognized as a distinct class of biologically functional protein domains. (shrink)

Technology permeates all walks of life. It has emerged as a global facilitator to improve learning and training, alleviating the temporal and spatial limitations of traditional learning systems. It is imperative to identify enablers or inhibitors of technology adoption by employees for sustainable change in education management systems. Using the theoretical lens of organizational support theory, this paper studies effect of institutional support on education management information systems use along with two individual traits of self-efficacy and innovative behavior of (...) academic employees in British higher educational institutions. Data for this cross-sectional study were collected through a questionnaire completed by 591 academic employees of 23 universities from 10 cities in the United Kingdom. Partial Least Square structural equation modeling was used to analyze data with smartPLS 3.2.9 software. Results indicate that institutional support promotes self-efficacy and innovative behavior that help develop positive employee perceptions. The model explains a 52.9% variance in intention to use. Post-hoc mediation analysis shows that innovativeness and self-efficacy mediate between institutional support and employee technology adoption behavior. As opposed to student samples in past studies on educational technology, this study adds to the literature by focusing on academic employees. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Rhetoric as a Balancing of Ends:Cicero and MachiavelliGary RemerIn his youthful work on rhetoric, De inventione (published about 86 B.C.E.), Cicero lists the ends for deliberative (political) oratory as honestas and utilitas (the good or honorable and the useful or expedient). In more mature writings, like De oratore (55 B.C.E.) and De officiis (44 B.C.E.), Cicero maintains a similar position: that the morally good and the beneficial are reconcilable. (...) For example, Cicero assumes in De officiis the identity of the honestum and the utile. He states there that "there is one rule for all cases;... either the thing that seems beneficial must not be dishonorable, or if it is dishonorable, it must not seem beneficial" (On Duties 3.81).1 In recent years, Victoria Kahn (1994) and J. Jackson Barlow (1999) have offered Machiavelli's "rhetorical politics"—a politics "attuned to the rhetorical concerns of effective political action" (Kahn 1994, 24)—as a more coherent and intellectually honest alternative to Cicero's attempt to reconcile irreconcilables.2 They contend that, unlike Cicero, Machiavelli accepts the impossibility of simultaneously upholding the morally good and the useful. For Machiavelli, the successful political actor must choose the utile over the honestum.Cicero, however, is not alone in his inconsistency. As Kahn demonstrates, Machiavelli's account of virtù is itself inconsistent. For example, he sometimes includes morality as an element of excellence (virtù) and at other times does not. I contend in this article, however, that Kahn's interpretation [End Page 1] of Machiavelli's contradictoriness as only "apparent," a variability, she argues, that is rhetorically inspired rather than logically deficient, applies not only to Machiavelli, as Kahn would have it, but also to Cicero. I argue that both Machiavelli and Cicero eschew "clear-cut or permanent distinctions" within virtù and between the honestum and the utile, respectively, because they wish to signal the political actor's need for flexibility (Kahn 1994, 30). Insofar as Cicero's internal contradictions, like Machiavelli's, are apparent but not real, I hold that Machiavelli does not offer a political approach that is superior to Cicero's, at least not in the sense of greater intellectual coherence.Despite their similarities, however, Cicero and Machiavelli differ from each other in that Cicero, in contrast to Machiavelli, openly affirms that politics is incomplete without a dual commitment to the good and the beneficial. I examine Machiavelli's focus on the useful and public as opposed to Cicero's additional commitment to the honorable and to the private. I analyze, in particular, the pursuit of glory in Machiavelli as it derives from early classical culture, which was preoccupied with appearances and the search for immortality. I argue that Cicero, while not abandoning the quest for glory, also vests this concept (under Stoic influence) with a private, moral character. In doing so, Cicero adheres to the rhetorical principle of decorum, which obliges orators to adapt themselves to context. This principle, I maintain, is not only a matter of expediency for Cicero but also a moral duty. While Cicero accommodates himself to a Roman world in which private morality was already an important part of one's life, Machiavelli violates decorum, attempting to resurrect a heroic ideal that disappeared long ago.Although most recent work on the revival of rhetorical ethics focuses on Aristotle (see Allen 2004, 140–59; Furley and Nehamas 1994; Garver 1994; Rorty 1996), I discuss Cicero in this essay. Not only has Cicero been the dominant influence on the Western tradition of rhetoric, but he also (unlike Aristotle) includes the honorable as one of the ends of deliberative oratory. Thus Cicero states in De inventione that while "Aristotle accepts advantage as the end [of deliberative oratory],... I prefer both honor and advantage" (2.52.156). And while Aristotle's position on deliberative oratory's ends does not mean that he ignores moral considerations, Cicero's decision to promote the good as an explicit rhetorical end forces his readers (and Machiavelli) to confront the relationship between virtue and expediency in a way that Aristotle's readers do not (Cox 1997, 1113). I concentrate, in particular, on Cicero's De officiis because... (shrink)

Many people believe that there is a Dutch Book argument establishing that the principle of countable additivity is a condition of coherence. De Finetti himself did not, but for reasons that are at first sight perplexing. I show that he rejected countable additivity, and hence the Dutch Book argument for it, because countable additivity conflicted with intuitive principles about the scope of authentic consistency constraints. These he often claimed were logical in nature, but he never attempted to relate this idea (...) to deductive logic and its own concept of consistency. This I do, showing that at one level the definitions of deductive and probabilistic consistency are identical, differing only in the nature of the constraints imposed. In the probabilistic case I believe that R.T. Cox's ‘scale-free’ axioms for subjective probability are the most suitable candidates. 1 Introduction 2 Coherence and Consistency 3 The Infinite Fair Lottery 4 The Puzzle Resolved—But Replaced by Another 5 Countable Additivity, Conglomerability and Dutch Books 6 The Probability Axioms and Cox's Theorem 7 Truth and Probability 8 Conclusion: ‘Logical Omniscience’ CiteULike Connotea Del.icio.us What's this? (shrink)

One of the near-to-invariant hallmarks of early apoptosis (programmed cell death) is mitochondrial membrane permeabilization (MMP). It appears that mitochondria fulfill a dual role during the apoptotic process. On the one hand, they integrate multiple different pro-apoptotic signal transducing cascades into a common pathway initiated by MMP. On the other hand, they coordinate the catabolic reactions accompanying late apoptosis by releasing soluble proteins that are normally sequestered within the intermembrane space. In a recent study,(1) Li et al. described a nuclear (...) transcription factor (Nur77/TR1/NGFI-B) that can translocate to mitochondrial membranes to induce MMP. Moreover, two groups(2,3) identified a novel intermembrane protein (Smac/DIABLO) that specifically neutralizes the inhibitor of apoptosis (IAP) proteins, thereby facilitating the activation of caspases, a class of proteases activated during apoptosis. These findings refine our knowledge how MMP connects to the cellular suicide machinery. BioEssays 23:111–115, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Neurosteroid 17 beta-estradiol (E2) is a steroid synthesized de novo in the nervous system that might influence neuronal activity and behavior. Nevertheless, the impact of E2 on the functioning of those neural systems in which it is slightly synthesized is less questioned. The vestibulo-ocular reflex (VOR) adaptation, may provide an ideal arena for investigating this issue. Indeed, E2 modulates cerebellar parallel fiber-Purkinje cell synaptic plasticity that underlies encoding of VOR adaptation. Moreover, aromatase expression in the cerebellum of adult rodents is (...) maintained at very low levels and localized to Purkinje cells. The significance of age-related maintenance of low levels of aromatase expression in the cerebellum on behavior, however, has yet to be explored. Our aim in this study was to determine whether E2 synthesis exerts an effective and persistent modulation of VOR adaptation in adult male rats. To answer this question, we investigated the acute effect of blocking E2 synthesis on gain increases and decreases in VOR adaptation using an oral dose (2.5 mg/kg) of the aromatase inhibitor Letrozole in peri-pubertal and post-pubertal male rats. We found that Letrozole acutely impaired gain increases and decreases in VOR adaptation without altering basal ocular-motor performance and that these effects were similar in peri-pubertal and post-pubertal rats. Thus, in adult male rats neurosteroid E2 effectively modulates VOR adaptation in both of the periods studied. These findings imply that the adult cerebellum uses E2 synthesis for modulating motor memory formation and suggest that low and extremely localized E2 production may play a role in adaptive phenomena. (shrink)

Discovery of a second, inducible prostaglandin synthase provides explanations for many previously puzzling observations, but also raises new questions about prostanoid synthesis. A cis‐acting sequence closely related to the cyclic AMP response element has been shown to play a role in both basal and induced prostaglandin synthase 2 gene expression. Aspirin and other currently available non‐steroidal anti‐inflammatory drugs that inhibit prostaglandin synthase activity do not effectively discriminate between the inducible prostaglandin synthase 2 and constitutive prostaglandin synthase 1 enzymes. Identification of (...) a second prostaglandin synthase, induced by inflammatory stimuli, initiated a search for isoform‐specific inhibitors. Use of prostaglandin synthase 2 specific inhibitors and antisense oligonucleotides has led to the suggestion that specific ligands activate alternative pathways of prostanoid production, using one of the prostaglandin synthase isoforms preferentially. The coupling mechanisms by which these pathways are activated in response to alternative stimuli should provide additional routes of intervention in prostanoid production. (shrink)

High‐molecular‐weight hyaluronan acts as a ligand of the tumor‐suppressive Hippo signal, whereas degradation of hyaluronan from a high‐molecular‐weight form to a low‐molecular‐weight forms by hyaluronidase 2 inhibits Hippo signal activation and thereby activates the pro‐oncogenic transcriptional coactivator yes‐associated protein (YAP), which creates a cancer‐predisposing microenvironment and drives neoplastic transformation of cells through both cell‐autonomous and non‐cell‐autonomous mechanisms. In fact, accumulation of low‐molecular‐weight hyaluronan in tissue stroma is observed in many types of cancers. Since inhibition of YAP activity suppresses tumor growth (...) in vivo, pharmacological intervention of the Hippo‐YAP signal is an attractive approach for future drug development. In this review, pharmacological intervention of excessive hyaluronan degradation as a novel approach for inhibition of the Hippo‐YAP signal is also discussed. Development of hyaluronidase inhibitors may provide novel therapeutic strategies for human malignant tumors. (shrink)