An important feature of male fertility is the physiological priming of spermatozoa by a multifaceted process collectively referred to as capacitation. The end point of this evasive process is the hyperactivated spermatozoa capable of binding to terminal sugar residues on the egg's extracellular coat, the zona pellucida (ZP), and undergoing acrosomal exocytosis (i.e., induction of the acrosome reaction). The hydrolytic action of acrosomal enzymes released at the site of zona binding, along with the enhanced thrust generated by the hyperactivated beat (...) pattern of the bound spermatozoa, are important factors that regulate the penetration of ZP and fertilization of the egg. Despite many advances in identifying sperm components that promote capacitation, the mechanism underlying the calcium‐triggered process remains elusive. The purpose of this review article is to focus on new advances that have enhanced our understanding of in vivo/in vitro capacitation, a prerequisite event resulting from a dramatic modification and reorganization of the sperm membrane molecules. Special emphasis has been laid on accumulating evidence suggesting potential similarities between the sperm capacitation and early phases of calcium‐triggered membrane fusion (i.e., tethering and docking) during secretory and endocytotic pathways among eukaryotes. BioEssays 26:281–290, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Most metazoan organisms have evolved a mildly acidified and calcium diminished sorting hub in the early secretory pathway commonly referred to as the Endoplasmic Reticulum‐Golgi intermediate compartment (ERGIC). These membranous vesicular‐tubular clusters are found tightly juxtaposed to ER subdomains that are competent for the production of COPII‐coated transport carriers. In contrast to many unicellular systems, metazoan COPII carriers largely transit just a few hundred nanometers to the ERGIC, prior to COPI‐dependent transport on to the cis‐Golgi. The mechanisms underlying formation and (...) maintenance of ERGIC membranes are poorly defined. However, recent evidence suggests an important role for Trk‐fused gene (TFG) in regulating the integrity of the ER/ERGIC interface. Moreover, in the absence of cytoskeletal elements to scaffold tracks on which COPII carriers might move, TFG appears to promote anterograde cargo transport by locally tethering COPII carriers adjacent to ERGIC membranes. This action, regulated in part by the intrinsically disordered domain of TFG, provides sufficient time for COPII coat disassembly prior to heterotypic membrane fusion and cargo delivery to the ERGIC. -/- . (shrink)

In vitro reconstitution assays are commonly used to study biological membrane fusion. However, to date, most ensemble and single‐vesicle experiments involving SNARE proteins have been performed only with lipid‐mixing, but not content‐mixing indicators. Through simultaneous detection of lipid and small content‐mixing indicators, we found that lipid mixing often occurs seconds prior to content mixing, or without any content mixing at all, during a 50‐seconds observation period, for Ca2+‐triggered fusion with SNAREs, full‐length synaptotagmin‐1, and complexin. Our results illustrate (...) the caveats of commonly used bulk lipid‐mixing fusion experiments. We recommend that proteoliposome fusion experiments should always employ content‐mixing indicators in addition to, or in place of, lipid‐mixing indicators. (shrink)

SNAREs (soluble N‐ethylmaleimide‐sensitive factor attachment protein receptors) are a large family of proteins that are present on all organelles involved in intracellular vesicle trafficking and secretion. The interaction of complementary SNAREs found on opposing membranes presents an attractive lock‐and‐key mechanism, which may underlie the specificity of vesicle trafficking. Moreover, formation of the tight complex between a vesicle membrane SNARE and corresponding target membrane SNAREs could drive membrane fusion. In synapses, this tight complex, also referred to as (...) the synaptic core complex, is essential for neurotransmitter release. However, recent observations in knockout mice lacking major synaptic SNAREs challenge the prevailing notion on the executive role of these proteins in fusion and open up several questions about their exact role(s) in neurotransmitter release. Persistence of a form of regulated neurotransmitter release in these mutant mice also raises the possibility that other cognate or non‐cognate SNAREs may partially compensate for the loss of a particular SNARE. Future analysis of SNARE function in central synapses will also have implications for the role of these molecules in other vesicle trafficking events such as endocytosis and vesicle replenishment. Such analysis can provide a molecular basis for synaptic processes including certain forms of short‐term synaptic plasticity. BioEssays 24:926–936, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Cell membranes experience frequent stretching and poking: from cytoskeletal elements, from osmotic imbalances, from fusion and budding of vesicles, and from forces from the outside. Are the ensuing changes in membrane tension localized near the site of perturbation, or do these changes propagate rapidly through the membrane to distant parts of the cell, perhaps as a mechanical mechanism of long‐range signaling? Literature statements on the timescale for membrane tension to equilibrate across a cell vary by a (...) factor of ≈106. This study reviews and discusses how apparently contradictory findings on tension propagation in cells can be evaluated in the context of 2D hydrodynamics and poroelasticity. Localization of tension in the cell membrane is likely critical in governing how membrane forces gate ion channels, set the subcellular distribution of vesicle fusion, and regulate the dynamics of cytoskeletal growth. Furthermore, in this study, it is proposed that cells can actively regulate the degree to which membrane tension propagates by modulating the density and arrangement of immobile transmembrane proteins. Also see the video abstract here https://youtu.be/T6K7AIAqqBs. (shrink)

As life extended into eukaryota, a great host of strategies emerged in the pursuit of cellular life. Some cells have been successful in solitude, some moved into cooperatives (i.e., multicellular organisms), but one additional strategy emerged. Throughout eukaryotes, many of the diverse multicellular cooperatives took life in partnership one step further. These cells came together and lost their singularity in the expanse of syncytial life. Recently in our search for this elusive “how”, we discovered the intriguing peculiarity of a nuclear, (...) RNA‐binding protein living a second life as a fusion manager at the surface of developing osteoclasts, ushering them into syncytia 1. It is from here that we will develop several thoughts about the advantages of multinucleated cells and discuss how these fusing cells pass through several hallmarks of cell death. We will propose that cell fusion shares much with cell death because cell fusion is a death of sorts for the cells that undergo it – a death of the life that was and the beginning of new life in a community without borders. (shrink)

Mammalian sperm undergo discharge of a single, anterior secretory granule following their attachment to the zona pellucida surrounding the oocyte. This secretory discharge is known for historical reasons as the acrosome reaction. It fulfils a number of purposes and without it, sperm are unable to penetrate the zona pellucida and fuse with the oocyte. In this review, we focus on the role of the acrosome reaction in the development of fusion competence in sperm. Any naturally occurring membrane (...) class='Hi'>fusion has two major sequential steps: a docking or adhesion step, in which two membranes adhere, and a fusion step, in which their lipid bilayers are destabilized and merged and a cellular compartment is either created or destroyed. Recent evidence suggests that there is an important role for oocyte integrins and sperm‐bound disintegrins in mammalian sperm/oocyte adhesion and fusion. The fusion mechanism employed by sperm remains poorly understood, however, and circumstantial evidence suggests it is more complex than the interaction between a single protein species and its target. Sperm/oocyte fusion is probably the most accessible eukaryotic model for intercellular fusion currently available, partly because it is temporally separated from gene expression. Elucidation of the mechanism of sperm/oocyte fusion may throw light on the mechanism of other intercellular fusions such as myoblast fusion, and the evolutionary relationship of intercellular membrane fusion to intracellular membrane fusion. (shrink)

The ability of two or more cells to unite to form a new syncytial cell has been utilized in metazoans throughout evolution to form many complex organs, such as muscles, bones and placentae. This requires migration, recognition and adhesion between cells together with fusion of their plasma membranes and rearrangement of their cytoplasmic contents. Until recently, understanding of the mechanisms of cell fusion was restricted to fusion between enveloped viruses and their target cells. The identification of new (...) factors that take part in developmental cell fusion in C. elegans opens the way to understanding how cells fuse and what the functions of this process are. In this review, we describe current knowledge on the mechanisms and putative roles of developmental cell fusion in C. elegans and how cell fusion is regulated, together with other intercellular processes to promote organogenesis. BioEssays 25:672–682, 2003. © 2003 Wiley Periodicals, Inc. (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)

The exocyst is a conserved octameric complex that physically tethers a vesicle to the plasma membrane, prior to membrane fusion. It is important not only for secretion and membrane delivery but also, in mammalian cells, for cytokinesis, ciliogenesis, autophagy, tumorigenesis, and host defense. The combination of genome editing and advanced light microscopy of exocyst subunits in living cells has recently shown the complex to be much more dynamic than previously appreciated, and exposed how little we still (...) know about its function and regulation. (shrink)

Different anesthetics are known to modulate different types of membrane-bound receptors. Their common mechanism of action is expected to alter the mechanism for consciousness. Consciousness is hypothesized as the integral of all the units of internal sensations induced by reactivation of inter-postsynaptic membrane functional LINKs during mechanisms that lead to oscillating potentials. The thermodynamics of the spontaneous lateral curvature of lipid membranes induced by lipophilic anesthetics can lead to the formation of non-specific inter-postsynaptic membrane functional LINKs by (...) different mechanisms. These include direct membrane contact by excluding the inter-membrane hydrophilic region and readily reversible partial membrane hemifusion. The constant reorganization of the lipid membranes at the lateral edges of the postsynaptic terminals (dendritic spines) resulting from AMPA receptor-subunit vesicle exocytosis and endocytosis can favor the effect of anesthetic molecules on lipid membranes at this location. Induction of a large number of non-specific LINKs can alter the conformation of the integral of the units of internal sensations that maintain consciousness. Anesthetic requirement is reduced in the presence of dopamine that causes enlargement of dendritic spines. Externally applied pressure can transduce from the middle ear through the perilymph, cerebrospinal fluid, and the recently discovered glymphatic pathway to the extracellular matrix space, and finally to the paravenular space. The pressure gradient reduce solubility and displace anesthetic molecules from the membranes into the paravenular space, explaining the pressure reversal of anesthesia. Changes in membrane composition and the conversion of membrane hemifusion to fusion due to defects in the checkpoint mechanisms can lead to cytoplasmic content mixing between neurons and cause neurodegenerative changes. The common mechanism of anesthetics presented here can operate along with the known specific actions of different anesthetics. (shrink)

At fertilization in mammals the sperm activates the egg by triggering a series of oscillations in the intracellular free Ca2+ concentration. The precise sequence of events that occur between sperm‐egg contact and the increases in intracellular Ca2+ remains unknown. Here, we discuss recent evidence supporting the hypothesis that a cytosolic sperm protein enters the egg after gamete membrane fusion and triggers Ca2+ oscillations from within the egg cytoplasm. Biochemical studies suggest that there exists a novel sperm protein, named (...) oscillin, that specifically comigrates with Ca2+ oscillation‐inducing activity. Oscillin has been immunolocalised to the region of the sperm that first fuses with the egg. The concept of a specific protein that triggers Ca2+ oscillations may have wider physiological significance since sperm oscillin can induce Ca2+ oscillations in somatic cells, such as neurons and hepatocytes. Unravelling the novel signalling system involved in mammalian fertilization may help reveal some fundamental molecular mechanisms responsible for triggering cytoplasmic Ca2+ oscillations. (shrink)

Intercellular communication is an essential process in all multicellular organisms. During this process, molecules secreted by one cell will bind to a receptor on the cognate cell leading to the subsequent uptake of the receptor‐ligand complex. Once inside, the cell then determines the fate of the receptor‐ligand complex and any other proteins that were endocytosed together. Approximately 80% of endocytosed material is recycled back to the plasma membrane either directly or indirectly via the Golgi apparatus and the remaining 20% (...) is delivered to the lysosome for degradation. Although most pathways have been identified, we still lack understanding on how specificity in sorting of recycling cargos into different pathways is achieved, and how the cell reaches high accuracy of these processes in the absence of clear sorting signals in the bulk of the client proteins. In this review, we will summarize our current understanding of the mechanism behind recycling cargo sorting and propose a model of differential affinities between cargo and cargo receptors/adaptors with regards to iterative sorting in endosomes. (shrink)

One of the most important cell–cell interactions is that of the sperm with the egg. This interaction, which begins with cell adhesion and culminates with membrane fusion, is mediated by multiple molecules on the gametes. One of the best-characterized of these molecules is fertilin β, a ligand on mammalian sperm and one of the first ADAMs (A Disintegrin and A Metalloprotease domain) to be identified. Fertilin β (also known as ADAM2) participates in sperm–egg membrane binding, and it (...) has long been hypothesized that this function is achieved through the interaction of the disintegrin domain of fertilin β with an integrin on the egg surface. There are now approximately 30 members of the ADAM family and, to date, five different ADAMs (fertilin β, ADAM9, ADAM12, ADAM15, ADAM23) have been described to interact with integrins (specifically α6β1, αvβ3, α9β1, αvβ5, and/or α5β1). This field will be discussed with respect to what is known about specific ADAMs and the integrins with which they interact, and what the implications are for sperm–egg interactions and for integrin function. These data will also be discussed in the context of recent knockout studies, which show that eggs lacking the α6 integrin subunit can be fertilized, and eggs lacking the integrin-associated tetraspanin protein CD9 fail to fertilize. Key issues in cell adhesion that pertain to gametes and fertilization will also be highlighted. BioEssays 23:628–639, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Progressive supranuclear palsy is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP and 3,247 controls followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the (...) stage 1 SNPs that yielded P ≤ 10-3. We found significant previously unidentified signals associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component. © 2011 Nature America, Inc. All rights reserved. (shrink)

A Paramecium cell has a stereotypically patterned surface, with regularly arranged cilia, dense‐core secretory vesicles and subplasmalemmal calcium stores. Less strikingly, there is also a patterning of molecules; for instance, some ion channels are restricted to certain regions of the cell surface. This design may explain very effective and selective responses, such as that to Ca2+ upon stimulation. It enables the cell to respond to a Ca2+ signal precisely secretion (exocytosis) or by changing its ciliary activity. These responses depend on (...) the location and/or type of signal, even though these two target structures co‐exist side‐by‐side, and normally only limited overlap occurs between the different functions. Furthermore, the patterning of exocytotic sites and the possibility of synchronous exocytosis induction in the sub‐second time range have considerably facilitated analyses, and thus led to new concepts of exocytotic membrane fusion. It has been possible to dissect complicated events like overlapping Ca2+ fluxes produced from external sources and from internal stores. Since molecular genetic approaches have become available for Paramecium, many different gene products have been identified only some of which are known from “higher” eukaryotes. Although a variety of basic cellular functions are briefly addressed to demonstrate the uniqueness of this unicellular organism, this article focuses on exocytosis regulation. BioEssays 24:649–658, 2002. © 2002 Wiley Periodicals, Inc. (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)

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)

The direction and specificity of endolysosomal membrane trafficking is tightly regulated by various cytosolic and membrane‐bound factors, including soluble NSF attachment protein receptors (SNAREs), Rab GTPases, and phosphoinositides. Another trafficking regulatory factor is juxta‐organellar Ca2+, which is hypothesized to be released from the lumen of endolysosomes and to be present at higher concentrations near fusion/fission sites. The recent identification and characterization of several Ca2+ channel proteins from endolysosomal membranes has provided a unique opportunity to examine the roles (...) of Ca2+ and Ca2+ channels in the membrane trafficking of endolysosomes. SNAREs, Rab GTPases, and phosphoinositides have been reported to regulate plasma membrane ion channels, thereby suggesting that these trafficking regulators may also modulate endolysosomal dynamics by controlling Ca2+ flux across endolysosomal membranes. In this paper, we discuss the roles of phosphoinositides, Ca2+, and potential interactions between endolysosomal Ca2+ channels and phosphoinositides in endolysosomal dynamics. (shrink)

We have discovered that a single sperm protein, phospholipase C‐zeta (PLCζ), can stimulate intracellular Ca2+ signalling in the unfertilized oocyte (‘egg’) culminating in the initiation of embryonic development. Upon fertilization by a spermatozoon, the earliest observed signalling event in the dormant egg is a large, transient increase in free Ca2+ concentration. The fertilized egg responds to the intracellular Ca2+ rise by completing meiosis. In mammalian eggs, the Ca2+ signal is delivered as a train of long‐lasting cytoplasmic Ca2+ oscillations that begin (...) soon after gamete fusion and persist beyond the completion of meiosis. Sperm PLCζ effects Ca2+ release from egg intracellular stores by hydrolyzing the membrane lipid PIP2 and consequent stimulation of the inositol 1,4,5‐trisphosphate (InsP3) receptor Ca2+‐signalling pathway, leading to egg activation and early embryogenesis. Recent advances have refined our understanding of how PLCζ induces Ca2+ oscillations in the egg and also suggest its potential dysfunction as a cause of male infertility. (shrink)

Cell communication plays a key role in multicellular organisms. In developing embryos as in adult organisms, cells communicate by coordinating their differentiation through the establishment and/or renewal of a variety of cell communication channels. Under both these conditions, cells interact by either receptor signalling, surface recognition of specific cell adhesion molecules or transfer of cytoplasmic components through junctional coupling. In recent years, it has become apparent that cells may also communicate through the extracellular release of microvesicles. They may originate as (...) either exosomes from the endosomal compartment upon fusion of multivesicular bodies with the plasma membrane or be shed directly from the plasma membrane via extensions of the cell surface. Microvesicles may disperse over long distances through body fluids and deliver their molecular cargo onto a variety of target cells. As a general rule, the metabolic fate of these cells is determined by the molecular nature of the vesicular cargo, while targeting itself depends on the affinity of the molecules expressed on the enclosing membrane. In this paper, we will be arguing that intercellular vesicular transfer is substantially different from other types of cell communication, allowing cells and molecules to interact on varying levels. Cells interacting via ligand signalling owe their specificity to the steric coupling with cognate receptor molecules. As such, it is a pure molecular process that affects target cells only upon integration into their responding repertoire. In this relationship, coupled cells are reciprocally adapted to each other through the selection of their respective signalling capacities, following exploration of their receptor specificity. Interaction by intercellular vesicles realizes a substantially different type of cell communication. Vesicular traffic allows donor cells to carry out a horizontal type of gene transfer and target this information over long distances via independently controlled mechanisms. Because of this independence, cells interacting via vesicular traffic are not expected to adapt their signalling correspondences, but to control instead the efficiency of their cargo delivery irrespective of the receptor repertoire expressed by the target tissue. In this paper, the multifaceted functions of the intercellular vesicular traffic will be discussed in a multilevel biosemiotic perspective with the aim of unravelling the cellular mechanisms devised by nature to accomplish communication. (shrink)

The origins and evolution of the Archaea, Bacteria, and Eukarya remain controversial. Phylogenomic‐wide studies of molecular features that are evolutionarily conserved, such as protein structural domains, suggest Archaea is the first domain of life to diversify from a stem line of descent. This line embodies the last universal common ancestor of cellular life. Here, we propose that ancestors of Euryarchaeota co‐evolved with those of Bacteria prior to the diversification of Eukarya. This co‐evolutionary scenario is supported by comparative genomic and phylogenomic (...) analyses of the distributions of fold families of domains in the proteomes of free‐living organisms, which show horizontal gene recruitments and informational process homologies. It also benefits from the molecular study of cell physiologies responsible for membrane phospholipids, methanogenesis, methane oxidation, cell division, gas vesicles, and the cell wall. Our theory however challenges popular cell fusion and two‐domain of life scenarios derived from sequence analysis, demanding phylogenetic reconciliation. (shrink)

The rate‐limiting step in the uptake and metabolism of Dglucose by insulin target cells is thought to be glucose transport mediated by glucose transporters (primarily the GLUT4 isoform) localized to the plasma membrane. However, subcellular fractionation, photolabelling and immunocytochemical studies have shown that the pool of GLUT4 present in the plasma membrane is only one of many subcellular pools of this protein. GLUT4 has been found in occluded vesicles at the plasma membrane, clathrin‐coated pits and vesicles, early (...) endosomes, and tubulo‐vesicular structures; the latter are analogous to known specialized secretory compartments. Tracking the movement of GLUT4 through these compartments, and defining the mechanism and site of action of insulin in stimulating this subcellular trafficking, are major topics of current investigation. Recent evidence focuses attention on the exocytosis of GLUT4 as the major site of insulin action. Increased exocytosis may be due to decreased retention of glucose transporters in an intracellular pool, or possibly to increased assembly of a vesicle docking and fusion complex. Although details are unknown, the presence in GLUT4 vesicles of a synaptobrevin homologue leads us to propose that a process analogous to that occurring in synaptic vesicle trafficking is involved in the assembly of GLUT4 vesicles into a form suitable for fusion with the plasma membrane. Evidence that the pathways of signalling from the insulin receptor and of GLUT4 vesicle exocytosis may converge at the level of the key signalling enzyme, phosphatidylinositol 3‐kinase, is discussed. (shrink)

Perception is a first-person internal sensation induced within the nervous system at the time of arrival of sensory stimuli from objects in the environment. Lack of access to the first-person properties has limited viewing perception as an emergent property and it is currently being studied using third-person observed findings from various levels. One feasible approach to understand its mechanism is to build a hypothesis for the specific conditions and required circuit features of the nodal points where the mechanistic operation of (...) perception take place for one type of sensation in one species and to verify it for the presence of comparable circuit properties for perceiving a different sensation in a different species. The present work explains visual perception in mammalian nervous system from a first-person frame of reference and provides explanations for the homogeneity of perception of visual stimuli above flicker fusion frequency, the perception of objects at locations different from their actual position, the smooth pursuit and saccadic eye movements, the perception of object borders, and perception of pressure phosphenes. Using results from temporal resolution studies and the known details of visual cortical circuitry, explanations are provided for (a) the perception of rapidly changing visual stimuli, (b) how the perception of objects occurs in the correct orientation even though, according to the third-person view, activity from the visual stimulus reaches the cortices in an inverted manner and (c) the functional significance of well-conserved columnar organization of the visual cortex. A comparable circuitry detected in a different nervous system in a remote species-the olfactory circuitry of the fruit fly Drosophila melanogaster-provides an opportunity to explore circuit functions using genetic manipulations, which, along with high-resolution microscopic techniques and lipid membrane interaction studies, will be able to verify the structure-function details of the presented mechanism of perception. (shrink)

Ambiguity is not the polysemy most words display as dictionary entries but results from the context's blocking of the reader's choice among competing meanings, as when, to use an example from Derrida, a French context hinders the reader from deciding whether plus de means "lack" or "excess" .1 In this case, the undecidability is due entirely to the fact that the reader is playing a score, the syntax, that will not let him choose. This must be because the score is (...) badly written; yet it is precisely this sort of willful neglect that critics have labeled poetic license, thereby underlining its literary nature. Undecidability has become a central feature in Derrida's analyses of literariness, and it is also the main underpinning of his creative writing.2 Better still, his own critical discourse has put undecidability to use, not a rare case of metalanguage imitating the very devices of the language it purports to analyze. My example are therefore drawn from Derrida on the assumption that his conscious practice of écriture, backed up by a sophisticated theory, will be particularly illuminating. For my own analysis of these phenomena, I shall be using a special word that Derrida has adopted and adapted from the terminology of ancient rhetoric. He proposes it in his commentary on this sentence of Mallarmé's: "La scène n'illustre que l'idée, pas une action effective, dans une hymen . . . entre le désir et l'accomplissement, la perpétration et son souvenir."3 Our critic points out that the grammar prevents the reader from choosing between hymen as "marriage," a symbolic union or fusion, and as "vaginal membrane," the barrier is broken through if desire is to reach what it desires. Undecidability is the effective mechanism of pantomime as an art form since from mimicry alone, without words, the spectator cannot tell whether a dreamed, or a remembered, or a present act is being set forth. This, in turn, Derrida shows to be fundamental to Mallarmé's concept of poetry. It is simply a pun or, as Derrida prefers to call it, a "syllepsis,"4 the trope that consists in understanding the same word in two different ways at the same time, one meaning being literal or primary, the other figurative.5 The second meaning is not just different from and incompatible with the first: it is tied to the first as its polar opposite or the way the reverse of a coin is bound to its obverse—the hymen as unbroken membrane is also metaphorical in both its meanings is irrelevant to its undecidability. What makes it undecidable is not that it is an image but that it embodies a structure, that is, the syllepsis. · 1. See Jacques Derrida's La Dissémination , p. 307.· 2. Because Derrida is a philosopher by trade, one would expect his undecidability to reflect the very precise logical and mathematical concepts of that discipline - which is to say, the limitations inherent in the axiomatic method. Kristeva, for example, tries to do this in her Le Texts du roman: Approche sèmiologique d'une structure discursive transformationnelle , pp. 76-78. So far as I can make out, however , Derrida's critical theory and reading practice do not pack more into the word "undecidable" than does the definition I offer in this paper.· 3. Stephane Mallarmé, Mimique, Oeuvres complètes , p. 310: "the scene [a drama, or rather a pantomime] bodies forth only an idea, not an action: it is like a hymen between desire and its realization, or between an act committed and the memory of it"; here and elsewhere, my translation unless otherwise cited. Derrida's commentary, "La Double Séance," has been rpt. in La Dissémination, pp. 199-317; see esp. pp. 240 ff.· 4. See La Dissémination, p. 249.· 5. This definition has prevailed ever since Dumarsais' treatise, Des Tropes . That syllepsis must be distinguished from the so-called grammatical syllepsis or the zeugma is apparent in Heinrich Lausberg's Handbuch der literarischen Rhetorik , pars. 702-7; on the acceptation chosen by Derrida, see pars. 7-8. Michael Riffaterre, Blanche W. Knopf Professor of French Literature and chairman of the department of French and Romance literatures at Columbia University, is the editor of Romantic Review. He is the author of Semiotics of Poetry, La Production du Texte, Typology of Intertextuality and A Grammar of Descriptive Poetry. "Syllepsis" developed out of seminars he led at the Irvine School of Criticism and Theory and at Johns Hopkins University. (shrink)

Both RalA and RalB interact with the ubiquitous calcium sensor, calmodulin (CaM). New structural and biophysical characterisation of these interactions strongly suggests that, in the native membrane‐associated state, only RalA can be extracted from the membrane by CaM and this non‐canonical interaction could underpin the divergent signalling roles of these closely related GTPases. The isoform specificity for RalA exhibited by CaM is hypothesised to contribute to the disparate signalling roles of RalA and RalB in mitochondrial dynamics. This would (...) lead to CaM shuttling RalA to the mitochondrial membrane but leaving RalB localisation unperturbed, and in doing so triggering mitochondrial fission pathways rather than mitophagy. (shrink)

Two fusions can be in the same place at the same time. So long as a house made of Tinkertoys is intact, the fusion of all its Tinkertoys parts coincides with the fusion of it walls and its roof. If none of the Tinkertoys is destroyed, their fusion persists through the complete disassembly of the house. (So the house is not a fusion of its Tinkertoy parts.) The fusion of the walls and roof does not (...) persist through the complete disassembly because the walls and the roof themselves do not persist. (So the walls and the roof are also not fusions of their Tinkertoy parts.). (shrink)

We have been invited to contribute a short assessment of Levine's response to Siderits’ position in the emerging debate between "fusion philosophy" and "comparative philosophy." Perhaps a brief word is in order regarding our backgrounds: Michael Nylan is a student of early China, with strong inter-disciplinary training and interests, who has attempted work in both philosophy and translation. Martin Verhoeven is a historian by training, a translator by avocation, and a Buddhist practitioner. Both of us have committed ourselves for (...) decades to past traditions that can only be accessed through classical Chinese language, and that surely colors our views. At the same time, those views are not identical, but stereophonic. (shrink)

Integral membrane proteins are found in all cellular membranes and fulfil many of the functions that are central to life. A critical step in the biosynthesis of membrane proteins is their insertion into the lipid bilayer. The mechanisms of membrane protein insertion and folding are becoming increasingly better understood, and efficient methods for the ab initio prediction of three‐dimensional protein structure from the primary amino acid sequence may be within reach. Already, the basic tools needed for engineering (...) and de novo design of integral membrane proteins seem to be at hand. (shrink)

We tested whether cognitive fusion impairs emotion differentiation and thereby mediates relations between cognitive fusion and depression and panic symptoms among 55 adults, 50.9% women). Using visual stimuli, we elicited multiple emotion states and measured emotional intensity – the subjective emotion intensity of elicited emotions, as well as emotional differentiation – the degree of co-activation of multiple negative emotions when a specific emotion was elicited. First, as hypothesised, we found that cognitive fusion predicted lower levels of emotion (...) differentiation. In contrast, as hypothesised, these effects were significantly greater than the effects of cognitive fusion on emotion intensity. Second, as predicted, MECA, but not SEI, predicted depression and panic symptoms. Finally, we found that MECA mediated the effects of cognitive fusion on depression and panic symptoms. The present findings contribute novel, preliminary empirical insight into associations between cognitive fusion, impaired emotion differentiation and mental ill-health. (shrink)

fusion theory challenges efforts to see theory as inhibiting by presenting an approach that is innovative, eclectic, and subtle in order to draw out competing and constellating ideas and opinions. This collected volume of essays examines fusion theory and demonstrates how the theory can be applied to the reading of various works of Indian English novelists.

‘Fusion’ is a philosophical term of art, with a variety of uses. First, it is often a synonym for ‘sum’. In this sense, a is a fusion of b, c and d iff b, c and d are parts of a, and every part of a shares a part with b, c or d. So a cat is a fusion of the cells which compose it, and the same cat is a fusion of the molecules which (...) compose it. Relatedly, ‘fusion’ can refer to the occurrence of such composition: philosophers disagree about whether fusion is widespread, about whether it can be a vague matter, and so on. (shrink)

Même si elle est emblématique de la pensée de Gadamer, la difficile notion d’une « fusion d’horizons » a été assez peu étudiée pour elle-même. Cet article se propose d’en faire ressortir le sens, la portée, mais aussi les difficultés. Il cherche surtout à montrer en quoi cette fusion d’horizons est l’œuvre du langage (lui-même pensé à partir de sa fusion avec l’être) et dans quelle mesure on peut y voir la version gadamérienne de l’adéquation entre l’être (...) et la pensée, suivant la conception classique de la vérité, que Gadamer ne renie jamais. (shrink)

I criticise a paper by Peter Forrest in which he argues that a principle of unrestricted countable fusion has paradoxical consequences. I argue that the paradoxical consequences that he exhibits may be due to his Whiteheadean assumptions about the nature of spacetime rather than to the principle of unrestricted countable fusion.

We define the interpolative fusion T∪∗ of a family i∈I of first-order theories over a common reduct T∩, a notion that generalizes many examples of random or generic structures in the model-theo...

The paper provides a new and detailed critique of Barker and Dowe’s argument against multi-location. This critique is not only novel but also less committal than previous ones in the literature in that it does not require hefty metaphysical assumptions. The paper also provides an analysis of some metaphysical relations between mereological and locational principles.

One persistent puzzle in the life sciences is the asymmetric lipid composition of the cellular plasma membrane: while the exoplasmic leaflet is enriched in lipids carrying predominantly saturated fatty acids, the cytoplasmic leaflet hosts preferentially lipids with (poly‐)unsaturated fatty acids. Given the high energy requirements necessary for cells to maintain this asymmetry, the question naturally arises regarding its inherent benefits. In this paper, we propose asymmetry to represent a potential solution for harmonizing two conflicting requirements for the plasma (...) class='Hi'>membrane: first, the need to build a barrier for the uncontrolled influx or efflux of substances; and second, the need to form a fluid and dynamic two‐dimensional substrate for signaling processes. We hence view here the plasma membrane as a composite material, where the exoplasmic leaflet is mainly responsible for the functional integrity of the barrier and the cytoplasmic leaflet for fluidity. We reinforce the validity of the proposed mechanism by presenting quantitative data from the literature, along with multiple examples that bolster our model. (shrink)

We introduce a new operator – belief fusion– which aggregates the beliefs of two agents, each informed by a subset of sources ranked by reliability. In the process we definepedigreed belief states, which enrich standard belief states with the source of each piece of information. We note that the fusion operator satisfies the invariants of idempotence, associativity, and commutativity. As a result, it can be iterated without difficulty. We also define belief diffusion; whereas fusion generally produces a (...) belief state with more information than is possessed by either of its two arguments, diffusion produces a state with less information. Fusion and diffusion are symmetric operators, and together define a distributive lattice. Finally, we show that AGM revision can be viewed as fusion between a novice and an expert. (shrink)

Lipid droplets (LDs) are ubiquitous, neutral lipid storage organelles that act as hubs of metabolic processes. LDs are structurally unique with a hydrophobic core that mainly consists of neutral lipids, sterol esters, and triglycerides, enclosed within a phospholipid monolayer. Nascent LD formation begins with the accumulation of neutral lipids in the endoplasmic reticulum (ER) bilayer. The ER membrane proteins such as seipin, LDAF1, FIT, and MCTPs are reported to play an important role in the formation of nascent LDs. As (...) the LDs grow, they unmix from the highly charged ER membrane to form mature LDs. LD biogenesis is an exciting, emerging research area, and herein, we discuss the recent progress in our understanding of the formation of eukaryotic nascent LDs. We focus on the role of ER membrane shaping proteins such as reticulons and reticulon‐like proteins, membrane lipids, and cytoskeleton proteins such as septin in the formation of nascent LDs. (shrink)

The synthesis of biological membranes requires the insertion of proteins into a lipid bilayer. The rough endoplasmic reticulum of eukaryotic cells is a principal site of membrane biogenesis. The insertion of proteins into the membrane of the endoplasmic reticulum is mediated by a resident proteinaceous machinery. Over the last five years several different experimental approaches have provided information about the components of the machinery and how it may function.

To obtain effective fusion results of multi source evidences with different importance, an evidence fusion method with importance discounting factors based on neutrosopic probability analysis in DSmT framework is proposed. First, the reasonable evidence sources are selected out based on the statistical analysis of the pignistic probability functions of single focal elements. Secondly, the neutrosophic probability analysis is conducted based on the similarities of the pignistic probability functions from the prior evidence knowledge of the reasonable evidence sources. Thirdly, (...) the importance discounting factors of the reasonable evidence sources are obtained based on the neutrosophic probability analysis and the reliability discounting factors of the real-time evidences are calculated based on probabilistic-based distances. Fourthly, the real-time evidences are discounted by the importance discounting factors and then the evidences with the mass assignments of neutrosophic empty sets are discounted by the reliability discounting factors. Finally, DSmT+PCR5 of importance discounted evidences is applied. Experimental examples show that the decision results based on the proposed fusion method are different from the results based on the existed fusion methods. Simulation experiments of recognition fusion are performed and the superiority of proposed method is testified well by the simulation results. (shrink)

We examined the influence of identity fusion and status of evaluator on willingness to fight for one’s group after group-descriptive or not group-descriptive feedback. The valence of evaluative information was varied as well: feedback either support negative group-stereotype or contradict negative group-stereotype. In two studies we partially replicated previous findings on self-verification. Individuals fused with one’s group were more prone than non fused to fight for group members after receiving, challenging, not group-describing feedback, but only when evaluator’s status was (...) high. When the evaluator’ status was low, fused participants engaged in self-enhancement strategies: that is they endorse radical behavior after negative, even if group-describing, feedback. We discuss the importance of identity fusion and evaluator’s status for determining when self-enhancement and self-verification will and will not be evoke. (shrink)

This paper studies the information of big data in the digital publishing industry chain and adopts advanced algorithms for its fusion calculation. The basic theory of digital publishing ecological chain is dissected, the construction requirements, construction methods, and construction paths of digital publishing ecological chain are analysed, and feasible construction measures are proposed. It also defines the connotation of the fusion of knowledge services between publishing institutions and libraries in the digital era; then analyses the characteristics and principles (...) of the fusion of knowledge services between publishing institutions and libraries in the digital era; and finally sorts out the theoretical foundations such as synergy theory, information integration service theory, and game theory. Meanwhile, this paper also studies the flow of digital publishing resources and empirically analyses the eco-efficiency of digital publishing eco-chain by using metabolic network analysis, population analysis, and life cycle analysis, and it finds the eco-efficiency problems of the existing e-book eco-chain from its analysis. Finally, the imbalance in the digital publishing ecological chain and its hazards are analysed, and specific regulation and optimization measures are proposed. The research in this paper makes up for the deficiencies of related studies and can well solve the problems that exist in the previous and provide theoretical support for the healthy development of digital publishing enterprises. (shrink)

Fusion genes formed by chromosomal rearrangements are common drivers of cancer. Recent innovations in the field of next‐generation sequencing (NGS) have seen a dynamic shift from traditional fusion detection approaches, such as visual characterization by fluorescence, to more precise multiplexed methods. There are many different NGS‐based approaches to fusion gene detection and deciding on the most appropriate method can be difficult. Beyond the experimental approach, consideration needs to be given to factors such as the ease of implementation, (...) processing time, associated costs, and the level of expertise required for data analysis. Here, the different NGS‐based methods for fusion gene detection, the basic principles underlying the techniques, and the benefits and limitations of each approach are reviewed. This article concludes with a discussion of how NGS will impact fusion gene detection in a clinical context and from where the next innovations are evolving. (shrink)

There is a structural proximity between the concept of the sublime and that of anguish; a proximity that, however, does not prevent the scene from being very different in terms of the affects involved. With regard to structure, at stake is a field that involves the pulsating, differential simultaneity of absence and presence, death and life. The principle of mutual exclusion is replaced by the logic of contradictory inclusion. I will limit myself, in this context, to recounting a brief stretch (...) of the history of the sublime, little travelled, in which the juxtaposition with anguish, a heterozygotic twin, brings to the fore the sameness of their structure - centred on the synchrony of opposites - and the inversion of the affects involved. The authors I will summon, in this brief stretch, are Jean-François Lyotard, as regards the sublime, and Jacques Lacan, as regards anguish. The theory of the sublime and that of anguish are frequently accompanied by the metaphorical evocation of membranes, tissue partitions. In what sense do the feeling of the sublime and the affection of anguish have to do with these tissue lacerations that, although belonging to the body, are, in truth, hors-corps? They are organs or parts of organs with such a slender structure as to be almost unreal, they are freed and go their own way, bearers of a pure life that slips and swirls, to the point of disquieting for a trait of immortality that they carry with them. (shrink)

The biological membranes of eukaryotic cells harbor sensitive surveillance systems to establish, sense, and maintain characteristic physicochemical properties that ultimately define organelle identity. They are fundamentally important for membrane homeostasis and play active roles in cellular signaling, protein sorting, and the formation of vesicular carriers. Here, we compare the molecular mechanisms of Mga2 and Ire1, two sensors involved in the regulation of fatty acid desaturation and the response to unfolded proteins and lipid bilayer stress in order to identify their (...) commonalities and specializations. We will speculate on the cellular significance of membrane property sensors in other organelles and discuss their putative mechanisms. Based on these findings, we propose membrane property sensors as an emerging class of proteins with wide implications for organelle communication and function. (shrink)

Tubulin is the ubiquitous protein that makes up the walls of the cytoskeletal elements known as microtubules. These 20 nm diameter cylindrical fibers are the spindle fibers for mitosis, provide the skeletal framework for cellular elongation, constitute the major structural and motile elements of cilia and flagella and probably play a number of other roles in eukaryote cells. In the electron microscope, they are never seen to attach or protrude directly into or on cellular membranes. It was therefore with much (...) skepticism that cell biologists responded to recent claims purporting to show that tubulin is (or can be) a membrane protein. This skepticism comes from a bias based on the generally understood function of cytoskeletal proteins as representing the intracellular ‘bones’ of cells. The traditional thinking was that microtubules may attach to cellular membranes but only via a cross‐linking connecting protein. In recent years, however, an increasing number of workers have come to believe that tubulin can exist as a normal membrane protein possibly independent of its role in microtubule function. (shrink)