To decode the function and molecular recognition of several recently discovered cytosine derivatives in the human genome – 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine – a detailed understanding of their effects on the structural, chemical, and biophysical properties of DNA is essential. Here, we review recent literature in this area, with particular emphasis on features that have been proposed to enable the specific recognition of modified cytosine bases by DNA-binding proteins. These include electronic factors, modulation of base-pair stability, flexibility, and radical changes (...) in duplex conformation. We explore these proposals and assess whether or not they are supported by current biophysical data. This analysis is focused primarily on the properties of epigenetically modified DNA itself, which provides a basis for discussion of the mechanisms of recognition by different proteins. 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine have recently been discovered in mammalian DNA and appear to have essential regulatory roles. Here, we summarize recent investigations into their effects on the structural, chemical, and biophysical properties of DNA, an understanding of which is essential to decoding their behavior in the genome. (shrink)

Physicians play a critical role in preventing and treating firearm injury, although the scope of that role remains contentious and lacks systematic definition. This piece aims to utilize the fundamental principles of medical ethics to present a framework for physician involvement in firearm violence. Physicians' agency relationship with their patients creates ethical obligations grounded on three principles of medical ethics — patient autonomy, beneficence, and nonmaleficence. Taken together, they suggest that physicians ought to engage in clinical screening and treatment related (...) to firearm violence. The principle of beneficence also applies more generally, but more weakly, to relations between physicians and society, creating nonobligatory moral ideals. Balanced against physicians' primary obligations to patient agency relationships, general beneficence suggests that physicians may engage in public advocacy to address gun violence, although they are not ethically obligated to do so. A fourth foundational principle — justice — requires that clinicians attempt to ensure that the benefits and burdens of healthcare are distributed fairly. (shrink)

Background: Family members are often required to act as substitute decision-makers when health care or research participation decisions must be made for an incapacitated relative. Yet most families are unable to accurately predict older adult preferences regarding future health care and willingness to engage in research studies. Discussion and documentation of preferences could improve proxies' abilities to decide for their loved ones. This trial assesses the efficacy of an advance planning intervention in improving the accuracy of substitute decision-making and increasing (...) the frequency of documented preferences for health care and research. It also investigates the financial impact on the healthcare system of improving substitute decision-making. Methods/DesignDyads (n = 240) comprising an older adult and his/her self-selected proxy are randomly allocated to the experimental or control group, after stratification for type of designated proxy and self-report of prior documentation of healthcare preferences. At baseline, clinical and research vignettes are used to elicit older adult preferences and assess the ability of their proxy to predict those preferences. Responses are elicited under four health states, ranging from the subject's current health state to severe dementia. For each state, we estimated the public costs of the healthcare services that would typically be provided to a patient under these scenarios. Experimental dyads are visited at home, twice, by a specially trained facilitator who communicates the dyad-specific results of the concordance assessment, helps older adults convey their wishes to their proxies, and offers assistance in completing a guide entitled My Preferences that we designed specifically for that purpose. In between these meetings, experimental dyads attend a group information session about My Preferences. Control dyads attend three monthly workshops aimed at promoting healthy behaviors. Concordance assessments are repeated at the end of the intervention and 6 months later to assess improvement in predictive accuracy and cost savings, if any. Copies of completed guides are made at the time of these assessments. DiscussionThis study will determine whether the tested intervention guides proxies in making decisions that concur with those of older adults, motivates the latter to record their wishes in writing, and yields savings for the healthcare system. Trial RegistrationISRCTN89993391. (shrink)

Socrates wrote nothing; Plato's accounts of Socrates helped to establish western politics, ethics, and metaphysics. Both have played crucial and dramatically changing roles in western culture. In the last two centuries, the triumph of democracy has led many to side with the Athenians against a Socrates whom they were right to kill. Meanwhile the Cold War gave us polar images of Plato as both a dangerous totalitarian and an escapist intellectual. And visions of Plato have proliferated at the heart of (...) postmodern critiques of the very idea of metaphysics and politics. Plato's Progeny begins with an account of modern responses to the trial of Socrates and the controversial question of Socrates' relation to Plato. At its centre are two chapters exploring the idea of Platonic origins in and for philosophy, and of Platonic foundations for philosophical politics. Exploring unfamiliar as well as familiar invocations of Plato, Melissa Lane argues that twentieth-century ideological battles have obscured the importance of Socratic individualism, the nature of Platonic ethics, and the value of Platonic politics. Succinct and clearly written, this is an ideal guide for everyone interested in the way philosophers are still writing footnotes to Plato. (shrink)

When we hear about a transgression, we may consider whether the perpetrator’s individual circumstances make their transgression more understandable or excusable. Mitigating circumstances may reduce the severity of punishment that is deemed appropriate, both intuitively and legally. But importantly, in courts of public opinion and of law, mitigating information is typically presented only after information about a perpetrator’s transgression. We explore whether this sequence influences the force of mitigating evidence. Specifically, in two studies, we examined whether presenting evidence about a (...) perpetrator’s background before or after evidence of their violation influenced how severely U.S. participants punished perpetrators. In Study 1 (N = 132), evidence about the perpetrator’s mitigating circumstances reduced punishment only when it was presented before evidence about the perpetrator’s violation. Study 2 (N = 316) additionally revealed this moderating effect of presentation order across a variety of premeditated and impulsive violations. These findings are consistent with person-centered theories of punishment and with the Story Model of adjudication. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:GOD'S KNOWLEDGE OF FUTURE CONTINGENTS: A REPLY TO WILLIAM LANE CRAIG DAVID B. BURRELL, c.s.c. University of Notre Dame Notre Dame, Indiana IT IS FORTUNATE that other duties kept me from responding to William Lane Craig's "Aquinas on God's Knowledge of Future Contingents" when it came out (Thomist 54 [1990]: 33-79), for my initial perusal found me at once impressed and dismayed, and quite unable to disentangle (...) the two responses. A more careful subsequent reading allows me, I believe, to pinpoint where he goes wrong in reaching the conclusion which he does, yet to do so in such a way as to send readers back to an essay which is otherwise quite remarkable in the way it learns from Aquinas and offers us useful ways to read him on these perplexing issues. In doing so, he corrects many a misreading, and amasses sufficient textual and conceptual clarifications as almost to correct his own misreading. And best of all, I can hope that my rejoinder will send readers back to Aquinas above all. Indeed, one cannot but feel that the current climate of controversy regarding the proper understanding of his nuanced synthesis in philosophical theology would please Aquinas far more than attempts earlier in this century to distill it all into a " doctrine." Craig's conclusion reads: In maintaining that God's knowledge is the cause of everything God knows, Thomas transforms the universe into a nexus which, though freely chosen by God, is causally determined from above, thus eliminating human freedom (79). I shall claim that he reaches this conclusion only because ( 1) he presumes God's knowledge to be propositional knowing (52-53), 317 318 DAVID B. BURRELL, C.S.C. even though he asserts that it is not (60, n.61); and (2) that such a presumption leads him to overlook the vast difference between scientia visionis and scientia simplicis intelligentiae, though he insists on the difference and formulates it nicely in parallel with practical and speculative knowing in God (40). Such presumptions about divine knowing are not uncommon, of course, and what they lead to is one's overlooking what Josef Pieper called the "hidden element in the philosophy of St. Thomas "-creation. Indeed, my critique could begin there, remarking how Craig's careful delineation of Aquinas on God's eternal knowing of contingent things proceeds oblivious of the central fact that God's knowing in such cases is that of a creator (" In summary, then, Thomas has appealed e%clusively to the tradition of God's timelessness in order to defuse the threat of fatalism" [61, emphasis mine]). The simple observation that the God in question is always the free creator of all-that-is would have allowed him to see that Aquinas does not make the relation of God to contingents turn solely on that of an eternal knower of temporal things, but that the eternity/time relation subserves that of creator/creature. (This ordering is the more crucial, we shall see, for its power to correct the endemic tendency to equate " eternal " with " timeless," which Craig manifests throughout.) And despite Pieper's reminder that creation is largely hidden, it remains sufficiently present to a careful reader that Craig must indeed confront it at the end. Yet by the time he does so, his earlier presumptions have led him to complain that Aquinas's insistence that "God's knowledge is the causa essendi of the things that are going to happen... seems nearly unintelligible " (73). Indeed what I shall offer as the key to resolving his crucial dilemmas, and so overturning his stated conclusion, Craig introduces as a " final issue [which] threatens to undermine Thomas's attempt to preserve contingency in the face of divine knowledge, [viz.] his doctrine that God's knowledge is the cause of its objects rather than the objects' being the cause of God's knowledge" (70-71). The theologian in me would prefer to begin right here, with the radical eruption into an Aristotelian world of a free creator, GOD'S KNOWELDGE OF FUTURE CONTINGENTS 319 whose relation to the universe is indeed such as to turn our sense of knowing inside-out.1... (shrink)

1. Ḥāshīyat al-Ṣabbān ʻalá al-Sharḥ al-Ṣaghīr lil-Mullawī ʻalá al-Sullam al-murawnaq -- 2. Taqrīrāt Ḥasan ibn Riḍwān al-Ḥusaynī.

Charles Peirce claimed that "anything is general in so far as the principle of excluded middle does not apply to it and is vague in so far as the principle of contradiction does not apply to it." This seems to imply that general propositions are neither true nor false and that vague propositions are both true and false. But this is not the case. I argue that Peirce's claim was intended to underscore relatively simple facts about quantification and negation, and (...) that it implies neither that general propositions are neither true nor false nor that vague propositions are both true and false. (shrink)