Macroautophagy is a major degradation mechanism of cell components via the lysosome. Macroautophagy greatly contributes to not only cell homeostasis but also the prevention of various diseases. Because macroautophagy proceeds through multi‐step reactions, researchers often face a persistent question of how macroautophagic activity can be measured correctly. To make a straightforward determination of macroautophagic activity, diverse monitoring assays have been developed. Direct measurement of lysosome‐dependent degradation of radioisotopically labeled cell proteins has long been applied. Meanwhile, indirect monitoring procedures have been (...) developed. In these assays, autophagosome marker proteins, microtubule‐associated proteins 1A/1B light chain 3B‐II (LC3B‐II) and gamma‐aminobutyric acid receptor‐associated protein‐II (GABARAP‐II) have been analyzed and the validity of the assays strongly depends on appropriate assessment of the fluctuation of LC3‐II and/or GABARAP‐II levels in the presence or absence of lysosomal inhibitors. This article describes these monitoring methods, paying special attention to the principles and characteristics of each procedure. (shrink)

Abnormalities in the ability of cells to properly degrade proteins have been identified in many neurodegenerative diseases. Recent work has implicated synaptojanin 1 (SynJ1) in Alzheimer's disease and Parkinson's disease, although the role of this polyphosphoinositide phosphatase in protein degradation has not been thoroughly described. Here, we dissected in vivo the role of SynJ1 in endolysosomal trafficking in zebrafish cone photoreceptors using a SynJ1‐deficient zebrafish mutant, nrca14. We found that loss of SynJ1 leads to specific accumulation of late endosomes and (...) autophagosomes early in photoreceptor development. An analysis of autophagic flux revealed that autophagosomes accumulate because of a defect in maturation. In addition we found an increase in vesicles that are highly enriched for PI(3)P, but negative for an early endosome marker in nrca14 cones. A mutational analysis of SynJ1 enzymatic domains found that activity of the 5'phosphatase, but not the Sac1 domain, is required to rescue both aberrant late endosomes and autophagosomes. Finally, modulating activity of the PI(4,5)P2 regulator, Arf6, rescued the disrupted trafficking pathways in nrca14 cones. Our study describes a specific role for SynJ1 in autophagosomal and endosomal trafficking and provides evidence that PI(4,5)P2 participates in autophagy in a neuronal cell type. -/- . (shrink)

This essay offers an original interpretation and defense of the doctrine of flux, as it is presented in Plato’s Theaetetus. The methodology of the paper’s analysis is in the style of rational reconstruction, and it is highly analytic in scope, in the sense that I will focus on the text itself, and only on certain parts of it too, while ignoring the rest of Plato’s extensive corpus, and without worrying about whether, how, and to what extent the interpretation of (...) the view coheres well with the other elements of the secret doctrine view discussed in the dialogue, as well. In the first part of the essay, I’ll offer my interpretation of the doctrine. Then, in the second part of the essay, I’ll examine two potential criticisms of the doctrine, including Socrates’s infamous linguistic paradox, and show how my interpretation of Heraclitean flux metaphysics is able to circumvent both. (shrink)

Ageing is associated with a decline in autophagy and elevated reactive oxygen species (ROS), which can breach the capacity of antioxidant systems. Resulting oxidative stress can cause further cellular damage, including DNA breaks and protein misfolding. This poses a challenge for longevous organisms, including humans. In this review, we hypothesise that in the course of human evolution selective autophagy receptors (SARs) acquired the ability to sense and respond to localised oxidative stress. We posit that in the vicinity of (...) protein aggregates and dysfunctional mitochondria oxidation of key cysteine residues in SARs induces their oligomerisation which initiates autophagy. The degradation of damaged cellular components thus could reduce ROS production and restore redox homeostasis. This evolutionarily acquired function of SARs may represent one of the biological adaptations that contributed to longer lifespan. Inversely, loss of this mechanism can lead to age‐related diseases associated with impaired autophagy and oxidative stress. (shrink)

Two key questions in the autophagy field are the mechanisms that underlie the signals for autophagy initiation and the source of membrane for expansion of the nascent membrane, the phagophore. In this review, we discuss recent findings highlighting the role of the classical endosomal pathway, from plasma membrane to lysosome, in the formation and expansion of the phagophore and subsequent degradation of the autophagosome contents. We also highlight the striking conservation of regulatory factors between the two pathways, including (...) those regulating membrane budding and fusion, and the role of the lysosome in sensing the nutrient status of the cell, regulating mTORC1 activity, and ultimately the initiation of autophagy.Editor's suggested further reading in BioEssays The evolution of dynamin to regulate clathrin‐mediated endocytosis Abstract. (shrink)

Extensive studies have attributed the lysosomal localization of the mechanistic target of rapamycin complex 1 (mTORC1) during its activation. However, the exact biological significance of this lysosomal localization of mTORC1 remains ill‐defined. Interestingly, findings have shown that localization of the lysosome itself is altered under conditions influencing mTORC1 activity. In this perspective, we hypothesize that the localization of mTORC1 and lysosome could be interconnected in a way that manifests regulation of autophagy that is already under progression at the time (...) of mTORC1 activation. This provides a new possibility for autophagy regulation whose complete mechanistic insights remain to be determined. (shrink)

Wilson R. Bachelor was a Tennessee native who moved with his family to Franklin County, Arkansas, in 1870. A country doctor and natural philosopher, Bachelor was impelled to chronicle his life from 1870 to 1902, documenting the family's move to Arkansas, their settling a farm in Franklin County, and Bachelor's medical practice. Bachelor was an avid reader with wide-ranging interests in literature, science, nature, politics, and religion, and he became a self-professed freethinker in the 1870s. He was driven by a (...) concept he called "fiat flux," an awareness of the "rapid flight of time" that motivated him to treat the people around him and the world itself as precious and fleeting. (shrink)

Heraclitean flux plays a large role in Plato 's « Theaetetus » and « Cratylus ». Yet Heraclitus himself did not hold the same conception of flux. The question of how the two thinkers differ, and why Plato treats Heraclitus as he does, is significant because the notion of flux has figured in subsequent philosophical conceptions of the persistence of identity through change. Comparison of Heraclitus, frr. B 12 and B 125 DK reveals that flux is (...) not motion simply, but motion productive of stability ; the unity of stability and flux is the « unapparent connection » that it is Heraclitus ' mission to reveal. Analysis of Tht. 179 C-181 B and Cra. 402 A 3-8 and 411 B-C shows neither any exegesis of Heraclitus ' words, nor any evidence that Plato has in mind any historical Heracliteans. The playful way in which Plato handles Heracliteanism, with comic and hyperbolic imagery, suggests that his audience would have recognized Heraclitean flux as a familiar theory from the context of contemporary oral dialectic. (shrink)

The paper explores the fundamental physical principles of quantum mechanics (in fact, quantum field theory) that limit the bit rate for long distances and examines the assumption used in this exploration that losses can be ignored. Propagation of photons in optical fibers is modelled using methods of quantum electrodynamics. We define the “photon duration” as the standard deviation of the photon arrival time; we find its asymptotics for long distances and then obtain the main result of the paper: the linear (...) dependence of photon duration on the distance when losses can be ignored. This effect puts the limit to joint increasing of the photon flux and the distance from the source and it has consequences for quantum communication. Once quantum communication develops into a real technology (including essential decrease of losses in optical fibres), it would be appealing to engineers to increase both the photon flux and the distance. And here our “photon flux/distance effect” has to be taken into account. This effect also may set an additional constraint to the performance of a loophole free test of Bell’s type—to close jointly the detection and locality loopholes. (shrink)

Does thinking have a history? If there are no necessarily changeless structures to be found in things and in our inquiry into them, then what knowledge of the world and ourselves is possible? In this boldly original and elegantly written study, Joseph Margolis argues for a radically historicized view of history that treats it as both a real process and a narrative account, each a product of continual change. Developing his argument through discussions of such influential philosophers of history and (...) the natural sciences as Vico, Danto, Collingwood, Habermas, Hempel, Popper, Putnam, and Gadamer, he provides a coherent theory of flux and invariance that resolves several deep puzzles regarding human nature and understanding. While maintaining a thorough command of Anglo-American philosophy, Margolis challenges many of its most cherished assumptions and demonstrates the sense in which history and interpretation are one and the same. Exploring one of the master themes of this century, his book offers a novel theory of the human condition whose conclusions and concerns seem certain to inform philosophy in the next century as well. (shrink)

From Edison’s invention of the phonograph through contemporary field recording and sound installation, artists have become attracted to those domains against which music has always defined itself: noise, silence, and environmental sound. Christoph Cox argues that these developments in the sonic arts are not only aesthetically but also philosophically significant, revealing sound to be a continuous material flow to which human expressions contribute but which precedes and exceeds those expressions. Cox shows how, over the course of the twentieth and twenty-first (...) centuries, philosophers and sonic artists have explored this “sonic flux.” Through the philosophical analysis of works by John Cage, Maryanne Amacher, Max Neuhaus, Christian Marclay, and many others, Sonic Flux contributes to the development of a materialist metaphysics and poses a challenge to the prevailing positions in cultural theory, proposing a realist and materialist aesthetics able to account not only for sonic art but for artistic production in general. (shrink)

Alzheimer's disease (AD) is a neurodegenerative disease exhibiting amyloid beta (Aβ) peptide accumulation as a key characteristic. Autophagy, which is dysregulated in AD, participates in the metabolism of Aβ. Unexpectedly, we recently found that autophagy, in addition to its degradative function, also mediates the secretion of Aβ. This finding adds Aβ to an increasing number of biomolecules, the secretion of which is mediated by autophagy. We also showed that inhibition of Aβ secretion through genetic deletion of (...) class='Hi'>autophagy leads to intracellular Aβ accumulation, which enhanced neurodegeneration induced by autophagy deficiency. Hence, autophagy may play a central role in two pathological hallmarks of AD: Aβ amyloidosis and neurodegeneration. Herein, we summarize the role of autophagy in AD with focus on Aβ metabolism in light of the recently established role of autophagy in protein secretion. We discuss potential routes for autophagy‐mediated Aβ secretion and suggest experimental approaches to further elucidate its mechanisms. (shrink)

Núñez et al. (2019) argue that cognitive science has failed either “to transition to a mature inter‐disciplinary coherent field” (p. 782) or “to generate a successful [Lakatosian] research program” (p. 789). We argue that the former was never the intention of many early researchers within the field, while the latter is an inappropriate criterion by which to judge an entire discipline. However, we concur with Núñez et al. (2019) that the individual disciplinary balance within cognitive science has changed over time. (...) Of particular concern is the fact that the use of computational methods appears to be on the wane. (shrink)

In this article, we examine the inter-relationship between moral theory and the unpredictable and complex world of primary health care, where the values of patient and doctor, or groups of patients and doctors, may often clash. We introduce complexity science and its relevance to primary care; going on to explore how it can assist in understanding ethical decision making, as well as considering implications for clinical practice. Throughout the article, we showcase aspects and key concepts using examples and a case (...) study developed from our day-to-day experience working as clinical practitioners in primary care. (shrink)

Autophagy and YAP1‐WWTR1/TAZ signalling are tightly linked in a complex control system of forward and feedback pathways which determine different cellular outcomes in differing cell types at different time‐points after perturbations. Here we extend our previous experimental and modelling approaches to consider two possibilities. First, we have performed additional mathematical modelling to explore how the autophagy‐YAP1 crosstalk may be controlled by posttranslational modifications of components of the pathways. Second, since analogous contrasting results have also been reported for (...) class='Hi'>autophagy as a regulator of other transduction pathways engaged in tumorigenesis (Wnt/β‐catenin, TGF‐β/Smads, NF‐kB or XIAP/cIAPs), we have considered if such discrepancies may be explicable through situations involving competing pathways and feedback loops in different cell types, analogous to the autophagy‐YAP/TAZ situation. Since distinct posttranslational modifications dominate those pathways in distinct cells, these need to be understood to enable appropriate cell type‐specific therapeutic strategies for cancers and other diseases. (shrink)

Does thinking have a history? If there are no necessarily changeless structures to be found in things and in our inquiry into them, then what knowledge of the world and ourselves is possible? In this boldly original and elegantly written study, Joseph Margolis argues for a radically historicized view of history that treats it as both a real process and a narrative account, each a product of continual change. Developing his argument through discussions of such influential philosophers of history and (...) the natural sciences as Vico, Danto, Collingwood, Habermas, Hempel, Popper, Putnam, and Gadamer, he provides a coherent theory of flux and invariance that resolves several deep puzzles regarding human nature and understanding. While maintaining a thorough command of Anglo-American philosophy, Margolis challenges many of its most cherished assumptions and demonstrates the sense in which history and interpretation are one and the same. Exploring one of the master themes of this century, his book offers a novel theory of the human condition whose conclusions and concerns seem certain to inform philosophy in the next century as well. (shrink)

The explanation of inertia based on “Mach's principle” is briefly revisited and an experiment whereby the gravitational origin of inertia can be tested is described. The test consists of detecting a small stationary force with a sensitive force sensor. The force is presumably induced when a periodic transient Mach effect mass fluctuation is driven in high voltage, high energy density capacitors that are subjected to 50 kHz, 1.3 kV amplitude voltage signal, and threaded by an alternating magnetic flux of (...) the same frequency. An effect of the sort predicted is shown to be present in the device tested. It has the expected magnitude and depends on the relative phase of the Mach effect mass fluctuation and the alternating magnetic flux as expected. The observed effect also displays scaling behaviors that are unique to Mach effects. Other tests for spurious signals suggest that the observed effect is real. (shrink)

Programmed cell death is a critical part of normal development, removing obsolete tissues or cells and sculpting body parts to assume their appropriate form and function. Most programmed cell death occurs by apoptosis of individual cells or autophagy of groups of cells. Although these pathways have distinct morphological characteristics, they also have a number of features in common, suggesting some overlap in their regulation. A recent paper by Lee and Baehrecke provides further support for this proposal.(1) These authors present, (...) for the first time, a genetic analysis of autophagy, using the steroid‐triggered metamorphosis of Drosophila as a model system. They demonstrate a remarkable degree of overlap between the control of apoptosis and autophagy as well as a key role for the steroid‐inducible gene E93 in directing the autophagic death response. This paper also shows that E93 can direct cell death independently from the known death‐inducer genes, defining a novel death pathway in Drosophila. BioEssays 23:677–682, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

The Sixth International Round Table on Law and Semiotics, sponsored and organized by "The Center for Semiotic Research in Law, Government and Economics," convened April 29, 30, May 1, 2, 1992, at Penn State-Berks. Under the general topic, "Flux, Complexity, Illusion," special sessions on the following topics resulted in this wide-ranging collection of papers: Legal Semiotics Theory; Law and Literature; Law and Economics: Intertexts in Legal Semiotics; Codification, Custom and Legal Norms. These papers represent interdisciplinary inquiry that explores the (...) assumptions that a) law is a complex sign-system which dialogically interacts with other social organizations; b) law is an indeterminate and open-ended concept in both theory and practice that contributes to the process of creating and affirming social values; and c) all sign-systems are self-correcting and self-directing. (shrink)

Paradigms in philosophy and cognitive science until recently have treated perception in typical human beings as relatively fixed and unchanging. Recent research instead supports the claim that perception can be altered over time by training, deliberate practice or mere exposure. If so, we do not all bring to a scene the same stock of perceptual capacities, and our differences are not just deficits or superpowers. This paper describes six questions an account of perceptual learning ought to address, which pose difficult (...) challenges to Kevin Connolly’s (2019) groundbreaking Offloading View of perceptual learning. In light of these questions, it sketches an alternative simple view according to which perceptual learning is acquiring a new or enhanced perceptual capacity in a particular way. The relevant capacity is a capacity perceptually to detect and differentiate a feature, where doing so constitutively if not wholly implicates perception. The relevant way is by means of an independently characterized learning process, rather than by adaptation, pure development, or mere accident. The perceptual change thus results from a smart process – one that is flexible, resilient, and responsive to feedback, rather than rigid, fragile and brute. Such a process can yield perceptual know-how. Thanks to perceptual learning, one comes to know how to perceive, in a sense that means being able to do so. Some specialists hone this to develop perceptual skills that are implicated in expert performance. (shrink)

This essay aims to answer the question: how does Žižek reconcile Hegel’s immanence of gap with Deleuze’s immanence of flux? The contrast between the Deleuzian flux and the Hegelian gap is positivity versus negativity, externality versus internality, and virtuality versus actuality. Via Lacanian not-all, Žižek inserts Hegelian negativity into the absolute positivity of the Deleuzian univocity. In keeping up with Hegelian immanence without externality, Žižek encloses Deleuzian externality by regarding anti-Oedipus as the inner transgression of desire via the (...) shift of perspective. Ending up with the subject supposed to know via retroactivities, the Deleuzian subject as desire finds an affinity with the Hegelian subject of letting-it-be. The reconciliation is mutual. Though Žižek tries to reconcile Deleuzian pure difference with self-identity, and pure repetition with self-sublation and negativity, Hegelian negativity is interpreted as the repetitive death drive, and a Hegelian coherent narration of Hegel-Kierkegaard-Freud-Deleuze is developed. What we get in the end is a Hegelian Deleuze, and Hegel as the Platonist of the virtual. (shrink)

I observe Iris Murdoch's distinctive use of the word ‘flux’ in discussion of Sartre's Nausea and show that her usage is persuasive and revolutionary, first as Sartre exegesis, second as Heraclitus exegesis, and throughout as a contribution to the philosophy of language. Murdoch's usage of ‘flux’ frames a comparison of Sartre's Roquentin with other figures who have had similarly flowing experience but without nausea. Roquentin's plight is shown to be ‘a philosopher's plight’ precipitated by a defective theory of (...) descriptive success. I then show how the Heraclitean fragments would support Murdoch's treatment of flux and on close analysis contradict the established view exemplified in the work of Wittgenstein and Jonathan Barnes. Flux is not a variety of change, and the river image ‘cannot be analysed into non-metaphorical components without a loss of substance’. (shrink)

In his various lectures and writings, Whitehead articulates an evolving metaphysical vision in which process and relationship, rather than stasis and independent fixity, are primary. In so doing he performs a valuable philosophical service, pointing the way towards liberation from certain constraining assumptions and habits of thought. However, there are components of his vision that retain elements of fixity and separateness. I find these to be the aspects of his philosophy that are the most problematic, both in respect to internal (...) con­ceptual coherency and in relation to my own philosophical and spiritual vision. My intention is to elucidate some of the ways in which these components of his philosophy are problematic, and to present an alternative vision in which these elements of fixity and ontological separateness dissolve into a dynamic openness of flux and interrelationship. (shrink)

In his various lectures and writings, Whitehead articulates an evolving metaphysical vision in which process and relationship, rather than stasis and independent fixity, are primary. In so doing he performs a valuable philosophical service, pointing the way towards liberation from certain constraining assumptions and habits of thought. However, there are components of his vision that retain elements of fixity and separateness. I find these to be the aspects of his philosophy that are the most problematic, both in respect to internal (...) con­ceptual coherency and in relation to my own philosophical and spiritual vision. My intention is to elucidate some of the ways in which these components of his philosophy are problematic, and to present an alternative vision in which these elements of fixity and ontological separateness dissolve into a dynamic openness of flux and interrelationship. (shrink)

The article is a reflection occasioned by an impression of Aristotle’s irritation at the views of the Heracliteans. It offers a reflection that is inspired by, companioned by Heraclitus. It looks at aspects of the approaches of Hegel and Nietzsche as also taking a companioning approach. There is something resistant in Heraclitus’s mode of articulation that makes one diffident in claiming that now at last one is the privileged one to understand him. Heraclitus offers us striking thoughts that strike one (...) into thought—that open up philosophical porosity to the deepest perplexities. In more detail, the author considers what is intended by flux-gibberish and how this bears on the determinacy and constancy of intelligibility. If some pervading sense of the flow of becoming must be granted, how does this bear on the constancy of intelligibility? How can we think the flow and the constancy together? (shrink)

The Influence of turbulence on nutrient fluxes towards phytoplankton cells has been previously estimated, but those studies did not take into account the intermittent nature of turbulent processes. This has been investigated here comparing the nutrient fluxes obtained using both mean and instantaneous turbulent energy dissipation rates. This approach shows that the size of cell potentially influenced by turbulence is lower than previously indicated, and that the spectral average estimate of the turbulence effect overestimates the flux. The capacity of (...) cell to use such intermittent flux is then discussed. (shrink)

Cet ouvrage interroge les articulations problématiques entre art, flux et contemporain, à partir de pratiques artistiques actuelles où interviennent le quotidien, le sociologique et le collectif. Traversé par des flux de toute sorte, le monde contemporain soulève la question de sa représentabilité, alors que les artistes ont, depuis toujours, éprouvé le besoin de se mettre en adéquation avec lui. Comment en effet montrer ce qui sans cesse se meut? Pourquoi suivre les mouvances du monde? Et finalement, que peut (...) l'art d'aujourd'hui? Il s'agit pour les artistes d'adopter une position de contemporanéité car toute observation du monde, fût-elle opérée sur un mode contemplatif, ne peut être l'objet de l'inactif et de l'inopérant. C'est pourquoi "devenir contemporain" est une nécessité, une injonction politique et éthique aussi bien qu'esthétique. Il nous faut dès lors entreprendre une "esthétique du contemporain", elle qui nous portera vers un "contemporain de l'esthétique" guidé par les flux et les devenirs. (shrink)

At first glance, Nietzsche and Bergson appear wholly opposed. Where the former pulls back the veil of all so-called reality to reveal the fictional constructions our bodily needs cast as what is re...

Joseph Agassi is a critic, a gadfly, a debunker and deflater; he is also a constructor, a speculator and an imaginative scholaro In the history and philosophy of science, he has been Peck's bad boy, delighting in sharp and pungent criticism, relishing directness and simplicity, and enjoying it all enormously. As one of that small group of Popper's students (ineluding Bartley, Feyerabend and Lakatos) who took Popper seriously enough to criticize him, Agassi remained his own man, holding Popper's work itself (...) to the criteria of critical refutation. Agassi's range is wide and his publications proliik. He has published serious studies in the historiography of science, applied sociology (on Hong Kong with LC. Jarvie), foundations of anthropology, interpretive scientific biography (Faraday), Judaic studies, philosophy of technology (which Agassi pioneered, particulady in distinguishing it from the philosophy of science), as weIl as the many works on the Iogic, methodoI­ ogy, and history of science. Even as we go to press, Agassi's works are appearing; we append an imperfect and selected bibliography. For Agassi, the test of relevance is whether something is interesting. (shrink)

Activity-dependent neuroprotective protein, discovered in our laboratory in 1999, has been characterized as a master gene vital for mammalian brain formation. ADNP de novo mutations in humans result in a syndromic form of autism-like spectrum disorder, including cognitive and motor deficits, the ADNP syndrome. One of the most important cellular processes associated with ADNP is the autophagy pathway, recently discovered by us as a key player in the pathophysiology of schizophrenia. In this regard, given the link between the microtubule (...) and autophagy systems, the ADNP microtubule end binding protein motif, namely, the neuroprotective NAP, was found to enhance autophagy while protecting microtubules and augmenting ADNP's association with both systems. Thus, linking autophagy and ADNP is proposed as a major target for intervention in brain diseases from autism to Alzheimer's disease and our findings introduce autophagy as a possible novel target for treating schizophrenia. Activity-dependent neuroprotective protein binds to microtubule-associated protein light chain 3, which forms the membrane of the autophagosome, a key organelle in the autophagy process and regulates beclin1 formation, an inducer of autophagy. Autophagy plays a major role in Alzheimer's disease and as recently discovered in schizophrenia and autism. (shrink)

Language, either oral or written, is meant both to convey and to preserve meaning. Semiotics is thediscipline which permits the extraction of a meaning from systems of linguistic signs. Written texts arestatic, while the world is about them is in flux. Meaning is thus intimately connected to this marriageof flux and stasis in texts.Here, three views on semiotics are examined:First, Plato’s treatment of signs and flux in the dialogue Kratylos is dissected. The conventional andmimetic aspects of signs (...) are contrasted, and a connection between inquiry and stasis is intimated.Next, the Augustinian theory of signs, as delineated in De Doctrina Christiana, is presented. Thediversity of signs and several principles of hermeneutics are considered. In addition, the existence ofthe some Post-Modern notions of polysemy, trace, and fore-structures of understanding in Augustine’sthought is indicated. Also, the concepts of ineffability and of res summa in De Doctrina Christiana areexamined as starting points for a deconstructive critique of Augustinian semiotics.Third, Derrida's treatment of signifiers in Of Grammatology is analyzed as a turn to a semiotics ofthe flux. Finally, the oral concept of memory reveals a connection between flux and stasis. Thememory plays a role in the system of signs in creating a "generative reconstruction". According toAugustine, sign-making is also "incarnational." Humans retain something of the signs in memory;memory preserves the basis of the sign. This mnemic fundament may be constantly adjusted to thepresent reality, i.e. the flux; the epistemological and semiotic data base in oral cultures is generative orfluid.Memory ameliorates the semiotic tension between the flux of the world and the stasis of information in the system of signs. (shrink)

Language, either oral or written, is meant both to convey and to preserve meaning. Semiotics is the discipline which permits the extraction of a meaning from systems of linguistic signs. Written texts are static, while the world is about them is in flux. Meaning is thus intimately connected to this marriage of flux and stasis in texts. Here, three views on semiotics are examined: First, Plato's treatment of signs and flux in the dialogue Kratylos is dissected. The (...) conventional and mimetic aspects of signs are contrasted, and a connection between inquiry and stasis is intimated. Next, the Augustinian theory of signs, as delineated in De Doctrina Christiana, is presented. The diversity of signs and several principles of hermeneutics are considered. In addition, the existence of the some Post-Modern notions of polysemy, trace, and fore-structures of understanding in Augustine's thought is indicated. Also, the concepts of ineffability and of res summa in De Doctrina Christiana are examined as starting points for a deconstructive critique of Augustinian semiotics. Third, Derrida's treatment of signifiers in Of Grammatology is analyzed as a turn to a semiotics of the flux. Finally, the oral concept of memory reveals a connection between flux and stasis. The memory plays a role in the system of signs in creating a "generative reconstruction". According to Augustine, sign-making is also "incarnational." Humans retain something of the signs in memory; memory preserves the basis of the sign. This mnemic fundament may be constantly adjusted to the present reality, i.e. the flux; the epistemological and semiotic data base in oral cultures is generative or fluid. Memory ameliorates the semiotic tension between the flux of the world and the stasis of information in the system of signs. (shrink)

The autophagy initiation complex is brought about via a highly ordered and stepwise assembly process. Two crucial signaling molecules, mTORC1 and AMPK, orchestrate this assembly by phosphorylating/dephosphorylating autophagy‐related proteins. Activation of Atg1 followed by recruitment of both Atg9 vesicles and the PI3K complex I to the PAS (phagophore assembly site) are particularly crucial steps in its formation. Ypt1, a small Rab GTPase in yeast cells, also plays an essential role in the formation of the autophagy initiation complex (...) through multiple regulatory pathways. In this review, our primary focus is to discuss how signaling molecules initiate the assembly of the autophagy initiation complex, and highlight the significant roles of Ypt1 in this process. We end by addressing issues that need future clarification. (shrink)

When a cell divides, it produces two daughter cells initially connected by a cytokinesis bridge, which is eventually cut through abscission. One of the two daughter cells inherits a bridge “remnant”, which has been proposed to be degraded by autophagy. The fate and function of remnants is attracting increasing attention, as their accumulation appears to influence proliferation versus differentiation of the daughter cells. Here, we present a simple model for bridge and remnant turnover in a dynamic cell population. We (...) demonstrate that remnant proportions depend on the ratio of remnant and bridge lifetimes to the cell population doubling time. Our results yield new alternative interpretations for published experimental data, leading us to believe that autophagy‐independent pathways for remnant degradation may exist. In addition, using the model, we determined experimentally inaccessible parameters such as remnant lifetime. Our model proves to be a useful tool for studying bridge and remnant populations. (shrink)

AMP‐activated protein kinase (AMPK) is an evolutionarily conserved cellular switch that activates catabolic pathways and turns off anabolic processes. In this way, AMPK activation can restore the perturbation of cellular energy levels. In physiological situations, AMPK senses energy deficiency (in the form of an increased AMP/ATP ratio), but it is also activated by metabolic insults, such as glucose or oxygen deprivation. Metformin, one of the most widely prescribed anti‐diabetic drugs, exerts its actions by AMPK activation. However, while the functions of (...) AMPK as a metabolic regulator are fairly well understood, its actions in neuronal cells only recently gained attention. This review will discuss newly emerged functions of AMPK in neuroprotection and neurodegeneration. Additionally, recent views on the role of AMPK in autophagy, an important catabolic process that is also involved in neurodegeneration and cancer, will be highlighted. (shrink)

La pensee de Ludwig Wittgenstein est animee, tout au long des annees 1930 et 1940, par une meditation de la question du temps. C'est un de ses aspects les plus mal connus. Ce livre vise a restituer cette meditation dans sa force et sa singularite, afin d'etablir la contribution qu'elle apporte a la tradition qui s'est consacree a cette question majeure de la philosophie. Il montre d'abord comment la tentation d'accorder un privilege au present constitue un element essentiel du projet (...) phenomenologique wittgensteinien de 1929, avant d'explorer le travail critique auquel Wittgenstein soumet ce projet au cours des deux decennies suivantes, et qui le conduit a situer dans un certain rapport a notre langage l'origine de notre facon de penser la temporalite. Une analyse originale du langage ordinaire permet ainsi de reevaluer les theories classiques du temps que proposent la phenomenologie, la philosophie de la psychologie et la philosophie du langage. (shrink)