Thymidylate synthase plays a central role in the biosynthesis of thymidylate, an essential precursor for DNA biosynthesis. In addition to its role in catalysis and cellular metabolism, it is now appreciated that thymidylate synthase functons as an RNA binding protein. Specifically, thymidylate synthase binds with high affinity to its own mRNA, resulting in translational repression. An extensive series of experiments has been performed to elucidate the molecular elements underlying the interaction between thymidylate synthase and its own mRNA. In addition to (...) characterization of the underlying cis‐ and trans‐acting elements, recent studies have shown that thymidylate synthase has the capacity to bind specifically to other cellular RNA species. While the biological significance of these other RNA/thymidylate synthase interactions remains to be defined, this work suggests a potential role for TS in coordinately regulating several critical aspects of cellular metabolism. (shrink)

Anna J Dare,1 Anthony RJ Phillips,1–3 Michael Chu,1 Anthony JR Hickey,2 Adam SJR Bartlett1–31Department of Surgery, 2Maurice Wilkins Centre for Biodiscovery, University of Auckland, Auckland, New Zealand; 3New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New ZealandBackground: Hepatic steatosis is increasingly encountered among organ donors. Currently, there is no consensus guideline as to the type or degree of donor steatosis considered acceptable for liver transplantation, and little is known about local practices in this area. The aim of this survey (...) was to evaluate current clinical practices amongst liver transplant surgeons in Australia and New Zealand in the evaluation and use of steatotic donor livers in LT.Methods: An anonymous online twelve-question survey was emailed to all practicing LT surgeons in ANZ in January 2010.Results: The response rate was 83%. Estimated prevalence of steatosis in donor livers was between 40% and 60%. In determining suitability for LT, 90% of respondents reported rejecting organs with "severe" steatosis based on visual and palpation grounds alone. A total of 68% sought further histological assessment if the donor liver looked bad and there were risk factors for steatosis. The majority of respondents performed only one biopsy of the liver, using hematoxylin and eosin staining for fat assessment. There was wide variation in the upper limit of steatosis considered to be acceptable for LT. A total of 21% of respondents still considered microvesicular steatosis a risk factor for primary graft nonfunction.Conclusion: This survey highlights the significant variation in the appraisal and use of steatotic grafts by LT surgeons in ANZ. Accurate evaluation and judicious use of mild and moderately steatotic grafts is required if we are to utilize the available donor pool best.Keywords: liver transplantation, steatosis, fatty liver, organ donors. (shrink)

BackgroundIn the Canadian Alliance for Healthy Hearts and Minds (CAHHM) cohort, participants underwent magnetic resonance imaging (MRI) of the brain, heart, and abdomen, that generated incidental findings (IFs). The approach to managing these unexpected results remain a complex issue. Our objectives were to describe the CAHHM policy for the management of IFs, to understand the impact of disclosing IFs to healthy research participants, and to reflect on the ethical obligations of researchers in future MRI studies.MethodsBetween 2013 and 2019, 8252 participants (...) (mean age 58 ± 9 years, 54% women) were recruited with a follow-up questionnaire administered to 909 participants (40% response rate) at 1-year. The CAHHM policy followed a restricted approach, whereby routine feedback on IFs was not provided. Only IFs of severe structural abnormalities were reported.ResultsSevere structural abnormalities occurred in 8.3% (95% confidence interval 7.7–8.9%) of participants, with the highest proportions found in the brain (4.2%) and abdomen (3.1%). The majority of participants (97%) informed of an IF reported no change in quality of life, with 3% of participants reporting that the knowledge of an IF negatively impacted their quality of life. Furthermore, 50% reported increased stress in learning about an IF, and in 95%, the discovery of an IF did not adversely impact his/her life insurance policy. Most participants (90%) would enrol in the study again and perceived the MRI scan to be beneficial, regardless of whether they were informed of IFs. While the implications of a restricted approach to IF management was perceived to be mostly positive, a degree of diagnostic misconception was present amongst participants, indicating the importance of a more thorough consent process to support participant autonomy.ConclusionThe management of IFs from research MRI scans remain a challenging issue, as participants may experience stress and a reduced quality of life when IFs are disclosed. The restricted approach to IF management in CAHHM demonstrated a fair fulfillment of the overarching ethical principles of respect for autonomy, concern for wellbeing, and justice. The approach outlined in the CAHHM policy may serve as a framework for future research studies.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/nct02220582. (shrink)

Chu spaces are a new model for information structure and mathematical structure in general. Their properties are usually developed as a form of category theory. In this note, we show how they may also be viewed as models for a two-sorted first-order language, and we determine the exact flow of information across the natural Chu transforms. Our analysis is akin to that of process graphs via bisimulation and modal formulas.

Background The allocation of scarce deceased donor kidneys is a complex process. Transplant providers are increasingly relying on constructs such as frailty and cognitive function to guide kidney transplant (KT) candidate selection. Patient views of the ethical issues surrounding the use of such constructs are unclear. We sought to assess KT candidates’ attitudes and beliefs about the use of frailty and cognitive function to guide waitlist selection.Methods KT candidates were randomly recruited from an ongoing single-center cohort study of frailty and (...) cognitive function. Semi-structured interviews were conducted, and thematic analysis was performed. Inductively derived themes were mapped onto bioethics principles.Results Twenty interviews were conducted (65% contact rate, 100% participation rate) (60% male; 70% White). With respect to the use of frailty and cognitive function in waitlisting decisions, four themes emerged in which participants: (1) valued maximizing a scarce resource (utility); (2) prioritized equal access to all patients (equity); (3) appreciated a proportional approach to the use of equity and utility (precautionary utility); and (4) sought to weigh utility- and equity-based concerns regarding social support. While some participants believed frailty and cognitive function were useful constructs to maximize utility, others believed their use would jeopardize equity. Patients were uncomfortable with using single factors such as frailty or cognitive impairment to deny someone access to transplantation; participants instead encouraged using the constructs to identify opportunities for intervention to improve frailty and cognitive function prior to KT.Conclusions KT candidates’ values mirrored the current allocation strategy, seeking to balance equity and utility in a just manner, albeit with conflicting viewpoints on the appropriate use of frailty and cognitive impairment in waitlisting decisions. (shrink)

This paper examines the role of the imagination in the Zhuangzi. There are many avenues through which the various types of imaginations in the Zhuangzi could be investigated, but this paper will concentrate on only one, namely the use of imagination to criticize Confucius’ way. Specifically, the Zhuangzi finds Confucius’ views on virtuosity, moral cultivation, and social roles to include exceedingly limited imagined restrictions. The Daoist classic thereby creates stories to inspire the imagination of its readers, with the goal of (...) broadening the ways in which people understand morality, society, and themselves. Accordingly, the Zhuangzi suggests that people can ‘zigzag’ through life, temporarily taking on different perspectives or roles, without cultivating a corresponding sense of self. Imagination is key for promoting this type of existential mode of existence—what the Zhuangzi calls ‘genuine’. (shrink)

In this volume Donald Munro, author of important studies on early and contemporary China, provides a critical analysis of the doctrines of the Sung Neo-Confucian philosopher Chu Hsi (1130-1200). For nearly six centuries Confucian orthodoxy was based on Chu Hsi's commentaries on Confucian classics. These commentaries were the core of the curriculum studied by candidates for the civil service in China until 1905 and provided guidelines both for personal behavior and for official policy. Munro finds the key to the complexities (...) of Chu Hsi's thought in his mode of discourse: the structural images of family, stream of water, mirror, body, plant, and ruler. Furthermore, he discloses the basic framework of Chu Hsi's ethics and the theory of human nature that is provided by these illustrative images. As revealed by Munro, Chu Hsi's thought is polarized between family duty and a broader altruism and between obedience to external authority and self-discovery of moral truth. To understand these tensions moves us toward clarifying the meaning of each idea in the sets. The interplay of these ideas, selectively emphasized over time by later Confucians, is a background for explaining modern Chinese thought. In it, among other things, Confucianism and Marxism-Leninism co-exist. Originally published in 1988. The Princeton Legacy Library uses the latest print-on-demand technology to again make available previously out-of-print books from the distinguished backlist of Princeton University Press. These editions preserve the original texts of these important books while presenting them in durable paperback and hardcover editions. The goal of the Princeton Legacy Library is to vastly increase access to the rich scholarly heritage found in the thousands of books published by Princeton University Press since its founding in 1905. (shrink)

本书包含三编,第1编为用图刻画的各种反基础公理系统(ZFCˉ+AFA(或者SAFA,FAFA以及反基础公理家族AFA~))建立不同的集论模型,从而证明各种反基础公理与ZFCˉ的相对协调性.第2编修正, 完善和丰富了巴威斯(J.Barwise)等人用代数方法——方程组刻画的反基础公理——解引理理论.第3编包括两个附录.附录1给出了结构之间的互摸拟理论.附录2给出了项目研究期间发表的部分论文.

Tandis que j’écrivais mon article sous le titre ‘L’utilitarisme est-il une éthique acceptable?’paru dans ce numéro de la Revue d’Etudes benthamiennes, j’ai eu la chance d’avoir accès, dans le cadre de mon travail au CHU de Rouen, à un ensemble d’entretiens avec des médecins au sujet de la connaissance qu’ils avaient de la loi Léonetti. Les entretiens ont été numérotés de I à XXVI; ils ne sont pas tous cités ici, d’autant que quelques-uns, prévus, n’ont pas eu lieu. Le propos (...) qui suit se trouve à la confluence de trois apports: celui de la thèse soutenue dans le n° 9 de la REB, celui de mon enseignement d’éthique à l’hôpital auprès de soignants et de philosophes, celui enfin de l’existence de ce précieux dossier réuni par les soins du Docteur Clémence Joly. Je livre ici des réflexions que j’ai assemblées et articulées. Il convient de préciser, pour la compréhension du texte suivant, que les entretiens ont eu cours auprès de médecins qui répondaient, au cours des derniers mois, aux mêmes questions liées à leur connaissance de la loi Léonetti de 2005. Quand ils ne la connaissaient pas –ce qui fut l’aveu du plus grand nombre-, l’entretien ne cessait pas pour autant et il était alors possible aux interviewés de découvrir cette loi; ainsi, article par article, ils donnaient, guidés par les questions de l’interrogatrice, leur avis de praticiens sur le détail d’une loi qu’ils connaissaient beaucoup mieuxqu’ilsle croyaient au départ. (shrink)

What are physical quantities, and in particular, what makes them quantitative? This book presents an original answer to this question through the novel position of substantival structuralism, arguing that quantitativeness is an irreducible feature of attributes, and quantitative attributes are best understood as substantival structured spaces.

The idea that immoral behaviour can sometimes be admirable, and that moral behaviour can sometimes be less than admirable, has led several of its supporters to infer that moral considerations are not always overriding, contrary to what has been traditionally maintained. In this paper I shall challenge this inference. My purpose in doing so is to expose and acknowledge something that has been inadequately appreciated, namely, the moral aspect of nonmoral goods and evils. I hope thereby to show that, even (...) if immorality can be admirable, this poses no threat to morality. (shrink)