Lipid-soluble molecules and some small molecules can permeate the membrane, but the lipid bilayer effectively repels the many large . When the cell is under stress, and the amount of ROS increases, the number of methionine "errors" is ramped up tenfold, allowing new proteins to be even more resistant to attack. It can also be produced by methylation of existing PE, while PE can be produced by the decarboxylation of PS. Hall ED, Wang JA, Miller DM, Cebak JE, & Hill RL (2018). Demonbreun AR, Quattrocelli M, Barefield DY, Allen MV, Swanson KE, & McNally EM (2016). Calcium entry after plasma membrane injury is required for repair. The .gov means its official. These observations suggest that lipids are not bystanders during the repair process, but are instead actively involved in organizing the playing field on which repair machinery operates. For example, caveolae are the site for assembling membrane repair proteins such as EHD2 and MG53 (Cai et al., 2009; Daumke et al., 2007; Marg et al., 2012). (A) Plasma membrane phospholipids are generated from biosynthetic pathways, which rely on formation of the molecule diacylglycerol (DAG) or cytidine diphosphate diacylglycerol (CDP-DAG) from phosphatidic acid (PA). Presence of LBPA at the plasma membrane through vesicle fusion could allow for ALIX recruitment and ESCRT assembly (Bissig et al., 2013); however, the presence of LBPA at membrane wound sites has not been directly observed. Of potential interest in this regard is the unconventional phospholipid lysobisphosphatidic acid (LBPA), which is found on endolysosomes. Bethesda, MD 20894, Web Policies While being a mostly non-polar molecule, owing to its steroid backbone and hydrocarbon chain, cholesterol does possess a hydroxyl group opposite the hydrocarbon chain. Minetti C, Sotgia F, Bruno C, Scartezzini P, Broda P, Bado M, Donati MA (1998). While much attention has been paid to the involvement of proteins in the membrane repair pathway, the role of lipids in facilitating plasma membrane repair remains poorly studied. This study showed that shear force on the membrane, as experienced by cells during mechanical injury, facilitated increased PLD activity through the process of lipid mixing. Without adequate remodeling, the plasma membrane protein and lipid composition would change dramatically, particularly after repeat injuries, and no longer function as in its pre-injury state. These observations on PIP2 kinetics line up remarkably well with the accumulation of F-actin at the injury site, which begins around 30 seconds after injury and extends for several minutes (Godin, Vergen, Prakash, Pagano, & Hubmayr, 2011; Horn et al., 2017). Unauthorized use of these marks is strictly prohibited. National Library of Medicine The physical and molecular mechanisms by which a cell can heal membrane ruptures and rebuild damaged or missing cellular structures remain poorly understood. To achieve these tasks, cells employ signaling networks, which respond to the changing microenvironment after injury and activate the diverse plasma membrane repair mechanisms with precise control in time and space. In addition to their structural role in shaping the physical properties of the plasma membrane, lipids also play an important signaling role in maintaining plasma membrane integrity. Repair of injured plasma membrane by rapid Ca2+-dependent endocytosis, Lipid peroxidation induces cholesterol domain formation in model membranes. Remorino A, De Beco S, Cayrac F, Di Federico F, Cornilleau G, Gautreau A, Coppey M (2017). and transmitted securely. This allows local and functional diversity between the two leaflets as well as various parts of the single contiguous plasma membrane (Figure 2B). Structurally, the conical ceramide molecule results in negative membrane curvature associated with rapid nucleation of ESCRT complex proteins (Lee, Kai, Carlson, Groves, & Hurley, 2015). Phospholipid biosynthetic pathways require the addition of different head groups to the DAG backbone. One of the roles of lipid mobility may be to allow for the movement of individual lipids to form microdomains near the site of injury, which has been shown to be important for repair (Vaughan et al., 2014), perhaps by facilitating lipid-mediated signaling. There are mechanisms that allow some products to enter or leave the cell either actively or passively. 2012 Sep-Oct;52(3-4):191-5. doi: 10.1016/j.ceca.2012.06.003. Gauthier NC, Fardin MA, Roca-Cusachs P, & Sheetz MP (2011). At each of these levels the structural and signaling aspects of lipids are critical for the cell to mount an efficient response to plasma membrane injury. Cell death occurs mainly by two methods: necrosis and apoptosis. The primary plasma membrane sphingolipid in mammalian cells is sphingomyelin, which utilizes a ceramide backbone (Merrill Jr, 2008). Would you like email updates of new search results? Zhu H, Lin P. h., De G, Choi K. h., Takeshima H, Weisleder N, & Ma J (2012). When . Phosphatidic acid regulation of PIPKI is critical for actin cytoskeletal reorganization. Horn A, Van der Meulen JH, Defour A, Hogarth M, Sreetama SC, Reed A, Jaiswal JK. Transient and local lipid peroxidation may affect membrane stabilization as peroxidation of polyunsaturated fatty acids changes head group separation and acyl chain interdigitation, increasing their molecular volume and causing formation of distinct cholesterol domains in the membrane, which increases the membrane rigidity (Jacob & Mason, 2005; Mason, Walter, & Mason, 1997). Temporary increase in plasma membrane tension coordinates the activation of exocytosis and contraction during cell spreading. Cells (whether entire unicellular organisms or parts of multicellular living systems) grow, metabolize nutrients (that is, chemically transform them), produce proteins and enzymes, replicate, and move. Rac1, a Rho family GTPase required for repair (Verboon & Parkhurst, 2015), forms nanoclusters at sites enriched in PA and PIP3, whose roles in regulating Rac1 appear to be non-overlapping (Maxwell et al., 2018). Lysosome fusion is required for the process of repair (Reddy, Caler, & Andrews, 2001). Membrane stabilization by modified steroid offers a potential therapy for muscular dystrophy due to dysferlin deficit, Transverse distribution of plasma membrane bilayer cholesterol: Picking sides. Individual lipids can serve as signaling molecules on their own or through binding proteins, and chemical changes to a single lipid can initiate change in local membrane composition. Cells respond to mechanical stress by rapid disassembly of caveolae. Accumulation of GRAF1 at the repair site occurs 2 minutes after injury, supporting its potential role in membrane remodeling following resealing. Semin Cell Dev Biol. This is especially important for membrane signaling functions as the liquid-ordered domains often serve to aggregate membrane-associated proteins (Cebecauer et al., 2018). Rapid actin-cytoskeletondependent recruitment of plasma membranederived dysferlin at wounds is critical for muscle membrane repair. These membrane invaginations require the presence of caveolin proteins, loss of which can result in poor membrane repair and muscular dystrophy (Gazzerro, Sotgia, Bruno, Lisanti, & Minetti, 2010; Minetti et al., 1998). In addition to their structural role, and often as an extension of it, lipids also provide a signaling function that facilitates plasma membrane repair. Pollet H, Conrard L, Cloos A-S, & Tyteca D (2018). sharing sensitive information, make sure youre on a federal Sphingosine 1-phosphate stimulates proliferation and migration of satellite cells: role of S1P receptors, Biochimica et Biophysica Acta (BBA)-Molecular Cell Research. Roach AN, Wang Z, Wu P, Zhang F, Chan RB, Yonekubo Y, Du G (2012). This preferential association between different lipids results in an important feature of the plasma membrane its transverse and lateral heterogeneity. Subsequent insult(s) of eccentric stretch result in a more severe wound and global hypercontraction, producing fiber retraction within the muscle bundle (53). Endocytosis can also occur at sites of membrane invagination known as caveolae, and caveolae internalization has been implicated in membrane repair (Corrotte et al., 2013). Plasma membrane damage caused by listeriolysin O is not repaired through endocytosis of the membrane pore. Sphingomyelin also confers different properties to the plasma membrane than the phospholipids, not least due to its preferential association with sterols (Ramstedt & Slotte, 2006). Along with the annexins, which act quickly to physically manipulate the membrane itself, reassembly of the cytoskeleton plays a crucial role in restoring membrane tension in the later stages of repair. Microfluidic guillotine reveals multiple timescales and mechanical modes of wound response in Stentor coeruleus. (D) The lipid make-up of the plasma membrane constantly changes. While the local accumulation of proteins such as annexins acts to stabilize the structurally unstable membrane after injury, remodeling of the membrane itself can achieve a similar outcome. Calcium has been identified as the key trigger to activate an effective membrane repair response that utilizes exocytosis and endocytosis to repair a membrane tear, or remove a membrane pore. In the case of lipid mobility, this principle is exemplified by the observation that decreasing the excessive lipid mobility in LGMD2B patient cells using a membrane permeant modified glucocorticoid improves repair (Sreetama et al., 2018). Endogenous mechanisms of repair in healthy cells appear to mimic the beneficial effect provided by poloxamer 188 by allowing for transient increases in lipid mobility while restricting fluidity increase to a relatively small spatial or temporal window. Boye TL, Maeda K, Pezeshkian W, Snder SL, Haeger SC, Gerke V, Nylandsted J. National Library of Medicine Thus, DAG acts as a scaffold that initiates and coordinates downstream signaling pathways within a tight spatial and temporal window rather than as a marker of membrane injury for fast-acting structural proteins. Annexin-A5 assembled into two-dimensional arrays promotes cell membrane repair. 2021 Apr 2;19(1):63. doi: 10.1186/s12915-021-00970-0. Such a role of CLIC/GEEC-mediated endocytosis in membrane remodeling is also supported by the observation that CLIC/GEEC is immediately activated in response to decreased membrane tension and has the capacity to turn over large amounts of plasma membrane (Thottacherry et al., 2018). 2022 Aug 4;11:e80778. Phosphatidylinositol is found in many cell types and tissues, but is particularly abundant in the brain. To do so, they must control the movement of liquids across their boundaries. Additionally, in contrast to PS, which recruits proteins directly involved in repair, DAG appears to recruit signaling proteins such as protein kinase C (PKC) (Vaughan et al., 2014; Zuzek, Fan, Spaeth, & Bittner, 2013). A single cell is often a complete organism in itself, such as a bacterium or yeast. These lipids also exist at the boundary of lipid-ordered domains, such as lipid rafts, indicating that GTPases are targeted to these regions where protein accumulation at the membrane is common (Moissoglu et al., 2014), increasing their relative signaling capacity. Membrane lipids: where they are and how they behave. The mystery of membrane organization: composition, regulation and roles of lipid rafts. cell, in biology, the basic membrane-bound unit that contains the fundamental molecules of life and of which all living things are composed. Viral infection controlled by a calcium-dependent lipid-binding module in ALIX. When a cell's DNA is damaged, it will typically detect the damage and try to repair it. However, these repair activities can also be observed at the single-cell level. The reduction in membrane tension is likely due directly to the addition of phospholipids to reduced lipid packing, as well as due in part to the cytoskeletal remodeling associated with vesicular transport at the plasma membrane. Presence of PS at the free membrane wound edge helps directs the annexin proteins to this site in a calcium-dependent manner, where they perform vital functions required for stabilization and shaping of the repairing membrane (see Section 3.3). Gazzerro E, Sotgia F, Bruno C, Lisanti MP, & Minetti C (2010). Other cells acquire specialized functions as they mature. This Goldilocks principle applies to several aspects of lipid involvement in the repair process. Honeybee immune systems depend more on protein diversity thanquantity. The tight packing, along with the preference of cholesterol to intercalate the acyl chains of sphingomyelin creates the liquid-ordered membrane domains, such as the so-called lipid rafts (Van Meer et al., 2008) (Figure 2C). Along with DAG, IP3 is also generated by the activity of PLC. These examples of organizational heterogeneity, along with the differences among the lipids that comprise the plasma membrane confer a variety of structural and signaling properties to the plasma membrane and allow the plasma membrane to mount and sustain localized signaling despite being fully interconnected and fluid. As discussed above, sphingolipids in the plasma membrane are an important regulator of plasma membrane repair. Sealing of transected neurites of rat B104 cells requires a diacylglycerol PKC-dependent pathway and a PKA-dependent pathway, Sezgin, Levental, Mayor, & Eggeling, 2017, Gauthier, Fardin, Roca-Cusachs, & Sheetz, 2011, Miyake, McNeil, Suzuki, Tsunoda, & Sugai, 2001, Skalman, Holst, Larsson, & Lundmark, 2018, Gazzerro, Sotgia, Bruno, Lisanti, & Minetti, 2010, Petersen, Chung, Nayebosadri, & Hansen, 2016, Lee, Kai, Carlson, Groves, & Hurley, 2015, Campelo, Fabrikant, McMahon, & Kozlov, 2010, Lamb, Harper, McKinney, Rzigalinski, & Ellis, 1997, Ligeti, Dagher, Hernandez, Koleske, & Settleman, 2004, Tran, Masedunskas, Weigert, & Ten Hagen, 2015, Godin, Vergen, Prakash, Pagano, & Hubmayr, 2011, Gurtner, Werner, Barrandon, & Longaker, 2008, Taverna, Nanney, Pollins, Sindona, & Caprioli, 2011, Nojima, Freeman, Gulbins, & Lentsch, 2015. This suggests the possibility that caveolae could act as mechanosensors that facilitate adaptation to membrane injury through gene transcription, although this remains to be explored. and transmitted securely. (B) Phospholipid biosynthesis depends on multiple inputs from metabolism (glycerol-3-phosphate) and extracellular import (choline and ethanolamine). In some cases, these forces are benign, such as membrane protrusion driven by cortical actin polymerization (Pontes, Monzo, & Gauthier, 2017). Simone LC, Caplan S, & Naslavsky N (2013). We have briefly discussed how such an integral role of lipids in plasma membrane repair also extends into tissue-level repair and restoration of organ function. The common eastern firefly produces light through a chemical reaction that energizes a molecule so it can release aphoton. FOIA The major differences between normal cells and cancer cells relate to growth, communication, cell repair and death, "stickiness" and spread, appearance, maturation, evasion of the immune system, function and blood supply . Lipids also react to the changing biochemical environment to become signaling molecules that determine the spatiotemporal dynamics of protein activation (Eyster, 2007) (Figure 1B). Each month, well bring you a selection of compelling updates to this ever-growing library of biological strategies and innovations. Leikina E, Defour A, Melikov K, Van der Meulen JH, Nagaraju K, Bhuvanendran S, Jaiswal JK (2015). Each of these lipids contributes their own qualities that affect the structural and signaling characteristics of the plasma membrane (Nicolson, 2014). Bennett APS, de la Torre-Escudero E, Dermott SSE, Threadgold LT, Hanna REB, Robinson MW. As MG53 interacts with the plasma membrane in a cholesterol-dependent manner ((Zhu et al., 2012); see Section 4), its extracellular role may involve a mode of action similar to poloxamer 188, where it inserts within membranes in a disordered lipid environment. Very large plasma membrane disruptions (micron diameter) require membrane patching. Shed microvesicles containing streptolysin-O have been shown to also contain annexins A1 and A6 (219). PLD-mediated activation of PI5K relies on the formation of PA, which itself is able to determine the spatial localization of PI5K as well as cause its activation (Roach et al., 2012). There are many differences between cancer cells and normal cells in noncancerous (benign) or cancerous (malignant) tumors. The basement membrane of the basal cells attaches via hemidesmosomes to the underlying Bowman's layer, while anchoring fibrils pass through . Tam C, Idone V, Devlin C, Fernandes MC, Flannery A, He X, Andrews NW (2010). This relies upon the coordinated action of the machinery that polarizes the repair response to the site of injury, resulting in resealing of the damaged membrane and subsequent remodeling to return the injured plasma membrane to its pre-injury state. Cong X, Hubmayr RD, Li C, & Zhao X (2017). Muscle fibers have a, Schematic representation of the structural, Schematic representation of the structural features of the protein families implicated in membrane, A cartoon depicting the potential role of dysferlin-mediated vesicle fusion in membrane repair., MeSH Microfluidic guillotine for single-cell wound repair studies. While intracellular MG53 is a redox-sensitive protein capable of facilitating vesicle aggregation, it is proposed to have multiple functions during membrane repair. Eukaryotic cells have been shown to utilize calcium-activated exocytosis to reduce membrane tension and promote repair via lipid-disorder driven attractions. Imagine a polymer wrapper that would heal when ripped during use, but would eventually decompose when placed in a compost heap. (Biomimicry Guild unpublished report). Interestingly, several methods for PIP2 micro-domain formation may allow for this to occur after plasma membrane injury. These cells cooperate with other specialized cells and become the building blocks of large multicellular . However, all cells are susceptible to plasma membrane damage, which results in the mixture of the intracellular fluid and extracellular milieu and can result in death if the damage is not rapidly repaired. However, lipid signaling also helps to coordinate downstream repair pathways that result in the membrane trafficking and cytoskeletal reorganization required for repair. Intriguingly, PIP2 is needed for PLD activity suggesting the possibility that a feed-forward loop leads to increasing PIP2 concentrations as repair progresses ultimately facilitating the necessary build-up of F-actin (Figure 1B). Dysferlin regulates cell membrane repair by facilitating injury-triggered acid sphingomyelinase secretion, Demonbreun AR, & McNally EM (2016). These same processes also work to dynamically control membrane fluidity by regulating the distribution of phospholipids, sphingolipids, and cholesterol in the membrane. Charged phospholipids such as PIP2, PS, and PE are almost exclusively found on the inner leaflet, while the glycosphingolipids are only found on the outer leaflet. The antioxidant requirement for plasma membrane repair in skeletal muscle. The vast majority of biochemical assembly and break down processeseven by the most complex organismsoccur within cells. Mechanism of Ca 2+-triggered ESCRT assembly and regulation of cell membrane repair. In this review, we will focus on the role of lipids during plasma membrane repair by discussing their functions as both structural and signaling molecules. Spontaneous resealing of plasma membrane, Spontaneous resealing of plasma membrane injuries in the nanometer range is opposed by, Calcium-activated exocytosis reduces membrane tension, Calcium-activated exocytosis reduces membrane tension and promotes spontaneous repair driven by lipid disorder, Very large plasma membrane disruptions (micron diameter) require membrane patching. Alterations in Phosphatidylcholine Metabolism of StretchInjured Cultured Rat Astrocytes. Lysosomes are involved with various cell processes. Unable to load your collection due to an error, Unable to load your delegates due to an error, Examples of self-repairing cells. In a similar manner, PS signaling may be involved in the early recruitment of other membrane repair proteins such as dysferlin (McDade et al., 2014; Middel et al., 2016) and MG53 (Cai et al., 2009). While it is unclear whether caveolae can provide structural assistance to the damaged membrane in the context of a large membrane injury (as opposed to sub-injury threshold stress, (Sinha et al., 2011)), caveolae may still provide a signaling function during the repair process. The spatial arrangement of lipids at the plasma membrane is not only important for GTPase recruitment, but also for their activity. The second stage of tissue repair, regeneration, makes use of signaling by different lipids, one of which is sphingolipid. Interphase has three stages: G1, S and G2. With an abundance of uncharged (zwitterionic) lipids and smaller amounts of neutral and anionic glycosphingolipids in the outer leaflet, and the negatively charged phosphatidylserine, phosphatidic acid and phosphatidylinositol within the inner leaflet, there exists a charge differential between the two plasma membrane leaflets (Steck & Lange, 2018; Zachowski, 1993). A surprise arrived when heart muscle cells were analyzed. Elife. This raises the intriguing possibility that MG53 may affect plasma membrane structural properties. Different cell-intrinsic PM repair mechanisms have been reported, including membrane fusion and replacement strategies (via exocytosis-mediated repair), removal of damaged membranes (by. Cell membrane disruption initially stimulates repair responses in the wounded cell itself, as described in this chapter, but other cells can subsequently respond to membrane disruption to "help" repair the membrane of the injured cell. increased lipid fluidity described in Section 3) and allows for the membrane associated PLD to diffuse outward from lipid rafts and interact with PIP2 in order to metabolize PC. Spaeth C, Fan J, Spaeth E, Robison T, Wilcott R, & Bittner G (2012). What's found inside a cell. Before Another broad group of lipid carriers that are recognized for their role in activating stem cells are extracellular vesicles (EVs), which are released locally at the site of injury or from a distant site and through their lipid and other cargoes regulate regeneration of injured tissues by way of stem cell activation (Riazifar, Pone, Ltvall, & Zhao, 2017). While a common thread in lipid signaling is the modification of a target protein, either directly or indirectly, the numerous mechanisms lipids use to achieve this outcome allows for a great diversity of signaling. Int J Mol Sci. Here the sugar (oligosaccharide) moiety faces the extracellular space interacting with other cells and extracellular ligands required for processes such as signaling, cell adhesion or intercellular interactions. Before Riazifar M, Pone EJ, Ltvall J, & Zhao W (2017). As muscle fibers have strong interfiber connections, muscle injuries may manifest both as shearing of the membrane from increased membrane tension and strain, as well as ripping of plasma membrane regions from fiber retraction or hypercontraction. Shear stress on the plasma membrane also results in the dissociation of the negative regulator RhoGDI and its binding partner Rho (Shao et al., 2018). EHD2 localization at caveolae results from its affinity for phosphatidylinositol 4,5-bisphosphate (PIP2), which is enriched around the caveolae boundary (Parton & Del Pozo, 2013; Simone, Caplan, & Naslavsky, 2013). . In contrast to PC, sphingomyelin forms a taller and narrower cylinder, which along with the configuration of its acyl chains, allowing this lipid to pack more tightly than phospholipids (Cebecauer et al., 2018). Muscle membrane integrity in Duchenne muscular dystrophy: recent advances in copolymer-based muscle membrane stabilizers. PIP2 dynamics after plasma membrane injury support a role for PIP2 in actin assembly during repair as its accumulation near the site of injury is generally delayed. Importantly, sequestration of cholesterol alone increased PLD activity, supporting the idea that transient increase in lipid fluidity after membrane injury may be required for PLD-mediated signaling. Proc Natl Acad Sci U S A. Careers. Epub 2008 Mar 3. Dystrophic heart failure blocked by membrane sealant poloxamer, Cytosolic proteins can exploit membrane localization to trigger functional assembly, Phospholipids in animal eukaryotic membranes: transverse asymmetry and movement, Phosphatidic acid signaling regulation of Ras superfamily of small guanosine triphosphatases, Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids. EHD2 is a mechanotransducer connecting caveolae dynamics with gene transcription. However, ceramide formation also changes membrane dynamics by forming rigid microdomains and potentially by displacing cholesterol from lipid rafts (London, 2004). PI5K activity is itself driven by regulators of membrane repair including Rho GTPases (Gilmore & Burridge, 1996) and PLD (Roach et al., 2012). For example, when inserted into a region abundant in phospholipids, cholesterol has a rigidifying effect; however, the opposite can be true with sphingolipids. Further, the addition of new membrane by increased calcium-triggered exocytosis also decreases membrane tension and is required for plasma membrane repair (Togo et al., 2000). Following this, accumulation of Annexin 4 and Annexin 6 results in folding and inward contraction of the injured membrane, respectively (Boye et al., 2017). The product of PC metabolism by PLD is the signaling lipid PA (Cazzolli, Shemon, Fang, & Hughes, 2006). The basement membrane plays an important role in cellular functions, including those involved in healing, by controlling the binding of growth factors and their local concentrations between cell layers. This form of membrane remodeling maintains lipid homeostasis and plasma membrane functionality. The organization of lipids within the membrane also affects the structure of underlying cortical cytoskeleton. While PLD is also activated by calcium, recent findings have provided insight into the role of mechanical stress on initiating lipid signaling regulated by PLD (Petersen et al., 2016). Calcium can activate proteins directly, and ultimately is the initiator of many downstream repair pathways. The lipids in the membrane are fluid, and therefore in motion, and are constantly adapting to the changing environment. However, shear force on the membrane increases the kinetic energy required for lipid mixing (i.e. Thus, it is clear that there is a need to acknowledge the role of lipids as an active participant in the processes of both cell and tissue repair. Their localization and function in response to injury is controlled by the patterning of anionic lipids such as PS, which is present at the wound edge and is a known binding partner of annexins (Gerke, Creutz, & Moss, 2005). 2023 Feb 28;24(5):4647. doi: 10.3390/ijms24054647. Bethesda, MD 20894, Web Policies Verweij FJ, Revenu C, Arras G, Dingli F, Loew D, Pegtel DM, Zimmermann P (2019). Regulation of Rac1 translocation and activation by membrane domains and their boundaries, Stressing caveolae new role in cell mechanics, Membrane cytoskeleton: PIP2 pulls the strings, The FluidMosaic Model of Membrane Structure: Still relevant to understanding the structure, function and dynamics of biological membranes after more than 40 years, Biochimica et Biophysica Acta (BBA)-Biomembranes. . FRET biosensor allows spatiotemporal observation of shear stress-induced polar RhoGDI activation. This remodeling is likely provided by processes described previously: membrane endocytosis (Section 3.1) and membrane shedding (Section 4.1). Lamb RG, Harper CC, McKinney JS, Rzigalinski BA, & Ellis EF (1997). Instead, there exists distinct inter- and intra-leaflet heterogeneity of lipids.
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