Surface exposure of phosphatidylserine in pathological cells

The asymmetric phospholipid distribution in plasma membranes is normally maintained by energy-dependent lipid transporters that translocate different phospholipids from one monolayer to the other against their respective concentration gradients. When cells are activated, or enter apoptosis, lipid asymmetry can be perturbed by other lipid transporters (scramblases) that shuttle phospholipids non-specifically between the two monolayers. This exposes phosphatidylserine (PS) at the cells outer surface. Since PS promotes blood coagulation, defective scramblase activity upon platelet stimulation causes a bleeding disorder (Scott syndrome). PS exposure also plays a pivotal role in the recognition and removal of apoptotic cells via a PS-recognizing receptor on phagocytic cells. Furthermore, expression of PS at the cell surface can occur in a wide variety of disorders. This review aims at highlighting how PS expression in different cells may complicate a variety of pathological conditions, including those that promote thromboembolic complications or produce aberrations in apoptotic cell removal.Received 26 November 2004; received after revision 3 January 2005; accepted 10 January 2005 Available online 09 March 2005     

Transmembrane movements of lipids

Membranes allow the rapid passage of unchanged lipids. Phospholipids on the other hand diffuse very slowly from one monolayer to another with a half-time of several hours. This slow spontaneous movement in a pure lipid bilayer can be selectively modulated in biological membranes by intrinsic proteins. In microsomes, and probably in bacterial membranes, non-specific phospholipid flippases allow the rapid redistribution of newly synthesized phospholipids. In eukaryotic plasma membranes, aminophospholipid translocase selectively pumps phosphatidylserine (PS) and phosphatidylethanolamine (PE) from the outer to the inner leaflet and establishes a permanent lipid asymmetry. The discovery of an aminophospholipid translocase in chromaffin granules proves that eukaryotic organelles may also contain lipid translocators.     

Activated scramblase and inhibited aminophospholipid translocase cause phosphatidylserine exposure in a distinct platelet fraction

Platelet procoagulant activity is mainly determined by the extent of surface-exposed phosphatidylserine (PS), controlled by the activity of aminophospholipid translocase and phospholipid scramblase. Here, we studied both transport activities in single platelets upon stimulation with various agonists. Besides the formation of procoagulant microparticles, the results show that a distinct fraction of the platelets exposes PS when stimulated. The extent of PS exposure in these platelet fractions was similar to that in platelets challenged with Ca²⁺-ionophore, where all cells exhibit maximal attainable PS exposure. The size of the PS-exposing fraction depends on the agonist and is proportional to the platelet procoagulant activity. Scramblase activity was observed only in the PS-exposing platelet fraction, whereas translocase activity was exclusively detectable in the fraction that did not expose PS. We conclude that, irrespective of the agonist, procoagulant platelets exhibit maximal surface exposure of PS by switching on scramblase and inhibiting translocase activity.Received 8 March 2005; received after revision 19 April 2005; accepted 13 May 2005     

P-glycoprotein and ‘lipid rafts’: some ambiguous mutual relationships (floating on them, building them or meeting them by chance?)

P-glycoprotein (P-gp) is an active membrane transporter responsible for cell detoxification against numerous amphiphilic compounds, leading to multidrug resistance in tumor cells. It displays entangled connections with its membrane environment since it recognizes its substrates within the cytosolic leaflet and it also translocates some endogenous lipids to the exoplasmic leaflet. Regarding its relationships with membrane microdomains, ‘lipid rafts’, a literature analysis concludes that (i) P-gp also exists in rafts and non-raft membrane domains, depending on the cell considered, the experimental conditions and the method used to test it; (ii) cholesterol has a positive influence on P-gp function, and this may be a direct effect of the free cholesterol present in membrane or an indirect effect mediated by the cholesterol-enriched microdomains; (iii) when present in rafts, P-gp interacts with protein partners regulating its activity; (iv) P-gp is a lipid translocase that handles the raft-constituting lipids with particular efficiency, and it also influences membrane trafficking in the cell. Received 18 November 2005; received after revision 23 December 2005; accepted 12 January 2006     

The life cycle of neutral lipids: synthesis, storage and degradation

Triacylglycerols (TAGs), steryl esters (SEs) and wax esters (WEs) form the group of neutral lipids. Whereas TAGs are present in all types of cell, the occurrence of SEs in prokaryotes is questionable, and the presence of WEs as storage molecules is restricted to plants and a few bacteria. Here, we summarize recent knowledge on the formation, storage and degradation of TAGs and SEs in various cell types. We describe the biochemical pathways involved in TAG and SE synthesis and discuss the subcellular compartmentation of these processes. Recently, several novel enzymes governing the metabolism of storage lipids have been identified and characterized. Regulatory aspects of neutral lipid storage are just beginning to be understood. Finally, we describe consequences of defects in neutral lipid metabolism. Since severe diseases like atherosclerosis, obesity and type 2 diabetes are caused by lipid accumulation, mechanisms underlying neutral lipid synthesis, depot formation and mobilization are of major interest for curing such diseases that are increasingly associated with modern civilization. Received 18 January 2006; received after revision 7 March 2006; accepted 16 March 2006     

Lipid flippases and their biological functions

The typically distinct phospholipid composition of the two leaflets of a membrane bilayer is generated and maintained by bi-directional transport (flip-flop) of lipids between the leaflets. Specific membrane proteins, termed lipid flippases, play an essential role in this transport process. Energy-independent flippases allow common phospholipids to equilibrate rapidly between the two monolayers and also play a role in the biosynthesis of a variety of glycoconjugates such as glycosphingolipids, N-glycoproteins, and glycosylphosphatidylinositol (GPI)-anchored proteins. ATP-dependent flippases, including members of a conserved subfamily of P-type ATPases and ATP-binding cassette transporters, mediate the net transfer of specific phospholipids to one leaflet of a membrane and are involved in the creation and maintenance of transbilayer lipid asymmetry of membranes such as the plasma membrane of eukaryotes. Energy-dependent flippases also play a role in the biosynthesis of glycoconjugates such as bacterial lipopolysaccharide. This review summarizes recent progress on the identification and characterization of the various flippases and the demonstration of their biological functions. Received 12 April 2006; received after revision 22 June 2006; accepted 30 August 2006     

Effect of taurine administration on liver lipids in guinea pig

Summary The oral administration of 0.4% taurine in drinking water for 14 consecutive days showed the following hepatic effects in male guinea pig. The percentage of tauro-conjugated biliary bile acids was increased from 17.2–54.2%; the ratio liver weight/body weight was increased, and fatty change was induced. Liver triglyceride concentration was accordingly increased; diglyceride and phosphatidylcholine concentrations were reduced by the treatment, while phosphatidylethanolamine level was not affected. These changes suggest an adverse effect of taurine administration on phosphatidylcholine hepatic synthesis.     

The assembly of lipids into lipoproteins during secretion

Summary The process of assembly and secretion of lipoproteins is discussed with particular reference to the role of lipids. The majority of circulating lipoproteins is produced by the liver (80%) with the remainder being supplied by the intestine. The liver secretes both very low density lipoproteins and high density lipoproteins, but the assembly and secretion of these two types of particles may follow different routes. The major lipid components of lipoproteins are triacylglycerols, cholesterol, cholesterol esters and phospholipids. The biosynthesis of these lipids occurs on membranes of the endoplasmic reticulum, with many of the enzymes also being present in the Golgi; the roles of these two subcellular organelles in the assembly of lipoproteins are discussed. There appears to be a compartmentalization of lipids in cells, such that defined pools, often those newly-synthesized, are preferred, or even required, for lipoprotein assembly. The process of hepatic very low density lipoprotein secretion appears to be regulated by the supply of lipids. Indeed, the synthesis of new lipid may be a major driving force in lipoprotein assembly and secretion.     

Estrogen and accessory sex gland lipids

Summary Administration of estradiol-17 elicited differential responses on accessory sex glands of rats. In caput epididymis, the estrogen treatment led to an accumulation of glycerides and phospholipids while in cauda epididymis, there was no significant change. However, in seminal vesicles, depletion of phospholipids was observed In prostate, the treatment, resulted in an accumulation of glycerides.Part of Ph.D. Thesis. Umapathy, E., Thesis. University of Madras, India, 1977.     

Mathematical models of regulatory mechanisms of sleep-wake rhythms

Studies of regulatory mechanisms of sleep-wake rhythms have benefited greatly from mathematical modeling. There are two major frameworks of modeling: one integrates homeostatic and circadian regulations and the other consists of multiple interacting oscillators. In this article, model constructions based on these respective frameworks and their characteristics are reviewed. The two-process model and the multioscillator model are explained in detail. An appropriate mathematical abstraction is also shown to provide a viewpoint unifying the model structures, which might seem to be distinct. Recently acquired knowledge of neural regulatory mechanisms of sleep-wake rhythm has prompted modeling at the neural network level. Such a detailed model is also reviewed, and could be used to explore a possible neural mechanism underlying a pathological state of sleep-wake rhythm.     

Metabolism and signaling activities of nuclear lipids

Apart from the lipids present in the nuclear envelope, the nucleus also contains lipids which are located further inside and are resistant to treatment with nonionic detergents. Evidence is being accumulated on the importance of internal nuclear lipid metabolism. Nuclear lipid metabolism gives rise to several lipid second messengers that function within the nucleus. Moreover, it is beginning to emerge that nuclear lipids not only act as precursors of bioactive second messengers but may be directly involved in regulation of nuclear structure and gene expression. Over the last 10years, especially the role of the inositol lipid cycle in nuclear signal transduction has been extensively studied. This cycle is activated following a variety of stimuli and is regulated independently from the inositide cycle located at the plasma membrane. However, the nucleus contain other lipids, such as phosphatidylcholine, sphingomyelin, fatty acids and eicosanoids. There are numerous reports which suggest that these classes of nuclear lipids may play roles in the nucleus as important as those of phosphoinositides. This review aims at highlighting the most important aspects regarding the metabolism and signaling activities of nuclear phosphatidylcholine, sphingomyelin, fatty acids and eicosanoids.Received 7 November 2003; received after revision 18 December 2003; accepted 29 December 2003     

Evidence for the intracellular accumulation of anandamide in adiposomes

Anandamide is a lipid messenger that carries out a wide variety of biological functions. It has been suggested that anandamide accumulation involves binding to a saturable cellular component. To identify the structure(s) involved in this process, we analyzed the intracellular distribution of both biotinylated and radiolabeled anandamide, providing direct evidence that lipid droplets, also known as adiposomes, constitute a dynamic reservoir for the sequestration of anandamide. In addition, confocal microscopy and biochemical studies revealed that the anandamide-hydrolase is also spatially associated with lipid droplets, and that cells with a larger adiposome compartment have an enhanced catabolism of anandamide. Overall, these findings suggest that adiposomes may have a critical role in accumulating anandamide, possibly by connecting plasma membrane to internal organelles along the metabolic route of this endocannabinoid. S. Oddi, F. Fezza: These authors contributed equally to the study.     

Control of sequences of movements in crayfish escape behavior

Summary Crayfish escape from predators by a series of rapid tailflips. The production of this seemingly simple behavior involves the interaction of multiple neural control mechanisms. The rapid flexion phase of the first tailflip is a fixed action pattern that is always organized by giant command neurons. Subsequent reextension is a chain reflex mediated by sensory feedback from the initial flexion. All following tailflips are produced by a non-gialnt system which is activated in parallel with the giant system by the escape-initiating stimulus. Proper integration of the giant system and the non-giant system is mediated by a reaction time mechanism.     

The industrial asymmetry of the stock price prediction with investor sentiment: Based on the comparison of predictive effects with SVR

As a representative emerging financial market, the Chinese stock market is more prone to volatility because of investor sentiment. It is reasonable to use efficient predictive methods to analyze the influence of investor sentiment on stock price forecasting. This paper conducts a comparative study about the predictive performance of artificial neural network, support vector regression (SVR) and autoregressive integrated moving average and selects SVR to study the asymmetry effect of investor sentiment on different industry index predictions. After studying the relevant financial indicators, the results divide the Shenwan first-class industries into two types and show that the industries affected by investor sentiment are composed of young companies with high growth and high operative pressure and there are a great number of investment bubbles in those companies.     

A new marker technique in cineradiography for the recording of movements in small vertebrates —Application to the study of jaw movements in soricids (Insectivora)

Summary Dental parapulpar pins (TMS^® Link Series) are reliable markers in cineradiography for the recording of movements in small vertebrates. The application of the pins to an analysis of mandibular movements of soricids allows a reconstruction of the complex movement pattern of both jaws during mastication.Authors in alphabetical order.     

Properties and modes of action of specific and non-specific phospholipid transfer proteins

Summary We have described the mode of action of the phosphatidylcholine transfer protein (PC-TP), the phosphatidylinositol transfer protein (PI-TP) and the non-specific lipid transfer protein (nsL-TP) isolated from bovine and rat tissues. PC-TP and PI-TP specifically bind one phospholipid molecule to be carried between membranes. PC-TP, and most likely PI-TP as well, have independent binding sites for thesn-1- andsn-2-fatty acyl chains. These sites have different properties, which may explain the ability of PC-TP and PI-TP to discriminate between positional phospholipid isomers. nsL-TP, which is identical to sterol carrier protein 2, transfers all common phospholipids, cholesterol and oxysterol derivatives between membranes. This protein is very efficient in mediating a net mass transfer of lipids to lipid-deficient membranes. Models for its mode of action, which is clearly different from that of PC-TP and PI-TP, are presented.     

International transmission mechanism of stock market movements: evidence from emerging equity markets

This paper investigates the transmission patterns of stock market movements between developed and emerging market economies by estimating a four‐variable VAR model. The underlying economic fundamentals and trade links are considered as possible determinants of differences in transmission patterns. The results of the impulse response functions and variance decompositions indicate that significant links exist between the stock markets of the USA and Mexico and weaker links between the markets of the USA, Argentina, and Brazil. Differences in the patterns of stock market responses are consistent with differences in trade flows. The response of emerging markets to a shock to the US market lasts longer than that of a developed market such as the UK. While no single emerging market can affect the US stock market, the combined effect of emerging markets on the US stock market is found to be statistically significant. These findings can be linked to differences in the speed of information processing and to the institutional structure governing the market. Overall the findings suggest that the transmission of stock market movements is in accord with underlying economic fundamentals rather than irrational contagion effects. Copyright © 2000 John Wiley & Sons, Ltd.     

Natriuretic peptide hormones promote radial water movements from the xylem of Tradescantia shoots

Immunological evidence suggests that plants, like vertebrates, contain natriuretic peptides (NPs) and that rat atrial NP (rANP) binds specifically to plant membranes and promotes concentration and conformation-dependent stomatal opening. Stomatal opening and specific increases in cGMP levels were also observed in response to immunoreactive plant NP (irPNP). Here we report that both 1 μM rANP and irPNP (100 ng total protein/100 μL) significantly increase radial water movements out of the xylem of shoots of Tradescantia multiflora. Enhanced radial water movements are also observed in response to the cell permeant cGMP analogue 8-Br-cGMP (100 nM). The water channel inhibitor mercuric chloride (HgCl₂) significantly inhibits radial water movements at concentrations of 50 μM, while the presence of 10 μM 2-hydroxyethylmercaptoethanol (ME) prevents the inhibitory effect of the mercurial. The guanylate cyclase inhibitor LY 83583 at a concentration of 20 μM and sodium azide (NaN₃) at concentrations of ≥ 1 μM both also reduce radial water movements. We therefore conclude that the regulation of radial water movement out of the xylem involves modulation of cGMP levels, water channels and respiration-dependent processes. In addition, we propose that NPs have a critical role to play in radial water movements out of the xylem and speculate that as in vertebrates, NP effects might, at least in part, be mediated via the regulation of guanylate cyclases and water channels. Received 15 June 1998; received after revision 7 August 1998; accepted 26 August 1998     

Enhancement of fluorescence of pyrene-containing lipids by polar media,detergents and phospholipids

Summary The fluorescence intensities of a medium-chain fatty acid and of several amphiphilic lipids, each containing pyrene in covalent linkage, were enhanced considerably by: 1) Dissolving in mixtures of a polar solvent (e.g. methanol, ethanol, tetrahydrofuran or dimethylsulfoxide) and water; for each individual compound, a certain ratio of solvent to water provided maximal fluorescence intensity. 2) Incorporating into micelles of reduced Triton X-100; an excess of detergent was used so that, statistically, only one molecule of lipid resided in one micelle of the Triton X-100. 3) Incorporating into liposomes of egg phosphatidylcholine; maximal fluorescence was observed using a large excess of phosphatidylcholine. When related to the fluorescence intensities in chloroform/methanol (21, by vol.) or water, the enhancement of fluorescence in the above three systems was about 2-6-fold or up to 60-fold, respectively.     

Constitutive relevance in cognitive science: The case of eye movements and cognitive mechanisms

In this paper I assess whether the recently proposed “No De-Coupling” (NDC) theory of constitutive relevance in mechanisms is a useful tool to reconstruct constitutive relevance investigations in scientific practice. The NDC theory has been advanced as a framework theoretically superior to the mutual manipulability (MM) account of constitutive relevance in mechanisms but, in contrast to the MM account, has not yet been applied to detailed case studies. I argue that the NDC account is also applicable to empirical practice and that it fares better than the MM account on both theoretical and empirical grounds. I elaborate these claims in terms of applications of the NDC theory to two case studies of cognitive science research on the role of eye movements in mechanisms for cognitive capacities.