It was, until recently, accepted that the two classes of acetylcholine (ACh) receptors are distinct in an important sense: muscarinic ACh receptors signal via heterotrimeric GTP binding proteins (G proteins), whereas nicotinic ACh receptors (nAChRs) open to allow flux of Na+, Ca2+, and K+ ions into the cell after activation. Here we present evidence of direct coupling between G proteins and nAChRs in neurons. Based on proteomic, biophysical, and functional evidence, we hypothesize that binding to G proteins modulates the activity (...) and signaling of nAChRs in cells. It is important to note that while this hypothesis is new for the nAChR, it is consistent with known interactions between G proteins and structurally related ligand‐gated ion channels. Therefore, it underscores an evolutionarily conserved metabotropic mechanism of G protein signaling via nAChR channels.Also watch the Video Abstract. (shrink)

It was, until recently, accepted that the two classes of acetylcholine (ACh) receptors are distinct in an important sense: muscarinic ACh receptors signal via heterotrimeric GTP binding proteins (G proteins), whereas nicotinic ACh receptors (nAChRs) open to allow flux of Na+, Ca2+, and K+ ions into the cell after activation. Here we present evidence of direct coupling between G proteins and nAChRs in neurons. Based on proteomic, biophysical, and functional evidence, we hypothesize that binding to G proteins modulates the activity (...) and signaling of nAChRs in cells. It is important to note that while this hypothesis is new for the nAChR, it is consistent with known interactions between G proteins and structurally related ligand‐gated ion channels. Therefore, it underscores an evolutionarily conserved metabotropic mechanism of G protein signaling via nAChR channels.Also watch the Video Abstract. (shrink)

Many organisms face a dilemma rooted in the unequal numbers of X chromosomes carried by the two sexes and the need to maintain equivalent expression of X‐linked genes. Several strategies have arisen to cope with this problem. All rely on accurately targeting epigenetic modifications to entire chromosomes. Targeting results from the action of recognition elements that attract modification and may rely on spreading of modification in cis along the affected chromosome. A recent report describing the first X chromosome recognition element (...) from C. elegans opens the way to defining the relative contributions of these factors to the compensation of X‐linked gene expression in worms.1 Extrachromosomal arrays composed of a C. elegans recognition element attract proteins that modify the C. elegans X chromosomes and interact genetically with mutations disrupting compensation. Moreover, examination of X:A translocations provides the first evidence for spreading of modification along C. elegans X chromosomes. BioEssays 26:707–710, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

BackgroundThere is increasing need for peer reviewers as the scientific literature grows. Formal education in biostatistics and research methodology during residency training is lacking. In this pilot study, we addressed these issues by evaluating a novel method of teaching residents about biostatistics and research methodology using peer review of standardized manuscripts. We hypothesized that mentored peer review would improve resident knowledge and perception of these concepts more than non-mentored peer review, while improving review quality.MethodsA partially blinded, randomized, controlled multi-center study (...) was performed. Seventy-eight neurology residents from nine US neurology programs were randomized to receive mentoring from a local faculty member or not. Within a year, residents reviewed a baseline manuscript and four subsequent manuscripts, all with introduced errors designed to teach fundamental review concepts. In the mentored group, mentors discussed completed reviews with residents. Primary outcome measure was change in knowledge score between pre- and post-tests, measuring epidemiology and biostatistics knowledge. Secondary outcome measures included level of confidence in the use and interpretation of statistical concepts before and after intervention, and RQI score for baseline and final manuscripts.ResultsSixty-four residents (82%) completed initial review with gradual decline in completion on subsequent reviews. Change in primary outcome, the difference between pre- and post-test knowledge scores, did not differ between mentored (−8.5%) and non-mentored (−13.9%) residents (p = 0.48). Significant differences in secondary outcomes (using 5-point Likert scale, 5 = strongly agree) included mentored residents reporting enhanced understanding of research methodology (3.69 vs 2.61; p = 0.001), understanding of manuscripts (3.73 vs 2.87; p = 0.006), and application of study results to clinical practice (3.65 vs 2.78; p = 0.005) compared to non-mentored residents. There was no difference between groups in level of interest in peer review (3.00 vs 3.09; p = 0.72) or the quality of manuscript review assessed by the Review Quality Instrument (RQI) (3.25 vs 3.06; p = 0.50).ConclusionsWe used mentored peer review of standardized manuscripts to teach biostatistics and research methodology and introduce the peer review process to residents. Though knowledge level did not change, mentored residents had enhanced perception in their abilities to understand research methodology and manuscripts and apply study results to clinical practice. (shrink)

Ehrenfeucht’s lemma asserts that whenever one element of a model of Peano arithmetic is definable from another, they satisfy different types. We consider here the analogue of Ehrenfeucht’s lemma for models of set theory. The original argument applies directly to the ordinal-definable elements of any model of set theory, and, in particular, Ehrenfeucht’s lemma holds fully for models of set theory satisfying V=HOD. We show that the lemma fails in the forcing extension of the universe by adding a Cohen real. (...) We go on to formulate a scheme of natural parametric generalizations of Ehrenfeucht’s lemma, namely, the principles of the form EL, which asserts that P-definability from A implies Q-discernibility. We also consider various analogues of Ehrenfeucht’s lemma obtained by using algebraicity in place of definability, where a set b is algebraic in a if it is a member of a finite set definable from a. Ehrenfeucht’s lemma holds for the ordinal-algebraic sets, we prove, if and only if the ordinal-algebraic and ordinal-definable sets coincide. Using a similar analysis, we answer two open questions posed earlier by the third author and C. Leahy, showing that algebraicity and definability need not coincide in models of set theory and the internal and external notions of being ordinal algebraic need not coincide. (shrink)

We offer a novel interpretation of the argumentative role that Meditation IV plays within the whole of the Meditations. This new interpretation clarifies several otherwise head-scratching claims that Descartes makes about Meditation IV, and it fully exonerates the Fourth Meditation from either raising or exacerbating Descartes’ circularity problems.

The notion that our society, its education system and its intellectual life, is characterised by a split between two cultures – the arts or humanities on one hand, and the sciences on the other – has a long history. But it was C. P. Snow's Rede lecture of 1959 that brought it to prominence and began a public debate that is still raging in the media today. This 50th anniversary printing of The Two Cultures and its successor piece, A Second (...) Look features an introduction by Stefan Collini, charting the history and context of the debate, its implications and its afterlife. The importance of science and technology in policy run largely by non-scientists, the future for education and research, and the problem of fragmentation threatening hopes for a common culture are just some of the subjects discussed. (shrink)

The notion that our society, its education system and its intellectual life, is characterised by a split between two cultures – the arts or humanities on one hand and the sciences on the other – has a long history. But it was C. P. Snow's Rede lecture of 1959 that brought it to prominence and began a public debate that is still raging in the media today. This fiftieth anniversary printing of The Two Cultures and its successor piece, A Second (...) Look features an introduction by Stefan Collini, charting the history and context of the debate, its implications and its afterlife. The importance of science and technology in policy run largely by non-scientists, the future for education and research, and the problem of fragmentation threatening hopes for a common culture are just some of the subjects discussed. (shrink)

Offering an original perspective on the central project of Descartes' Meditations, this book argues that Descartes' free will theodicy is crucial to his refutation of skepticism. A common thread runs through Descartes' radical First Meditation doubts, his Fourth Meditation discussion of error, and his pious reconciliation of providence and freedom: each involves a clash of perspectives-thinking of God seems to force conclusions diametrically opposed to those we reach when thinking only of ourselves. Descartes fears that a skeptic could exploit this (...) clash of perspectives to argue that Reason is not trustworthy because self-contradictory. To refute the skeptic and vindicate the consistency of Reason, it is not enough for Descartes to demonstrate that our Creator is perfect; he must also show that our errors cannot prove God's imperfection. To do this, Descartes invokes the idea that we err freely. However, prospects initially seem dim for this free will theodicy, because Descartes appears to lack any consistent or coherent understanding of human freedom. In an extremely in-depth analysis spanning four chapters, Ragland argues that despite initial appearances, Descartes consistently offered a coherent understanding of human freedom: for Descartes, freedom is most fundamentally the ability to do the right thing. Since we often do wrong, actual humans must therefore be able to do otherwise-our actions cannot be causally determined by God or our psychology. But freedom is in principle compatible with determinism: while leaving us free, God could have determined us to always do the good. Though this conception of freedom is both consistent and suitable to Descartes' purposes, when he attempts to reconcile it with divine providence, Descartes's strategy fails, running afoul of his infamous doctrine that God created the eternal truths. (shrink)

: The principle of alternative possibilities (PAP) says that doing something freely implies being able to do otherwise. I show that Descartes consistently believed not only in PAP, but also in clear and distinct determinism (CDD), which claims that we sometimes cannot but judge true what we clearly perceive. Because Descartes thinks judgment is always a free act, PAP and CDD seem contradictory, but Descartes consistently resolved this apparent contradiction by distinguishing between two senses of 'could have done otherwise.' In (...) one sense alternative possibilities are necessary for freedom and in another they are not. I discuss three possible interpretations of the two senses. (shrink)

The principle of alternative possibilities (PAP) says that doing something freely implies being able to do otherwise. I show that Descartes consistently believed not only in PAP, but also in clear and distinct determinism (CDD), which claims that we sometimes cannot but judge true what we clearly perceive. Because Descartes thinks judgment is always a free act, PAP and CDD seem contradictory, but Descartes consistently resolved this apparent contradiction by distinguishing between two senses of 'could have done otherwise.' In one (...) sense alternative possibilities are necessary for freedom and in another they are not. I discuss three possible interpretations of the two senses. (shrink)

In an influential article, Anthony Kenny charged that (a) the view of freedom in Descartes’ “1645 letter to Mesland” is incoherent, and (b) that this incoherence was present in Descartes’ thought from the beginning. Against (b), I argue that such incoherence would rather support Gilson’s suspicions that the 1645 letter is dishonest. Against (a), I offer a close reading of the letter, showing that Kenny’s objection seems plausible only if we misconstrue a key ambiguity in the text. I close by (...) defending Descartes against some related worries of my own about the degrees of Cartesian freedom. I conclude that there is really no good reason to deny that Descartes’ view in the 1645 letter is both internally coherent and a genuine explication of the Meditations’ account of freedom. (shrink)

God’s providence appears to threaten the existence of human freedom. This paper examines why Descartes considered this threat merelyapparent. Section one argues that Descartes did not reconcile providence and freedom by adopting a compatibilist conception of freedom. Sections two and three argue that for Descartes, God’s superior knowledge allows God to providentially arrange free choices without causally determining them. Descartes’ position thus strongly resembles the “middle knowledge” solution of the Jesuits. Section four examines the problematic relationship between this solution and (...) the creation of the eternal truths, arguing that Descartes’ position depends on his unique understanding of divine simplicity. (shrink)

On étudie dans cet article l'apparence morphologique des plantes à travers des modèles géométriques et statiques puis on examine quelques caractères-clés des processus de croissance à la lumière des propriétés de certains systèmes différentiels.