The eukaryotic helicase is an 11-subunit machine containing an Mcm2-7 motor ring that encircles DNA, Cdc45 and the GINS tetramer, referred to as CMG. CMG is “built” on DNA at origins in two steps. First, two Mcm2-7 rings are assembled around duplex DNA at origins in G1 phase, forming the Mcm2-7 “double hexamer.” In a second step, in S phase Cdc45 and GINS are assembled onto each Mcm2-7 ring, hence producing two CMGs that ultimately form two replication forks that travel (...) in opposite directions. Here, we review recent findings about CMG structure and function. The CMG unwinds the parental duplex and is also the organizing center of the replisome: it binds DNA polymerases and other factors. EM studies reveal a 20-subunit core replisome with the leading Pol ϵ and lagging Pol α-primase on opposite faces of CMG, forming a fundamentally asymmetric architecture. Structural studies of CMG at a replication fork reveal unexpected details of how CMG engages the DNA fork. The structures of CMG and the Mcm2-7 double hexamer on DNA suggest a completely unanticipated process for formation of bidirectional replication forks at origins. Here, we review the structure and function of CMG, the 11 subunit helicase for eukaryotic DNA replication. Two CMGs are assembled at origins starting from two Mcm2-7 hexamers oriented N-to-N. The orientation of CMG at a forked DNA implies that the two CMGs at an origin pass one another. (shrink)

Drawing on a landscape analysis of existing data-sharing initiatives, in-depth interviews with expert stakeholders, and public deliberations with community advisory panels across the U.S., we describe features of the evolving medical information commons. We identify participant-centricity and trustworthiness as the most important features of an MIC and discuss the implications for those seeking to create a sustainable, useful, and widely available collection of linked resources for research and other purposes.

Although the E-Z Reader model accounts well for eye-tracking data, it will be judged by new predictions and consistency with evidence from brain imaging methodologies. The stage architecture proposed for lexical access seems somewhat arbitrary and calculated timings are conservatively slow. There are certain effects in the literature that seem incompatible with the model.

O'Donnell, J. R. Anton Charles Pegis on the occasion of his retirement.--Conlan, W. J. The definition of faith according to a question of MS. Assisi 138: study and edition of text.--Spade, P. V. Five logical tracts by Richard Lavenham.--Maurer, A. Henry of Harclay's disputed question on the plurality of forms.--Brown, V. Giovanni Argiropulo on the agent intellect: an edition of Ms. Magliabecchi V 42.--Synan, E. A. The Exortacio against Peter Abelard's Dialogus inter philosophum, Iudaeum et Christianum.--Fitzgerald, W. Nugae Hyginianae.--Sheehan, (...) M. M. Marriage and family in English conciliar and synodal legislation.--Shook, L. K. Riddles relating to the Anglo-Saxon scriptorium.--Boyle, L. E. The De regno and the two powers.--Colledge, E. A Middle English Christological poem.--Gough, M. R. E. Three forgotten martyrs of Anazarbus in Cilicia.--Häring, N. Chartres and Paris revisited.--Hayes, W. Greek recentiores, (Ps.) Basil, Adversus eunomium, IV-V.--Owens, J. The physical world of Parmenides. (shrink)

DNA polymerases which duplicate cellular chromosomes are multiprotein complexes. The individual functions of the many proteins required to duplicate a chromosome are not fully understood. The multiprotein complex which duplicates the Escherichia coli chromosome, DNA polymerase III holoenzyme (holoenzyme), contains a DNA polymerase subunit and nine accessory proteins. This report summarizes our current understanding of the individual functions of the accessory proteins within the holoenzyme, lending insight into why a chromosomal replicase needs such a complex structure.

This volume explores how Catholicism began and continues to open its doors to the wider world and to other confessions in embracing ecumenism, thanks to the vision and legacy of the Second Vatican Council. It explores such themes as the twentieth century context preceding the council; parallels between Vatican II and previous councils; its distinctively pastoral character; the legacy of the council in relation to issues such as church-world dynamics, as well as to ethics, social justice, economic activity. Several chapters (...) discuss the role of women in the church before, during, and since the council. Others discern inculturation in relation to Vatican II. The book also contains a wide and original range of ecumenical considerations of the council, including by and in relation to Free Church, Reformed, Orthodox, and Anglican perspectives. Finally, it considers the Council’s ongoing promise and remaining challenges with regard to ecumenical issues, including a groundbreaking essay on the future of ecumenical dialogue by Cardinal Walter Kasper. (shrink)

Is it ethical to perform a surgery whose purpose is to make a male look like a female or a female to appear male? Is it medically appropriate? Sexual reassignment surgery (SRS) violates basic medical and ethical principles and is therefore not ethically or medically appropriate. (1) SRS mutilates a healthy, non-diseased body. To perform surgery on a healthy body involves unnecessary risks; therefore, SRS violates the principle primum non nocere, “first, do no harm.” (2) Candidates for SRS may believe (...) that they are trapped in the bodies of the wrong sex and therefore desire or, more accurately, demand SRS; however, this belief is generated by a disordered perception of self. Such a fixed, irrational belief is appropriately described as a delusion. SRS, therefore, is a “category mistake”—it offers a surgical solution for psychological problems such as a failure to accept the goodness of one’s masculinity or femininity, lack of secure attachment relationships in childhood with same-sex peers or a parent, self-rejection, untreated gender identity disorder, addiction to masturbation and fantasy, poor body image, excessive anger, and severe psychopathology in a parent. (3) SRS does not accomplish what it claims to accomplish. It does not change a person’s sex; therefore, it provides no true benefit. (4) SRS is a “permanent,” effectively unchangeable, and often unsatisfying surgical attempt to change what may be only a temporary (i.e., psychotherapeutically changeable) psychological/psychiatric condition. National Catholic Bioethics Quarterly 9.1 (Spring2009): 97–125. (shrink)

An unconventional formalization of the canonical square of opposition in the notation of classical symbolic logic secures all but one of the canonical square’s grid of logical interrelations between four A-E-I-O categorical sentence types. The canonical square is first formalized in the functional calculus in Frege’s Begriffsschrift, from which it can be directly transcribed into the syntax of contemporary symbolic logic. Difficulties in received formalizations of the canonical square motivate translating I categoricals, ‘Some S is P’, into symbolic logical notation, (...) not conjunctively as \, but unconventionally instead in an ontically neutral conditional logical symbolization, as \. The virtues and drawbacks of the proposal are compared at length on twelve grounds with the explicit existence expansion of A and E categoricals as the default strategy for symbolizing the canonical square preserving all original logical interrelations. (shrink)

L'A. pubblica una quaestio di Gilberto di Stratton, contenuta nel ms. Assisi, Bibl. Comunale, 158 dal titolo Utrum aliquod eviternum potuit fuisse Deo coeternum che, a suo avviso, rappresenta forse il primo esempio di difesa della posizione assunta da Tommaso all'interno del dibattito de aeterniate mundi, posizione che, come è noto, fu oggetto di condanna nel 1277 . Nella breve introd. che precede il testo, l'A. sottolinea il fatto che Gilberto oltre a riprendere e ad assumere la posizione di Tommaso, (...) ed in particolare quella della non contradditorietà tra l'esse factum e l'esse aeternum, mostra di conoscere le critiche che aveva mosso Bonaventura al Doctor angelicus e gli argomenti ex infinito formulati dal maestro francescano per dimostrare l'inizio temporale del mondo. Di Gilberto esiste un'altra quaestio contenuta nello stesso ms. e che sembra una versione alterata del De aeternitate di Tommaso e che l'A. ha pubblicato con O. Argerami in Leiden 1993. (shrink)

In 1886, Nietzsche wrote: ‘I am still waiting for a philosophical doctor in the extraordinary sense of the term’: a doctor who pursues not truth, but an exceptional kind of health. Nietzsche's will to health, his theory of drive organisation, and his insistence that the philosopher put himself at risk, all work together in his overall project, which consists of taking up the very role of the highly revalued physician for whom he is waiting. Deleuze and Guattari engage this same (...) task of a revalued doctoring in the Capitalisme et Schizophrénie books, attacking the disease of oedipality and providing instructions for the deorganisation of the organism as self-cure. Offering tips on this radical treatment, they employ the figure of the hypochondriac to show how it can fail. Both Nietzsche and Deleuze and Guattari perform a revaluation of health as a condition of chronic critique, a condition that wraps itself around illness to keep itself critical. (shrink)

It is widely believed that philosophical pessimism is committed to fatalism about the sufferings that characterize the human condition, and that it encourages resignation and withdrawal from the political realm in response. This paper offers an explanation for and argument against this perception by distinguishing two functions that pessimism can serve. Pessimism’s skeptical mode suggests that fundamental cross-cultural constraints on the human condition bar us from the good life (however defined). These constraints are often represented as immune to political amelioration, (...) leading to the perception that pessimism is intrinsically fatalistic and resigned. Yet pessimism’s critical function emphasizes the political, economic, and cultural contingency of many sources of suffering and crisis while exhorting us to reject and reimagine the social forces that actively harm our capacity to flourish. It also offers an internal critique of skeptical pessimism’s tendency to naturalize and depoliticize the sources of our sufferings. These sometimes contradictory skeptical and critical tendencies should both be grouped under the pessimist banner, and we should see pessimism’s critical mode as especially valuable to political critique. -/- . (shrink)

This comprehensive, general introduction to Schelling's philosophy shows that it was Schelling who set the agenda for German idealism and defined the term of its characteristic problems.

After critiquing some earlier attempts (including those of Marcus Singer and Frances Howard–Snyder) to ground objections to actual–consequence act utilitarianism (ACAU) on human cognitive limitations, I present two new objections with this same foundation. Both start with the observation that, because human cognitive abilities are not up to the task of reliably recognizing utility–maximizing actions, any agents who are recognizably human – including the best possible humans, morally speaking – are certain to perform many actions every day that ACAU says (...) are immoral, and to perform some actions over the course of their lives that it says are highly immoral. The first objection is that, if Mill's analysis of what it means to call an action wrong is accurate, then ACAU entails a conclusion that no one will accept, viz., that the morally–best humans possible ought to undergo constant punishment. The second objection is that ACAU entails that even the morally–best humans possible are bad moral agents in some respect. This conclusion, while unpalatable, is not so obviously unacceptable as the first. However, I do briefly consider some ways in which it might be possible to demonstrate that it is false and thereby complete a reductio of ACAU. (shrink)

Rule consequentialism holds that an action's moral standing depends on its relation to the moral code whose general adoption would have the best consequences. Heretofore rule consequentialists have understood the notion of a code's being generally adopted in terms of its being generally obeyed or, more commonly, its being generally accepted. I argue that these ways of understanding general adoption lead to unacceptable formulations of the theory. For instance, Brad Hooker, Michael Ridge, and Holly Smith have recently offered different answers (...) to the question of what ‘acceptance rate’ we should build into our formulation of rule consequentialism, and all are unsatisfactory. I argue instead for a novel approach to formulating rule consequentialism, ‘uniform-moral-education’ rule consequentialism, on which what it means for a moral code to be generally adopted is not for it to be generally followed or generally accepted, but instead for it to be generally taught. (shrink)

Hayek argued that the central question of economics is the coordination problem: How does the spontaneous interaction of many purposeful individuals, each having dispersed bits of subjective knowledge, generate an order in which the actors' subjective data are coordinated in a way that enables them to dovetail their plans and activities successfully? In attempting to solve this problem, Hayek outlined an approach to economic theorizing that takes seriously the limited, subjective nature of human knowledge. Despite purporting to have appropriated Hayek's (...) thought by acknowledging the information-transmitting role of prices, mainstream economists have missed Hayek's point. The predominant tool of formal economics—equilibrium analysis—begins by assuming the data held by actors to have been pre-reconciled, and so evades the problem to be solved. Even the more advanced tools for modeling knowledge in economic analysis, such as the economics of information, assume away either the subjectivism of knowledge and expectations (rendering the coordination of beliefs and plans a trivial matter) or the frictions and “imperfections” of reality (rendering the coordination problem indeterminate). (shrink)

I consider whether Mill intends for us to see the arguments that constitute his defense of the “Liberty of Thought and Discussion” in chapter 2 ofOn Libertyas a part of his larger case for the “harm” or “liberty” principle (LP). Several commentators depict this chapter as a digression that interrupts the flow between his introduction of this principle in the first chapter and his exposition and defense of it in the final three. I will argue instead for a reading ofOn (...) Libertyon which chapter 2 is well integrated with the rest of the essay and is in fact where Mill starts constructing his case for LP. (shrink)

The project of this paper is to deliver a semantics for a broad subset of bare plural generics about racial kinds, a class which I will dub 'Type C generics.' Examples include 'Blacks are criminal' and 'Muslims are terrorists.' Type C generics have two interesting features. First, they link racial kinds with ​ socially perspectival predicates ​ (SPPs). SPPs lead interpreters to treat the relationship between kinds and predicates in generic constructions as nomic or non-accidental. Moreover, in computing their content, (...) interpreters must make implicit reference to socially privileged​ ​ perspectives which are treated as authoritative about whether a given object fits into the extension of the predicate. Such deference grants these authorities influence over both the conventional meaning of these terms and over the nature of the ​ objects ​ in the social ontology that these terms purport to describe, much the way a baseball umpire is authoritative over the meaning and metaphysics of 'strike'/​ strike ​. Second, terms like 'criminal' and 'terrorist' receive default ​ racialized ​ interpretations in which these terms conventionally token racial or ethnic identities. I show that neither of these features can be explained by Sarah-Jane Leslie's influential 'weak semantics' for generics, and show how my own 'socially perspectival semantics' fares better on both counts. Finally, I give an analysis of 'Blacks are criminal' which explores the semantic mechanisms that underlie default racialized interpretations. (shrink)

Insofar as John Stuart Mill can be accurately described as a socialist, his is a socialism that a classical liberal ought to be able to live with, if not to love. Mill's view is that capitalist economies should at some point undergo a `spontaneous' and incremental process of socialization, involving the formation of worker-controlled `socialistic' enterprises through either the transformation of `capitalistic' enterprises or creation de novo. This process would entail few violations of core libertarian principles. It would proceed by (...) way of a series of voluntary transactions. Capitalists' property rights would be respected throughout. The process would take place within a national system of laws that permits private ownership of productive property and competition, and would not result in that system's overthrow. And, if we accept some basic tenets of Mill's social philosophy, the outcome at which we should expect the process to arrive is a `patchwork' economy in which capitalistic and socialistic enterprises exist side by side. Key Words: Ludwig von Mises • John Stuart Mill • socialism • capitalism • worker control. (shrink)

Dynamin is a GTPase that regulates late events in clathrin‐coated vesicle formation. Our current working model suggests that dynamin is targeted to coated pits in its unoccupied or GDP‐bound form, where it is initially distributed uniformly throughout the clathrin lattice. GTP/GDP exchange triggers its release from these sites and its assembly into short helices that encircle the necks of invaginated coated pits like a collar. GTP hydrolysis, which is required for vesicle detachment, presumably induces a concerted conformation change, tightening the (...) collar. Unlike most of its GTPase cousins that serve as molecular switches, dynamin has a low affinity for GTP, a very high intrinsic rate of GTP hydrolysis and functions as a homo‐oligomer. A concerted conformational change resulting from coordinated GTP hydrolysis by the dynamin oligomer might be sufficient to generate force. In this case, dynamin would be the first GTPase identified that acts as a structural protein with mechano‐chemical function. (shrink)

Over the last decade, there has been a considerable expansion of mindfulness programmes into a number of different domains of contemporary life, such as corporations, schools, hospitals and even the military. Understanding the reasons for this phenomenon involves, I argue, reflecting upon the nature of contemporary capitalism and mapping the complexity of navigating new digital technologies that make multiple and accelerated solicitations upon attention and our affective lives. Whilst acknowledging the benefits of mindfulness practice, this article argues that it is (...) equally important to attend to the ethical framework that gives orientation to these practices and the outer conditions that shape lived daily experience, such as school or work environments. I suggest that the well-meaning efforts to secularise mindfulness, provide scientific evidence for its effectiveness, and introduce it to wider publics may have served to impoverish the rich contribution that practices of mindfulness, situated within a broader ethical framework, can make to human lives, and arguably contribute to the educational endeavour. For example, the emphasis on transforming inner conditions of students’ lives can lead to the neglect of outer conditions, such as structural inequality, or unhealthy and exploitative work practices. This can result in practices that privilege individual wellbeing over compassion and concern for the happiness of others, providing a buffer against loving attention to the world and others. Instead, I ask how mindfulness in educational settings could come to be viewed in a different light if we reflect upon the ways in which school environments and curricula can promote mindfulness, awareness, sensitive inquiry, and contemplative practices through the day, rather than offering it as a discrete intervention focused on the self and wellbeing. (shrink)

In a way that harks back to Anglo-American philosophy of the 1950s and 1960s, this essay contends that the traditional “free will” problem is a spurious problem generated by systematic misuse of the terms employed in discussing moral responsibility. Illustrations of these misuses from sources old and new are provided, mainly in the footnotes. Attention is called to the proper use of the terms, which allows us to frame the questions pertinent to the determination of someone’s moral responsibility for a (...) particular action or omission. No attempt is made to answer these questions because the justifications for the answers would require reference to the particular facts surrounding any given case, as well as estimations of their relevance and importance. The value of the essay lies rather in redirecting attention away from irrelevant matters and towards those that do count. (shrink)

In a corporate context, would interrupting affect the perceived power, identity traits, job performance, and interpersonal relationships of equally situated male and female speakers? The gender of both the interrupter and the interrupted speaker was varied in hypothetical transcripts of conversations between two corporate vice-presidents. There were no significant effects of interrupting or being interrupted on perceptions of the relative power of men and women speakers. However, the interrupter, regardless of gender, was perceived as more successful and driving, but less (...) socially acceptable, reliable, and companionable than the interrupted speaker. (shrink)

Evidence that an animal is capable of some degree of symbolic, human language processing supports the argument that the animal's consciousness is to some degree human-like. In this paper, we reinterpret the findings of Savage- Rumbaugh et al. using the twin tools of Deacon's referential hierarchy and Systemic Functional Linguistics, with a view to providing further corroborative evidence for a Bonobo ape's symbolic processing abilities, and as a result to open a window into the consciousness of at least one non-human (...) primate. (shrink)

In The Second-Person Standpoint, Stephen Darwall offers an interpretation of P. F. Strawson’s “Freedom and Resentment” according to which the essay advances the thesis that good consequences are the “wrong kind of reason” to justify “practices of punishment and moral responsibility.” Darwall names this thesis “Strawson’s Point.” I argue for a different reading of Strawson, one according to which he holds this thesis only in a qualified way and, more generally, is not the unequivocal critic of consequentialism that Darwall makes (...) him out to be. In fact, I contend, Strawson’s account of the reactive attitudes can potentially be a useful resource for consequentialists. (shrink)

In 'Axiological Actualism' Josh Parsons argues that 'axiological actualism', which is 'the doctrine that ethical theory should refrain from assigning levels of welfare, or preference orderings, or anything of the sort to merely possible people', lends plausibility to 'the converse intuition'. This is the proposition that 'the welfare a person would have, were they actual, can give us a reason not to bring that person into existence'. I show that Parsons's argument delivers less than he promises. It could be convincing (...) only to actualists who hold certain views about normative ethics, and could at most convince them to heed the converse intuition only under certain circumstances. (shrink)

In 'Axiological Actualism' Josh Parsons argues that 'axiological actualism', which is 'the doctrine that ethical theory should refrain from assigning levels of welfare, or preference orderings, or anything of the sort to merely possible people', lends plausibility to 'the converse intuition'. This is the proposition that 'the welfare a person would have, were they actual, can give us a reason not to bring that person into existence'. I show that Parsons's argument delivers less than he promises. It could be convincing (...) only to actualists who hold certain views about normative ethics, and could at most convince them to heed the converse intuition only under certain circumstances. (shrink)

In this article, I argue that the reading of Mill that D.G. Brown presents in ‘Mill’s Moral Theory: Ongoing Revisionism’ is inconsistent with several key passages in Mill’s writings. I also show that a rule-utilitarian interpretation that is very close to the one developed by David Lyons is able to account for these passages without difficulty.

In The Second-Person Standpoint and subsequent essays, Stephen Darwall develops an account of morality that is “second-personal” in virtue of holding that what we are morally obligated to do is what others can legitimately demand that we do, i.e., what they can hold us accountable for doing through moral reactive attitudes like blame. Similarly, what it would be wrong for us to do is what others can legitimately demand that we abstain from doing. As part of this account, Darwall argues (...) for the proposition that we have a distinctive “second-personal reason” to fulfill all of our obligations and to avoid all wrong-actions, an “authority-regarding” reason that derives from the legitimate demands the “moral community” makes of us. I show that Darwall offers an insufficient case for this proposition. My criticism of this aspect of Darwall’s account turns in part on the fact that we have compunction-based or “compunctive” reasons to fulfill all of our obligations and to avoid all wrong actions, a type of reason that Darwall seemingly overlooks. (shrink)

James questions the validity of the very tentative statement made in the final sentence of our paper. Our claim concerned the proportion of twins in Britain in the 1990s that might have arisen through subfertility treatment and was linked to the suggestion that the natural twinning rate might still be in decline. If this were true, we, like James, would regard that prospect with concern.