The multistep pathway of eukaryotic gene expression involves a series of highly regulated events in the nucleus and cytoplasm. In the nucleus, genes are transcribed into pre‐messenger RNAs which undergo a series of nuclear processing steps. Mature mRNAs are then transported to the cytoplasm, where they are translated into protein and degraded at a rate dictated by transcript‐ and cell‐type‐specific cues. Until recently, these individual nuclear and cytoplasmic events were thought to be primarily regulated by different RNA‐ and DNA‐binding proteins (...) that are localized either only in the nucleus or only the cytoplasm. Here, we describe multifunctional proteins that control both nuclear and cytoplasmic steps of gene expression. One such class of multifunctional proteins (e.g., Bicoid and Y‐box proteins) regulates both transcription and translation whereas another class (e.g., Sex‐lethal) regulates both nuclear RNA processing and translation. Other events controlled by multifunctional proteins include assembly of spliceosome components, spliceosome recycling, RNA editing, cytoplasmic mRNA localization, and cytoplasmic RNA stability. The existence of multifunctional proteins may explain the paradoxical involvement of the nucleus in an RNA surveillance pathway (nonsense‐mediated decay) that detects cytoplasmic signals (premature termination codons). We speculate that shuttling multifunctional proteins serve to efficiently link RNA metabolism in the cytoplasmic and nuclear compartments. BioEssays 23:775–787, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Many kinds of multifunctional regulatory proteins have been identified that perform distinct biochemical functions in the nucleus, the cytoplasm, or both. Here we describe the recent discovery by Hall et al. (2004)1 of a new type of multifunctional protein: a metabolic enzyme that doubles as a transcription factor. This enzyme, Arg5,6, functions as a catalytic enzyme in ornithine biosynthesis and also binds and regulates the promoters of nuclear and mitochondrial genes. It may also regulate precursor mRNA metabolism. We discuss how (...) proteins that serve as both metabolic enzymes and transcription factors might have evolved. BioEssays 27:467–471, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

The RNA-binding protein, UPF1, is best known for its central role in the nonsense-mediated RNA decay pathway. Feng et al. now report a new function for UPF1—it is an E3 ubiquitin ligase that specifically promotes the decay of a key pro-muscle transcription factor: MYOD. UPF1 achieves this through its RING-like domain, which confers ubiquitin E3 ligase activity. Feng et al. provide evidence that the ability of UPF1 to destabilize MYOD represses myogenesis. In the future, it will be important to define (...) other protein substrates of UPF1-driven ubiquitination and to determine whether this biochemical activity is responsible for some of UPF1's previously defined biological functions, including in development and stress responses. The exciting findings presented by Feng et al. open up the possibility that protein turnover and RNA turnover are coupled processes. The RNA-binding protein, UPF1, is best known for its central role in the nonsense-mediated RNA decay pathway. Here we discuss a new role for UPF1—it is directly involved in protein decay. This hidden talent raises the possibility that protein turnover and RNA turnover are coupled processes. (shrink)

The RNA-binding protein, UPF1, is best known for its central role in the nonsense-mediated RNA decay pathway. Feng et al. now report a new function for UPF1—it is an E3 ubiquitin ligase that specifically promotes the decay of a key pro-muscle transcription factor: MYOD. UPF1 achieves this through its RING-like domain, which confers ubiquitin E3 ligase activity. Feng et al. provide evidence that the ability of UPF1 to destabilize MYOD represses myogenesis. In the future, it will be important to define (...) other protein substrates of UPF1-driven ubiquitination and to determine whether this biochemical activity is responsible for some of UPF1's previously defined biological functions, including in development and stress responses. The exciting findings presented by Feng et al. open up the possibility that protein turnover and RNA turnover are coupled processes. The RNA-binding protein, UPF1, is best known for its central role in the nonsense-mediated RNA decay pathway. Here we discuss a new role for UPF1—it is directly involved in protein decay. This hidden talent raises the possibility that protein turnover and RNA turnover are coupled processes. (shrink)

It is a standing temptation for philosophers to find anticipations of their own views in the great thinkers of the past, but few have been so bold in the search for precursors, and so utterly mistaken, as Berkeley when he claimed Plato and Aristotle as allies to his immaterialist idealism. InSiris: A Chain of Philosophical Reflexions and Inquiries Concerning the Virtues of Tar-Water, which Berkeley published in his old age in 1744, he reviews the leading philosophies of antiquity and finds (...) them on the whole a good deal more sympathetic to his own ideas than the ‘modern atheism’, as he calls it, of Hobbes and Spinoza or the objectionable principles of ‘the mechanic and geometrical philosophers’ such as Newton. But his strongest and, I think, his most interesting claim is that neither Plato nor Aristotle admitted ‘an absolute actual existence of sensible or corporeal things’. (shrink)

High-dose chemotherapy and autologous stem cell transplantation is used to treat some advanced malignancies. It is a traumatic procedure, with a high complication rate and significant mortality. ASCT patients and their carers draw on many sources of information as they seek to understand the procedure and its consequences. Some seek information from beyond orthodox medicine. Alternative beliefs and practices may conflict with conventional understanding of the theory and practice of ASCT, and ‘contested understandings’ might interfere with patient adherence to the (...) strict and demanding protocols required for successful ASCT.The present study, conducted in Sydney, Australia, examines narrative-style interviews with 10 sequentially recruited ASCT patients and nine of their carers conducted at the time of transplant and three months later. Transcripts were read for instances of mention of alternative advice, and for instances of contested understanding of information relevant to the transplant.Patients and carer pairs expressed closely concordant views about alternative advice. Five pairs were consulting alternative practitioners. Contested understanding was expressed in four domains—understandings of the transplant itself and its underlying theory, of the relationship between the components of the ‘transplant’, of the nature and role of stem cells, and of beliefs about bodily function and life-style. Contested understandings of the transplant treatment were expressed as predominantly personal interpretations of orthodox informationPatients and carers seemed to recognise that alternative and conventional systems were discordant, yet they were able to separate the two, and adhere to each practice without prejudicing their medical treatment. A single case of late, post-transplant repudiation of Western medicine is discussed to emphasise some of the possible determinants of dissonance when it does occur. (shrink)

BackgroundECMO is a particularly scarce resource during the COVID-19 pandemic. Its allocation involves ethical considerations that may be different to usual times. There is limited pre-pandemic literature on the ethical factors that ECMO physicians consider during ECMO allocation. During the pandemic, there has been relatively little professional guidance specifically relating to ethics and ECMO allocation; although there has been active ethical debate about allocation of other critical care resources. We report the results of a small international exploratory survey of ECMO (...) clinicians’ views on different patient factors in ECMO decision-making prior to and during the COVID-19 pandemic. We then outline current ethical decision procedures and recommendations for rationing life-sustaining treatment during the COVID-19 pandemic, and examine the extent to which current guidelines for ECMO allocation (and reported practice) adhere to these ethical guidelines and recommendations.MethodsAn online survey was performed with responses recorded between mid May and mid August 2020. Participants (n = 48) were sourced from the ECMOCard study group—an international group of experts (n = 120) taking part in a prospective international study of ECMO and intensive care for patients during the COVID-19 pandemic. The survey compared the extent to which certain ethical factors involved in ECMO resource allocation were considered prior to and during the pandemic.ResultsWhen initiating ECMO during the pandemic, compared to usual times, participants reported giving more ethical weight to the benefit of ECMO to other patients not yet admitted as opposed to those already receiving ECMO, (p < 0.001). If a full unit were referred a good candidate for ECMO, participants were more likely during the pandemic to consider discontinuing ECMO from a current patient with low chance of survival (53% during pandemic vs. 33% prior p = 0.002). If the clinical team recommends that ECMO should cease, but family do not agree, the majority of participants indicated that they would continue treatment, both in usual circumstances (67%) and during the pandemic (56%).ConclusionsWe found differences during the COVID-19 pandemic in prioritisation of several ethical factors in the context of ECMO allocation. The ethical principles prioritised by survey participants were largely consistent with ECMO allocation guidelines, current ethical decision procedures and recommendations for allocation of life-sustaining treatment during the COVID-19 pandemic. (shrink)

Narrative analysis is well established as a means of examining the subjective experience of those who suffer chronic illness and cancer. In a study of perceptions of the outcomes of treatment of cancer of the colon, we have been struck by the consistency with which patients record three particular observations of their subjective experience: the immediate impact of the cancer diagnosis and a persisting identification as a cancer patient, regardless of the time since treatment and of the presence or absence (...) of persistent or recurrent disease; a state of variable alienation from social familiars, expressed as an inability to communicate the nature of the experience of the illness, its diagnosis and treatment; and a persistent sense of boundedness, an awareness of limits to space, empowerment and available time. These subjectivities were experienced in varying degree by all patients in our study. Individual responses to these experiences were complex and variable. The experiences are best understood under the rubric of a category we call “liminality”. We believe that all cancer patients enter and experience liminality as a process which begins with the first manifestations of their malignancy. An initial acute phase of liminality is marked by disorientation, a sense of loss and of loss of control, and a sense of uncertainty. An adaptive, enduring phase of suspended liminality supervenes, in which each patient constructs and reconstructs meaning for their experience by means of narrative. This phase persists, probably for the rest of the cancer patient’s life. The experience of liminality is firmly grounded in the changing and experiencing body that houses both the disease and the self. Insights into the nature of the experience can be gained from the Existentialist philosophers and from the history of attitudes to death. Understanding liminality helps us to understand what it is that patients with cancer seek from the system to which they turn for help. Its explication should therefore be important for those who provide health care, those who educate health care workers and those concerned to study and use outcomes as administrative and policy making instruments. (shrink)

Discourse communities are groups of people who share common ideologies, and common ways of speaking about things. They can be sharply or loosely defined. We are each members of multiple discourse communities. Discourse can colonize the members of discourse communities, taking over domains of thought by means of ideology. The development of new discourse communities can serve positive ends, but discourse communities create risks as well. In our own work on the narratives of people with interests in health care, for (...) example, we find that patients speak of their illness experiences as victims of circumstance; policy makers construct adverse experiences and challenges as opportunities to be taken; health care workers speak from a mixed perspective, seeing themselves as both victims and opportunists depending on context. To be trapped within the discourse of a particular community is to put at risk the ability to communicate across discourses. Membership of a discourse community can impair the habit of critique, and deny opportunities for heteroglossic discourse. Privileging critique as a mode of discourse perhaps might define the ethical community, suggesting that ethical community may be an antidote to the constraining effects of conventional discourse community. (shrink)

Pigs have long held great symbolic import for the people of Vanuatu, a sprawling archipelago 1,000 miles northeast of Australia. In most of the indigenous, small-scale communities which comprised traditional Vanuatu society, pig ownership and pig killing conveyed status, wealth, and informal power. Such rituals were the sole measure of social standing and political rank. In this study, I show how the cultural valuation of an animal, in this case the pig, can evolve as a society undergoes socio-economic development, (...) and also how it can be used to foster nationalistic, partisan. and other political ends. I show how competing nationalist leaders used pig symbolism in their struggle to create a unified national identit_v,for-varying island groups, and how even today, local leaders derive their legitimacy through the manipulation of traditional animal rites. (shrink)

Illness narratives from patients with colorectal cancer commonly record patterns of change in social relationships that follow the diagnosis and treatment of the condition. We believe that these changes are best explained as a process of facework, which reflects losses of face on the part of the patient, and which assists in the creation of new faces that convey new senses of identity. Facework is familiar in the work by E. Goffman (1955) and has been extensively reworked since his time. (...) There is considerable agreement that face is a pervasive and universal constituent of all social interaction, and that it expresses the subject's view of the way he or she would like to be considered by others in interactions. Ho's concept of multiple faces negotiated dynamically according to social context is particularly useful in understanding the purpose and techniques of facework (D. Y.-F. Ho, 1994). We propose a model of face that uses dignity as the face-expression of personal attributes and acquisitions, and honor as the face-expression of systemic capabilities and attainments. This model can be used to examine individual variations in response and adaptation to colon cancer and its treatment, and it provides a useful means of teaching health care workers about the experience of illness. (shrink)

The majority of traditional students enrolled at most colleges and universities are a part of what has been termed the Millennial Generation, also known as Generation Y, which typically describes the group of individuals born in most of the 1980s and 1990s. This cohort’s life has been shaped by corporate scandals, economic instability, and worldwide tragedies. Concurrently, business ethics has become a popular topic in the news within the last 2 decades due to the increase in the number of high-profile (...) business scandals. Unfortunately, this trend has also been accompanied by an increased number of reported incidents of academic dishonesty at many major universities. Two underresearched factors that may be related to academic dishonesty and cheating behavior are religiosity and spirituality. This article attempts to shed more light on the relationship between religious beliefs and unethical behavior, with a focus on millennial college students. It is posited that religiosity and spirituality influence an individual’s attitudes, views, decisions, and ultimately behaviors. The results of this study indicate that religiosity but not spirituality is a predictor of students’ attitudes toward cheating and cheating behavior. (shrink)

It is understandable that Iran’s December 2006 hosting of an international conference casting doubts on the historicity of the Holocaust would raise questions about treatments of the Shoah elsewhere in the Third World. In fact, indigenization the Holocaust—the manifold ways in which serious scholars, activists, and writers from Asia, Africa, and Latin America have come to incorporate the Holocaust in their intellectual work—has been positive overall. Within the framework of intellectual globalization, much of the Third World intelligentsia has come to (...) include this most Western of human rights violations within the framework of their own cultures and histories. Although some of the indigenization of the Holocaust is political and instrumental, the deviant variant expressed at the Tehran Holocaust conference is atypical. Governmental respect for the memory of victims of genocide should be considered as an emerging human right. (shrink)

The neural basis of progress monitoring has received relatively little attention compared to other sub-processes that are involved in goal directed behavior such as motor control and response inhibition. Studies of error-monitoring have identified the dorsal anterior cingulate cortex (dACC) as a structure that is sensitive to conflict detection, and triggers corrective action. However, monitoring goal progress involves monitoring correct as well as erroneous events over a period of time. In the present research, 20 healthy participants underwent fMRI while playing (...) a game that involved monitoring progress towards either a numerical or a visuo-spatial target. The findings confirmed the role of the dACC in detecting situations in which the current state may conflict with the desired state, but also revealed activations in the frontal and parietal regions, pointing to the involvement of processes such as attention and working memory in monitoring progress over time. In addition, activation of the cuneus was associated with monitoring progress towards a specific target presented in the visual modality. This is the first time that activation in this region has been linked to higher-order processing of goal-relevant information, rather than low-level anticipation of visual stimuli. Taken together, these findings identify the neural substrates involved in monitoring progress over time, and how these extend beyond activations observed in conflict and error monitoring. (shrink)

This book assesses how Vatican II opened up the Catholic Church to encounter, dialogue, and engagement with other world religions. Opening with a contribution from the President of the Pontifical Council for Interreligious Dialogue, Cardinal Jean-Louis Tauran, it next explores the impact, relevance, and promise of the Declaration Nostra Aetate before turning to consider how Vatican II in general has influenced interfaith dialogue and the intellectual and comparative study of world religions in the postconciliar decades, as well as the contribution (...) of particular past and present thinkers to the formation of current interreligious and comparative theological methods. Additionally, chapters consider interreligious dialogue vis-à-vis theological anthropology in conciliar documents; openness to the spiritual practices of other faith traditions as a way of encouraging positive interreligious encounter; the role of lay and new ecclesial movements in interreligious dialogue; and the development of Monastic Interreligious Dialogue. Finally, it includes a range of perspectives on the fruits and future of Vatican’s II’s opening to particular faiths such as Judaism, Islam, Hinduism, and Buddhism. (shrink)

The subject of this paper are the implications of Lyotard's critique of the intellectual as a public actor. It is shown that Lyotard's critique of politics results in a rejection of political theory, real politics and political involvement of the intellectual. In place of that, Lyotard develops his concept of "philosophical politics", i.e. "reflexive writing" as a specific form of political disengagement. The author argues that Lyotard's critique of the political involvement of the intellectual is acceptable, but that Lyotard's concept (...) of "philosophical politics" cannot compensate for the lack of an acceptable real politics and an appropriate political theory. It can be viewed only as an individual-existential posture of resistance to the dominant political patterns which, as preconditions of its own possibility, must presuppose the existence of an acceptable real politics and appropriate political doctrine. Osnovni predmet ovog rada predstavljaju implikacije Liotarove kritike intelektualca kao politickog delatnika. Autor najpre pokazuje da Liotarova kritika politike rezultira odbacivanjem politicke teorije, realne politike i politickog angazmana intelektualca. Umesto toga, Liotar razvija koncept "filozofske politike", tj. "refleksivnog pisanja", kao specifican oblik politickog dezangazmana. Za autora je Liotarova kritika politickog angazmana intelektualca prihvatljiva, ali naglasava da Liotarov koncept "filozofske politike "ne moze nadoknaditi nedostatak prihvatljive realne politike i odgovarajuce politicke teorije. Naime, ona moze da se shvati samo kao jedan individualno-egzistencijalni stav otpora prema vladajucim politickim obrascima, koji mora da pretpostavi postojanje prihvatljive realne politike i odgovarajuce politicke doktrine kao uslov sopstvene mogucnosti. (shrink)

This dissertation examines the relationship of skepticism and philosophy in the work of G.W.F. Hegel. Whereas other commentators have come to recognize the epistemological significance of Hegel's encounter with skepticism, emphasizing the strength of his system against skeptical challenges to the possibility of knowledge, I argue that Hegel develops his metaphysics in part through his ongoing engagement with the skeptical tradition. As such, I argue that Hegel's interest is not in refuting skepticism, but in defining its legitimate role within the (...) project of philosophical science. Hegel finds that historical forms of skepticism have misunderstood their own activity and thus have drawn the wrong conclusions from the epistemological challenges that they raise. For Hegel, these challenges lead not to the suspension of judgment, as many skeptics have assumed, but to an insight into the fundamental nature of reality itself. For this reason, I argue that it is important to distinguish between historical forms of skepticism (e.g., Pyrrhonism) and the "self-completing skepticism" that Hegel describes in the Phenomenology of Spirit. It is the latter sense of skepticism, I argue, that one finds at work in Hegel's own philosophical project at nearly every stage of his career. (shrink)

Robert F. is an eighty-five-year-old who suffered a heart attack at home in a rural location some thirty minutes from any major hospital. By the time the paramedics arrived, he was unconscious and nonresponsive. After spontaneous return of circulation, they began their standard procedure of therapeutic hypothermia. Robert's core temperature was lowered using ice packs, and cold intravenous fluids were initiated. Soon afterward, Robert started to shiver when his body temperature reached 35.6° Celsius. He was then given a bolus of (...) vecuronium as a neuromuscular blockade, sedated, and intubated. He was also given a low-dose vasopressin for blood-pressure control. Shortly after Robert arrived in the emergency room, his daughter, his medical decision-maker, produced an advance directive documenting that her father has a do-not-resuscitate order, and she demanded that the breathing tube and any other life-sustaining treatments be withdrawn immediately. The medical staff is very reluctant to comply with this demand for immediate action. Until the neuromuscular blockade wears off, removing the ventilator will prevent Robert from breathing. Furthermore, it may take some time to reverse the therapeutic hypothermia procedure to the point that the patient is at normal temperature. In addition, therapeutic hypothermia itself often causes arrest, so the patient may need to be resuscitated again. Should the staff wait until the patient is warm or honor the decision of his daughter, who holds his medical power of attorney? (shrink)

It will come as no surprise that I have a different interpretation of the four passages in which, McRae claims, Descartes “definitely includes extension and its modes in what is given through the senses”. In the first, Descartes includes extension, etc., among his ideas of corporeal bodies. This is not to say that he includes them among his adventitious ideas, though. All adventitious ideas are ideas of external bodies. But the converse is not true. Not all ideas of corporeal bodies (...) are ipso facto adventitious ideas, for, as I see it, the idea of the true and immutable nature of body is non-sensible and innate. McRae slides from “all adventitious ideas seem to be ideas of external bodies” to “all ideas of external bodies are adventitious”. (shrink)

The development of new technologies that enable autonomous weapon systems poses a challenge to policymakers and technologists trying to balance military requirements with international obligations and ethical norms. Some have called for new international agreements to restrict or ban lethal autonomous weapon systems. Given the tactical and strategic value of the technologies and the proliferation of threats, the military continues to explore the development of new autonomous technologies to execute national security missions. The rapid global diffusion and dual-use nature of (...) autonomous systems necessitate a proactive approach and a shared understanding of the technical realities, threats, military relevance, and strategic implications of these technologies from these communities. Ultimately, developing AI-enabled defense systems that adhere to global norms and relevant treaty obligations, leverage emerging technologies, and provide operational advantages is possible. The development of a workable and realistic regulatory framework governing the use of lethal autonomous weapons and the artificial intelligence that underpins autonomy will be best supported through a coordinated effort of the regulatory community, technologists, and military to create requirements that reflect the global proliferation and rapidly evolving threat of autonomous weapon systems. This essay seeks to demonstrate that: (1) the lack of coherent dialogue between the technical and policy communities can create security, ethical, and legal dilemmas; and (2) bridging the military, technical, and policy communities can lead to technology with constraints that balance the needs of military, technical, and policy communities. It uses case studies to show why mechanisms are needed to enable early and continuous engagement across the technical, policymaking, and operational communities. The essay then uses twelve interviews with AI and autonomy experts, which provide insight into what the technical and policymaking communities consider fundamental to the progression of responsible autonomous development. It also recommends practical steps for connecting the relevant stakeholders. The goal is to provide the Department of Defense with concrete steps for building organizational structures or processes that create incentives for engagement across communities. (shrink)

Michael Morris' Knowledge and Ideology is an original and valuable contribution to the philosophical debate concerning the meaning and validity of the concept of ideology critique. While the concept of ideology has occupied a pivotal role within the tradition of critical social theory, as Terry Eagleton had already pointed out in his 1994 study, the term nevertheless has "a whole range of useful meanings, not all of which are compatible with one another." Morris takes Eagleton's analysis as his point of (...) departure, distinguishing between "epistemic" and "functional" varieties of ideology critique. Unlike Eagleton's earlier study, however, which focused on the historical development of these two dominant ways of conceiving ideology, Morris' work attempts to show how the cognitive and non-cognitive dimensions of belief can be productively reconciled in a "Neo-Hegelian variation of epistemic ideology critique." Morris' work makes a compelling case that critical social theory can be sensitive to the social dimensions of belief without abandoning the legitimate goals of the traditional epistemological project. I have some questions, however, regarding how he proposes to reconcile these two competing visions of ideology critique. (shrink)

Miles Little is an Australian surgeon, poet, and philosopher whose published work spans diverse topics in surgery, medicine, philosophy, and bioethics. In 1974 he co-authored a survey that included an analysis of interviews conducted with amputees. This was his first foray into qualitative research. Twenty years later he established a research centre at the University of Sydney that initiated a programme of qualitative research in cancer medicine. For twenty years after that, the centre acted as a hub for research (...) that applied qualitative methods from the social sciences to study the experiences of people who endure illness and onerous treatments and to reveal their evaluations of what medicine does to and for them. This essay explains why Little turned to qualitative research instead of pursuing two other research paradigms that were better established in the 1990s, namely, evidence-based medicine and quality-of-life research. It also notes a development in qualitative research methods that Little’s legacy helps to explain, one which can augment the symbolic power of socially marginalized individuals and groups. With reference to a current controversy in surgery, I argue that Little’s survey of amputees models a laudable response to criticism, and in this respect, it is still relevant today. (shrink)

Wilkinson (1991) suggests that the problems of polarity decisions and homoplasy in a cladistic analysis may be solved if cladists simply accept plesiomorphy as a reliable indicator of monophyly. Here we argue that: (1) Wilkinson's argument is based on misapprehension of synapomorphy and the problem of homoplasy; (2) His proposed methodology fails to consider the full ramifications of rooting, polarity, and parsimony; and (3) His method does not solve the problems he raises. We demonstrate the limitations of this (...) methodology by using Wilkinson's practical example. We find no justification for the assertion that plesiomorphy may reliably delimit monophyly and recommend against Wilkinson's suggested methodological revisions. (shrink)