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1

Errington, Wesley J., Bence Bruncsics, and Casim A. Sarkar. "Mechanisms of noncanonical binding dynamics in multivalent protein–protein interactions." Proceedings of the National Academy of Sciences 116, no. 51 (November 27, 2019): 25659–67. http://dx.doi.org/10.1073/pnas.1902909116.

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Protein multivalency can provide increased affinity and specificity relative to monovalent counterparts, but these emergent biochemical properties and their mechanistic underpinnings are difficult to predict as a function of the biophysical properties of the multivalent binding partners. Here, we present a mathematical model that accurately simulates binding kinetics and equilibria of multivalent protein–protein interactions as a function of the kinetics of monomer–monomer binding, the structure and topology of the multidomain interacting partners, and the valency of each partner. These properties are all experimentally or computationally estimated a priori, including approximating topology with a worm-like chain model applicable to a variety of structurally disparate systems, thus making the model predictive without parameter fitting. We conceptualize multivalent binding as a protein–protein interaction network: ligand and receptor valencies determine the number of interacting species in the network, with monomer kinetics and structural properties dictating the dynamics of each species. As predicted by the model and validated by surface plasmon resonance experiments, multivalent interactions can generate several noncanonical macroscopic binding dynamics, including a transient burst of high-energy configurations during association, biphasic equilibria resulting from interligand competition at high concentrations, and multiexponential dissociation arising from differential lifetimes of distinct network species. The transient burst was only uncovered when extending our analysis to trivalent interactions due to the significantly larger network, and we were able to predictably tune burst magnitude by altering linker rigidity. This study elucidates mechanisms of multivalent binding and establishes a framework for model-guided analysis and engineering of such interactions.
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Kauscher, Ulrike, and Bart Jan Ravoo. "Mannose-decorated cyclodextrin vesicles: The interplay of multivalency and surface density in lectin–carbohydrate recognition." Beilstein Journal of Organic Chemistry 8 (September 17, 2012): 1543–51. http://dx.doi.org/10.3762/bjoc.8.175.

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Cyclodextrin vesicles are versatile models for biological cell membranes since they provide a bilayer membrane that can easily be modified by host–guest interactions with functional guest molecules. In this article, we investigate the multivalent interaction of the lectin concanavalin A (ConA) with cyclodextrin vesicles decorated with mannose–adamantane conjugates with one, two or three adamantane units as well as one or two mannose units. The carbohydrate–lectin interaction in this artificial, self-assembled glycocalyx was monitored in an agglutination assay by the increase of optical density at 400 nm. It was found that there is a close relation between the carbohydrate density at the cyclodextrin vesicle surface and the multivalent interaction with ConA, and the most efficient interaction (i.e., fastest agglutination at lowest concentration) was observed for mannose–adamantane conjugates, in which both the cyclodextrin–adamantane and the lectin–mannose interaction is inherently multivalent.
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3

Zhulina, E. B., O. V. Borisov, and T. M. Birshtein. "Polyelectrolyte Brush Interaction with Multivalent Ions." Macromolecules 32, no. 24 (November 1999): 8189–96. http://dx.doi.org/10.1021/ma981811e.

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4

Schamel, Wolfgang W. A., Ignacio Arechaga, Ruth M. Risueño, Hisse M. van Santen, Pilar Cabezas, Cristina Risco, José M. Valpuesta, and Balbino Alarcón. "Coexistence of multivalent and monovalent TCRs explains high sensitivity and wide range of response." Journal of Experimental Medicine 202, no. 4 (August 8, 2005): 493–503. http://dx.doi.org/10.1084/jem.20042155.

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A long-standing paradox in the study of T cell antigen recognition is that of the high specificity–low affinity T cell receptor (TCR)–major histocompatibility complex peptide (MHCp) interaction. The existence of multivalent TCRs could resolve this paradox because they can simultaneously improve the avidity observed for monovalent interactions and allow for cooperative effects. We have studied the stoichiometry of the TCR by Blue Native–polyacrylamide gel electrophoresis and found that the TCR exists as a mixture of monovalent (αβγεδεζζ) and multivalent complexes with two or more ligand-binding TCRα/β subunits. The coexistence of monovalent and multivalent complexes was confirmed by electron microscopy after label fracture of intact T cells, thus ruling out any possible artifact caused by detergent solubilization. We found that although only the multivalent complexes become phosphorylated at low antigen doses, both multivalent and monovalent TCRs are phosphorylated at higher doses. Thus, the multivalent TCRs could be responsible for sensing low concentrations of antigen, whereas the monovalent TCRs could be responsible for dose-response effects at high concentrations, conditions in which the multivalent TCRs are saturated. Thus, besides resolving TCR stoichiometry, these data can explain how T cells respond to a wide range of MHCp concentrations while maintaining high sensitivity.
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5

Tang, Jo Sing Julia, Sophia Rosencrantz, Lucas Tepper, Sany Chea, Stefanie Klöpzig, Anne Krüger-Genge, Joachim Storsberg, and Ruben R. Rosencrantz. "Functional Glyco-Nanogels for Multivalent Interaction with Lectins." Molecules 24, no. 10 (May 15, 2019): 1865. http://dx.doi.org/10.3390/molecules24101865.

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Interactions between glycans and proteins have tremendous impact in biomolecular interactions. They are important for cell–cell interactions, proliferation and much more. Here, we emphasize the glycan-mediated interactions between pathogens and host cells. Pseudomonas aeruginosa, responsible for a huge number of nosocomial infections, is especially the focus when it comes to glycan-derivatives as pathoblockers. We present a microwave assisted protecting group free synthesis of glycomonomers based on lactose, melibiose and fucose. The monomers were polymerized in a precipitation polymerization in the presence of NiPAm to form crosslinked glyco-nanogels. The influence of reaction parameters like crosslinker type or stabilizer amount was investigated. The gels were characterized in lectin binding studies using model lectins and showed size and composition-dependent inhibition of lectin binding. Due to multivalent presentation of glycans in the gel, the inhibition was clearly stronger than with unmodified saccharides, which was compared after determination of the glycan loading. First studies with Pseudomonas aeruginosa revealed a surprising influence on the secretion of virulence factors. Functional glycogels may be in the future potent alternatives or adjuvants for antibiotic treatment of infections based on glycan interactions between host and pathogen.
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6

Wang, Yanyan, Srinivas Chalagalla, Tiehai Li, Xue-long Sun, Wei Zhao, Peng G. Wang, and Xiangqun Zeng. "Multivalent interaction-based carbohydrate biosensors for signal amplification." Biosensors and Bioelectronics 26, no. 3 (November 15, 2010): 996–1001. http://dx.doi.org/10.1016/j.bios.2010.08.025.

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7

Tõugu, V., T. Kesvatera, A. Lääne, and A. Aaviksaa. "Acetylcholinesterase as polyelectrolyte: interaction with multivalent cationic inhibitors." Biochimica et Biophysica Acta (BBA) - General Subjects 1157, no. 3 (July 1993): 199–203. http://dx.doi.org/10.1016/0304-4165(93)90065-g.

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8

Brissonnet, Yoan, Coralie Assailly, Amélie Saumonneau, Julie Bouckaert, Mike Maillasson, Clémence Petitot, Benoit Roubinet, et al. "Multivalent Thiosialosides and Their Synergistic Interaction with Pathogenic Sialidases." Chemistry - A European Journal 25, no. 9 (January 11, 2019): 2358–65. http://dx.doi.org/10.1002/chem.201805790.

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9

Cousin, Jonathan M., and Mary J. Cloninger. "Glycodendrimers: tools to explore multivalent galectin-1 interactions." Beilstein Journal of Organic Chemistry 11 (May 12, 2015): 739–47. http://dx.doi.org/10.3762/bjoc.11.84.

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Four generations of lactose-functionalized polyamidoamine (PAMAM) were employed to further the understanding of multivalent galectin-1 mediated interactions. Dynamic light scattering and fluorescence microscopy were used to study the multivalent interaction of galectin-1 with the glycodendrimers in solution, and glycodendrimers were observed to organize galectin-1 into nanoparticles. In the presence of a large excess of galectin-1, glycodendrimers nucleated galectin-1 into nanoparticles that were remarkably homologous in size (400–500 nm). To understand augmentation of oncologic cellular aggregation by galectin-1, glycodendrimers were used in cell-based assays with human prostate carcinoma cells (DU145). The results revealed that glycodendrimers provided competitive binding sites for galectin-1, which diverted galectin-1 from its typical function in cellular aggregation of DU145 cells.
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10

Nörpel, Julia, Simone Cavadini, Andreas D. Schenk, Alexandra Graff-Meyer, Daniel Hess, Jan Seebacher, Jeffrey A. Chao, and Varun Bhaskar. "Structure of the human C9orf72-SMCR8 complex reveals a multivalent protein interaction architecture." PLOS Biology 19, no. 7 (July 23, 2021): e3001344. http://dx.doi.org/10.1371/journal.pbio.3001344.

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A major cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) spectrum disorder is the hexanucleotide G4C2 repeat expansion in the first intron of the C9orf72 gene. Many underlying mechanisms lead to manifestation of disease that include toxic gain-of-function by repeat G4C2 RNAs, dipeptide repeat proteins, and a reduction of the C9orf72 gene product. The C9orf72 protein interacts with SMCR8 and WDR41 to form a trimeric complex and regulates multiple cellular pathways including autophagy. Here, we report the structure of the C9orf72-SMCR8 complex at 3.8 Å resolution using single-particle cryo-electron microscopy (cryo-EM). The structure reveals 2 distinct dimerization interfaces between C9orf72 and SMCR8 that involves an extensive network of interactions. Homology between C9orf72-SMCR8 and Folliculin-Folliculin Interacting Protein 2 (FLCN-FNIP2), a GTPase activating protein (GAP) complex, enabled identification of a key residue within the active site of SMCR8. Further structural analysis suggested that a coiled-coil region within the uDenn domain of SMCR8 could act as an interaction platform for other coiled-coil proteins, and its deletion reduced the interaction of the C9orf72-SMCR8 complex with FIP200 upon starvation. In summary, this study contributes toward our understanding of the biological function of the C9orf72-SMCR8 complex.
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11

Miura, Yoshiko, and Tomohiro Fukuda. "Morphology Control of Alzheimer Amyloid β Peptide (1-42) on the Multivalent Sulfonated Sugar Interface." MRS Proceedings 1498 (2013): 203–6. http://dx.doi.org/10.1557/opl.2013.337.

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ABSTRACTThe amyloidosis of amyloid β (1-42) was investigated by the well-defined glyco-cluster interface. We prepared monovalent, divalent, and trivalent 6-sulfo-N-acetyl-D-glucosamine immobilized substrates. The interaction between amyloid β and 6-sulfo-N-acetyl-D-glucosamine was amplified by multivalency of divalent and trivalent 6-sulfo-N-acetyl-D-glucosamine. The morphology of amyloid β were investigated by AFM, and we found the morphology of amyloid β aggregates were determined by the kinds of displayed saccharide-valency. Amyloid β had tendency to form spherical objects on the multivalent 6-sulfo-N-acetyl-D-glucosamine, but form fibrils on the monovalent 6-sulfo-N-acetyl-D-glucosamine. Spherical amyloid β was more toxic than fibrillar amyloid β to HeLa cells. These results suggested that the multivalency of was significant in its morphology and aggregation effects at the surface of the cell membrane mimic.
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12

Hu, Jun, Xue-Meng Sun, Jing-Yun Su, Yu-Fen Zhao, and Yong-Xiang Chen. "Different phosphorylation and farnesylation patterns tune Rnd3–14-3-3 interaction in distinct mechanisms." Chemical Science 12, no. 12 (2021): 4432–42. http://dx.doi.org/10.1039/d0sc05838f.

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13

Gensler, Manuel, Christian Eidamshaus, Maurice Taszarek, Hans-Ulrich Reissig, and Jürgen P. Rabe. "Mechanical stability of bivalent transition metal complexes analyzed by single-molecule force spectroscopy." Beilstein Journal of Organic Chemistry 11 (May 15, 2015): 817–27. http://dx.doi.org/10.3762/bjoc.11.91.

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Multivalent biomolecular interactions allow for a balanced interplay of mechanical stability and malleability, and nature makes widely use of it. For instance, systems of similar thermal stability may have very different rupture forces. Thus it is of paramount interest to study and understand the mechanical properties of multivalent systems through well-characterized model systems. We analyzed the rupture behavior of three different bivalent pyridine coordination complexes with Cu2+ in aqueous environment by single-molecule force spectroscopy. Those complexes share the same supramolecular interaction leading to similar thermal off-rates in the range of 0.09 and 0.36 s−1, compared to 1.7 s−1 for the monovalent complex. On the other hand, the backbones exhibit different flexibility, and we determined a broad range of rupture lengths between 0.3 and 1.1 nm, with higher most-probable rupture forces for the stiffer backbones. Interestingly, the medium-flexible connection has the highest rupture forces, whereas the ligands with highest and lowest rigidity seem to be prone to consecutive bond rupture. The presented approach allows separating bond and backbone effects in multivalent model systems.
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14

Lin, Kenneth, and Andrea M. Kasko. "Multivalent 3D Display of Glycopolymer Chains for Enhanced Lectin Interaction." Bioconjugate Chemistry 26, no. 8 (June 25, 2015): 1504–12. http://dx.doi.org/10.1021/acs.bioconjchem.5b00140.

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15

Otremba, Tobias, and Bart Jan Ravoo. "Dynamic multivalent interaction of phenylboronic acid functionalized dendrimers with vesicles." Tetrahedron 73, no. 33 (August 2017): 4972–78. http://dx.doi.org/10.1016/j.tet.2017.04.043.

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16

Zakharova, S. S., S. U. Egelhaaf, L. B. Bhuiyan, C. W. Outhwaite, D. Bratko, and J. R. C. van der Maarel. "Multivalent ion–DNA interaction: Neutron scattering estimates of polyamine distribution." Journal of Chemical Physics 111, no. 23 (December 15, 1999): 10706–16. http://dx.doi.org/10.1063/1.480425.

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17

OOYA, Tooru, Masaru EGUCHI, and Nobuhiko YUI. "Design of Biodegradable Polyrotaxanes for Multivalent Interaction with Biological Systems." KOBUNSHI RONBUNSHU 59, no. 12 (2002): 734–41. http://dx.doi.org/10.1295/koron.59.734.

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18

Hall, Pamela R., Brian Hjelle, David C. Brown, Chunyan Ye, Virginie Bondu-Hawkins, Kathleen A. Kilpatrick, and Richard S. Larson. "Multivalent Presentation of Antihantavirus Peptides on Nanoparticles Enhances Infection Blockade." Antimicrobial Agents and Chemotherapy 52, no. 6 (April 7, 2008): 2079–88. http://dx.doi.org/10.1128/aac.01415-07.

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ABSTRACT Viral entry into susceptible host cells typically results from multivalent interactions between viral surface proteins and host entry receptors. In the case of Sin Nombre virus (SNV), a New World hantavirus that causes hantavirus cardiopulmonary syndrome, infection involves the interaction between viral membrane surface glycoproteins and the human integrin αvβ3. Currently, there are no therapeutic agents available which specifically target SNV. To address this problem, we used phage display selection of cyclic nonapeptides to identify peptides that bound SNV and specifically prevented SNV infection in vitro. We synthesized cyclic nonapeptides based on peptide sequences of phage demonstrating the strongest inhibition of infection, and in all cases, the isolated peptides were less effective at blocking infection (9.0% to 27.6% inhibition) than were the same peptides presented by phage (74.0% to 82.6% inhibition). Since peptides presented by the phage were pentavalent, we determined whether the identified peptides would show greater inhibition if presented in a multivalent format. We used carboxyl linkages to conjugate selected cyclic peptides to multivalent nanoparticles and tested infection inhibition. Two of the peptides, CLVRNLAWC and CQATTARNC, showed inhibition that was improved over that of the free format when presented on nanoparticles at a 4:1 nanoparticle-to-virus ratio (9.0% to 32.5% and 27.6% to 37.6%, respectively), with CQATTARNC inhibition surpassing 50% when nanoparticles were used at a 20:1 ratio versus virus. These data illustrate that multivalent inhibitors may disrupt polyvalent protein-protein interactions, such as those utilized for viral infection of host cells, and may represent a useful therapeutic approach.
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19

Apgar, J. R. "Association of the crosslinked IgE receptor with the membrane skeleton is independent of the known signaling mechanisms in rat basophilic leukemia cells." Cell Regulation 2, no. 3 (March 1991): 181–91. http://dx.doi.org/10.1091/mbc.2.3.181.

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Crosslinking of the IgE receptor on the surface of rat basophilic leukemia (RBL) cells by multivalent antigen induces an association of these receptors with the detergent-insoluble membrane skeleton. Detergent insolubility of the receptor can also be induced on purified plasma membranes isolated from RBL cells by the use of either IgE oligomers or IgE monomers plus multivalent antigen. The critical event in initiating this interaction between the receptor and the membrane skeleton is cross-linking of the receptor. This association is rapid, and, when triggered by multivalent antigen, it is quickly reversed by the addition of excess monovalent antigen. The fact that this association occurs with the use of purified plasma membranes indicates that all of the components necessary for this interaction are present in the plasma membrane and that intracellular components are not required. Although crosslinking of the receptor activates phospholipase C and phospholipase A2 leading to the generation of several second messengers, none of these signaling mechanisms appears to be involved in IgE receptor interaction with the membrane skeleton. This interaction cannot be induced by phorbol 12-myristate 13-acetate (PMA), ionomycin, or a combination of these two reagents, although this will result in degranulation. Furthermore, receptor detergent insolubility is temperature independent when triggered by multivalent antigen, thus indicating that enzyme-catalyzed reactions are not important. This was verified by the fact that a variety of inhibitors that block phosphatidylinositol metabolism, arachidonic acid metabolism, Ca2+ influx, and protein kinase C (PKC) activation had no effect on antigen-induced association of the receptor with the membrane skeleton. These results indicate that the signaling mechanisms leading to the degranulation response are not involved in the association of the crosslinked receptor with the membrane skeleton.
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Ortiz-Muñoz, Andrés, Héctor F. Medina-Abarca, and Walter Fontana. "Combinatorial protein–protein interactions on a polymerizing scaffold." Proceedings of the National Academy of Sciences 117, no. 6 (January 24, 2020): 2930–37. http://dx.doi.org/10.1073/pnas.1912745117.

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Scaffold proteins organize cellular processes by bringing signaling molecules into interaction, sometimes by forming large signalosomes. Several of these scaffolds are known to polymerize. Their assemblies should therefore not be understood as stoichiometric aggregates, but as combinatorial ensembles. We analyze the combinatorial interaction of ligands loaded on polymeric scaffolds, in both a continuum and discrete setting, and compare it with multivalent scaffolds with fixed number of binding sites. The quantity of interest is the abundance of ligand interaction possibilities—the catalytic potential Q—in a configurational mixture. Upon increasing scaffold abundance, scaffolding systems are known to first increase opportunities for ligand interaction and then to shut them down as ligands become isolated on distinct scaffolds. The polymerizing system stands out in that the dependency of Q on protomer concentration switches from being dominated by a first order to a second order term within a range determined by the polymerization affinity. This behavior boosts Q beyond that of any multivalent scaffold system. In addition, the subsequent drop-off is considerably mitigated in that Q decreases with half the power in protomer concentration than for any multivalent scaffold. We explain this behavior in terms of how the concentration profile of the polymer-length distribution adjusts to changes in protomer concentration and affinity. The discrete case turns out to be similar, but the behavior can be exaggerated at small protomer numbers because of a maximal polymer size, analogous to finite-size effects in bond percolation on a lattice.
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Kim, Eun-Hye, Boyang Ning, Masuki Kawamoto, Hideyuki Miyatake, Eiry Kobatake, Yoshihiro Ito, and Jun Akimoto. "Conjugation of biphenyl groups with poly(ethylene glycol) to enhance inhibitory effects on the PD-1/PD-L1 immune checkpoint interaction." Journal of Materials Chemistry B 8, no. 44 (2020): 10162–71. http://dx.doi.org/10.1039/d0tb01729a.

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22

Muñoz, Antonio, Laura Rodríguez-Pérez, Santiago Casado, Beatriz M. Illescas, and Nazario Martín. "Multivalent fullerene/π-extended TTF electroactive molecules – non-covalent interaction with graphene and charge transfer implications." Journal of Materials Chemistry C 7, no. 29 (2019): 8962–68. http://dx.doi.org/10.1039/c9tc02277e.

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New multivalent [60]fullerene hexakis-adducts endowed with 12 or 24 π-exTTF electron donor units interact supramolecularly with exfoliated graphene revealing an efficient electronic communication confirmed by Raman and XPS studies.
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23

Bertuzzi, Sara, Ana Gimeno, Ane Martinez-Castillo, Marta G. Lete, Sandra Delgado, Cristina Airoldi, Marina Rodrigues Tavares, et al. "Cross-Linking Effects Dictate the Preference of Galectins to Bind LacNAc-Decorated HPMA Copolymers." International Journal of Molecular Sciences 22, no. 11 (June 1, 2021): 6000. http://dx.doi.org/10.3390/ijms22116000.

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The interaction of multi-LacNAc (Galβ1-4GlcNAc)-containing N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers with human galectin-1 (Gal-1) and the carbohydrate recognition domain (CRD) of human galectin-3 (Gal-3) was analyzed using NMR methods in addition to cryo-electron-microscopy and dynamic light scattering (DLS) experiments. The interaction with individual LacNAc-containing components of the polymer was studied for comparison purposes. For Gal-3 CRD, the NMR data suggest a canonical interaction of the individual small-molecule bi- and trivalent ligands with the lectin binding site and better affinity for the trivalent arrangement due to statistical effects. For the glycopolymers, the interaction was stronger, although no evidence for forming a large supramolecule was obtained. In contrast, for Gal-1, the results indicate the formation of large cross-linked supramolecules in the presence of multivalent LacNAc entities for both the individual building blocks and the polymers. Interestingly, the bivalent and trivalent presentation of LacNAc in the polymer did not produce such an increase, indicating that the multivalency provided by the polymer is sufficient for triggering an efficient binding between the glycopolymer and Gal-1. This hypothesis was further demonstrated by electron microscopy and DLS methods.
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Huerta, Vivian, Patricia Toledo, Noralvis Fleitas, Alejandro Martín, Dianne Pupo, Alexis Yero, Mónica Sarría, et al. "Receptor-activated human α2-macroglobulin interacts with the envelope protein of dengue virus and protects virions from temperature-induced inactivation through multivalent binding." Journal of General Virology 95, no. 12 (December 1, 2014): 2668–76. http://dx.doi.org/10.1099/vir.0.068544-0.

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Based on the hypothesis that interactions between virions and serum components may influence the outcome of dengue virus (DENV) infections, we decided to use affinity chromatography with domain III from the envelope (E) protein of DENV2 (DIIIE2) as a ligand to isolate virus-binding proteins from human plasma. This approach yielded serum amyloid P (SAP) and α2-macroglobulin (α2M) as novel viral interactors. After confirming the specific binding of both SAP and α2M to DIIIE2 by ELISA, the latter interaction was examined in greater detail. We obtain evidence suggesting that the binding species was actually the receptor-activated form of α2M (α2M*), that α2M* could bind monovalently to recombinant domain III from all four DENV serotypes with affinities in the micromolar range ranking as DENV4>DENV1~DENV2>DENV3 and that this interaction exhibited a strong avidity effect when multivalent binding was favoured (K D 8×10−8 M for DIIIE2). We also showed that α2M* bound to DENV virions of the four serotypes, protecting the virus from temperature-induced inactivation in the absence of serum and enhancing infectivity. The latter effect exhibited an ED50 of 2.9×10−8 M, also suggesting an avidity effect due to multivalent binding. These results will further contribute to the characterization of the virus–host factor interaction network during human DENV infection.
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Hidayat, Chusnul, Mikio Nakajima, Mutsumi Takagi, and Toshiomi Yoshida. "Multivalent binding interaction of alcohol dehydrogenase on dye-metal affinity matrix." Journal of Bioscience and Bioengineering 96, no. 2 (January 2003): 168–73. http://dx.doi.org/10.1016/s1389-1723(03)90120-4.

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26

Fujihara, Shingo, and Ryo Akiyama. "Attractive interaction between macroanions mediated by multivalent cations in biological fluids." Journal of Molecular Liquids 200 (December 2014): 89–94. http://dx.doi.org/10.1016/j.molliq.2014.06.022.

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Shahinuzzaman, MD, and Dipak Barua. "A Multiscale Algorithm for Spatiotemporal Modeling of Multivalent Protein–Protein Interaction." Journal of Computational Biology 24, no. 12 (December 2017): 1275–83. http://dx.doi.org/10.1089/cmb.2017.0178.

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28

Shahinuzzaman, Md, Jawahar Khetan, and Dipak Barua. "A spatio-temporal model reveals self-limiting Fc ɛ RI cross-linking by multivalent antigens." Royal Society Open Science 5, no. 9 (September 2018): 180190. http://dx.doi.org/10.1098/rsos.180190.

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Aggregation of cell surface receptor proteins by multivalent antigens is an essential early step for immune cell signalling. A number of experimental and modelling studies in the past have investigated multivalent ligand-mediated aggregation of IgE receptors (Fc ɛ RI) in the plasma membrane of mast cells. However, understanding of the mechanisms of Fc ɛ RI aggregation remains incomplete. Experimental reports indicate that Fc ɛ RI forms relatively small and finite-sized clusters when stimulated by a multivalent ligand. By contrast, modelling studies have shown that receptor cross-linking by a trivalent ligand may lead to the formation of large receptor superaggregates that may potentially give rise to hyperactive cellular responses. In this work, we have developed a Brownian dynamics-based spatio-temporal model to analyse Fc ɛ RI aggregation by a trivalent antigen. Unlike the existing models, which implemented non-spatial simulation approaches, our model explicitly accounts for the coarse-grained site-specific features of the multivalent species (molecules and complexes). The model incorporates membrane diffusion, steric collisions and sub-nanometre-scale site-specific interaction of the time-evolving species of arbitrary structures. Using the model, we investigated temporal evolution of the species and their diffusivities. Consistent with a recent experimental report, our model predicted sharp decay in species mobility in the plasma membrane in response receptor cross-linking by a multivalent antigen. We show that, due to such decay in the species mobility, post-stimulation receptor aggregation may become self-limiting. Our analysis reveals a potential regulatory mechanism suppressing hyperactivation of immune cells in response to multivalent antigens.
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29

Linne, Christine, Daniele Visco, Stefano Angioletti-Uberti, Liedewij Laan, and Daniela J. Kraft. "Direct visualization of superselective colloid-surface binding mediated by multivalent interactions." Proceedings of the National Academy of Sciences 118, no. 36 (August 31, 2021): e2106036118. http://dx.doi.org/10.1073/pnas.2106036118.

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Reliably distinguishing between cells based on minute differences in receptor density is crucial for cell–cell or virus–cell recognition, the initiation of signal transduction, and selective targeting in directed drug delivery. Such sharp differentiation between different surfaces based on their receptor density can only be achieved by multivalent interactions. Several theoretical and experimental works have contributed to our understanding of this “superselectivity.” However, a versatile, controlled experimental model system that allows quantitative measurements on the ligand–receptor level is still missing. Here, we present a multivalent model system based on colloidal particles equipped with surface-mobile DNA linkers that can superselectively target a surface functionalized with the complementary mobile DNA-linkers. Using a combined approach of light microscopy and Foerster resonance energy transfer (FRET), we can directly observe the binding and recruitment of the ligand–receptor pairs in the contact area. We find a nonlinear transition in colloid-surface binding probability with increasing ligand or receptor concentration. In addition, we observe an increased sensitivity with weaker ligand–receptor interactions, and we confirm that the timescale of binding reversibility of individual linkers has a strong influence on superselectivity. These unprecedented insights on the ligand–receptor level provide dynamic information into the multivalent interaction between two fluidic membranes mediated by both mobile receptors and ligands and will enable future work on the role of spatial–temporal ligand–receptor dynamics on colloid-surface binding.
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Li, Yuqi, Yaxiang Lu, Philipp Adelhelm, Maria-Magdalena Titirici, and Yong-Sheng Hu. "Intercalation chemistry of graphite: alkali metal ions and beyond." Chemical Society Reviews 48, no. 17 (2019): 4655–87. http://dx.doi.org/10.1039/c9cs00162j.

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This review compares the intercalation behaviors of alkali metal ions in graphite, offers insight for the host-guest interaction mechanisms, and expands the intercalation chemistry of pure ions to complex anions, ion-solvent, and multivalent ions.
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31

Bender, Dawn, Eulália Maria Lima Da Silva, Jingrong Chen, Annelise Poss, Lauren Gawey, Zane Rulon, and Susannah Rankin. "Multivalent interaction of ESCO2 with the replication machinery is required for sister chromatid cohesion in vertebrates." Proceedings of the National Academy of Sciences 117, no. 2 (December 26, 2019): 1081–89. http://dx.doi.org/10.1073/pnas.1911936117.

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The tethering together of sister chromatids by the cohesin complex ensures their accurate alignment and segregation during cell division. In vertebrates, sister chromatid cohesion requires the activity of the ESCO2 acetyltransferase, which modifies the Smc3 subunit of cohesin. It was shown recently that ESCO2 promotes cohesion through interaction with the MCM replicative helicase. However, ESCO2 does not significantly colocalize with the MCM complex, suggesting there are additional interactions important for ESCO2 function. Here we show that ESCO2 is recruited to replication factories, sites of DNA replication, through interaction with PCNA. We show that ESCO2 contains multiple PCNA-interaction motifs in its N terminus, each of which is essential to its ability to establish cohesion. We propose that multiple PCNA-interaction motifs embedded in a largely flexible and disordered region of the protein underlie the unique ability of ESCO2 to establish cohesion between sister chromatids precisely as they are born during DNA replication.
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Maslanka Figueroa, Sara, Daniel Fleischmann, Sebastian Beck, and Achim Goepferich. "The Effect of Ligand Mobility on the Cellular Interaction of Multivalent Nanoparticles." Macromolecular Bioscience 20, no. 4 (February 20, 2020): 1900427. http://dx.doi.org/10.1002/mabi.201900427.

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33

Kondo, Michio, Hiroshi Kitajima, Teruo Yasunaga, Hiroaki Kodama, Tommaso Costa, and Yasuyuki Shimohigashi. "A Tetrameric Enkephalin Analog for the Putative Multivalent Interaction with Opioid Receptors." Bulletin of the Chemical Society of Japan 68, no. 11 (November 1995): 3161–67. http://dx.doi.org/10.1246/bcsj.68.3161.

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34

Vico, Raquel V., Jens Voskuhl, and Bart Jan Ravoo. "Multivalent Interaction of Cyclodextrin Vesicles, Carbohydrate Guests, and Lectins: A Kinetic Investigation†." Langmuir 27, no. 4 (February 15, 2011): 1391–97. http://dx.doi.org/10.1021/la1038975.

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35

Ambrosi, Moira, Neil R. Cameron, Benjamin G. Davis, and Snjezana Stolnik. "Investigation of the interaction between peanut agglutinin and synthetic glycopolymeric multivalent ligands." Organic & Biomolecular Chemistry 3, no. 8 (2005): 1476. http://dx.doi.org/10.1039/b411555b.

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36

Wang, Deyun, Jaclyn Iera, Heather Baker, Priscilla Hogan, Roger Ptak, Lu Yang, Tracy Hartman, et al. "Multivalent binding oligomers inhibit HIV Tat–TAR interaction critical for viral replication." Bioorganic & Medicinal Chemistry Letters 19, no. 24 (December 2009): 6893–97. http://dx.doi.org/10.1016/j.bmcl.2009.10.078.

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37

Yoon, Seon-Joo, Ken-ichi Nakayama, Noriko Takahashi, Hirokazu Yagi, Natalia Utkina, Helen Ying Wang, Koichi Kato, Martin Sadilek, and Sen-itiroh Hakomori. "Interaction of N-linked glycans, having multivalent GlcNAc termini, with GM3 ganglioside." Glycoconjugate Journal 23, no. 9 (November 18, 2006): 639–49. http://dx.doi.org/10.1007/s10719-006-9001-4.

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38

Yoon, Seon-Joo, Ken-ichi Nakayama, Noriko Takahashi, Hirokazu Yagi, Natalia Utkina, Helen Ying Wang, Koichi Kato, Martin Sadilek, and Sen-itiroh Hakomori. "Interaction of N-linked glycans, having multivalent GlcNAc termini, with GM3 ganglioside." Glycoconjugate Journal 24, no. 2-3 (January 19, 2007): 181. http://dx.doi.org/10.1007/s10719-006-9027-7.

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39

Zhang, Bailing, Xiyao Cheng, Meng Gao, Yongqi Huang, and Zhengding Su. "Rational Design of Multivalent Anticancer Peptides Inhibiting PD-1/PD-L1 Interaction." Biophysical Journal 120, no. 3 (February 2021): 297a. http://dx.doi.org/10.1016/j.bpj.2020.11.1900.

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40

Koschek, Katharina, Vedat Durmaz, Oxana Krylova, Marek Wieczorek, Shilpi Gupta, Martin Richter, Alexander Bujotzek, et al. "Peptide–polymer ligands for a tandem WW-domain, an adaptive multivalent protein–protein interaction: lessons on the thermodynamic fitness of flexible ligands." Beilstein Journal of Organic Chemistry 11 (May 18, 2015): 837–47. http://dx.doi.org/10.3762/bjoc.11.93.

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Three polymers, poly(N-(2-hydroxypropyl)methacrylamide) (pHPMA), hyperbranched polyglycerol (hPG), and dextran were investigated as carriers for multivalent ligands targeting the adaptive tandem WW-domain of formin-binding protein (FBP21). Polymer carriers were conjugated with 3–9 copies of the proline-rich decapeptide GPPPRGPPPR-NH2 (P1). Binding of the obtained peptide–polymer conjugates to the tandem WW-domain was investigated employing isothermal titration calorimetry (ITC) to determine the binding affinity, the enthalpic and entropic contributions to free binding energy, and the stoichiometry of binding for all peptide–polymer conjugates. Binding affinities of all multivalent ligands were in the µM range, strongly amplified compared to the monovalent ligand P1 with a K D > 1 mM. In addition, concise differences were observed, pHPMA and hPG carriers showed moderate affinity and bound 2.3–2.8 peptides per protein binding site resulting in the formation of aggregates. Dextran-based conjugates displayed affinities down to 1.2 µM, forming complexes with low stoichiometry, and no precipitation. Experimental results were compared with parameters obtained from molecular dynamics simulations in order to understand the observed differences between the three carrier materials. In summary, the more rigid and condensed peptide–polymer conjugates based on the dextran scaffold seem to be superior to induce multivalent binding and to increase affinity, while the more flexible and dendritic polymers, pHPMA and hPG are suitable to induce crosslinking upon binding.
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41

Force Aldred, Shelley, Andrew Boudreau, Ben Buelow, Starlynn Clarke, Kevin Dang, Laura Davison, Katherine Harris, et al. "Multispecific antibodies targeting CD38 show potent tumor-specific cytotoxicity." Journal of Clinical Oncology 36, no. 5_suppl (February 10, 2018): 57. http://dx.doi.org/10.1200/jco.2018.36.5_suppl.57.

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57 Background: Multivalent antibodies targeting either CD38 alone or CD38 in conjunction with PD-L1 may yield therapeutics with superior biological activities and provide benefit for treating malignancies expressing low levels of CD38 (MCL, NHL, T cell lymphomas and Daratumumab refractory MM). Multivalent, multispecific antibodies kill CD38low cells through a variety of mechanisms including stronger and more specific engagement of CD38. Potent and directed immune checkpoint inhibition is realized by adding an anti-PD-L1 binding domain. Teneobio’s discovery platform utilizes VH domains (UniDabs) of fully human heavy chain antibodies (UniAbs) to develop bi-, tri-, and tetravalent antibodies. Methods: Individual UniDabs targeting CD38 and PDL1 were identified using our unique sequence-based discovery platform and high-throughput lead evaluation pipeline (TeneoSeek). This robust screening workflow enables evaluation of a large diversity of natural fully human antibodies, targeting multiple epitopes on a single antigen and uncovering important sequence activity relationships. UniDabs from transgenic rats are ideal building blocks for the generation of potent and highly manufacturable multivalent antibody therapeutics. Results: We have identified UniDabs that efficiently block PD-1/PD-L1 interaction as well as additional UniDabs that bind to five different functional epitopes on human CD38. Using different combinations and arrangements of UniDabs, a variety of multivalent antibodies were constructed and evaluated in in vitro models. Specific combinations of UniDabs show more potent cytotoxic effects than Daratumumab for multiple mechanisms including CDC and direct apoptosis. Conclusions: Data from a range of assay types show that multivalent UniAbs targeting CD38 can be engineered to display superior tumor cell cytotoxicity through multiple mechanisms of action.
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42

Jeffery, Heather M., and Robert O. J. Weinzierl. "Multivalent and Bidirectional Binding of Transcriptional Transactivation Domains to the MED25 Coactivator." Biomolecules 10, no. 9 (August 19, 2020): 1205. http://dx.doi.org/10.3390/biom10091205.

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The human mediator subunit MED25 acts as a coactivator that binds the transcriptional activation domains (TADs) present in various cellular and viral gene-specific transcription factors. Previous studies, including on NMR measurements and site-directed mutagenesis, have only yielded low-resolution models that are difficult to refine further by experimental means. Here, we apply computational molecular dynamics simulations to study the interactions of two different TADs from the human transcription factor ETV5 (ERM) and herpes virus VP16-H1 with MED25. Like other well-studied coactivator-TAD complexes, the interactions of these intrinsically disordered domains with the coactivator surface are temporary and highly dynamic (‘fuzzy’). Due to the fact that the MED25 TAD-binding region is organized as an elongated cleft, we specifically asked whether these TADs are capable of binding in either orientation and how this could be achieved structurally and energetically. The binding of both the ETV5 and VP16-TADs in either orientation appears to be possible but occurs in a conformationally distinct manner and utilizes different sets of hydrophobic residues present in the TADs to drive the interactions. We propose that MED25 and at least a subset of human TADs specifically evolved a redundant set of molecular interaction patterns to allow binding to particular coactivators without major prior spatial constraints.
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43

Nakase, I., N. Ueno, M. Katayama, K. Noguchi, T. Takatani-Nakase, N. B. Kobayashi, T. Yoshida, I. Fujii, and S. Futaki. "Receptor clustering and activation by multivalent interaction through recognition peptides presented on exosomes." Chemical Communications 53, no. 2 (2017): 317–20. http://dx.doi.org/10.1039/c6cc06719k.

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44

Lim, C. W., O. Crespo-Biel, M. C. A. Stuart, D. N. Reinhoudt, J. Huskens, and B. J. Ravoo. "Intravesicular and intervesicular interaction by orthogonal multivalent host guest and metal ligand complexation." Proceedings of the National Academy of Sciences 104, no. 17 (April 16, 2007): 6986–91. http://dx.doi.org/10.1073/pnas.0611123104.

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45

de Wildt, R. M. T., I. M. Tomlinson, J. L. Ong, and P. Holliger. "Isolation of receptor-ligand pairs by capture of long-lived multivalent interaction complexes." Proceedings of the National Academy of Sciences 99, no. 13 (June 25, 2002): 8530–35. http://dx.doi.org/10.1073/pnas.132008499.

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46

Porret, Estelle, Jean-Baptiste Fleury, Lucie Sancey, Mylène Pezet, Jean-Luc Coll, and Xavier Le Guével. "Augmented interaction of multivalent arginine coated gold nanoclusters with lipid membranes and cells." RSC Advances 10, no. 11 (2020): 6436–43. http://dx.doi.org/10.1039/c9ra10047d.

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A library of ultra-small red photoluminescent gold nanoclusters (Au NCs) were synthesized with an increasing amount of positive charges provided by the addition of mono-, di- or trivalent-glutathione modified arginine peptides.
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47

Han, Suyeong, Yu‐na Kim, Gyunghee Jo, Young Eun Kim, Ho Min Kim, Jeong‐Mo Choi, and Yongwon Jung. "Multivalent‐Interaction‐Driven Assembly of Discrete, Flexible, and Asymmetric Supramolecular Protein Nano‐Prisms." Angewandte Chemie 132, no. 51 (October 15, 2020): 23444–51. http://dx.doi.org/10.1002/ange.202010054.

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48

Han, Suyeong, Yu‐na Kim, Gyunghee Jo, Young Eun Kim, Ho Min Kim, Jeong‐Mo Choi, and Yongwon Jung. "Multivalent‐Interaction‐Driven Assembly of Discrete, Flexible, and Asymmetric Supramolecular Protein Nano‐Prisms." Angewandte Chemie International Edition 59, no. 51 (October 15, 2020): 23244–51. http://dx.doi.org/10.1002/anie.202010054.

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49

Hashidzume, Akihito, Takahiro Itami, Yuri Kamon, and Akira Harada. "A Simplified Model for Multivalent Interaction Competing with a Low Molecular Weight Competitor." Chemistry Letters 49, no. 11 (November 5, 2020): 1306–8. http://dx.doi.org/10.1246/cl.200501.

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50

Curk, Tine, Jure Dobnikar, and Daan Frenkel. "Optimal multivalent targeting of membranes with many distinct receptors." Proceedings of the National Academy of Sciences 114, no. 28 (June 26, 2017): 7210–15. http://dx.doi.org/10.1073/pnas.1704226114.

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Cells can often be recognized by the concentrations of receptors expressed on their surface. For better (targeted drug treatment) or worse (targeted infection by pathogens), it is clearly important to be able to target cells selectively. A good targeting strategy would result in strong binding to cells with the desired receptor profile and barely binding to other cells. Using a simple model, we formulate optimal design rules for multivalent particles that allow them to distinguish target cells based on their receptor profile. We find the following: (i) It is not a good idea to aim for very strong binding between the individual ligands on the guest (delivery vehicle) and the receptors on the host (cell). Rather, one should exploit multivalency: High sensitivity to the receptor density on the host can be achieved by coating the guest with many ligands that bind only weakly to the receptors on the cell surface. (ii) The concentration profile of the ligands on the guest should closely match the composition of the cognate membrane receptors on the target surface. And (iii) irrespective of all details, the effective strength of the ligand–receptor interaction should be of the order of the thermal energy kBT, where T is the absolute temperature and kB is Boltzmann’s constant. We present simulations that support the theoretical predictions. We speculate that, using the above design rules, it should be possible to achieve targeted drug delivery with a greatly reduced incidence of side effects.
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