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1
Melese, Fekadu. "Improved Performance of Raft Foundation Using Detached Pile Columns in Loose Subsoil Conditions." Advances in Civil Engineering 2022 (March 8, 2022): 1–18. http://dx.doi.org/10.1155/2022/4002545.
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Piles act as settlement reducers in case of connected piled-raft foundation and hence decrease the settlements of the raft. The design concept of the connected piled-raft foundations is to lessen the number of piles and utilize the bearing capacity of the system piled raft. Due to significant straining actions at the pile head-raft connection, an alternative technique is proposed to disconnect the piles from the raft. A granular layer (cushion) beneath the raft is incorporated. The disconnection has a beneficial effect on reducing axial load compared to connected piles. For small piled rafts, nonconnected piled rafts show less stiffness than connected piled rafts, and the soil is highly stressed and shows greater raft settlement. In the case of the large piled raft, nonconnected piled rafts show greater settlement efficiency. Cushion stiffness was realized to be more substantial for a nonconnected piled raft with shorter piles than one with longer piles. The results show that the load transfer mechanism in a nonconnected piled raft is mainly governed by the thickness and stiffness of the cushion layer and by the stiffness of the subsoil.
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Singh, Ajay Pratap, Rathor ., and Jitendra Kumar Sharma. "Engineering Significance of Annular Raft Foundations over Solid Raft FoundationsJ." International Journal for Research in Applied Science and Engineering Technology 11, no. 9 (September 30, 2023): 930–34. http://dx.doi.org/10.22214/ijraset.2023.55783.
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Abstract: Raft foundations play a pivotal role in distributing structural loads to the underlying soil, thereby ensuring the stability and integrity of various civil engineering structures. The choice between different types of raft foundations, such as solid and annular rafts, significantly impacts the overall performance and durability of a structure. This paper explores the engineering significance of annular raft foundations in comparison to solid raft foundations. The traditional solid raft foundation offers uniform load distribution and settlement control; however, it often encounters challenges when dealing with non-uniform soil profiles, differential settlements, and expansive soils. Annular raft foundations, a relatively innovative approach, address these challenges by featuring a central void within the raft. This void introduces a controlled differential settlement mechanism, enabling the foundation to accommodate non-uniform soil conditions effectively. Moreover, annular rafts offer improved structural performance in regions prone to ground movements, as the central void allows the foundation to adjust to soil displacements more flexibly than a solid raft. The engineering significance of annular rafts extends to their enhanced loadbearing capacity and reduction in material usage compared to solid rafts. The design of annular rafts takes advantage of the arching effect within the void, which enables the foundation to support heavier loads while minimizing the amount of concrete and reinforcement required. This not only contributes to cost savings but also aligns with sustainable construction practices by reducing the environmental impact associated with excessive material consumption.
3
Leitinger, Birgit, and Nancy Hogg. "The involvement of lipid rafts in the regulation of integrin function." Journal of Cell Science 115, no. 5 (March 1, 2002): 963–72. http://dx.doi.org/10.1242/jcs.115.5.963.
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Integrin activity on cells such as T lymphocytes is tightly controlled. Here we demonstrate a key role for lipid rafts in regulating integrin function. Without stimulation integrin LFA-1 is excluded from lipid rafts, but following activation LFA-1 is mobilised to the lipid raft compartment. An LFA-1 construct from which the I domain has been deleted mimics activated integrin and is constitutively found in lipid rafts. This correlation between integrin activation and raft localisation extends to a second integrin,α4β1, and the clustering of α4β1 is also raft dependent. Both LFA-1 and α4β1-mediated adhesion is dependent upon intact lipid rafts providing proof of the functional relevance of the lipid raft localisation. Finally we find that non-raft integrins are excluded from the rafts by cytoskeletal constraints. The presence of integrin in lipid rafts under stimulating conditions that activate these receptors strongly indicates that the rafts have a key role in positively regulating integrin activity.
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Tsuchiya, Hironori, and Maki Mizogami. "Interaction of drugs with lipid raft membrane domains as a possible target." Drug Target Insights 14, no. 1 (December 22, 2020): 34–47. http://dx.doi.org/10.33393/dti.2020.2185.
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Introduction: Plasma membranes are not the homogeneous bilayers of uniformly distributed lipids but the lipid complex with laterally separated lipid raft membrane domains, which provide receptor, ion channel and enzyme proteins with a platform. The aim of this article is to review the mechanistic interaction of drugs with membrane lipid rafts and address the question whether drugs induce physicochemical changes in raft-constituting and raft-surrounding membranes.
Methods: Literature searches of PubMed/MEDLINE and Google Scholar databases from 2000 to 2020 were conducted to include articles published in English in internationally recognized journals. Collected articles were independently reviewed by title, abstract and text for relevance.
Results: The literature search indicated that pharmacologically diverse drugs interact with raft model membranes and cellular membrane lipid rafts. They could physicochemically modify functional protein-localizing membrane lipid rafts and the membranes surrounding such domains, affecting the raft organizational integrity with the resultant exhibition of pharmacological activity. Raft-acting drugs were characterized as ones to decrease membrane fluidity, induce liquid-ordered phase or order plasma membranes, leading to lipid raft formation; and ones to increase membrane fluidity, induce liquid-disordered phase or reduce phase transition temperature, leading to lipid raft disruption.
Conclusion: Targeting lipid raft membrane domains would open a new way for drug design and development. Since angiotensin-converting enzyme 2 receptors which are a cell-specific target of and responsible for the cellular entry of novel coronavirus are localized in lipid rafts, agents that specifically disrupt the relevant rafts may be a drug against coronavirus disease 2019.
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Bavari, Sina, Catharine M. Bosio, Elizabeth Wiegand, Gordon Ruthel, Amy B. Will, Thomas W. Geisbert, Michael Hevey, Connie Schmaljohn, Alan Schmaljohn, and M. Javad Aman. "Lipid Raft Microdomains." Journal of Experimental Medicine 195, no. 5 (March 4, 2002): 593–602. http://dx.doi.org/10.1084/jem.20011500.
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Spatiotemporal aspects of filovirus entry and release are poorly understood. Lipid rafts act as functional platforms for multiple cellular signaling and trafficking processes. Here, we report the compartmentalization of Ebola and Marburg viral proteins within lipid rafts during viral assembly and budding. Filoviruses released from infected cells incorporated raft-associated molecules, suggesting that viral exit occurs at the rafts. Ectopic expression of Ebola matrix protein and glycoprotein supported raft-dependent release of filamentous, virus-like particles (VLPs), strikingly similar to live virus as revealed by electron microscopy. Our findings also revealed that the entry of filoviruses requires functional rafts, identifying rafts as the site of virus attack. The identification of rafts as the gateway for the entry and exit of filoviruses and raft-dependent generation of VLPs have important implications for development of therapeutics and vaccination strategies against infections with Ebola and Marburg viruses.
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Savla, Hemali M., Isha V. Naik, Chandrashekhar Gargote, Nischal Shashidhar, Sneha Nair, and Mala D. Menon. "Physicochemical properties of various alginate-based raft-forming antacid products: a comparative study." International Journal of Basic & Clinical Pharmacology 10, no. 12 (November 22, 2021): 1330. http://dx.doi.org/10.18203/2319-2003.ijbcp20214449.
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Background: Alginate-based, raft-forming antacid products with reflux suppressant activity are complex formulations expected to achieve effective raft formation and cause elimination or displacement of the acid pocket, which is typically manifested in gastroesophageal reflux disease (GERD).Methods: In the present study, six alginate-based raft-forming products commercially available in the Indian market were compared in terms of their acid neutralization properties, strength, resilience and structural and thermal properties of their rafts. Percent alginate content was also determined.Results: Rafts of products containing calcium-based antacids formed voluminous, porous and floating rafts within seconds of addition to the simulated gastric fluid (SGF) compared with the products that contained aluminium and magnesium-based antacids. Marked differences were not evident in the ANC (acid neutralization capacity) values of the various products. No correlation was observed between ANC and raft-forming capacity or duration of neutralization. Raft structures affected their neutralization profiles. Rafts of porous and absorbent nature could retain their ANC probably due to release of trapped antacids. Further, raft strengths of only two products were above the British Pharmacopoeia specification of not less than 7.5 g. Sodium alginate content was within specifications (85-115%) for three of the six products.Conclusions: Raft-forming formulations with higher alginate content and calcium-based antacids have better physicochemical properties such as ANC, neutralization profiles, raft strength and raft resilience than those with lower alginate content or those containing aluminium or magnesium-based antacids.
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Kenworthy, Anne K., Benjamin J. Nichols, Catha L. Remmert, Glenn M. Hendrix, Mukesh Kumar, Joshua Zimmerberg, and Jennifer Lippincott-Schwartz. "Dynamics of putative raft-associated proteins at the cell surface." Journal of Cell Biology 165, no. 5 (June 1, 2004): 735–46. http://dx.doi.org/10.1083/jcb.200312170.
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Lipid rafts are conceptualized as membrane microdomains enriched in cholesterol and glycosphingolipid that serve as platforms for protein segregation and signaling. The properties of these domains in vivo are unclear. Here, we use fluorescence recovery after photobleaching to test if raft association affects a protein's ability to laterally diffuse large distances across the cell surface. The diffusion coefficients (D) of several types of putative raft and nonraft proteins were systematically measured under steady-state conditions and in response to raft perturbations. Raft proteins diffused freely over large distances (>4 μm), exhibiting Ds that varied 10-fold. This finding indicates that raft proteins do not undergo long-range diffusion as part of discrete, stable raft domains. Perturbations reported to affect lipid rafts in model membrane systems or by biochemical fractionation (cholesterol depletion, decreased temperature, and cholesterol loading) had similar effects on the diffusional mobility of raft and nonraft proteins. Thus, raft association is not the dominant factor in determining long-range protein mobility at the cell surface.
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Sharma, V. J., S. A. Vasanvala, and C. H. Solanki. "Behaviour of Load-Bearing Components of a Cushioned Composite Piled Raft Foundation Under Axial Loading." Slovak Journal of Civil Engineering 22, no. 4 (December 1, 2014): 25–34. http://dx.doi.org/10.2478/sjce-2014-0020.
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Abstract In the last decade piled raft foundations have been widely used around the world as intermediate foundation systems between piles and rafts to control the settlement of foundations. However, when those piles are structurally connected to rafts, relatively high axial stresses develop in relatively small numbers of piles, which are often designed to fully mobilize their geotechnical capacities. To avoid a concentration of stress at the head of piles in a traditional piled raft foundation, the raft is disconnected from the piles, and a cushion is introduced between them. Also, to tackle an unfavourable soil profile for a piled raft foundation, the conventional piled raft has been modified into a cushioned composite piled raft foundation, where piles of different materials are used. In the current study the behavior of cushioned foundation components, which transfer the load from the structure to the subsoil, are analyzed in detail, i.e., the thickness of the raft, the length of a long pile and the modulus of a flexible pile.
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Shvartsman, Dmitry E., Mariana Kotler, Renee D. Tall, Michael G. Roth, and Yoav I. Henis. "Differently anchored influenza hemagglutinin mutants display distinct interaction dynamics with mutual rafts." Journal of Cell Biology 163, no. 4 (November 17, 2003): 879–88. http://dx.doi.org/10.1083/jcb.200308142.
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Lipid rafts play important roles in cellular functions through concentrating or sequestering membrane proteins. This requires proteins to differ in the stability of their interactions with lipid rafts. However, knowledge of the dynamics of membrane protein–raft interactions is lacking. We employed FRAP to measure in live cells the lateral diffusion of influenza hemagglutinin (HA) proteins that differ in raft association. This approach can detect weak interactions with rafts not detectable by biochemical methods. Wild-type (wt) HA and glycosylphosphatidylinositol (GPI)-anchored HA (BHA-PI) diffused slower than a nonraft HA mutant, but became equal to the latter after cholesterol depletion. When antigenically distinct BHA-PI and wt HA were coexpressed, aggregation of BHA-PI into immobile patches reduced wt HA diffusion rate, suggesting transient interactions with BHA-PI raft patches. Conversely, patching wt HA reduced the mobile fraction of BHA-PI, indicating stable interactions with wt HA patches. Thus, the anchoring mode determines protein–raft interaction dynamics. GPI-anchored and transmembrane proteins can share the same rafts, and different proteins can interact stably or transiently with the same raft domains.
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Mańka, Rafał, Pawel Janas, Karolina Sapoń, Teresa Janas, and Tadeusz Janas. "Role of RNA Motifs in RNA Interaction with Membrane Lipid Rafts: Implications for Therapeutic Applications of Exosomal RNAs." International Journal of Molecular Sciences 22, no. 17 (August 30, 2021): 9416. http://dx.doi.org/10.3390/ijms22179416.
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RNA motifs may promote interactions with exosomes (EXO-motifs) and lipid rafts (RAFT-motifs) that are enriched in exosomal membranes. These interactions can promote selective RNA loading into exosomes. We quantified the affinity between RNA aptamers containing various EXO- and RAFT-motifs and membrane lipid rafts in a liposome model of exosomes by determining the dissociation constants. Analysis of the secondary structure of RNA molecules provided data about the possible location of EXO- and RAFT-motifs within the RNA structure. The affinity of RNAs containing RAFT-motifs (UUGU, UCCC, CUCC, CCCU) and some EXO-motifs (CCCU, UCCU) to rafted liposomes is higher in comparison to aptamers without these motifs, suggesting direct RNA-exosome interaction. We have confirmed these results through the determination of the dissociation constant values of exosome-RNA aptamer complexes. RNAs containing EXO-motifs GGAG or UGAG have substantially lower affinity to lipid rafts, suggesting indirect RNA-exosome interaction via RNA binding proteins. Bioinformatics analysis revealed RNA aptamers containing both raft- and miRNA-binding motifs and involvement of raft-binding motifs UCCCU and CUCCC. A strategy is proposed for using functional RNA aptamers (fRNAa) containing both RAFT-motif and a therapeutic motif (e.g., miRNA inhibitor) to selectively introduce RNAs into exosomes for fRNAa delivery to target cells for personalized therapy.
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Verma, Dileep, Dinesh Gupta, and Sunil Lal. "Host Lipid Rafts Play a Major Role in Binding and Endocytosis of Influenza A Virus." Viruses 10, no. 11 (November 18, 2018): 650. http://dx.doi.org/10.3390/v10110650.
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Influenza still remains one of the most challenging diseases, posing a significant threat to public health. Host lipid rafts play a critical role in influenza A virus (IAV) assembly and budding, however, their role in polyvalent IAV host binding and endocytosis had remained elusive until now. In the present study, we observed co-localization of IAV with a lipid raft marker ganglioside, GM1, on the host surface. Further, we isolated the lipid raft micro-domains from IAV infected cells and detected IAV protein in the raft fraction. Finally, raft disruption using Methyl-β-Cyclodextrin revealed significant reduction in IAV host binding, suggesting utilization of host rafts for polyvalent binding on the host cell surface. In addition to this, cyclodextrin mediated inhibition of raft-dependent endocytosis showed significantly reduced IAV internalization. Interestingly, exposure of cells to cyclodextrin two hours post-IAV binding showed no such reduction in IAV entry, indicating use of raft-dependent endocytosis for host entry. In summary, this study demonstrates that host lipid rafts are selected by IAV as a host attachment factors for multivalent binding, and IAV utilizes these micro-domains to exploit raft-dependent endocytosis for host internalization, a virus entry route previously unknown for IAV.
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Samofalov, Michail, Vytautas Papinigis, and Mantas Tūnaitis. "Mechanical state analysis of different variants of piled rafts." BALTIC JOURNAL OF ROAD AND BRIDGE ENGINEERING 10, no. 1 (March 10, 2015): 1–10. http://dx.doi.org/10.3846/bjrbe.2015.01.
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Traditional raft design methods describe unpiled and fully piled rafts. The current paper aims to discuss intermediate raft design variants when the raft is at the same time partially supported by piles and partially rests on the ground. The loading conditions of all variants as well as mechanical properties assumed to be identical, general numerical simulation assumptions are also the same. The task is to analyse the stress and strain state of the raft for all variants (unpiled raft, partially piled raft, fully piled raft), to compare the results and to determine the most rational case. Raft settlements, bending moments and expenses of the materials are compared on the basis of the results.
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Chore, Hemant, Junaid Siddiqui, and Ashish Kishore. "Parametric Investigations into the Analysis of Piled Raft for Multi-Storeyed Building." Journal of Civil Engineering Frontiers 3, no. 02 (February 6, 2023): 67–73. http://dx.doi.org/10.38094/jocef30260.
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This paper presents the analysis of the piled raft for a 50-story building using an approximate method to estimate the settlement and load distribution of the foundation. The pile and soils are considered to be interacting springs, and the raft is represented as a thin plate. The model takes into account both the resistance of the piles and the resistance of the raft foundation. It is calculated how the raft, soil, and pile interact. The suggested technique enables the use of the finite element based program ETABS to quickly address the issues of small, non-uniformly arranged rafts and big, non-uniformly ordered rafts. The effect of different pile length and diameter is evaluated on the behaviour of piled raft. With an increase in pile lengths, the moments in the raft are found to increase while the settlement of the pile decreases. Further, increases in pile diameter are found to increase the moments in the raft while decreasing the settlement of the raft. The parameters such as pile diameter and pile length have a considerable effect on the response of a foundation considered in the present study
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Hashimoto-Tane, Akiko, Tadashi Yokosuka, Chitose Ishihara, Machie Sakuma, Wakana Kobayashi, and Takashi Saito. "T-Cell Receptor Microclusters Critical for T-Cell Activation Are Formed Independently of Lipid Raft Clustering." Molecular and Cellular Biology 30, no. 14 (May 24, 2010): 3421–29. http://dx.doi.org/10.1128/mcb.00160-10.
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ABSTRACT We studied the function of lipid rafts in generation and signaling of T-cell receptor microclusters (TCR-MCs) and central supramolecular activation clusters (cSMACs) at immunological synapse (IS). It has been suggested that lipid raft accumulation creates a platform for recruitment of signaling molecules upon T-cell activation. However, several lipid raft probes did not accumulate at TCR-MCs or cSMACs even with costimulation and the fluorescence resonance energy transfer (FRET) between TCR or LAT and lipid raft probes was not induced at TCR-MCs under the condition of positive induction of FRET between CD3ζ and ZAP-70. The analysis of LAT mutants revealed that raft association is essential for the membrane localization but dispensable for TCR-MC formation. Careful analysis of the accumulation of raft probes in the cell interface revealed that their accumulation occurred after cSMAC formation, probably due to membrane ruffling and/or endocytosis. These results suggest that lipid rafts control protein translocation to the membrane but are not involved in the clustering of raft-associated molecules and therefore that the lipid rafts do not serve as a platform for T-cell activation.
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Wang, Limin, Annapoorna R. Sapuri-Butti, Hnin Hnin Aung, Atul N. Parikh, and John C. Rutledge. "Triglyceride-rich lipoprotein lipolysis increases aggregation of endothelial cell membrane microdomains and produces reactive oxygen species." American Journal of Physiology-Heart and Circulatory Physiology 295, no. 1 (July 2008): H237—H244. http://dx.doi.org/10.1152/ajpheart.01366.2007.
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Triglyceride-rich lipoprotein (TGRL) lipolysis may provide a proinflammatory stimulus to endothelium. Detergent-resistant plasma membrane microdomains (lipid rafts) have a number of functions in endothelial cell inflammation. The mechanisms of TGRL lipolysis-induced endothelial cell injury were investigated by examining endothelial cell lipid rafts and production of reactive oxygen species (ROS). Lipid raft microdomains in human aortic endothelial cells were visualized by confocal microscopy with fluorescein isothiocyanate-labeled cholera toxin B as a lipid raft marker. Incubation of Atto565-labeled TGRL with lipid raft-labeled endothelial cells showed that TGRL colocalized with the lipid rafts, TGRL lipolysis caused clustering and aggregation of lipid rafts, and colocalization of TGRL remnant particles on the endothelial cells aggregated lipid rafts. Furthermore, TGRL lipolysis caused translocation of low-density lipoprotein receptor-related protein, endothelial nitric oxide synthase, and caveolin-1 from raft regions to nonraft regions of the membrane 3 h after treatment with TGRL lipolysis. TGRL lipolysis significantly increased the production of ROS in endothelial cells, and both NADPH oxidase and cytochrome P-450 inhibitors reduced production of ROS. Our studies suggest that alteration of lipid raft morphology and composition and ROS production could contribute to TGRL lipolysis-mediated endothelial cell injury.
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Rajamanickam, Gayathri D., John P. Kastelic, and Jacob C. Thundathil. "Testis-Specific Isoform of Na/K-ATPase (ATP1A4) Interactome in Raft and Non-Raft Membrane Fractions from Capacitated Bovine Sperm." International Journal of Molecular Sciences 20, no. 13 (June 28, 2019): 3159. http://dx.doi.org/10.3390/ijms20133159.
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The plasma membrane of sperm contains highly dynamic lipid microdomains (rafts), which house signaling proteins with a role in regulating capacitation. We reported that ATP1A4, the testis-specific isoform of Na/K-ATPase, interacted with caveolin-1, Src, epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinases 1/2 (ERK1/2) in raft and non-raft domains of the plasma membrane of bovine sperm during capacitation. The objective of the present study was to use a proteomic approach to characterize the ATP1A4 interactome in rafts and non-rafts from capacitated bovine sperm. The non-raft interactome included hexokinase 1, plakophilin 1, desmoglein 1, 14-3-3 protein ζ/δ, cathepsin D and heat shock protein beta1 proteins exclusively, whereas glutathione S-transferase and annexin A2 were unique to raft interactome. However, a disintegrin and metalloprotease 32 (ADAM 32), histone H4, actin, acrosin, serum albumin and plakoglobin were identified in both raft and non-raft fractions of capacitated sperm. Based on gene ontology studies, these differentially interacted proteins were implicated in cell–cell adhesion, signal transduction, fertilization, metabolism, proteolysis and DNA replication, in addition to acting as transport/carrier and cytoskeletal proteins. Overall, we identified proteins not previously reported to interact with ATP1A4; furthermore, we inferred that ATP1A4 may have a role in sperm capacitation.
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PIKE, Linda J. "Lipid rafts: heterogeneity on the high seas." Biochemical Journal 378, no. 2 (March 1, 2004): 281–92. http://dx.doi.org/10.1042/bj20031672.
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Lipid rafts are membrane microdomains that are enriched in cholesterol and glycosphingolipids. They have been implicated in processes as diverse as signal transduction, endocytosis and cholesterol trafficking. Recent evidence suggests that this diversity of function is accompanied by a diversity in the composition of lipid rafts. The rafts in cells appear to be heterogeneous both in terms of their protein and their lipid content, and can be localized to different regions of the cell. This review summarizes the data supporting the concept of heterogeneity among lipid rafts and outlines the evidence for cross-talk between raft components. Based on differences in the ways in which proteins interact with rafts, the Induced-Fit Model of Raft Heterogeneity is proposed to explain the establishment and maintenance of heterogeneity within raft populations.
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Lacalle, Rosa Ana, Emilia Mira, Concepción Gómez-Moutón, Sonia Jiménez-Baranda, Carlos Martínez-A., and Santos Mañes. "Specific SHP-2 partitioning in raft domains triggers integrin-mediated signaling via Rho activation." Journal of Cell Biology 157, no. 2 (April 15, 2002): 277–89. http://dx.doi.org/10.1083/jcb.200109031.
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Cell signaling does not occur randomly over the cell surface, but is integrated within cholesterol-enriched membrane domains, termed rafts. By targeting SHP-2 to raft domains or to a non-raft plasma membrane fraction, we studied the functional role of rafts in signaling. Serum-depleted, nonattached cells expressing the raft SHP-2 form, but not non-raft SHP-2, display signaling events resembling those observed after fibronectin attachment, such as β1 integrin clustering, 397Y-FAK phosphorylation, and ERK activation, and also increases Rho-GTP levels. Expression of the dominant negative N19Rho abrogates raft-SHP-2–induced signaling, suggesting that Rho activation is a downstream event in SHP-2 signaling. Expression of a catalytic inactive SHP-2 mutant abrogates the adhesion-induced feedback inhibition of Rho activity, suggesting that SHP-2 contributes to adhesion-induced suppression of Rho activity. Because raft recruitment of SHP-2 occurs physiologically after cell attachment, these results provide a mechanism by which SHP-2 may influence cell adhesion and migration by spatially regulating Rho activity.
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Al-Mosawi, Mosa J., Mohammed Y. Fattah, and Abbas A. O. Al-Zayadi. "EXPERIMENTAL OBSERVATIONS ON THE BEHAVIOR OF A PILED RAFT FOUNDATION." Journal of Engineering 17, no. 04 (August 1, 2011): 807–28. http://dx.doi.org/10.31026/j.eng.2011.04.13.
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The piled raft is a geotechnical composite construction consisting of three elements: piles, raft and soil.In the design of piled rafts, the load shared between the piles and the raft, and the piles are used up to aload level that can be of the same order of magnitude as the bearing capacity of a comparable singlepile or even greater. Therefore, the piled raft foundation allows reduction of settlements in a veryeconomic way as compared to traditional foundation concepts.This paper presents experimental study to investigate the behavior of piled raft system in sandysoil. A small scale “prototype” model was tested in a sand box with load applied to the system througha compression machine. The settlement was measured at the center of the raft, strain gages were usedto measure the strains and calculate the total load carried by piles. Four configurations of piles (2x1,3x1, 2x2 and 3x2) were tested in the laboratory, in addition to rafts with different sizes. The effects ofpile length, pile diameter, and raft thickness on the load carrying capacity of the piled raft system areincluded in the load-settlement presentation.It was found that the percentage of the load carried by piles to the total applied load of thegroups (2x1, 3x1, 2x2, 3x2) with raft thickness of 5 mm, pile diameter of 9 mm, and pile length of 200mm was 28% , 38% , 56% , 79% , respectively. The percent of the load carried by piles increases withthe increase of number of piles.
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Bowie, Rachel V., Simona Donatello, Clíona Lyes, Mark B. Owens, Irina S. Babina, Lance Hudson, Shaun V. Walsh, et al. "Lipid rafts are disrupted in mildly inflamed intestinal microenvironments without overt disruption of the epithelial barrier." American Journal of Physiology-Gastrointestinal and Liver Physiology 302, no. 8 (April 15, 2012): G781—G793. http://dx.doi.org/10.1152/ajpgi.00002.2011.
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Intestinal epithelial barrier disruption is a feature of inflammatory bowel disease (IBD), but whether barrier disruption precedes or merely accompanies inflammation remains controversial. Tight junction (TJ) adhesion complexes control epithelial barrier integrity. Since some TJ proteins reside in cholesterol-enriched regions of the cell membrane termed lipid rafts, we sought to elucidate the relationship between rafts and intestinal epithelial barrier function. Lipid rafts were isolated from Caco-2 intestinal epithelial cells primed with the proinflammatory cytokine interferon-γ (IFN-γ) or treated with methyl-β-cyclodextrin as a positive control for raft disruption. Rafts were also isolated from the ilea of mice in which colitis had been induced in conjunction with in vivo intestinal permeability measurements, and lastly from intestinal biopsies of ulcerative colitis (UC) patients with predominantly mild or quiescent disease. Raft distribution was analyzed by measuring activity of the raft-associated enzyme alkaline phosphatase and by performing Western blot analysis for flotillin-1. Epithelial barrier integrity was estimated by measuring transepithelial resistance in cytokine-treated cells or in vivo permeability to fluorescent dextran in colitic mice. Raft and nonraft fractions were analyzed by Western blotting for the TJ proteins occludin and zonula occludens-1 (ZO-1). Our results revealed that lipid rafts were disrupted in IFN-γ-treated cells, in the ilea of mice with subclinical colitis, and in UC patients with quiescent inflammation. This was not associated with a clear pattern of occludin or ZO-1 relocalization from raft to nonraft fractions. Significantly, a time-course study in colitic mice revealed that disruption of lipid rafts preceded the onset of increased intestinal permeability. Our data suggest for the first time that lipid raft disruption occurs early in the inflammatory cascade in murine and human colitis and, we speculate, may contribute to subsequent disruption of epithelial barrier function.
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Brown, Deborah A. "Lipid Rafts, Detergent-Resistant Membranes, and Raft Targeting Signals." Physiology 21, no. 6 (December 2006): 430–39. http://dx.doi.org/10.1152/physiol.00032.2006.
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Lipid rafts are liquid-ordered (lo) phase microdomains proposed to exist in biological membranes. Rafts have been widely studied by isolating lo-phase detergent-resistant membranes (DRMs) from cells. Recent findings have shown that DRMs are not the same as preexisting rafts, prompting a major revision of the raft model. Nevertheless, raft-targeting signals identified by DRM analysis are often required for protein function, implicating rafts in a variety of cell processes.
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Klappe, Karin, Anne-Jan Dijkhuis, Ina Hummel, Annie van Dam, Pavlina T. Ivanova, Stephen B. Milne, David S. Myers, H. Alex Brown, Hjalmar Permentier, and Jan W. Kok. "Extensive sphingolipid depletion does not affect lipid raft integrity or lipid raft localization and efflux function of the ABC transporter MRP1." Biochemical Journal 430, no. 3 (August 27, 2010): 519–29. http://dx.doi.org/10.1042/bj20091882.
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We show that highly efficient depletion of sphingolipids in two different cell lines does not abrogate the ability to isolate Lubrol-based DRMs (detergent-resistant membranes) or detergent-free lipid rafts from these cells. Compared with control, DRM/detergent-free lipid raft fractions contain equal amounts of protein, cholesterol and phospholipid, whereas the classical DRM/lipid raft markers Src, caveolin-1 and flotillin display the same gradient distribution. DRMs/detergent-free lipid rafts themselves are severely depleted of sphingolipids. The fatty acid profile of the remaining sphingolipids as well as that of the glycerophospholipids shows several differences compared with control, most prominently an increase in highly saturated C16 species. The glycerophospholipid headgroup composition is unchanged in sphingolipid-depleted cells and cell-derived detergent-free lipid rafts. Sphingolipid depletion does not alter the localization of MRP1 (multidrug-resistance-related protein 1) in DRMs/detergent-free lipid rafts or MRP1-mediated efflux of carboxyfluorescein. We conclude that extensive sphingolipid depletion does not affect lipid raft integrity in two cell lines and does not affect the function of the lipid-raft-associated protein MRP1.
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Nothdurfter, Caroline, Sascha Tanasic, Barbara Di Benedetto, Manfred Uhr, Eva-Maria Wagner, Kate E. Gilling, Chris G. Parsons, et al. "Lipid raft integrity affects GABAA receptor, but not NMDA receptor modulation by psychopharmacological compounds." International Journal of Neuropsychopharmacology 16, no. 6 (July 1, 2013): 1361–71. http://dx.doi.org/10.1017/s146114571200140x.
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Abstract Lipid rafts have been shown to play an important role for G-protein mediated signal transduction and the function of ligand-gated ion channels including their modulation by psychopharmacological compounds. In this study, we investigated the functional significance of the membrane distribution of NMDA and GABAA receptor subunits in relation to the accumulation of the tricyclic antidepressant desipramine (DMI) and the benzodiazepine diazepam (Diaz). In the presence of Triton X-100, which allowed proper separation of the lipid raft marker proteins caveolin-1 and flotillin-1 from the transferrin receptor, all receptor subunits were shifted to the non-raft fractions. In contrast, under detergent-free conditions, NMDA and GABAA receptor subunits were detected both in raft and non-raft fractions. Diaz was enriched in non-raft fractions without Triton X-100 in contrast to DMI, which preferentially accumulated in lipid rafts. Impairment of lipid raft integrity by methyl-β-cyclodextrine (MβCD)-induced cholesterol depletion did not change the inhibitory effect of DMI at the NMDA receptor, whereas it enhanced the potentiating effect of Diaz at the GABAA receptor at non-saturating concentrations of GABA. These results support the hypothesis that the interaction of benzodiazepines with the GABAA receptor likely occurs outside of lipid rafts while the antidepressant DMI acts on ionotropic receptors both within and outside these membrane microdomains.
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Lee, Jia-Lin, Mei-Jung Wang, Putty-Reddy Sudhir, and Jeou-Yuan Chen. "CD44 Engagement Promotes Matrix-Derived Survival through the CD44-SRC-Integrin Axis in Lipid Rafts." Molecular and Cellular Biology 28, no. 18 (July 21, 2008): 5710–23. http://dx.doi.org/10.1128/mcb.00186-08.
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ABSTRACT CD44 is present in detergent-resistant, cholesterol-rich microdomains, called lipid rafts, in many types of cells. However, the functional significance of CD44 in lipid rafts is still unknown. We have previously demonstrated that osteopontin-mediated engagement of CD44 spliced variant isoforms promotes an extracellular matrix-derived survival signal through integrin activation. By using a series of CD44 mutants and pharmacological inhibitors selectively targeted to various cellular pathways, we show in this study that engagement of CD44 induces lipid raft coalescence to facilitate a CD44-Src-integrin signaling axis in lipid rafts, leading to increased matrix-derived survival. Palmitoylation of the membrane-proximal cysteine residues and carboxyl-terminal linkage to the actin cytoskeleton both contribute to raft targeting of CD44. The enrichment of integrin β1 in lipid rafts is tightly coupled to CD44 ligation-elicited lipid raft reorganization and associated with temporally delayed endocytosis. Through the interaction with the CD44 carboxyl-terminal ankyrin domain, Src is cotranslocated to lipid rafts, where it induces integrin activation via an inside-out mechanism. Collectively, this study demonstrates an important role of the dynamic raft reorganization induced by CD44 clustering in eliciting the matrix-derived survival signal.
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Ahmad, Syed S., and Peter N. Walsh. "Lipid Raft Association of a Shared Factor X/Prothrombin Binding Site on Human Platelets Is Mediated by the Gla Domain." Blood 104, no. 11 (November 16, 2004): 222. http://dx.doi.org/10.1182/blood.v104.11.222.222.
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Factor X (FX) initially binds to a high-capacity, low-affinity platelet binding site shared with prothrombin (FII) which then presents FX to a specific, high-affinity site consisting of FVIIIa bound to a high-affinity, low-capacity receptor on activated platelets. We have demonstrated the localization of FX in lipid rafts and shown that FX-raft association requires Ca2+ and is enhanced by saturating concentrations of FVIIIa. Here we investigate FII-raft association and define the domains through which shared FX and FII sites are mediated on the surface of human platelets. Activated (thrombin receptor peptide, SFLLRN, 25 μM) gel-filtered platelets (3.5 x 108/ml) were incubated with 125I-FII or 125I-FX to determine direct platelet binding and then they were lysed with Triton-X100 (0.025-0.25%) followed by sucrose density gradient centrifugation. FII was localized to lipid rafts in SFLLRN stimulated (~25% total binding) but not to unactivated platelets. The optimal associations of FX and FII with lipid rafts required Ca2+ and were not affected by the presence of EGR-FIXa or FIX (45 nM). The association of FII with lipid rafts was completely abolished in the presence of FX (1.5 μM) whereas, Gla (des) FX was unable to compete with raft associated FII. Similarly, 125I-FII fragment 1 association with lipid rafts was inhibited by FX but not by Gla (des) FX. Prothrombin and FII fragment 1 (residues 1-155) were equipotent inhibitors of FX-raft association. FVIIIa (20 nM) had no effect on FII-raft association but significantly increased (~2-fold to ~45%) FX-raft association. In contrast, the presence of FVa (20 nM) had no effect on FX-raft association but significantly (~2-fold to ~45%) increased FII-raft association. The structural integrity of lipid rafts was completely disrupted by 10 mM methyl-β-cyclodextrin (MβCD), a known cholesterol depleting drug, which completely prevented FII or FX association with lipid rafts, and this removal was reversed by cholesterol repletion. Furthermore, MβCD (up to 40 mM) had no effect on the amount of FII or FX bound to activated platelets, thus suggesting that neither platelet activation by SFLLRN nor the exposure of FII receptors was affected by MβCD treatment. These experiments demonstrate the localization of a shared FX/FII site in lipid rafts and support the hypothesis that these interactions are mediated by the Gla-domains of FX and FII and are specific and essential for the assembly of F-X activating complex on the activated platelet membrane.
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Morgan, Pooranee K., Longhou Fang, Graeme I. Lancaster, and Andrew J. Murphy. "Hematopoiesis is regulated by cholesterol efflux pathways and lipid rafts: connections with cardiovascular diseases." Journal of Lipid Research 61, no. 5 (August 30, 2019): 667–75. http://dx.doi.org/10.1194/jlr.tr119000267.
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Lipid rafts are highly ordered regions of the plasma membrane that are enriched in cholesterol and sphingolipids and play important roles in many cells. In hematopoietic stem and progenitor cells (HSPCs), lipid rafts house receptors critical for normal hematopoiesis. Lipid rafts also can bind and sequester kinases that induce negative feedback pathways to limit proliferative cytokine receptor cycling back to the cell membrane. Modulation of lipid rafts occurs through an array of mechanisms, with optimal cholesterol efflux one of the major regulators. As such, cholesterol homeostasis also regulates hematopoiesis. Increased lipid raft content, which occurs in response to changes in cholesterol efflux in the membrane, can result in prolonged receptor occupancy in the cell membrane and enhanced signaling. In addition, certain diseases, like diabetes, may contribute to lipid raft formation and affect cholesterol retention in rafts. In this review, we explore the role of lipid raft-related mechanisms in hematopoiesis and CVD (specifically, atherosclerosis) and discuss how defective cholesterol efflux pathways in HSPCs contribute to expansion of lipid rafts, thereby promoting myelopoiesis and thrombopoiesis. We also discuss the utility of cholesterol acceptors in contributing to lipid raft regulation and disruption, and highlight the potential to manipulate these pathways for therapeutic gain in CVD as well as other disorders with aberrant hematopoiesis.
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CHU, Chia Lin, J. Ann BUCZEK-THOMAS, and Matthew A. NUGENT. "Heparan sulphate proteoglycans modulate fibroblast growth factor-2 binding through a lipid raft-mediated mechanism." Biochemical Journal 379, no. 2 (April 15, 2004): 331–41. http://dx.doi.org/10.1042/bj20031082.
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We investigated how lipid raft association of HSPG (heparan sulphate proteoglycans) modulates FGF-2 (fibroblast growth factor-2/basic fibroblast growth factor) interactions with vascular smooth-muscle cells. When lipid rafts were disrupted with sterol-binding agents, methyl-β-cyclodextrin and filipin, FGF-2 binding to HSPG was reduced 2–5-fold, yet the amount and turnover of cell-surface HSPG were unaffected. Approx. 50–65% of bound FGF-2 was in lipid raft-associated fractions based on insolubility in cold Triton X-100 and flotation in OptiPrep density gradients, and this level was increased with higher FGF-2 concentrations. Less FGF-2 (50–90%) was associated in raft fractions when cholesterol was depleted or HSPG were degraded with heparinase III. To investigate how lipid raft–HSPG interactions altered binding, we compared the rates of FGF-2 dissociation with native, MβCD (methyl-β-cyclodextrin)- and filipin-treated cells. We found that FGF-2 dissociation rates were increased when lipid rafts were disrupted. These results suggest that localization of HSPG within lipid rafts creates high local concentrations of binding sites such that dissociation of FGF-2 is hindered. The localization of FGF-2 and HSPG to lipid rafts also correlated with the activation of protein kinase Cα. Thus raft association of HSPG might create growth factor traps resulting in increased binding and signal transduction to enhance cell sensitivity.
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Tabe, Yoko, Linhua Jin, Zhou Yixin, Naoki Ichikawa, Kazuhisa Iwabuchi, Takashi Miida, Jorge Cortes, Michael Andreeff, and Marina Konopleva. "Role of Stromal Microenvironment In Non-Pharmacological Resistance of CML to Tyrosine Kinase Inhibitors through Lyn/CXCR4 Interactions In Lipid Rafts." Blood 116, no. 21 (November 19, 2010): 3390. http://dx.doi.org/10.1182/blood.v116.21.3390.3390.
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Abstract Abstract 3390 In chronic myeloid leukemia (CML), the mechanisms of resistance to tyrosine kinase inhibitors (TKIs) beyond the Bcr-Abl mutations are not well understood. We have previously reported that TKI imatinib induces cell-surface expression of the chemokine receptor CXCR4, which results in enhanced migration towards CXCL12-producing BM stromal cells, promotes cell quiescence and development of the microenvironment-mediated, non-pharmacological drug resistance (Jin, Mol Cancer Ther 2008;7:48). Bcr-Abl tyrosine kinase directly activates Src-related kinase Lyn known to frequently localize in lipid raft plasma membrane microdomains and interact with CXCL12/CXCR4 signaling and is directly activated by p210Bcr-Abl. In this study, we investigated the effects of TKIs on the localization and interaction of CXCR4 and Lyn in the lipid rafts, and the role of lipid rafts as the signal transduction platform for CML cell migration. Confocal microscopy and discontinuous sucrose density gradient fractionation demonstrated that in CML cells CXCR4 primarily localized in the non-raft cell surface regions, while Lyn was present both in the lipid raft and non-raft fractions. In turn, the active, phosphorylated form (p-)LynTyr396 is present within the lipid rafts, while inactive p-LynTyr507 in non-raft fractions. Imatinib treatment under co-culture with mesenchymal stem cells (MSC) induced CXCR4 clustering in lipid raft fractions, which was directly co-immunoprecipitaed with Lyn. Under these culture conditions, imatinib repressed p-LynTyr507, but failed to deplete p-LynTyr396. Knock-down of Lyn by siRNA, Src inhibitor treatment, or lipid raft destruction by methyl-b cyclodextrin (MbCD) abrogated imatinib-induced KBM5 migration to MSCs and CXCL12 without affecting CXCR4 surface expression. Consistent with its effects on Src, dual Src/Abl kinase inhibitor dasatinib induced significantly less migration of CML cells to CXCL12 compared with imatinib or nilotinib (p =0.04). In summary, our data indicate that stromal cells interfere with inhibitory effects of TKI on active Lyn (p-Lyn)Tyr396 in CML cells and promote clustering of CXCR4 in lipid rafts where it co-localizes with p-LynTyr396 and facilitates migration of CML cells to the MSC monolayer. Lipid raft disruption by cholesterol depletion inhibit CML cells migration, suggesting that lipid rafts represent one of the key signaling modules responsible for interactions of CML cells with cells of BM niche. We propose that pharmacological disruption of lipid rafts may eliminate BM-resident CML cells through interference with microenvironment-mediated resistance. Disclosures: No relevant conflicts of interest to declare.
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Alnuaim, A. M., H. El Naggar, and M. H. El Naggar. "Performance of micropiled raft in sand subjected to vertical concentrated load: centrifuge modeling." Canadian Geotechnical Journal 52, no. 1 (January 2015): 33–45. http://dx.doi.org/10.1139/cgj-2014-0001.
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Initial applications of micropiles have involved retrofitting foundations of existing buildings. In these applications, the overall performance of the micropiles–raft (MPR) foundation system is similar to a piled raft foundation where the load is transmitted through both the raft and micropiles. However, there is no guidance available regarding the performance of MPR foundations. In this study, geotechnical centrifuge testing was conducted to investigate the behavior of MPR foundations in sand and evaluate their performance characteristics. The study investigated the effect of raft flexibility on a number of important design parameters, including raft total and differential settlements, raft contact pressure, raft bending moment, and load sharing between the raft and micropiles. In addition, the use of micropiles as settlement reducers was investigated. The results showed that the micropiles carried 42%–59% of the applied load for the MPR configuration considered, which resulted in redistribution of the raft contact pressure. It was found that the Poulos–Davis–Randolph (PDR) method can be used to evaluate the performance of MPR systems with relatively stiff rafts; however, it is not applicable for MPR with flexible raft. A correction factor was proposed to account for the raft flexibility in the PDR method.
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Pralle, A., P. Keller, E. L. Florin, K. Simons, and J. K. H. Hörber. "Sphingolipid–Cholesterol Rafts Diffuse as Small Entities in the Plasma Membrane of Mammalian Cells." Journal of Cell Biology 148, no. 5 (March 6, 2000): 997–1008. http://dx.doi.org/10.1083/jcb.148.5.997.
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To probe the dynamics and size of lipid rafts in the membrane of living cells, the local diffusion of single membrane proteins was measured. A laser trap was used to confine the motion of a bead bound to a raft protein to a small area (diam ≤ 100 nm) and to measure its local diffusion by high resolution single particle tracking. Using protein constructs with identical ectodomains and different membrane regions and vice versa, we demonstrate that this method provides the viscous damping of the membrane domain in the lipid bilayer. When glycosylphosphatidylinositol (GPI) -anchored and transmembrane proteins are raft-associated, their diffusion becomes independent of the type of membrane anchor and is significantly reduced compared with that of nonraft transmembrane proteins. Cholesterol depletion accelerates the diffusion of raft-associated proteins for transmembrane raft proteins to the level of transmembrane nonraft proteins and for GPI-anchored proteins even further. Raft-associated GPI-anchored proteins were never observed to dissociate from the raft within the measurement intervals of up to 10 min. The measurements agree with lipid rafts being cholesterol-stabilized complexes of 26 ± 13 nm in size diffusing as one entity for minutes.
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Park, Donggyu, and Junhwan Lee. "Interaction effects on load-carrying behavior of piled rafts embedded in clay from centrifuge tests." Canadian Geotechnical Journal 52, no. 10 (October 2015): 1550–61. http://dx.doi.org/10.1139/cgj-2014-0336.
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In the present study, various interaction effects and load-carrying behavior of piled rafts embedded in clay were investigated. For this purpose, a series of centrifuge load tests were conducted using different types of model foundations, including single pile, group piles, piled raft, and unpiled raft. Different clay conditions were considered to prepare for centrifuge specimens. It was found that the pile group effect in clays is significant within initial loading range, showing lower load-carrying capacity. As settlement increases, the pile group effect becomes less pronounced. For both soft and stiff conditions, the values of the raft-to-pile (R-P) interaction factor varied initially, which became converged to some values around unity with increasing settlement. Similar tendency was observed for the pile-to-raft (P-R) interaction factor. The load responses of different pile components within the piled raft were not significantly different for the soft condition. For the stiff condition, the corner and inner piles showed the highest and lowest load-carrying capacities, respectively, due to piled-raft interaction effects. Correlations to cone resistance were analyzed and presented for the base and shaft resistances of piles for piled rafts.
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Nishimura, Yuhei, Daishi Yamakawa, Katsunori Uchida, Takashi Shiromizu, Masatoshi Watanabe, and Masaki Inagaki. "Primary cilia and lipid raft dynamics." Open Biology 11, no. 8 (August 2021): 210130. http://dx.doi.org/10.1098/rsob.210130.
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Primary cilia, antenna-like structures of the plasma membrane, detect various extracellular cues and transduce signals into the cell to regulate a wide range of functions. Lipid rafts, plasma membrane microdomains enriched in cholesterol, sphingolipids and specific proteins, are also signalling hubs involved in a myriad of physiological functions. Although impairment of primary cilia and lipid rafts is associated with various diseases, the relationship between primary cilia and lipid rafts is poorly understood. Here, we review a newly discovered interaction between primary cilia and lipid raft dynamics that occurs during Akt signalling in adipogenesis. We also discuss the relationship between primary cilia and lipid raft-mediated Akt signalling in cancer biology. This review provides a novel perspective on primary cilia in the regulation of lipid raft dynamics.
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Jachowski, Jacek, Edyta Książkiewicz, and Izabela Szwoch. "Determination of the Aerodynamic Drag of Pneumatic Life Rafts as a Factor for Increasing the Reliability of Rescue Operations." Polish Maritime Research 28, no. 3 (September 1, 2021): 128–36. http://dx.doi.org/10.2478/pomr-2021-0040.
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Abstract Ensuring the safety of ship crews at sea is of the utmost importance. Life rafts are one of the basic components of any seagoing vessel and ensuring their stability is an important component of maritime research. This study concerns the determination of the aerodynamic drag coefficients of pneumatic life rafts in a full range of wind speed and directions. The drag coefficients are based on full-scale experimental studies and numerical calculations (computational fluid dynamics) carried out with Flow-3D software. Two types of life rafts are analysed in the numerical simulations, namely, a non-deformed raft and a raft deformed under the influence of wind pressure at a given flow velocity. The shape of the deformed pneumatic life raft is recreated on the basis of photographic documentation from experimental studies. The results of the numerical calculations are verified on the basis of full-scale flow experiments carried out at the Low Speed Wind Tunnel T-3 Laboratory at the Institute of Aviation in Warsaw. This study shows that there is a dependence of aerodynamic drag on the degree of deformation of the above-water part of the life raft, as well as the angle of the raft setting to the wind. In real water conditions, this angle depends mainly on the anchor point of the drift anchor and therefore should be considered at the design stage, which will directly reduce the wind leeway of the raft.
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Chhuon, Cerina, Shao-Yu Zhang, Vincent Jung, Daniel Lewandowski, Joanna Lipecka, André Pawlak, Dil Sahali, Mario Ollero, and Ida Chiara Guerrera. "A sensitive S-Trap-based approach to the analysis of T cell lipid raft proteome." Journal of Lipid Research 61, no. 11 (August 7, 2020): 1512–23. http://dx.doi.org/10.1194/jlr.d120000672.
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The analysis of T cell lipid raft proteome is challenging due to the highly dynamic nature of rafts and the hydrophobic character of raft-resident proteins. We explored an innovative strategy for bottom-up lipid raftomics based on suspension-trapping (S-Trap) sample preparation. Mouse T cells were prepared from splenocytes by negative immunoselection, and rafts were isolated by a detergent-free method and OptiPrep gradient ultracentrifugation. Microdomains enriched in flotillin-1, LAT, and cholesterol were subjected to proteomic analysis through an optimized protocol based on S-Trap and high pH fractionation, followed by nano-LC-MS/MS. Using this method, we identified 2,680 proteins in the raft-rich fraction and established a database of 894 T cell raft proteins. We then performed a differential analysis on the raft-rich fraction from nonstimulated versus anti-CD3/CD28 T cell receptor (TCR)-stimulated T cells. Our results revealed 42 proteins present in one condition and absent in the other. For the first time, we performed a proteomic analysis on rafts from ex vivo T cells obtained from individual mice, before and after TCR activation. This work demonstrates that the proposed method utilizing an S-Trap-based approach for sample preparation increases the specificity and sensitivity of lipid raftomics.
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Ma, Yuanqing, Elizabeth Hinde, and Katharina Gaus. "Nanodomains in biological membranes." Essays in Biochemistry 57 (February 6, 2015): 93–107. http://dx.doi.org/10.1042/bse0570093.
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Lipid rafts are defined as cholesterol- and sphingomyelin-enriched membrane domains in the plasma membrane of cells that are highly dynamic and cannot be resolved with conventional light microscopy. Membrane proteins that are embedded in the phospholipid matrix can be grouped into raft and non-raft proteins based on their association with detergent-resistant membranes in biochemical assays. Selective lipid–protein interactions not only produce heterogeneity in the membrane, but also cause the spatial compartmentalization of membrane reactions. It has been proposed that lipid rafts function as platforms during cell signalling transduction processes such as T-cell activation (see Chapter 13 (pages 165–175)). It has been proposed that raft association co-localizes specific signalling proteins that may yield the formation of the observed signalling microclusters at the immunological synapses. However, because of the nanometre size and high dynamics of lipid rafts, direct observations have been technically challenging, leading to an ongoing discussion of the lipid raft model and its alternatives. Recent developments in fluorescence imaging techniques have provided new opportunities to investigate the organization of cell membranes with unprecedented spatial resolution. In this chapter, we describe the concept of the lipid raft and alternative models and how new imaging technologies have advanced these concepts.
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Rocha, Kathy, Gwenny Fuhler, Joseph Johnson, Justine Clark, Gisela Caceres, Lubomir Sokol, and Alan F. List. "Membrane Raft Localization Is Critical for Erythropoietin Receptor Signaling." Blood 114, no. 22 (November 20, 2009): 2506. http://dx.doi.org/10.1182/blood.v114.22.2506.2506.
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Abstract Abstract 2506 Poster Board II-483 Erythropoietin (EPO) is the principal regulator of erythroid progenitor proliferation, differentiation, and survival. Upon ligand engagement, the EPO-receptor (R) homodimerizes to activate the tyrosine kinases, Janus kinase-2 (JAK-2) and Lyn, which in turn phosphorylate the signal transducer and activator of transcription (STAT)-5. Although recent investigations have identified key negative regulators of the EPO-R signal, little is known about the membrane localization and dynamic control of receptor signal fidelity. Here we show a critical role for membrane raft microdomains in the creation of signaling platforms that are essential for signal integrity. Using UT-7 cells, we showed that recombinant human EPO (rhuEPO) stimulation rapidly induced raft formation and aggregation. Confocal microscopy quantitation of the raft ganglioside GM-1 fluorescence showed that raft aggregates increased from a mean of 4.3 ± 1.4 (SE) per cell to 25.6 ± 3.2 aggregates per cell after cytokine stimulation (p≤0.001), accompanied by a greater than 3-fold increase in cluster size (mean stimulated to untreated aggregate size ratio: 3.33 ± 0.11, p≤0.001). Isolation and immunoblot analysis of detergent insoluble raft fractions showed that the EPO-R translocated to lipid rafts after EPO stimulation of UT-7 cells. Confocal microscopy confirmed translocation of the EPO-R into membrane rafts in EPO-stimulated UT-7 cells and normal erythroid bursts. Receptor recruitment into rafts was accompanied by Jak2, Lyn and STAT5 loading into membrane raft fractions upon EPO stimulation. Treatment with methyl-β-cyclodextrin (MBCD) to deplete raft cholesterol and disrupt raft integrity extinguished EPO-induced STAT5 phosphorylation in UT-7 cells and human bone marrow progenitors. Similarly, membrane cholesterol-sequestration by nystatin markedly reduced EPO induced STAT5 phosphorylation in UT-7 cells. MBCD pretreatment of these cells prior to stimulation with phorbol 12-myristate 13-acetate (PMA) did not alter mitogen-activated protein kinase (MAPK) phosphorylation, indicating preservation of non-receptor, non-raft signal integrity despite depletion of cholesterol rich microdomains. These data establish a critical role for membrane raft microdomains in the recruitment and physical assembly of the EPO-R and its signaling intermediates into discrete platforms necessary to optimize signal integrity Disclosures: No relevant conflicts of interest to declare.
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K. Lakshmana, Madepalli, Subhojit Roy, Kaihong Mi, and David E. Kang. "Amyloidogenic Processing of APP in Lipid Rafts." Open Biology Journal 3, no. 1 (March 19, 2010): 21–31. http://dx.doi.org/10.2174/18741967010030100021.
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Increased generation of amyloid β peptide (Aβ) derived from amyloid precursor protein (APP) is the primary pathological characteristic of Alzheimer’s disease (AD). However, the sub cellular compartment in which APP undergoes cleavage by secretases to generate Aβ is not precisely known. Compelling evidences suggest that amyloidogenic processing of APP occurs in lipid rafts. An indirect support for lipid raft processing of APP includes the localization of Aβ, APP C-terminal fragments (CTFs), APP holoprotein and secretases in the lipid raft microdomains, although few studies failed to find APP in the lipid rafts. The indirect support also comes from both experimental and clinical studies involving modulation of cholesterol levels and its effect on Aβ generation. Moderate depletion of cholesterol results in significant reduction in Aβ levels and increased dietary intake of cholesterol leads to higher levels of Aβ production suggesting that amyloidogenic processing of APP strongly depends on cholesterol levels and therefore on lipid raft integrity. More convincing evidence that lipid rafts are critical for amyloidogenic processing of APP comes from studies using antibody-mediated co-patching of APP and BACE1 which results in lipid raft association of APP and BACE1 and increased Aβ generation. Further, an endosome/lipid raft targeting of β-secretase inhibitor by sterol-mediated anchoring leading to reduced Aβ generation also suggests that lipid rafts are pivotal for amyloidogenic processing of APP. In the absence of an effective therapy for AD, proteins responsible for delivery of APP to lipid rafts including LRP, RanBP9 and ApoER2 may be excellent therapeutic targets in AD.
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KABOURIDIS, Panagiotis S. "Selective interaction of LAT (linker of activated T cells) with the open-active form of Lck in lipid rafts reveals a new mechanism for the regulation of Lck in T cells." Biochemical Journal 371, no. 3 (May 1, 2003): 907–15. http://dx.doi.org/10.1042/bj20021578.
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In T cells, the lipid raft-associated Lck is strongly tyrosine phosphorylated and has reduced enzymic activity in contrast with the detergent-soluble pool, which has substantial activity. Lck tagged at the C-terminus (Lck/V5-His) was efficiently captured by epitope-specific reagents from the detergent-soluble fraction but not from lipid rafts. Binding was restored following urea denaturation, suggesting that Lck/V5-His is in a ‘closed’ conformation in these domains. In agreement with this hypothesis, the Tyr505 → Phe/V5-His and Arg154 → Lys/V5-His mutants, which disrupt the SH2-Tyr505 intramolecular interaction, were efficiently precipitated from lipid rafts. In contrast to Lck, Fyn/V5-His was precipitated equally well from both fractions. In the LAT (linker of activated T cells)-deficient J.CaM2 cells, Tyr505 phosphorylation of raft-associated Lck was reduced whereas its enzymic activity was elevated. This correlated with decreased levels of raft-localized Csk (C-terminal Src kinase) kinase. Increased tyrosine phosphorylation of Lck was restored in LAT-reconstituted J.CaM2 cells suggesting that LAT negatively regulates Lck activity in lipid rafts. Co-immunoprecipitation experiments from Tyr505 → Phe/V5-His-expressing cells revealed that LAT preferentially interacts with the ‘open’ form of Lck in T cell raft domains. These results demonstrate that, unlike the non-raft pool, Lck in lipid rafts has a ‘closed’-inactive structure, and that LAT plays a role in maintaining this conformation, possibly by facilitating critical associations within lipid rafts via its capacity to interact with the ‘open’ form of the kinase.
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Campbell, Shahan, Katharina Gaus, Robert Bittman, Wendy Jessup, Suzanne Crowe, and Johnson Mak. "The Raft-Promoting Property of Virion-Associated Cholesterol, but Not the Presence of Virion-Associated Brij 98 Rafts, Is a Determinant of Human Immunodeficiency Virus Type 1 Infectivity." Journal of Virology 78, no. 19 (October 1, 2004): 10556–65. http://dx.doi.org/10.1128/jvi.78.19.10556-10565.2004.
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ABSTRACT Lipid rafts are enriched in cholesterol and sphingomyelin and are isolated on the basis of insolubility in detergents, such as Brij 98 and Triton X-100. Recent work by Holm et al. has shown that rafts insoluble in Brig 98 can be found in human immunodeficiency virus type 1 (HIV-1) virus-like particles, although it is not known whether raft-like structures are present in authentic HIV-1 and it is unclear whether a virion-associated raft-like structure is required for HIV replication. Independently, it was previously reported that virion-associated cholesterol is critical for HIV-1 infectivity, although the specific requirement of virion cholesterol in HIV-1 was not examined. In the present study, we have demonstrated that infectious wild-type HIV-1 contains Brij 98 rafts but only minimal amounts of Triton X-100 rafts. To directly assess the functional requirement of virion-associated rafts and various features of cholesterol on HIV-1 replication, we replaced virion cholesterol with exogenous cholesterol analogues that have demonstrated either raft-promoting or -inhibiting capacity in model membranes. We observed that variable concentrations of exogenous analogues are required to replace a defined amount of virion-associated cholesterol, showing that structurally diverse cholesterol analogues have various affinities toward HIV-1. We found that replacement of 50% of virion cholesterol with these exogenous cholesterol analogues did not eliminate the presence of Brij 98 rafts in HIV-1. However, the infectivity levels of the lipid-modified HIV-1s directly correlate with the raft-promoting capacities of these cholesterol analogues. Our data provide the first direct assessment of virion-associated Brij 98 rafts in retroviral replication and illustrate the importance of the raft-promoting property of virion-associated cholesterol in HIV-1 replication.
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Chang, Der-Wen, Chih-Wei Lu, Yu-Jhang Tu, and Shih-Hao Cheng. "Settlements and Subgrade Reactions of Surface Raft Foundations Subjected to Vertically Uniform Load." Applied Sciences 12, no. 11 (May 28, 2022): 5484. http://dx.doi.org/10.3390/app12115484.
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The settlements and corresponding soil reactions of a surface raft foundation subjected to vertically uniform load at the sites of granular or cohesive soils have been qualitatively introduced to engineers in the past. This study intends to verify the foundation load-response mechanism using three-dimensional finite-element analyses. The Mohr–Coulomb soil model was used to simulate the nonlinear effects of the granular and cohesive soils. The coefficients of subgrade reactions of the soil were back-calculated and compared to those obtained from the rigid foundation model. For all the square surface rafts studied, non-uniform settlements with the largest value at the center can be found. For the smallest rafts located in clay, the soil reactions were found to be rather consistent. For larger rafts in clay, the soil reactions would be changed according to the soil stiffness and raft dimensions. For surface rafts in sand, the effects of soil stiffness on soil reactions appeared to be insignificant. The soil reactions were generally higher at the center and varied with raft dimensions. For the smallest raft in sand, large soil reactions can be found at the edge. The coefficients of subgrade reactions were found to be more consistent with the smallest values occurring at the center. The results of this study indicate that the load-response mechanism of the raft foundation is rather complicated. Such load-response mechanisms are strongly affected by the relative rigidity of the foundation depending on soil stiffness and foundation dimensions.
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Четверикова and Irina Chetverikova. "Calculation the durationandthe way formation multi-row raft." Forestry Engineering Journal 6, no. 1 (April 19, 2016): 131–39. http://dx.doi.org/10.12737/18735.
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We describe the construction of raft that does not require forced stop before the formation. A brief review of design of rafts, designed to re-adjust the water flow, schematic diagram of the improved raft, shows the output of the formulas that determine the kinematic and dynamic per-formance of the reconfiguration process. Considered view of the formation of raft involving changes its dimensions in terms of at constant volume.
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Harder, Thomas, Peter Scheiffele, Paul Verkade, and Kai Simons. "Lipid Domain Structure of the Plasma Membrane Revealed by Patching of Membrane Components." Journal of Cell Biology 141, no. 4 (May 18, 1998): 929–42. http://dx.doi.org/10.1083/jcb.141.4.929.
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Lateral assemblies of glycolipids and cholesterol, “rafts,” have been implicated to play a role in cellular processes like membrane sorting, signal transduction, and cell adhesion. We studied the structure of raft domains in the plasma membrane of non-polarized cells. Overexpressed plasma membrane markers were evenly distributed in the plasma membrane. We compared the patching behavior of pairs of raft markers (defined by insolubility in Triton X-100) with pairs of raft/non-raft markers. For this purpose we cross-linked glycosyl-phosphatidylinositol (GPI)-anchored proteins placental alkaline phosphatase (PLAP), Thy-1, influenza virus hemagglutinin (HA), and the raft lipid ganglioside GM1 using antibodies and/or cholera toxin. The patches of these raft markers overlapped extensively in BHK cells as well as in Jurkat T–lymphoma cells. Importantly, patches of GPI-anchored PLAP accumulated src-like protein tyrosine kinase fyn, which is thought to be anchored in the cytoplasmic leaflet of raft domains. In contrast patched raft components and patches of transferrin receptor as a non-raft marker were sharply separated. Taken together, our data strongly suggest that coalescence of cross-linked raft elements is mediated by their common lipid environments, whereas separation of raft and non-raft patches is caused by the immiscibility of different lipid phases. This view is supported by the finding that cholesterol depletion abrogated segregation. Our results are consistent with the view that raft domains in the plasma membrane of non-polarized cells are normally small and highly dispersed but that raft size can be modulated by oligomerization of raft components.
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Kim, Jayoung, Rosalyn M. Adam, Keith R. Solomon, and Michael R. Freeman. "Involvement of Cholesterol-Rich Lipid Rafts in Interleukin-6-Induced Neuroendocrine Differentiation of LNCaP Prostate Cancer Cells." Endocrinology 145, no. 2 (February 1, 2004): 613–19. http://dx.doi.org/10.1210/en.2003-0772.
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Abstract IL-6 is an inflammatory cytokine that has been linked to aggressive prostate cancer (PCa). Previous studies have demonstrated that IL-6 can enhance the differentiation of PCa cells toward a neuroendocrine (NE) phenotype, a possible indicator of hormone-refractory disease. In this report, we present evidence that the mechanism of IL-6-stimulated NE differentiation employs a detergent-resistant (lipid raft) membrane compartment for signal transduction in LNCaP PCa cells. Signal transducer and activator of transcription (STAT)3, a mediator of IL-6 signaling, was rapidly phosphorylated and translocated to the nucleus in LNCaP cells treated with IL-6. Both processes were inhibited by filipin, a cholesterol-binding compound that disrupts plasma membrane lipid rafts. Isolation of Triton X-100-insoluble raft fractions from LNCaP cells by discontinuous sucrose gradient centrifugation demonstrated that the 80-kDa IL-6 receptor localized almost exclusively to the raft compartment. Although STAT3 was located predominantly in the Triton X-100-soluble subcellular fraction in exponentially growing cells, abundant phosphorylated STAT3 was detected in the raft fraction after stimulation with IL-6. Increases in expression of the NE marker, neuron-specific enolase, and neuron-specific enolase promoter activity after IL-6 treatment were reduced after membrane rafts were disrupted by filipin treatment. LNCaP cells expressed the raft-resident proteins flotillin-2 and Giα2, but notably not caveolins, the predominant structural protein present in caveolar membrane rafts in many tissues and tumor cells. These results are the first to define a role for lipid raft membrane microdomains in signal transduction mechanisms capable of promoting the NE phenotype in PCa cells, and they demonstrate that the raft compartment is capable of mediating such signals in the absence of caveolins. Our results also suggest a mechanistic role for membrane cholesterol in cell signaling events relevant to PCa progression.
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Golub, Tamara, and Caroni Pico. "Spatial control of actin-based motility through plasmalemmal PtdIns(4,5)P2-rich raft assemblies." Biochemical Society Symposia 72 (January 1, 2005): 119–27. http://dx.doi.org/10.1042/bss0720119.
Full textAbstract:
The interactions of cells with their environment involve regulated actin-based motility at defined positions along the cell surface. Sphingolipid- and cholesterol-dependent microdomains (rafts) order proteins at biological membranes, and have been implicated in most signalling processes at the cell surface. Many membrane-bound components that regulate actin cytoskeleton dynamics and cell-surface motility associate with PtdIns(4,5)P2-rich lipid rafts. Although raft integrity is not required for substrate-directed cell spreading, or to initiate signalling for motility, it is a prerequisite for sustained and organized motility. Plasmalemmal rafts redistribute rapidly in response to signals, triggering motility. This process involves the removal of rafts from sites that are not interacting with the substrate, apparently through endocytosis, and a local accumulation at sites of integrin-mediated substrate interactions. PtdIns(4,5)P2-rich lipid rafts can assemble into patches in a process depending on PtdIns(4,5)P2, Cdc42 (cell-division control 42), N-WASP (neural Wiskott-Aldrich syndrome protein) and actin cytoskeleton dynamics. The raft patches are sites of signal-induced actin assembly, and their accumulation locally promotes sustained motility. The patches capture microtubules, which promote patch clustering through PKA (protein kinase A), to steer motility. Raft accumulation at the cell surface, and its coupling to motility are influenced greatly by the expression of intrinsic raft-associated components that associate with the cytosolic leaflet of lipid rafts. Among them, GAP43 (growth-associated protein 43)-like proteins interact with PtdIns(4,5)P2 in a Ca2+/calmodulin and PKC (protein kinase C)-regulated manner, and function as intrinsic determinants of motility and anatomical plasticity. Plasmalemmal PtdIns(4,5)P2-rich raft assemblies thus provide powerful organizational principles for tight spatial and temporal control of signalling in motility.
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Shrimpton, Corie N., Gautam Borthakur, Susana Larrucea, Miguel A. Cruz, Jing-Fei Dong, and José A. López. "Localization of the Adhesion Receptor Glycoprotein Ib-IX-V Complex to Lipid Rafts Is Required for Platelet Adhesion and Activation." Journal of Experimental Medicine 196, no. 8 (October 14, 2002): 1057–66. http://dx.doi.org/10.1084/jem.20020143.
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The platelet glycoprotein (GP) Ib-IX-V complex mediates the attachment of platelets to the blood vessel wall by binding von Willebrand factor (VWF), an interaction that also transmits signals for platelet activation and aggregation. Because the complex is extensively palmitoylated, a modification known to target proteins to lipid rafts, we investigated the role of raft localization in GP Ib-IX-V functions. In unstimulated platelets, a minor portion of the complex localized to Triton-insoluble raft fractions; this portion increased three to sixfold with platelet activation by VWF. Raft-associated GP Ib-IX-V was selectively palmitoylated, with GP Ib-IX-V–associated palmitate increasing in the raft fraction on VWF-mediated activation. The raft fraction was also the site of association between GP Ib-IX-V and the Fc receptor FcγRIIA. The importance of this association was demonstrated by the ability of the FcγRIIA antibody IV.3 to inhibit shear-induced platelet aggregation. Disruption of rafts by depleting membrane cholesterol impaired several GP Ib-IX-V–dependent platelet fractions: aggregation to VWF under static conditions and under shear stress, tyrosine phosphorylation, and adhesion to a VWF surface. Partial restoration of membrane cholesterol content partially restored shear-induced platelet aggregation and tyrosine phosphorylation. Thus, localization of the GP Ib-IX-V complex within rafts is crucial for both platelet adhesion and postadhesion signaling.
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Ediriweera, Meran Keshawa, Jeong Yong Moon, Yen Thi-Kim Nguyen, and Somi Kim Cho. "10-Gingerol Targets Lipid Rafts Associated PI3K/Akt Signaling in Radio-Resistant Triple Negative Breast Cancer Cells." Molecules 25, no. 14 (July 10, 2020): 3164. http://dx.doi.org/10.3390/molecules25143164.
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10-Gingerol is a major phenolic lipid found in the rhizomes of ginger (Zingiber officinale). Being amphiphilic in nature, phenolic lipids have the ability to incorporate into cell membranes and modulate membrane properties. The purpose of the present study was to evaluate the effects of 10-gingerol on lipid raft/membrane raft modulation in radio-resistant triple negative breast cancer (MDA-MB-231/IR) cells. The effects of 10-gingerol on MDA-MB-231/IR cells’ proliferation, clonogenic growth, migration, and invasion were assayed using MTT, colony formation, cell migration, and invasion assays, respectively. Sucrose density gradient centrifugation was used to extract lipid rafts. Western blotting and immunofluorescence were employed to assess the effects of 10-gingerol on lipid raft/membrane raft modulation and lipid rafts-associated PI3K/Akt signaling. Cholesterol measurements were carried out using a commercially available kit. 10-gingerol suppressed the proliferation, migration, invasion, and induced apoptosis through targeting the PI3K/Akt signaling pathway in MDA-MB-231/IR cells. Moreover, 10-gingerol was found to modulate the lipid rafts of MDA-MB-231/IR cells and attenuate the key PI3K/Akt signaling components in lipid rafts. The cholesterol content of the lipid rafts and rafts-resident Akt signaling were also affected by exposure to 10-gingerol. The results of the present study highlight rafts-associated PI3K/Akt signaling as a new target of 10-gingerol in MDA-MB-231/IR cells, thus rationalizing a new rafts-mediated treatment approach for radio-resistant triple negative breast cancer cells.
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Rahman, Arief, Ferry Fatnanta, and Syawal Satibi. "Analysis of the capability of pile assembly foundations in soft soil in physical modeling of variationsiin laboratory scale distances." astonjadro 12, no. 1 (January 4, 2023): 136. http://dx.doi.org/10.32832/astonjadro.v12i1.8139.
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<p>The capacity of raft foundations, pile foundations and pile rafts on soft soil with variations in the distance between the piles. Perform analysis of the carrying capacity and settlement of each foundation test and then compare the results of the theoretical carrying capacity research with the analysis of carrying capacity calculations. The implementation of the test prepares the test along with samples of the raft foundation, pile foundation and pile raft foundation. The test were carried out using a gradual load then a dial gauge is placed at both ends of the sample raft and the load reading is taken. The pile foundation was tested with a decrease of 10 cm while the settlement on the raft foundation and the pile raft foundation was 3 cm, the carrying capacity of the raft foundation was 24 kg, the pile foundation varied 4D distances; 6D and 8D, namely 7.5 kg and the foundation of the pile raft with variations in 4D distance; 6D and 8D are 26 ; 32 and 32 kg. In the interpretation method, the pile raft foundation with various distances increased from 4D to 6D but decreased in 8D. Pile raft foundations with various distances between pile have not a significant effect where raft foundations are more dominant in supporting resistance than pile foundations.</p>
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Lou, Zhenkun, Dragan Jevremovic, Daniel D. Billadeau, and Paul J. Leibson. "A Balance between Positive and Negative Signals in Cytotoxic Lymphocytes Regulates the Polarization of Lipid Rafts during the Development of Cell-Mediated Killing." Journal of Experimental Medicine 191, no. 2 (January 17, 2000): 347–54. http://dx.doi.org/10.1084/jem.191.2.347.
Full textAbstract:
Plasma membrane microdomains containing sphingolipids and cholesterol (lipid rafts) are enriched in signaling molecules. The cross-linking of certain types of cell surface receptors initiates the redistribution of these lipid rafts, resulting in the formation of signaling complexes. However, little is known about the regulation of the initial raft redistribution and whether negative regulatory signaling pathways target this phase of cellular activation. We used natural killer (NK) cells as a model to investigate the regulation of raft redistribution, as both positive and negative signals have been implicated in the development of their cellular function. Here we show that after NK cells form conjugates with sensitive tumor cells, rafts become polarized to the site of target recognition. This redistribution of lipid rafts requires the activation of both Src and Syk family protein tyrosine kinases. In contrast, engagement of major histocompatibility complex (MHC)-recognizing killer cell inhibitory receptors (KIRs) on NK cells by resistant, MHC-bearing tumor targets blocks raft redistribution. This inhibition is dependent on the catalytic activity of KIR-associated SHP-1, a Src homology 2 (SH2) domain containing tyrosine phosphatase. These results suggest that the influence of integrated positive and negative signals on raft redistribution critically influences the development of cell-mediated cytotoxicity.
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Luga, Valbona, Sarah Mclean, Christine Le Roy, Maureen O'Connor-Mccourt, Jeffrey L. Wrana, and Gianni M. Di Guglielmo. "The extracellular domain of the TGFβ type II receptor regulates membrane raft partitioning." Biochemical Journal 421, no. 1 (June 12, 2009): 119–31. http://dx.doi.org/10.1042/bj20081131.
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Cell-surface TGFβ (transforming growth factor β) receptors partition into membrane rafts and the caveolin-positive endocytic compartment by an unknown mechanism. In the present study, we investigated the determinant in the TGFβ type II receptor (TβRII) that is necessary for membrane raft/caveolar targeting. Using subcellular fractionation and immunofluorescence microscopy techniques, we demonstrated that the extracellular domain of TβRII mediates receptor partitioning into raft and caveolin-positive membrane domains. Pharmacological perturbation of glycosylation using tunicamycin or the mutation of Mgat5 [mannosyl(α-1,6)-glycoprotein β-1,6-N-acetylglucosaminyltransferase V] activity interfered with the raft partitioning of TβRII. However, this was not due to the glycosylation state of TβRII, as a non-glycosylated TβRII mutant remained enriched in membrane rafts. This suggested that other cell-surface glycoproteins associate with the extracellular domain of TβRII and direct their partitioning in membrane raft domains. To test this we analysed a GMCSF (granulocyte/macrophage colony-stimulating factor)–TβRII chimaeric receptor, which contains a glycosylated GMCSF extracellular domain fused to the transmembrane and intracellular domains of TβRII. This chimaeric receptor was found to be largely excluded from membrane rafts and caveolin-positive structures. Our results indicate that the extracellular domain of TβRII mediates receptor partitioning into membrane rafts and efficient entrance into caveolin-positive endosomes.
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Laliberte, Jason P., Lori W. McGinnes, Mark E. Peeples, and Trudy G. Morrison. "Integrity of Membrane Lipid Rafts Is Necessary for the Ordered Assembly and Release of Infectious Newcastle Disease Virus Particles." Journal of Virology 80, no. 21 (November 1, 2006): 10652–62. http://dx.doi.org/10.1128/jvi.01183-06.
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ABSTRACT Membrane lipid raft domains are thought to be sites of assembly for many enveloped viruses. The roles of both classical lipid rafts and lipid rafts associated with the membrane cytoskeleton in the assembly of Newcastle disease virus (NDV) were investigated. The lipid raft-associated proteins caveolin-1, flotillin-2, and actin were incorporated into virions, while the non-lipid raft-associated transferrin receptor was excluded. Kinetic analyses of the distribution of viral proteins in lipid rafts, as defined by detergent-resistant membranes (DRMs), in non-lipid raft membranes, and in virions showed an accumulation of HN, F, and NP viral proteins in lipid rafts early after synthesis. Subsequently, these proteins exited the DRMs and were recovered quantitatively in purified virions, while levels of these proteins in detergent-soluble cell fractions remained relatively constant. Cholesterol depletion of infected cells drastically altered the association of viral proteins with DRMs and resulted in an enhanced release of virus particles with reduced infectivity. Decreased infectivity was not due to effects on subsequent virus entry, since the extraction of cholesterol from intact virus did not significantly reduce infectivity. Particles released from cholesterol-depleted cells had very heterogeneous densities and altered ratios of NP and glycoproteins, demonstrating structural abnormalities which potentially contributed to their lowered infectivity. Taken together, these results indicate that lipid rafts, including cytoskeleton-associated lipid rafts, are sites of NDV assembly and that these domains are important for ordered assembly and release of infectious Newcastle disease virus particles.