A host of metabolic enzymes reversibly self‐assemble to form membrane‐less, intracellular filaments under normal physiological conditions and in response to stress. Often, these enzymes reside at metabolic control points, suggesting that filament formation affords an additional regulatory mechanism. Examples include cytidine‐5′‐triphosphate (CTP) synthase (CTPS), which catalyzes the rate‐limiting step for the de novo biosynthesis of CTP; inosine‐5′‐monophosphate dehydrogenase (IMPDH), which controls biosynthetic access to guanosine‐5′‐triphosphate (GTP); and ∆1‐pyrroline‐5‐carboxylate (P5C) synthase (P5CS) that catalyzes the formation of P5C, which links the (...) Krebs cycle, urea cycle, and proline metabolism. Intriguingly, CTPS can exist in co‐assemblies with IMPDH or P5CS. Since GTP is an allosteric activator of CTPS, the association of CTPS and IMPDH filaments accords with the need to coordinate pyrimidine and purine biosynthesis. Herein, a hypothesis is presented furnishing a biochemical connection underlying co‐assembly of CTPS and P5CS filaments – potent inhibition of CTPS by glutamate γ‐semialdehyde, the open‐chain form of P5C. (shrink)

Two enzymes involved in the synthesis of pyrimidine and purine nucleotides, CTP synthase (CTPS) and IMP dehydrogenase (IMPDH), can assemble into a single or very few large filaments called rods and rings (RR) or cytoophidia. Most recently, asymmetric cytoplasmic distribution of organelles during cell division has been described as a decisive event in hematopoietic stem cell fate. We propose that cytoophidia, which could be considered as membrane‐less organelles, may also be distributed asymmetrically during mammalian cell division as previously described (...) for Schizosaccharomyces pombe. Furthermore, because each type of nucleotide intervenes in distinct processes (e.g., membrane synthesis, glycosylation, and G protein‐signaling), alterations in the rate of synthesis of specific nucleotide types could influence cell differentiation in multiple ways. Therefore, we hypothesize that whether a daughter cell inherits or not CTPS or IMPDH filaments determines its fate and that this asymmetric inheritance, together with the dynamic nature of these structures enables plasticity in a cell population. (shrink)

Spatial evolutionary game theory explains how cooperative traits can survive the intense competition in biological systems. If the spatial distribution allows cooperators to interact with each other frequently, the benefits of cooperation will outweigh the losses due to exploitation by selfish organisms. However, for a cooperative behavior to get established in a system, it needs to be found initially in a sufficiently large cluster to allow a high frequency of intracooperator interactions. Since mutations are rare events, this poses the question (...) of how cooperation can arise in a biological system in the first place. We present a simple model which captures two concepts from genetics that can explain how evolution overcomes the emergence problem. The first concept is, often in nature, a gene may not express its phenotype except under specific environmental conditions, rendering it to be a “silent” gene. The second key idea is that a neutral gene, one that does not harm or improve an organism’s survival chances, can still spread through a population if it is physically near to another gene that is positively selected. Through these two ideas, our model offers a possible solution to the fundamental problem of emergence of cooperation in biological systems. (shrink)

Positive frequency dependent selection is a natural selection regime where the fitness of a phenotype increases with its frequency in the population. Examples can be typically found in the spread of disease tolerance strategies in a population. A characterizing feature of PFDS is that the focal allele may experience favorable selection only when it becomes more frequent in the population, while being selected against when it is rare. In this paper, by applying a solution concept from evolutionary game theory, we (...) hypothesize that the process of emergence of such alleles triggers selection for silence, where the emergence of alleles that can stay unexpressed for a period of time will be favored by selection forces. We illustrate our hypothesis using a mathematical model of a population of single locus diploid organisms with two alleles where a single mutant of an allele that experiences positive frequency dependent selection appears in a population where the other allele is a dominant. The model results show that the longer the silence interval of the new mutant before its expression, the better its chances of getting fixed in the population. However, this effect will be observable only to a certain limit after which further increase in the interval will not have an effect on the expected fixation rate. Two divergences from the simple scenario are also investigated: the nonsynchronous expression of the focal allele and its emergence in a spatial grid limited by a migration bottleneck. In all cases, it is shown that there is an evolutionary pressure inherent in the dynamics of positive frequency dependent selection on the genes to have a delayed expression. It is hypothesized that the regulation systems of such traits will be under selection for either internal silencing mechanisms or to be triggered by an external environmental condition. (shrink)

L'impérieux amour de Pascal. - Discours sur les passions de l'amour. - Lettres de Pascal à Charlotte de Roannez. - Pensées de Pascal sur l'amitié. - Pensées de Pascal sur le coeur. - Pensées de Pascal sur l'amour. - Pensées de Pascal sur la concupisence.

La notion de désobéissance civile connaît aujourd'hui un regain d'intérêt qui n'exclut pas toujours les approximations. Les noms de Thoreau, de Gandhi, de King, étroitement liés à son histoire, font désormais partie de la culture générale. Mais sait-on que l'idée d'une obéissance conditionnelle l'État et à ses lois émerge, sous la plume d'un John Locke, dès le XVIIe siècle ouvrant ainsi une brèche féconde dans les théories modernes du contrat social? Sait-on que la désobéissance civile fut, à l'exemple des universitaires (...) norvégiens en 1942, un des modes de résistance à l'occupation nazie? Se souvient-on qu'en Pologne, notamment, c'est une authentique campagne de désobéissance civile qui précipita l'effondrement du régime communiste? De Tolstoï à John Rawls, de la " marche du sel " en Inde aux " enseignants désobéisseurs " en France, ce concept s'est sans cesse enrichi sur les plans philosophiques et stratégiques. En un dialogue fertile avec les textes fondateurs et les grandes campagnes historiques, l'auteur nous montre ce qu'est la désobéissance civile : avant tout, un impératif éthique d'éprouver la légitimité de la loi et, le cas échéant, la faculté de rompre avec son cadre rassurant. Ce livre, qui se veut aussi un manuel pratique, montre que cette forme d'action directe non-violente, souvent efficace contre la tyrannie, peut et doit également contribuer à la respiration de nos démocraties essoufflées.-. (shrink)

1. Le comte de Gobineau et l'arayanisme historique -- 2. Apôllon ou Dionysos : étude critique sur Fréderic Nietzsche et l'utilitarisme impérialiste -- 3. L'impérialisme démocratique -- 4. Le mal romantique essai sur l'impérialisme irrationnel.

Les textes de la troisième "Critique" d'Emmanuel Kant révèlent le paradoxe de sa philosophie du droit illustré par la contrainte du droit et l'enthousiasme pour la Révolution de 1789. Pour le philosophe, ce signe d'histoire annonce la question d'un progrès irréversible pour l'humanité.

Abstract11β‐hydroxysteroid dehydrogenases regulate glucocorticoid concentrations and 17β‐hydroxysteroid dehydrogenases regulate estrogen and androgen concentrations in mammals. Phylogenetic analysis of the sequences from two 11β‐hydroxysteroid dehydrogenases and four mammalian 17β‐hydroxysteroid dehydrogenases indicates unusual evolution in these enzymes. Type 1 11β‐ and 17β‐hydroxysteroid dehydrogenases are on the same branch; Type 2 enzymes cluster on another branch with β‐hydroxybutyrate dehydrogenase, 11‐cis retinol dehydrogenase and retinol dehydrogenase; Type 3 17β‐hydroxysteroid dehydrogenase is on a third branch; while the pig dehydrogenase clusters (...) with a yeast multifunctional enzyme on a fourth branch. Pig 17β‐hydroxysteroid dehydrogenase appears to have evolved independently from the other three 17β‐hydroxysteroid dehydrogenase dehydrogenases; in which case, the evolution of 17β‐hydroxysteroid dehydrogenase activity is an example of functional convergence. The phylogeny also suggests that independent evolution of specificity toward C11 substituents on glucocorticoids and C17 substituents on androgens and estrogens has occurred in Types 1 and 2 11β‐ and 17β‐hydroxysteroid dehydrogenases. (shrink)

Abstractα/β barrels have an ill‐defined origin. Evidence exists which favours their divergent evolution from a common ancestral barrel and convergent evolution to a stable fold. However, recent sequence and structural information for the flavin oxidase/dehydrogenase family of barrel enzymes indicate that sub‐families of α/β barrels have evolved divergently. The modular fusion of barrel domains with core structures from other gene families has also contributed to the evolution of related but catalytically distinct enzyme molecules within each sub‐family of the flavin (...) oxidases/dehydrogenases. An analysis of the structures and sequences of the flavin oxidases/dehydrogenases has now enabled studies focusing on the evolutionary origins and modular assembly of this important family of proteins to be initiated. (shrink)

By presenting new elements discovered during on-site research and comparing them to previous findings, this Note supports the view that the graffiti made by lansquenets in the Stanze of the Vatican Palace and in the Villa Farnesina in 1527 and 1528 during the sack of Rome should be seen in the context of an iconographic interaction with, rather than mere destruction of, the original artworks.

Recently several authors have argued that accuracy-first epistemology ends up licensing problematic epistemic bribes. They charge that it is better, given the accuracy-first approach, to deliberately form one false belief if this will lead to forming many other true beliefs. We argue that this is not a consequence of the accuracy-first view. If one forms one false belief and a number of other true beliefs, then one is committed to many other false propositions, e.g., the conjunction of that false belief (...) with any of the true beliefs. Once we properly account for all the falsehoods that are adopted by the person who takes the bribe, it turns out that the bribe does not increase accuracy. (shrink)

Em "O Fim do Império Cognitivo" Boaventura de Sousa Santos desenvolve o seu conceito de «Epistemologias do Sul», delineando um universo teórico, metodológico e pedagógico que desafia o domínio do pensamento eurocêntrico. À semelhança de uma coleção de con.

Les animaux ont-ils la vertu morale? À l'époque impériale, cette hypothèse est rejetée par les stoïciens, mais défendue par un groupe composite: les partisans de l'intelligence animale. Cet essai reconstitue l'arrière-plan philosophique du débat antique et ouvre des pistes de réflexion modernes.

L'idee d'une multiplicite de causes, introduite dans la philosophie grecque a partir des dialogues de Platon, a trouve chez Aristote sa realisation grandiose et complexe.La discussion sur les causes a l'epoque hellenistique et imperiale confirme l'importance et l'extreme richesse de cette idee. Le titre du volume veut souligner les rapports dialectiques, parfois conflictuels et souvent polemiques, que les doctrines de la causalite de cette epoque presentent entre elles, aussi bien de maniere independante que et par rapport a la systematisation aristotelicienne. (...) Les principaux auteurs (Theophraste, Alexandre d'Aphrodise, Plotin) et les principales ecoles philosophiques (Peripatetique, Stoicienne, Epicurienne, Sceptique) de l'age hellenistique et imperial y ont ete abordes dans le but de produire un apercu le plus complet et le plus articule possible du probleme de la causalite a cette epoque. (shrink)

Aldehyde dehydrogenase 2 (ALDH2) deficiency constitutes one of the most common hereditary enzyme deficiencies, affecting 35% to 40% of East Asians and 8% of the world population. It causes the well-known Asian Alcohol Flush Syndrome, characterized by facial flushing, palpitation, tachycardia, nausea, and other unpleasant feelings when alcohol is consumed. It is also associated with a marked increase in the risk of a variety of serious disorders, including esophageal cancer and osteoporosis. Our recent studies with murine models have demonstrated (...) that a one-time administration of an adeno-associated virus (AAV) gene transfer vector expressing the human ALDH2 coding sequence (AAVrh.10hALDH2) will correct the deficiency state and prevent alcohol-induced abnormalities of the esophagus and bone. If successful in humans, such strategy would reduce the increased risk-associated disorders such as esophageal cancer and osteoporosis, but also prevent the Asian Alcohol Flush Syndrome. This treatment thus raises ethical concerns: although it would potentially prevent fatal disease, it could also allow affected individuals to drink alcohol without suffering the Asian Alcohol Flush Syndrome and, hence, potentially enable personal destructive behavior. Here we explore the ethical arguments against the development of a gene therapy for ALDH2 deficiency and we find them wanting. We contend that development of such treatments is ethically appropriate and should be part and parcel of the solutions offered against the condition. (shrink)

The regulation of glucose dehydrogenase (GLD) in Drosophila illustrates the combinatorial aspects of gene regulation in development. Furthermore, the findings serve to point up a general question about cukaryotic structural gene control: is regulation of expression always optimal?

Malignant cells are characterized by an increased content of endogenous formaldehyde formed as a by‐product of biosynthetic processes. Accumulation of formaldehyde in cancer cells is combined with activation of the processes of cellular formaldehyde clearance. These mechanisms include increased ALDH and suppressed ADH5/FDH activity, which oncologists consider poor and favorable prognostic markers, respectively. Here, the sources and regulation of formaldehyde metabolism in cancer cells are reviewed. The authors also analyze the participation of oncoproteins such as fibulins, FGFR1, HER2/neu, FBI‐1, and (...) MUC1‐C in the control of genes related to formaldehyde metabolism, suggesting the existence of two mutually exclusive processes in cancer cells: 1) production and 2) oxidation and elimination of formaldehyde from the cell. The authors hypothesize that the study of the anticancer properties of disulfiram and alpha lipoic acid – which affect the balance of formaldehyde in the body – may serve as the basis of future anticancer therapy. (shrink)

There are convincing counter-examples to the widely accepted thesis that we cannot believe at will. For it seems possible that the truth of a proposition depend on whether or not one believes it. I call such scenarios cases of Truth Depends on Belief and I argue that they meet the main criteria for believing at will that we find in the literature. I reply to five objections that one might level against the thesis that TDB cases show that believing at (...) will is possible, namely that mind-reading is impossible, in TDB cases, one's belief is caused by one's desire, in TDB scenarios, one chooses not a belief but something else, TDB cases are reducible to Feldman cases, and that if truth depends on belief, we are on the road to a regress. Of course, TDB scenarios hardly, if ever, occur in real life. For three reasons, they are nonetheless important. First, they show that the thesis that it is conceptually impossible to believe at will is simply false. Second, they provide us with an imp.. (shrink)

Preface: The dog's bollocks-- at the media dinner party -- Introduction: "The Marx brothers", "The Elvis of cultural theory", and other media clichés -- The mediated imp of the perverse -- Žižek's tickling shtick -- Big (Br)other : psychoanalysing the media -- Understanding the media : the sublime objectification of ideology -- The media's violence -- The joker's little shop of ideological horrors -- Conclusion: Don't just do it : negative dialectics in the age of Nike.

For ambitious metaphysical neo-sentimentalists, all normative facts are grounded in fitting attitudes, where fittingness is understood in naturalistic terms. In this paper, I offer a neo-sentimentalist account of blameworthiness in terms of the reactive attitudes of a morally authoritative subject I label a Nagelian Imp. I also argue that moral impermissibility is indirectly linked to blameworthiness: roughly, an act is morally impermissible if and only if and because it is not *possible* in the circumstances to adopt a plan of performing (...) it without meriting blame, assuming the agent is rational, informed, and meets the conditions of accountability. (shrink)

We analyze the effect of replacing several natural uses of definability in set theory by the weaker model-theoretic notion of algebraicity. We find, for example, that the class of hereditarily ordinal algebraic sets is the same as the class of hereditarily ordinal definable sets; that is, $\mathrm{HOA}=\mathrm{HOD}$. Moreover, we show that every algebraic model of $\mathrm{ZF}$ is actually pointwise definable. Finally, we consider the implicitly constructible universe Imp—an algebraic analogue of the constructible universe—which is obtained by iteratively adding not only (...) the sets that are definable over what has been built so far, but also those that are algebraic over the existing structure. While we know that $\mathrm{Imp}$ can differ from $L$, the subtler properties of this new inner model are just now coming to light. Many questions remain open. (shrink)

Sorensen provides a panoramic view of paradoxes of theoretical and practical rationality. These puzzles are organized as apparent counterexamples to attractive principles such as the principle of charity, the transitivity of preferences, and the principle that we should maximize expected utility. The following paradoxes are discussed: fearing fictions, the surprise test paradox, Pascal’s Wager, Pollock’s Ever Better wine, Newcomb’s problem, the iterated prisoner’s dilemma, Kavka’s paradoxes of deterrence, backward inductions, the bottle imp, the preface paradox, Moore’s problem, Buridan’s ass, Condorcet’s (...) paradox of cyclical majorities, the St. Petersburg paradox, weakness of will, the Ellsberg paradox, Allais’s paradox, and Peter Cave’s puzzle of self-fulfilling beliefs. (shrink)