The number of cellular events identified as being directly or indirectly modulated by phosphoinositides dramatically increased in the recent years. Part of the complexity results from the fact that the seven phosphoinositides play second messenger functions in many different areas of growth factors and insulin signaling, cytoskeletal organization, membrane dynamics, trafficking, or nuclear signaling. PtdIns(3,4)P2 is commonly reported as a product of the SH2 domain‐containing inositol 5‐phosphatases 1/2 (SHIP1 and SHIP2) that dephosphorylate PtdIns(3,4,5)P3 at the 5‐position. Here we discuss (...) recent interest in PtdIns(3,4)P2 signaling highlighting its involvement in key cellular mechanisms such as cell adhesion, migration, and cytoskeletal regulation. We question and discuss the involvement of SHIP2 either as a PI 5‐phosphatase or as a scaffold protein in insulin signaling, cytoskeletal dynamics, and endocytosis of growth factor receptors. (shrink)

Recently, we have presented data supporting the notion that PIKfyve not only produces the majority of constitutive phosphatidylinositol 5‐phosphate (PtdIns5P) in mammalian cells but that it does so through direct synthesis from PtdIns. Another group, albeit obtaining similar data, suggests an alternative pathway whereby the low‐abundance PtdIns(3,5)P2 undergoes hydrolysis by unidentified 3‐phosphatases, thereby serving as a precursor for most of PtdIns5P. Here, we review the experimental evidence supporting constitutive synthesis of PtdIns5P from PtdIns by PIKfyve. We further emphasize that (...) the experiments presented in support of the alternative pathway are also compatible with a direct mechanism for PIKfyve‐catalyzed synthesis of PtdIns5P. While agreeing with the authors that constitutive PtdIns5P could theoretically be produced from PtdIns(3,5)P2 by 3‐dephosphorylation, we argue that until direct evidence for such an alternative pathway is obtained, we should adhere to the existing experimental evidence and quantitative considerations, which favor direct PIKfyve‐catalyzed synthesis for most constitutive PtdIns5P. (shrink)

Phosphatidylinositol 3‐phosphate (PtdIns3P) is generated on the cytosolic leaflet of cellular membranes, primarily by phosphorylation of phosphatidylinositol by class II and class III phosphatidylinositol 3‐kinases. The bulk of this lipid is found on the limiting and intraluminal membranes of endosomes, but it can also be detected in domains of phagosomes, autophagosome precursors, cytokinetic bridges, the plasma membrane and the nucleus. PtdIns3P controls cellular functions through recruitment of specific protein effectors, many of which contain FYVE or PX domains. Cellular processes known (...) to be controlled by PtdIns3P and its effectors include endosomal fusion, sorting and motility, autophagy, cytokinesis, regulated exocytosis and signal transduction. Here we discuss how Ptdins3P is generated on specific cellular membranes, how its localizations and functions can be studied, and how its effectors serve to control cellular functions.Editor's suggested further reading in BioEssays:Phosphatidylinositol 4,5‐bisphosphate: Targeted production and signalingAbstractHow does SHIP1/2 balance PtdIns(3,4)P2 and does it signal independently of its phosphatase activity?AbstractPhosphatidylinositol‐3,4,5‐trisphosphate: Tool of choice for class I PI 3‐kinasesAbstractPhosphatidylinositol‐4‐phosphate: The Golgi and beyondAbstract. (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)

Class I PI 3‐kinases signal by producing the signaling lipid phosphatidylinositol(3,4,5) trisphosphate, which in turn acts by recruiting downstream effectors that contain specific lipid‐binding domains. The class I PI 3‐kinases comprise four distinct catalytic subunits linked to one of seven different regulatory subunits. All the class I PI 3‐kinases produce the same signaling lipid, PIP3, and the different isoforms have overlapping expression patterns and are coupled to overlapping sets of upstream activators. Nonetheless, studies in cultured cells and in animals have (...) demonstrated that the different isoforms are coupled to distinct ranges of downstream responses. This review focuses on the mechanisms by which the production of a common product, PIP3, can produce isoform‐specific signaling by PI 3‐kinases.Editor's suggested further reading in BioEssays: Phosphatidylinositol 4,5‐bisphosphate: Targeted production and signaling AbstractHow does SHIP1/2 balance PtdIns(3,4)P2 and does it signal independently of its phosphatase activity? Abstract. (shrink)

Phosphatidylinositol‐3‐kinases (PI3Ks) are lipid kinases that produce 3‐phosphorylated derivatives of phosphatidylinositol upon activation by various cues. These 3‐phosphorylated lipids bind to various protein effectors to control many cellular functions. Lipid phosphatases such as phosphatase and tensin homolog (PTEN) terminate PI3K‐derived signals and are critical to ensure appropriate signaling outcomes. Many lines of evidence indicate that PI3Ks and PTEN, as well as some specific lipid effectors are highly compartmentalized, either in plasma membrane nanodomains or in endosomal compartments. We examine the (...) evidence for specific recruitment of PI3Ks, PTEN, and other related enzymes to membrane nanodomains and endocytic compartments. We then examine the hypothesis that scaffolding of the sources (PI3Ks), terminators (PTEN), and effectors of these lipid signals with a common plasma membrane nanodomain may achieve highly localized lipid signaling and ensure selective activation of specific effectors. This highlights the importance of spatial regulation of PI3K signaling in various physiological and disease contexts. (shrink)

Joining an antagonistic phosphoinositide (PtdInsP) kinase and phosphatase into a single protein complex may regulate rapid and local PtdInsP changes. This may be important for processes such as membrane fission that require a specific PtdInsP and that are innately local and rapid. Such a complex could couple vesicle formation, with erasing of the identity of the donor organelle from the vesicle prior to its fusion with target organelles, thus preventing organelle identity intermixing. Coordinating signals are postulated to switch the relative (...) activities of the kinase and phosphatase in a spatio‐temporal manner that matches membrane fission events. The discovery of two such complexes supports this hypothesis. One regulates the interconversion of phosphatidylinositol and PtdIns(3)P by joining the Vps34 PtdIns 3‐kinase and the myotubularin 3‐phosphatases. The other regulates the interconversion between PtdIns(3)P and PtdIns(3,5)P2 through the Fab1/PIKfyve kinase and the Fig4/mFig4 phosphatase. These lipids are essential components of the endosomal identity code. (shrink)

Sister chromatid cohesion mediated by the ring‐shaped cohesin complex is essential for faithful chromosome segregation. A tight spatial and temporal control of cohesin release is observed in mitosis and meiosis, and a family of proteins known as shugoshins play a major role in this process. Shugoshin (Sgo) protects centromeric cohesin from dissociation in early mitosis and from cleavage by separase in meiosis I. Three exciting new reports indicate that this is accomplished by recruiting the serine/threonine protein phosphatase 2A (PP2A) to (...) centromeres.(1–3) The proposed targets of PP2A activity include cohesin and Sgo, both of which would otherwise dissociate from chromosomes upon phosphorylation by Polo kinase. Thus, a balance of kinase and phosphatase activities seems to be the key to the conserved mechanism that regulates the stepwise release of cohesin from mitotic and meiotic chromosomes. Additional evidence, however, suggests that this is only part of the story, and that Sgo has also a role independent of PP2A. BioEssays 28: 775–779, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

The three cycles of cell division immediately following theformation of the cellular blastoderm during Drosophila embryogenesis display an invariant pattern(1,2). Bursts of transcription of a gene called string are required and sufficient to trigger mitosis at this time during development(3). The activator of mitosis encoded by the string gene is a positive regulator of cdc2 kinase and a Drosophila homologue of the Saccharomyces pombe cdc25 tyrosine phosphatase(4,5). Evidence presented in a recent paper(6) demonstrates that transcription of string, and hence the (...) timing and pattern of mitosis in the postblastoderm embryo, is under complex developmental control. Several lines of evidence support this interpretation, including the analysis of string transcription in pattern formation mutants, cell cycle arrest mutants, and the preliminary characterization of an extensive cis‐acting regulatory region. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Response 3: Transgressive Utopianism and Direct ActivismHeather AlberroThis is an important time to revisit questions concerning the historical underpinnings of utopianism as a mode of praxis and theoretical endeavor, its potential oversights and where it ought to venture in the decades to come. The multidisciplinary Hispanic utopian project Histopia discussed by Ramirez-Blanco offers a helpful starting point for this discussion. Especially noteworthy, in my view, is Histopia’s recognition of (...) and interest in engaging with manifestations of utopianism beyond academia and examining the full spectrum of the utopian imaginary, from texts to social movements. Similarly important is what Ramirez-Blanco alludes to as Histopia’s laudable attempts to “decenter” the discipline toward the Spanish-speaking world. This recalls the wider, vital work of decolonizing utopian studies highlighted by Edwards and others in this piece so that it is inclusive of the immeasurably diverse array of utopian imaginaries and modes of praxis around the globe. To reduce such diverse manifestations to the lens of a single medium or cultural-historical context would be a profound intellectual and ethical misdeed.A related example of such decolonial work is Histopia’s emphasis on history as opposed to the canon’s traditional emphasis on texts. Here, I was [End Page 550] wondering if you (Ramirez-Blanco) could elaborate further on what this entails. That is, what is Histopia’s conceptualization of history vis-à-vis the now and “to-come,” and their relation more generally to the utopian impulse? Is this conceptualization akin to the (Western) utopian conception of time as a linear progression from an archaic past toward a radiant future toward some “advanced” end state?1 Or does it depart from this modernist construct and, if so, in what ways? What is the role of prefigurative (utopian) activist movements in the history of social transformation, in your view?With movements like 15M in Spain that you discuss, what do you see as the transformative utopian potential of their denunciations of the status quo, however fleeting? What of their annunciations? That is, what were they gesturing toward, and what did their imaginings of “a better” consist of? How do public assemblies as “performances” factor into these visions? I’m curious to know what patterns, if any, can be traced across contemporary left-social movements. My own research with radical environmental activists has found that they exhibit the former aspect of the utopian mode—denunciation—with immense power and potency. Like the 15M movement, their direct activism is postparliamentary given their profound disaffection with the capitalist state and its perceived collusion with extractive industries driving ecological breakdown. The aspect of annunciation for them, however, is much more complex and fragmented. They are similarly engaged in constant deliberations over the relative strengths and weaknesses of alternative modes of political organization and participation, particularly concerning which actors may be excluded. However, they do exhibit a consensus on certain things—especially their fervent desire for a renewed abundance of terrestrial life forms and an equally fervent refusal of the worst of possible worlds consisting of substantially diminished other-than-human life forms.The question raised by Antonis concerning blueprints, or utopian modalities that provide fleshed-out visions of better worlds, is a similarly pertinent one for two key reasons: (1) in connection with the aforementioned vital work of decolonizing the utopian canon and imaginary, and (2) as a possible response to the mounting socio-ecological depredations of late-stage capitalism and the theft of the now and to-come from growing portions of the earth’s inhabitants. As Antonis highlights, some have suggested that utopianism’s pursuit of human and societal perfectibility—especially “blueprint” modalities aiming to implement a particular conception of “the good society”—harbor seeds of totalitarianism and intolerance of difference.2 [End Page 551] Indeed, inklings toward domination can be seen within some totalizing/blue-printing utopias and their cultural-historical links to Enlightenment projects of universal conquest, namely the hegemonic “utopias” of Western modernity in the form of colonial-capitalism.3 These totalizing visions of progress and “the good life” have been systematically ending other-than-Western worlds for centuries, leading to our present state of ruination.Hence why subsequent modalities... (shrink)

The most important things in this seminal paper are (a) showing that the first part of the chapter is only setting up the aporia and does not provide the solution; (b) showing that the rest of the chapter provides the material for resolving the aporia; (c) showing that the question is not about how we perceive that we perceive, but how we can distinguish between seeing and hearing—how we are aware that we are seeing rather than hearing; (c) showing that (...) this is reducible to how we are aware that a colour is not a sound, and how we perceive the unity of objects that present themselves under more than one sense-modality. Hence the remainder of De anima 3.2 presents both the materials for the solution (actuality of sense and sensed object are one thing) and the solution (there is a common perceiver who receives the input from several senses and can unite them and also differentiate). De anima 3.2 is not about perceiving that we perceive, nor about reflexive self-awareness. The problems of interpretation and of the unity of the chapter are resolved once we see that the topic is how we can tell the difference between input from different sense modalities, how we distinguish between white things and sweet things, or between seeing and hearing, and how we perceive objects as a unity when they present themselves to separate senses. (shrink)

L'A. étudie la concurrence entre la matière, la forme et la composition de matière et de forme, pour le titre de substance première ousia dans la «Métaphysique» Z, 3 d'Aristote. L'A. s'oppose à l'interprétation qu'en donne L. Gill dans son livre «Aristotle on Substance: The Paradox of Unity», selon laquelle l'ει~δο et la composition sont toutes deux premières. L'A. propose une explication qui s'inscrit dans le cadre métaphysique de la théorie de la recherche.

The purpose of this article is to discuss some basic problems and methodological steps concerning the encounter between Hebrews and Greeks in the Classical period and its impact on the Hellenistic era. The relationship between the Old Testament and Ancient Greek literature will be examined on the basis of Genesis 2–3 and Alcibiades’s speech in Plato’s Symposium. The following considerations and models of interpretation can arise from the analysis of Alcibiades’s speech compared to M- and LXX-Genesis 2–3: Ancient Greek writers (...) were familiar with Old Testament oral or written traditions through improvised translations. They prepared the way for the LXX and, in their compositions, were in dispute with them although they do not make specific references to the Hebrews and their literature; Hebrew authors knew the works of Ancient Greek authors and used Greek philosophical terminology which they creatively adapted to Semitic models; Both models are possible. One should not rush to any decisions but examine each case individually, in the original language. (shrink)

We present some results on countable homogeneous 3-hypergraphs. In particular, we show that there is no unexpected homogeneous 3-hypergraph determined by a single constraint.

Necessary and sufficient conditions ofinvariance on four-vectors under the Poincaré group E(3, 1) and its subgroups are exploited. As an example the Euclidean group in three dimensions and its subgroups are explicitly considered. Their invariant “potentials” are systematically derived.

Hoje eu gostaria de completar o que iniciei anteriormente a respeito da parrhesia e a crise das instituições democráticas no século 4 a.C. E, a seguir, gostaria de deslocarme para outra forma de parrhesia: a parrhesia no campo das relações pessoais, ou parrhesia e o cuidado de si.