Phosphatidylinositol 4,5‐bisphosphate (PI4,5P2) is a key lipid signaling molecule that regulates a vast array of biological activities. PI4,5P2 can act directly as a messenger or can be utilized as a precursor to generate other messengers: inositol trisphosphate, diacylglycerol, or phosphatidylinositol 3,4,5‐trisphosphate. PI4,5P2 interacts with hundreds of different effector proteins. The enormous diversity of PI4,5P2 effector proteins and the spatio‐temporal control of PI4,5P2 generation allow PI4,5P2 signaling to control a broad spectrum of cellular functions. PI4,5P2 is synthesized by (...) phosphatidylinositol phosphate kinases (PIPKs). The array of PIPKs in cells enables their targeting to specific subcellular compartments through interactions with targeting factors that are often PI4,5P2 effectors. These interactions are a mechanism to define spatial and temporal PI4,5P2 synthesis and the specificity of PI4,5P2 signaling. In turn, the regulation of PI4,5P2 effectors at specific cellular compartments has implications for understanding how PI4,5P2 controls cellular processes and its role in diseases. (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‐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)

Recent studies of the low abundant signaling lipid, phosphatidylinositol 3,5‐bisphosphate (PI(3,5)P2), reveal an intriguingly diverse list of downstream pathways, the intertwined relationship between PI(3,5)P2 and PI5P, as well as links to neurodegenerative diseases. Derived from the structural lipid phosphatidylinositol, PI(3,5)P2 is dynamically generated on multiple cellular compartments where interactions with an increasing list of effectors regulate many cellular pathways. A complex of proteins that includes Fab1/PIKfyve, Vac14, and Fig4/Sac3 mediates the biosynthesis of PI(3,5)P2, and mutations that disrupt complex (...) function and/or formation cause profound consequences in cells. Surprisingly, mutations in this pathway are linked with neurological diseases, including Charcot‐Marie‐Tooth syndrome and amyotrophic lateral sclerosis. Future studies of PI(3,5)P2 and PI5P are likely to expand the roles of these lipids in regulation of cellular functions, as well as provide new approaches for treatment of some neurological diseases. (shrink)

Currently, a central question in biology is how signals from the cell surface modulate intracellular processes. In recent years phosphoinositides have been shown to play a key role in signal transduction. Two phosphoinositide pathways have been characterized, to date. In the canonical phosphoinositide turnover pathway, activation of phosphatidylinositol‐specific phospholipase C results in the hydrolysis of phosphatidylinositol 4,5‐bisphospate and the generation of two second messengers, inositol 1,4,5‐trisphosphate and diacylglycerol. The 3‐phosphoinositide pathway involves protein‐tyrosine kinase‐mediated recruitment and activation of (...) class='Hi'>phosphatidylinositol 3‐kinase, resulting in the production of phosphatidylinositol 3,4‐bisphosphate and phosphatidylinositol 3,4,5‐trisphosphate. The 3‐phosphoinositides are not substrates of any known phospholipase C, are not components of the canonical phosphoinositide turnover pathway, and may themselves act as intracellular mediators. The 3‐phosphoinositide pathway has been implicated in growth factor‐dependent mitogenesis, membrane ruffling and glucose uptake. Furthermore the homology of the yeast vps34 with the mammalian phosphatidylinositol 3‐kinase has suggested a role for this pathway in vesicular trafficking.In this review the different mechanisms employed by protein‐tyrosine kinases to activate phosphatidylinositol 3‐kinase, and its involvement in the signaling cascade initiated by tyrosine phosphorylation, are examined. (shrink)

Disabled‐2 (Dab2) is a multimodular scaffold protein with signaling roles in the domains of cell growth, trafficking, differentiation, and homeostasis. Emerging evidences place Dab2 as a novel modulator of cell–cell interaction; however, its mode of action has remained largely elusive. In this review, we highlight the relevance of Dab2 function in cell signaling and development and provide the most recent and comprehensive analysis of Dab2's action as a mediator of homotypical and heterotypical interactions. Accordingly, Dab‐2 controls the extent of platelet (...) aggregation through various motifs within its N‐terminus. Dab2 interacts with the cytosolic tail of the integrin receptor blocking inside‐out signaling, whereas extracellular Dab2 competes with fibrinogen for integrin αIIbβ3 receptor binding and, thus, modulates outside‐in signaling. An additional level of regulation results from Dab2's association with cell surface lipids, an event that defines the extent of cell–cell interactions. As a multifaceted regulator, Dab2 acts as a mediator of endocytosis through its association with the [FY]xNPx[YF] motifs of internalized cell surface receptors, phosphoinositides, and clathrin. Other emerging roles of Dab2 include its participation in developmental mechanisms required for tissue formation and in modulation of immune responses. This review highlights the various novel mechanisms by which Dab2 mediates an array of signaling events with vast physiological consequences. (shrink)

SummaryMuch excitement surrounded the proposal that a family of endo‐lysosomal channels, the two‐pore channels (TPCs) were the long sought after targets of the Ca2+‐mobilising messenger, nicotinic acid adenine dinucleotide phosphate (NAADP). However, the role of TPCs in NAADP signalling may be more complex than originally envisaged. First, NAADP may not bind directly to TPCs but via an accessory protein. Second, two papers recently challenged the notion that TPCs are NAADP‐regulated Ca2+ channels by suggesting that they are highly selective Na+ channels (...) regulated by the lipid phosphatidylinositol 3,5‐bisphosphate and by ATP. This paper aims critically to evaluate the evidence for TPCs as NAADP targets and to discuss how the new findings fit in with what we know about endo‐lysosomal Ca2+ stores. (shrink)

Phagocytosis is an uptake of large particles governed by the actin-based cytoskeleton. Binding of particles to specific cell surface receptors is the first step of phagocytosis. In higher Eucaryota, the receptors able to mediate phagocytosis are expressed almost exclusively in macrophages, neutrophils, and monocytes, conferring immunodefence properties to these cells. Receptor clustering is thought to occur upon particle binding, that in turn generates a phagocytic signal. Several pathways of phagocytic signal transduction have been identified, including the activation of tyrosine kinases (...) and (or) serine/threonine kinase C in pivotal roles. Kinase activation leads to phosphorylation of the receptors and other proteins, recruited at the sites of phagocytosis. Monomeric GTPases of the Rho and ARF families are likely to be engaged downstream of activated receptors. The GTPases, in cooperation with phosphatidylinositol 4-phosphate 5-kinase and phosphatidylinositol 3-kinase lipid modifying enzymes, can modulate locally the assembly of the submembranous actin filament system leading to particle internalization. BioEssays 21:422–431, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

Initially identified as a key phosphoinositide that controls membrane trafficking at the Golgi complex, phosphatidylinositol‐4‐phosphate (PI4P) has emerged as a key molecule in the regulation of a diverse array of cellular functions. In this review we will discuss selected examples of the findings that in the last few years have significantly increased our awareness of the regulation and roles of PI4P in the Golgi complex and beyond. We will also highlight the role of PI4P in infection and cancer. We (...) believe that, with the increasing number of regulators and effectors of PI4P identified, the time is ripe for a more integrated approach of study. A first step in this direction is the delineation of PI4P‐centered molecular networks that we provide using data from low and high throughput studies in yeast and mammals. (shrink)

The type II phosphatidylinositol 4-kinases produce the lipid phosphatidylinositol 4-phosphate and participate in a confusing variety of membrane trafficking and signaling roles. This review argues that both historical and contemporary evidence supports the function of the PI4KIIs in numerous trafficking pathways, and that the key to understanding the enzymatic regulation is through membrane interaction and the intrinsic membrane environment. By summarizing new research and examining the trafficking roles of the PI4KIIs in the context of recently solved molecular structures, (...) I highlight how mechanisms of PI4KII function and regulation are providing insights into the development of cancer and in neurological disease. I present an integrated view connecting the cell biology, molecular regulation, and roles in whole animal systems of these increasingly important proteins. The type II phosphatidylinositol 4-kinases are versatile mediators of membrane trafficking, controlling pathways that impact on disease. Recent advances suggest that the membrane lipid environment regulates enzyme activity and that the complexity of trafficking routes can be explained by the ability of these kinases to promote membrane trafficking in different directions. (shrink)

This paper examines the puruṣa concept in the Caraka Saṃhitā, an early text of Ayurveda, and its relation to Indic thinking about phenomenal worldhood. It argues that, contrary to the usual interpretation, early Ayurveda does not consider the person to be a microcosmic replication of the macrocosmos. Instead, early Ayurveda asserts that personhood is worldhood, and thus the person is non-different from the phenomenal totality of his existence. This is confirmed by the CS’s several definitions of puruṣa, which are alternately (...) posed in terms familiar to Vaiśeṣika, early Sāṃkhya, early Buddhism, and Upaniṣadic monism. It is likewise confirmed by the Ayurvedic logic of sāmānya, which governs the meaning of the list of person-to-world correspondences in CS 4.5 and its often misinterpreted claim, puruṣo’yam lokasaṃmitaḥ. Finally it is confirmed in the program of Ayurvedic therapeutics, which aims at establishing various kinds of “appropriateness” for the sake of effecting samayoga—the “harmonious joining” of person and world. (shrink)

Hoc tempore velut per universum orbem Romanum, bellicum canentibus bucinis, excitae gentes saevissimae, limites sibi proximos persultabant. Gallias Raetiasque simul Alamanni poputabantur; Sarmatae Pannonias et Quadi; Picti Saxonesque et Scotci, et Attacotti Brittanos aerumnis vexavere continuis; Austoriani Mauricaeque aliae gentes, Africam solito acrius incursabant; Thracias et diripiebant praedatorii globi Gothorum. Persarum rex manus Armeniis iniectabat, eos in suam dicionem ex integro vocare vi nimia properans, sed iniuste, causando, quod post Ioviani excessum, cum quo foedera firmarat et pacem, nihil obstare debebit, (...) quo minus ea recuperaret, quae antea ad maiores suos pertinuisse monstrabat. (shrink)

La narración de la experiencia visionaria del culto celestial en Ap 4-5 desvela dramá- ticamente el culto celestial. Los seres celestiales tributan el culto al que está sentado en el trono y al Cordero. Ambos, el Sentado y el Cordero, son los únicos dignos destinatarios de este culto. Todas las criaturas los reconocen como seres divinos. El hecho de dar culto a ambos supone una modificación innovadora del monoteísmo judío del segundo templo. Así, en su visión, Juan participó en el (...) culto celestial reconociendo la divinidad del Cordero que compartió los mismos honores con el Creador del universo. (shrink)

Εκτενής Βιβλιοκριτική της έκδοσης: Plotinus Ennead VI.4 and VI.5: On the Presence of Being, One and the Same, Everywhere as a Whole («The Enneads of Plotinus with Philosophical Commentaries»). Εισαγωγή, αγγλική μετάφραση, υπόμνημα Eyjolfur Kjalar Emilsson & Steven Keith Strange. Las Vegas/Zurich/Athens: Parmenides Publishing 2015, 305 σ., 36 €.

Die Beiträge zur Altertumskunde enthalten Monographien, Sammelbände, Editionen, Übersetzungen und Kommentare zu Themen aus den Bereichen Klassische, Mittel- und Neulateinische Philologie, Alte Geschichte, Archäologie, Antike Philosophie sowie Nachwirken der Antike bis in die Neuzeit. Dadurch leistet die Reihe einen umfassenden Beitrag zur Erschließung klassischer Literatur und zur Forschung im gesamten Gebiet der Altertumswissenschaften.

Phosphatidylinositol 5‐phosphate (PtdIns5P), the least characterized among the three phosphatidylinositol monophosphates, is emerging as a bioactive lipid involved in the control of several cellular functions. Similar to PtdIns3P, it is present in low amounts in mammalian cells, and can be detected at the plasma membrane and endomembranes as well as in the nucleus. Changes in PtdIns5P levels are observed in mammalian cells following specific stimuli or stresses, and in human diseases. Recently, the contribution of several enzymes such as (...) PIKfyve, myotubularins, and type II PtdInsP‐kinases to PtdIns5P metabolism has gained a strong experimental support. Here, we provide a picture emerging from recent studies showing how this lipid can be generated and act as a regulator of membrane and cytoskeleton dynamics, and as a modulator of gene expression. We briefly summarize the current methods and tools for studying PtdIns5P, and discuss how PtdIns5P can integrate and coordinate different functions in a spatiotemporal manner. (shrink)

This essay considers how current theories of narrative inform how we read the complexities of the relationship among Abraham, Sarah, and Hagar in Gen. 16.4-5. It argues that, while we may no longer have access to the oral counter narrative of Gen. 16.4-5, deconstructive criticism, which–among other things – teaches us that a text can be most revealing in those places in which it is most notably silent, may allow for a possible recovery of the oral, unrecorded narrative of the (...) servant Hagar. (shrink)

In the passage about the flax plant, lini natura et miracula at the beginning of Book 19 of his Naturalis historia, Pliny launches into a moralizing diatribe on man's assault against Nature, fulminating against the evils which man brings upon himself by taking to the high seas in ships with sails. The passage culminates in the rhetorical outburst audax uita, scelerumque plena, which serves as something of a moral aphorism for the jeremiad as a whole. Although it has been the (...) subject of much discussion in Plinian scholarship, the text still remains in need of attention : audax uita, scelerumque plena! aliquid seri, ut uentos procellasque capiat, 5. et parum esse fluctibus solis uehi, iam uero nec uela satis esse maiora nauigiis, sed, cum uix amplitudini antemnarum singulae arbores sufficiant, super eas tamen addi alia uela, praeterque alia in proris et alia in puppibus pandi, ac tot modis prouocari mortem, denique tam paruo semine nasci quod orbem terrarum ultro citro portet, tam gracili auena, tam non alte a tellure tolli, neque id uiribus suis necti, sed fractum tunsumque et in mollitiem lanae coactum iniuria ad summam audaciam peruenire! (shrink)

Notre article analyse deux passages curieux du traité Sur les difficultés relatives à l’âme III. De la vision (Enn. IV.5,3 et 8), dans lesquels Plotin paraît concevoir la possibilité d’un autre univers, situé en dehors du nôtre. Or, cet autre univers doit rester inconnu pour nous à jamais, quand bien même il y aurait un « oeil placé sur le dos du Ciel » qui voudrait le voir. En outre, nous ne saurons même pas décider si cet univers existe ou (...) non. En effet, explique Plotin, plusieurs univers ne peuvent absolument pas communiquer entre eux, précisément parce qu’ils forment des univers différents. S’ils communiquaient, ils seraient autant de parties du même univers et non pas des univers séparés, parce que la communication (la sympathie dans les termes de Plotin) circule seulement à l’intérieur du même univers. Nous rapprochons cet intéressant argument de certaines idées astrophysiques modernes et de la philosophie « des mondes possible » de David Lewis, sans pour autant pratiquer une lecture « modernisante » de Plotin. (shrink)

In this paper, the author offers an introduction to Marsilius of Inghen’s treatment of expositiones of sentences de incipit and de desinit in his treatise on Consequentiae, with an analysis of the various modi exponendi presented by Marsilius and an edition of the text. The author argues that, in the split between physical and logical approaches to the issues arising in analyses of incipit and desinit, Marsilius’ theory presents some hybrid features, but tends towards the logical end of the spectrum.