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1
Wang, Zhong, Xiuying Yang, Nicholas Zhou Lee, and Xudong Cao. "Multivalent Aptamer Approach: Designs, Strategies, and Applications." Micromachines 13, no. 3 (March 12, 2022): 436. http://dx.doi.org/10.3390/mi13030436.
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Aptamers are short and single-stranded DNA or RNA molecules with highly programmable structures that give them the ability to interact specifically with a large variety of targets, including proteins, cells, and small molecules. Multivalent aptamers refer to molecular constructs that combine two or more identical or different types of aptamers. Multivalency increases the avidity of aptamers, a particularly advantageous feature that allows for significantly increased binding affinities in comparison with aptamer monomers. Another advantage of multivalency is increased aptamer stabilities that confer improved performances under physiological conditions for various applications in clinical settings. The current study aims to review the most recent developments in multivalent aptamer research. The review will first discuss structures of multivalent aptamers. This is followed by detailed discussions on design strategies of multivalent aptamer approaches. Finally, recent developments of the multivalent aptamer approach in biosensing and biomedical applications are highlighted.
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Gillies, C. B., J. Kuspira, and R. N. Bhambhani. "Genetic and cytogenetic analyses of the A genome of Triticum monococcum. IV. Synaptonemal complex formation in autotetraploids." Genome 29, no. 2 (April 1, 1987): 309–18. http://dx.doi.org/10.1139/g87-051.
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Electron microscopy of synaptonemal complex spreads from autotetraploid Triticum monococcum (2n = 4x = 28) revealed a minimum mean of 3.59 multivalents per zygotene–pachytene nucleus. The range of values was from 1 to 6 multivalents per nucleus. Most of the multivalents were quadrivalents with single, medially located pairing partner switch points. Lateral element pairing switches, particularly the few multiple switches, were often accompanied by extensive asynapsis around the switch point. The synaptonemal complex multivalent frequency is considerably higher than the metaphase I quadrivalent frequency previously reported for the same material. Calculations of expected pachytene quadrivalent frequency from metaphase I data, using several published theoretical models, gave values that did not agree with the results obtained here. The difference between the multivalent frequencies at pachytene and metaphase I does not appear to be the result of a correction process. Instead, it could be caused by a combination of preferential pairing or crossing-over and the effects of the position of partner switches and asynapsis associated with switches. Key words: autotetraploid, multivalents, synaptonemal complex, pairing effects.
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Yeldell, Sean B., and Oliver Seitz. "Nucleic acid constructs for the interrogation of multivalent protein interactions." Chemical Society Reviews 49, no. 19 (2020): 6848–65. http://dx.doi.org/10.1039/d0cs00518e.
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Sequence-programmed self-assembly provides multivalent nucleic acid–ligand constructs used as tailor-made probes for unravelling and exploiting the mechanisms of multivalency-enhanced interactions on protein receptors.
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Sybenga, J., and G. K. Rickards. "The orientation of multivalents at meiotic metaphase I: a workshop report." Genome 29, no. 4 (August 1, 1987): 612–20. http://dx.doi.org/10.1139/g87-102.
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During a workshop with 13 participants, several aspects of multivalent orientation at meiotic (pro)metaphase were discussed in an attempt to resolve some of the most prominent controversies with respect to terminology, interpretation of observations, and the validity of hypotheses and theories. For several terms and concepts, descriptive definitions were formulated that are recommended for general use. In the analysis of the behaviour of the multivalent in meiosis preprometaphase shape and position as important factors in final orientation were discussed, as well as the first contact between spindle and kinetochores and the role of reorientation. Specific characteristics of different multivalents and expected frequencies of different orientation types were considered. Finally, a few remarks on data collection and analytical procedures were made Key words: meiosis, multivalents, orientation, workshop.
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Ciuk, Anna K., and Thisbe K. Lindhorst. "Synthesis of carbohydrate-scaffolded thymine glycoconjugates to organize multivalency." Beilstein Journal of Organic Chemistry 11 (May 7, 2015): 668–74. http://dx.doi.org/10.3762/bjoc.11.75.
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Multivalency effects are essential in carbohydrate recognition processes as occurring on the cell surface. Thus many synthetic multivalent glycoconjugates have been developed as important tools for glycobiological research. We are expanding this collection of molecules by the introduction of carbohydrate-scaffolded divalent glycothymine derivatives that can be intramolecularily dimerized by [2 + 2] photocycloaddition. Thus, thymine functions as a control element that allows to restrict the conformational flexibility of the scaffolded sugar ligands and thus to “organize” multivalency. With this work we add a parameter to multivalency studies additional to valency.
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Muramatsu, Mikio. "Cytogenetics of decaploid Agropyron elongatum (Elytrigia elongata) (2n = 70). I. Frequency of decavalent formation." Genome 33, no. 6 (December 1, 1990): 811–17. http://dx.doi.org/10.1139/g90-122.
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The multivalents that appeared in the decaploid strain of Agropyron elongatum (2n = 10x = 70), a relative of wheat, ranged from trivalent to decavalent. Few univalents occurred. The metaphase I chromosome association in 12 cells where all configurations could clearly be identified averaged 0.42 ring X + 0.17 chain X + 0.42 ring VIII + 0.17 branched VIII + 0.25 chain VIII + 0.17 chain VII + 1.17 ring VI + 0.33 branched VI + 0.5 chain VI + 1.67 ring IV + 0.42 branched IV + 0.58 chain IV + 0.08 branched III + 0.17 chain III + 12.58 ring II + 3.75 open II + 0.25 I. The occurrence of decavalents, up to two in one cell, and of a cell with five multivalents, each of which involved more than five chromosomes, and many multivalents of ring shape indicated that the strain is autodecaploid.The chromosome associations of each cell can be interpreted as seven groups of 10 homologous chromosomes. The high frequency of bivalents indicated a tendency toward reduced multivalent formation, for which an explanation is suggested.Key words: Agropyron elongatum, meiotic configuration, decaploid, multivalent.
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Santos, J. L., D. Alfaro, E. Sanchez-Moran, S. J. Armstrong, F. C. H. Franklin, and G. H. Jones. "Partial Diploidization of Meiosis in Autotetraploid Arabidopsis thaliana." Genetics 165, no. 3 (November 1, 2003): 1533–40. http://dx.doi.org/10.1093/genetics/165.3.1533.
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Abstract Meiosis was analyzed cytogenetically in autotetraploids of Arabidopsis, including both established lines and newly generated autotetraploid plants. Fluorescent in situ hybridization with 5S and 45S rDNA probes was used to identify the different chromosomes at metaphase I of meiosis. Multivalents were observed frequently in all the lines analyzed, but there were significant differences in multivalent frequency not only between the newly generated tetraploids and the established lines but also among the different established lines. The new tetraploids showed high multivalent frequencies, exceeding the theoretical 66.66% predicted by the simple random-end pairing model, in some cases significantly, thus indicating that Arabidopsis autotetraploids have more than two autonomous pairing sites per chromosome, despite their small sizes. The established lines showed fewer multivalents than the new autotetraploids did, but the extent of this reduction was strongly line and chromosome dependent. One line in particular showed a large reduction in multivalents and a concomitant increase in bivalents, while the other lines showed lesser reductions in multivalents. The reduction in multivalents was not uniformly distributed across chromosomes. The smaller chromosomes, especially chromosomes 2 and 4, showed the most marked reductions while the largest chromosome (1) showed virtually no reduction compared to the new tetraploids. It is concluded that the established autotetraploid lines have undergone a partial diploidization of meiosis, but not necessarily genetical diploidization, since their creation. Possible mechanisms for the resulting change in meiotic chromosome behavior are discussed.
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Reisbeck, Felix, Stefanie Wedepohl, Mathias Dimde, Ann-Cathrin Schmitt, Jens Dernedde, Miguel Álvaro-Benito, Christian Freund, and Rainer Haag. "Synthesis and functionalization of dendritic polyglycerol-based nanogels: application in T cell activation." Journal of Materials Chemistry B 10, no. 1 (2022): 96–106. http://dx.doi.org/10.1039/d1tb02144c.
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Synthesis of a dPG- and NG-based nanoplatform conjugated to avidin for the multivalent display of biotinylated biomolecules. Carriers were coupled to antibodies and their capability to activate T cells was assessed, showing a multivalency effect.
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Abu-Muhanna, Y., and A. Lyzzaik. "A geometric criterion for decomposition and multivalence." Mathematical Proceedings of the Cambridge Philosophical Society 103, no. 3 (May 1988): 487–95. http://dx.doi.org/10.1017/s0305004100065099.
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AbstractWe give a quite general geometric criterion for a function analytic in the unit disc to be a polynomial of a univalent function, and hence a criterion for multivalence. We believe that this is the essence why multivalent close-to-convex functions enjoy the latter decomposition property. As another application, we study, as suggested by T. Sheil-Small ‘9’, the geometry of classes of analytic functions which arise from his recent investigation of multivalent harmonic mappings.
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Jenkins, G., J. White, and J. S. Parker. "Elimination of multivalents during meiotic prophase in Scilla autumnalis. II. Tetraploid." Genome 30, no. 6 (December 1, 1988): 940–46. http://dx.doi.org/10.1139/g88-150.
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The pairing behaviour of chromosomes during meiotic prophase in two Scilla autumnalis tetraploids was investigated by observing synaptonemal complexes from serial sections and whole-mount surface spreads. In one of the tetraploids with the genomic constitution AAB7B7 pairing at first metaphase of meiosis is restricted to homologous chromosomes and only bivalents appear. In the second tetraploid, AB7B7B7, some multivalents are found at first metaphase, but most of the configurations are bivalent. The bivalents, however, result from chiasma formation between homoeologous as well as homologous chromosomes. Both tetraploids show extensive multivalent formation at zygotene. The transformation of these multivalents to bivalents is described and interpreted in the two tetraploid forms.Key words: Scilla autumnalis, synaptonemal complex, multivalents, elimination, polyploids.
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Wang, Yali, Jian Xiao, Aiguo Meng, and Chunyan Liu. "Multivalent Pyrrolidine Iminosugars: Synthesis and Biological Relevance." Molecules 27, no. 17 (August 24, 2022): 5420. http://dx.doi.org/10.3390/molecules27175420.
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Recently, the strategy of multivalency has been widely employed to design glycosidase inhibitors, as glycomimetic clusters often induce marked enzyme inhibition relative to monovalent analogs. Polyhydroxylated pyrrolidines, one of the most studied classes of iminosugars, are an attractive moiety due to their potent and specific inhibition of glycosidases and glycosyltransferases, which are associated with many crucial biological processes. The development of multivalent pyrrolidine derivatives as glycosidase inhibitors has resulted in several promising compounds that stand out. Herein, we comprehensively summarized the different synthetic approaches to the preparation of multivalent pyrrolidine clusters, from total synthesis of divalent iminosugars to complex architectures bearing twelve pyrrolidine motifs. Enzyme inhibitory properties and multivalent effects of these synthesized iminosugars were further discussed, especially for some less studied therapeutically relevant enzymes. We envision that this comprehensive review will help extend the applications of multivalent pyrrolidine iminosugars in future studies.
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Lourenço, Luciana Bolsoni, Shirlei M. Recco-Pimentel, and Adão José Cardoso. "A second case of multivalent meiotic configurations in diploid species of Anura." Genetics and Molecular Biology 23, no. 1 (March 2000): 131–33. http://dx.doi.org/10.1590/s1415-47572000000100024.
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We analyzed the meiotic chromosomes of specimens from the two karyological groups of Physalaemus petersi (Jiménez de la Espada, 1872) described in the literature. Multivalent configurations (rings or chains) were observed in both groups. This meiotic organization resulted from the terminal association of non-homologous chromosomes, and an analysis of C-banded multivalents indicated no involvement of heterochromatic regions in these associations. A possible explanation for such meiotic configurations is the occurrence of heterozygous translocations. Thus, multivalents may indicate the involvement of translocation events in the karyotypic evolution of P. petersi.
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Chatterjee, R., and G. Jenkins. "Meiotic chromosome interactions in inbred autotetraploid rye (Secale cereale)." Genome 36, no. 1 (February 1, 1993): 131–38. http://dx.doi.org/10.1139/g93-016.
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Electron microscopy of whole-mount surface-spread synaptonemal complex complements and conventional light microscopy of chromosomes at first metaphase of meiosis were used to compare the relative frequencies of pairing configurations at the two stages in inbred autotetraploid rye (Secale cereale L.). Statistical tests showed significantly fewer multivalents at first metaphase than expectations based on random initiation of synapsis at each telomeric site within each group of four homologues. Direct observations of synaptic behaviour of chromosomes showed that this deviation is due primarily to a preponderance of bivalents during zygotene and pachytene. It is also the result of a significant drop in multivalent frequency from meiotic prophase to metaphase I, which is attributable both to a lack of chiasmata with which to consolidate multivalents and inhibition of chiasma formation in synaptonemal complex segments of multivalents that are nonhomologous.Key words: autotetraploid, rye, synaptonemal complex, multivalents, chiasmata.
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Allinson, Robert Elliott. "How to Say What Cannot be Said: Metaphor in the Zhuangzi." Journal of Chinese Philosophy 41, no. 3-4 (March 2, 2014): 268–86. http://dx.doi.org/10.1163/15406253-0410304003.
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I argue that it is only on the condition of a preconceptual understanding that Zhuangzi’s metaphors can be cognitive. Kimchong Chong holds that the choice between metaphors as noncognitive and cognitive is a choice between Allinson and Davidson. Chong’s view of metaphors possessing multivalence is reducible to Davidson’s choice, because there is no built-in parameter between multivalence and limitless valence. If Zhuangzi’s metaphors were multivalent, the text would be subject to infinite interpretive viewpoints and the logical consequence of relativism. It is only if metaphors are cognitive that the text of the Zhuangzi can convey the message of transcendent freedom.
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Scheepers, M. R. W., L. J. van IJzendoorn, and M. W. J. Prins. "Multivalent weak interactions enhance selectivity of interparticle binding." Proceedings of the National Academy of Sciences 117, no. 37 (August 28, 2020): 22690–97. http://dx.doi.org/10.1073/pnas.2003968117.
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Targeted drug delivery critically depends on the binding selectivity of cargo-transporting colloidal particles. Extensive theoretical work has shown that two factors are necessary to achieve high selectivity for a threshold receptor density: multivalency and weak interactions. Here, we study a model system of DNA-coated particles with multivalent and weak interactions that mimics ligand–receptor interactions between particles and cells. Using an optomagnetic cluster experiment, particle aggregation rates are measured as a function of ligand and receptor densities. The measured aggregation rates show that the binding becomes more selective for shorter DNA ligand–receptor pairs, proving that multivalent weak interactions lead to enhanced selectivity in interparticle binding. Simulations confirm the experimental findings and show the role of ligand–receptor dissociation in the selectivity of the weak multivalent binding.
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Farhadi, Shaheen A., and Gregory A. Hudalla. "Engineering galectin–glycan interactions for immunotherapy and immunomodulation." Experimental Biology and Medicine 241, no. 10 (May 2016): 1074–83. http://dx.doi.org/10.1177/1535370216650055.
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Galectins, a 15-member family of soluble carbohydrate-binding proteins, are receiving increasing interest as therapeutic targets for immunotherapy and immunomodulation due to their role as extracellular signals that regulate innate and adaptive immune cell phenotype and function. However, different galectins can have redundant, synergistic, or antagonistic signaling activity in normal immunological responses, such as resolution of inflammation and induction of antigen-specific tolerance. In addition, certain galectins can be hijacked to promote progression of immunopathologies, such as tumor immune privilege, metastasis, and viral infection, while others can inhibit these processes. Thus, eliciting a desired immunological outcome will likely necessitate therapeutics that can precisely enhance or inhibit particular galectin–glycan interactions. Multivalency is an important determinant of the affinity and specificity of natural galectin–glycan interactions, and is emerging as a key design element for therapeutics that can effectively manipulate galectin bioactivity. This minireview surveys current molecular and biomaterial engineering approaches to create therapeutics that can stabilize galectin multivalency or recapitulate natural glycan multivalency (i.e. “the glycocluster effect”). In particular, we highlight examples of using natural and engineered multivalent galectins for immunosuppression and immune tolerance, with a particular emphasis on treating autoimmune diseases or avoiding transplant rejection. In addition, we present examples of multivalent inhibitors of galectin–glycan interactions to maintain or restore T-cell function, with a particular emphasis on promoting antitumor immunity. Finally, we discuss emerging opportunities to further engineer galectin–glycan interactions for immunotherapy and immunomodulation.
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Kim, Hokyung, Hayeon Choi, Yoonji Heo, Cheoljae Kim, Min Kim, and Ki Tae Kim. "Biosensors Based on Bivalent and Multivalent Recognition by Nucleic Acid Scaffolds." Applied Sciences 12, no. 3 (February 7, 2022): 1717. http://dx.doi.org/10.3390/app12031717.
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Several biological macromolecules adopt bivalent or multivalent interactions to perform various cellular processes. In this regard, the development of molecular constructs presenting multiple ligands in a specific manner is becoming crucial for the understanding of multivalent interactions and for the detection of target macromolecules. Nucleic acids are attractive molecules to achieve this goal because they are capable of forming various, structurally well-defined 2D or 3D nanostructures and can bear multiple ligands on their structures with precisely controlled ligand–ligand distances. Thanks to the features of nucleic acids, researchers have proposed a wide range of bivalent and multivalent binding agents that strongly bind to target biomolecules; consequently, these findings have uncovered new biosensing strategies for biomolecule detection. To date, various bivalent and multivalent interactions of nucleic acid architectures have been applied to the design of biosensors with enhanced sensitivity and target accuracy. In this review, we describe not only basic biosensor designs but also recently designed biosensors operating through the bivalent and multivalent recognition of nucleic acid scaffolds. Based on these designs, strategies to transduce bi- or multivalent interaction signals into readable signals are discussed in detail, and the future prospects and challenges of the field of multivalence-based biosensors are explored.
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Attia, T., and G. Röbbelen. "Meiotic pairing in haploids and amphidiploids of spontaneous versus synthetic origin in rape, Brassica napus L." Canadian Journal of Genetics and Cytology 28, no. 3 (June 1, 1986): 330–34. http://dx.doi.org/10.1139/g86-049.
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Newly resynthesized AC amphihaploids, which were characterized by high meiotic pairing and multivalent formulation, after doubling of their chromosome number showed preferential pairing and bivalent formation in the resynthesized amphidiploid Brassica napus (AACC). However, univalents as well as multivalents were also formed indicating that their chromosome behaviour was not fully diploidized. Stabilization of chromosome pairing in newly resynthesized amphidiploids can be achieved through genetic control or structural modification of the homoeologous chromosomes. A comparison of the meiotic behaviour of spontaneous haploids of natural rapeseed with that of the newly synthesized AC amphihaploids provides some evidence that both processes may be involved in the regulation of chromosome pairing in Brassica.Key words: Brassica, amphihaploid, amphidiploid, meiosis, univalents, multivalents.
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Charpentier, A., M. Feldman, and Y. Cauderon. "Genetic control of meiotic chromosome pairing in tetraploid Agropyron elongatum. I. Pattern of pairing in natural and induced tetraploids and in F1 triploid hybrids." Canadian Journal of Genetics and Cytology 28, no. 5 (October 1, 1986): 783–88. http://dx.doi.org/10.1139/g86-110.
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Meiotic chromosome pairing was studied in natural and induced tetraploid Agropyron elongatum, as well as in triploid hybrids between natural tetraploid and diploid cytotypes. The natural tetraploids showed a highly regular, diploid-like pairing, while the induced ones showed an average of two to three multivalents per cell. A high level of pairing was exhibited by the triploid hybrids, 4.15 bivalents and 2.82 trivalents per cell, supporting the assumption that the natural tetraploid is of an autoploid origin. Frequencies of meiotic configurations of the induced tetraploid and of the F1 triploid hybrids deviated significantly from the expected values based on a model assuming random pairing within one homologous group in autoploids: the observed data were characterized by fewer multivalents than expected, indicating a tendency towards bivalentization. This tendency is fully realized in the natural tetraploid. The presence of a pairing-control system in these autoploids, most probably a genetic one, that determines bivalent rather than multivalent pairing is suggested.Key words: Agropyron, pairing, bivalentization, tetraploid, multivalents.
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Heitner, Tara, Noboru Satozawa, Kirk Mclean, David Vogel, Ronald R. Cobb, Bing Liu, Mithra Mahmoudi, et al. "Obligate Multivalent Recognition of Cell Surface Tomoregulin following Selection from a Multivalent Phage Antibody Library." Journal of Biomolecular Screening 11, no. 8 (December 2006): 985–95. http://dx.doi.org/10.1177/1087057106293841.
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A therapeutic antibody candidate (AT-19) isolated using multivalent phage display binds native tomoregulin (TR) as a mul-timer not as a monomer. This report raises the importance of screening and selecting phage antibodies on native antigen and reemphasizes the possibility that potentially valuable antibodies are discarded when a monomeric phage display system is used for screening. A detailed live cell panning selection and screening method to isolate multivalently active antibodies is described. AT-19 is a fully human antibody recognizing the cell surface protein TR, a proposed prostate cancer target for therapeutic antibody internalization. AT-19 was isolated from a multivalent single-chain variable fragment (scFv) antibody library rescued with hyperphage. The required multivalency for isolation of AT-19 is supported by fluorescence activated cell sorting data demonstrating binding of the multivalent AT-19 phage particles at high phage concentrations and failure of monovalent particles to bind. Pure monomeric scFv AT-19 does not bind native receptor on cells, whereas dimeric scFv or immunoglobulin G binds with nanomolar affinity. The isolation of AT-19 antibody with obligate bivalent binding activity to native TR is attributed to the use of a multivalent display of scFv on phage and the method for selecting and screening by alternate use of 2 recombinant cell lines.
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Khawaja, H. I. T., J. R. Ellis, and J. Sybenga. "Cytogenetics of Lathyrus palustris, a natural autohexaploid." Genome 38, no. 4 (August 1, 1995): 827–31. http://dx.doi.org/10.1139/g95-107.
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American as well as British forms of the perennial plant Lathyrus palustris have 2n = 42 chromosomes with one group of 6 long submetacentric chromosomes, two groups of 6 medium-long subacrocentric chromosomes, three groups of 6 medium-long to medium-short submetacentric to subacrocentric chromosomes, and one group of 6 medium-short metacentric chromosomes. One haploid complement measures 45.8 μm at somatic metaphase. At meiotic first metaphase both forms show extensive multivalent formation. In 50 metaphase I cells of one plant of the British form there were 51 ring hexavalents, 80 chain and open-branched hexavalents of various forms, 2 quinquivalents, 41 ring quadrivalents, 58 chain quadrivalents, 20 branched quadrivalents of various forms, 1 trivalent, 128 ring bivalents, 280 open bivalents, and 9 univalents. It is concluded that L. palustris is most likely a natural autohexaploid with frequent multivalent pairing, many points of pairing initiation, several partner exchanges per multivalent, and many interstitial chiasmata. It may well be the first fully documented true natural autohexaploid reported. Pollen fertility was 56.2% and seed set 37%, apparently sufficient for a perennial plant species.Key words: Lathyrus, natural, autohexaploid, meiosis, multivalents.
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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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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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Lee, JuYeon, Yugang Bai, Ullas V. Chembazhi, Shaohong Peng, Kevin Yum, Long M. Luu, Lauren D. Hagler, et al. "Intrinsically cell-penetrating multivalent and multitargeting ligands for myotonic dystrophy type 1." Proceedings of the National Academy of Sciences 116, no. 18 (April 11, 2019): 8709–14. http://dx.doi.org/10.1073/pnas.1820827116.
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Developing highly active, multivalent ligands as therapeutic agents is challenging because of delivery issues, limited cell permeability, and toxicity. Here, we report intrinsically cell-penetrating multivalent ligands that target the trinucleotide repeat DNA and RNA in myotonic dystrophy type 1 (DM1), interrupting the disease progression in two ways. The oligomeric ligands are designed based on the repetitive structure of the target with recognition moieties alternating with bisamidinium groove binders to provide an amphiphilic and polycationic structure, mimicking cell-penetrating peptides. Multiple biological studies suggested the success of our multivalency strategy. The designed oligomers maintained cell permeability and exhibited no apparent toxicity both in cells and in mice at working concentrations. Furthermore, the oligomers showed important activities in DM1 cells and in a DM1 liver mouse model, reducing or eliminating prominent DM1 features. Phenotypic recovery of the climbing defect in adult DM1Drosophilawas also observed. This design strategy should be applicable to other repeat expansion diseases and more generally to DNA/RNA-targeted therapeutics.
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Martin, Harlei, Hannah Masterson, Kevin Kavanagh, and Trinidad Velasco-Torrijos. "The Synthesis and Evaluation of Multivalent Glycopeptoids as Inhibitors of the Adhesion of Candida albicans." Pathogens 10, no. 5 (May 8, 2021): 572. http://dx.doi.org/10.3390/pathogens10050572.
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Multivalency is a strategy commonly used by medicinal carbohydrate chemists to increase the affinity of carbohydrate-based small molecules for their protein targets. Although this approach has been very successful in enhancing binding to isolated carbohydrate-binding proteins, anticipating the multivalent presentations that will improve biological activity in cellular assays remains challenging. In this work we investigate linear molecular scaffolds for the synthesis of a low valency presentation of a divalent galactoside 1, previously identified by us as an inhibitor of the adhesion of opportunistic fungal pathogen Candida albicans to buccal epithelial cells (BECs). Adhesion inhibition assays revealed that multivalent glycoconjugate 3 is more effective at blocking C. albicans adherence to BECs upon initial exposure to epithelial cells. Interestingly, 3 did not seem to have any effect when it was pre-incubated with yeast cells, in contrast to the original lead compound 1, which caused a 25% reduction of adhesion. In competition assays, where yeast cells and BECs were co-incubated, multivalent glycoconjugate 3 inhibited up to 49% C. albicans adherence in a dose-dependent manner. The combined effect of compound 1 towards both yeast cells and BECs allowed it to achieve over 60% inhibition of the adhesion of C. albicans to BECs in competition assays.
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Sohrabi-Jahromi, Salma, and Johannes Söding. "Thermodynamic modeling reveals widespread multivalent binding by RNA-binding proteins." Bioinformatics 37, Supplement_1 (July 1, 2021): i308—i316. http://dx.doi.org/10.1093/bioinformatics/btab300.
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Abstract Motivation Understanding how proteins recognize their RNA targets is essential to elucidate regulatory processes in the cell. Many RNA-binding proteins (RBPs) form complexes or have multiple domains that allow them to bind to RNA in a multivalent, cooperative manner. They can thereby achieve higher specificity and affinity than proteins with a single RNA-binding domain. However, current approaches to de novo discovery of RNA binding motifs do not take multivalent binding into account. Results We present Bipartite Motif Finder (BMF), which is based on a thermodynamic model of RBPs with two cooperatively binding RNA-binding domains. We show that bivalent binding is a common strategy among RBPs, yielding higher affinity and sequence specificity. We furthermore illustrate that the spatial geometry between the binding sites can be learned from bound RNA sequences. These discovered bipartite motifs are consistent with previously known motifs and binding behaviors. Our results demonstrate the importance of multivalent binding for RNA-binding proteins and highlight the value of bipartite motif models in representing the multivalency of protein-RNA interactions. Availability and implementation BMF source code is available at https://github.com/soedinglab/bipartite_motif_finder under a GPL license. The BMF web server is accessible at https://bmf.soedinglab.org. Supplementary information Supplementary data are available at Bioinformatics online.
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Chang, Ru-ying, William Tai, and Z. Fan. "Cytogenetic studies of aneuploids in rapeseed. II. Morphology, fertility, and cytology of self-pollinated progenies of monosomic plants of Brassica napus L." Genome 29, no. 1 (February 1, 1987): 174–79. http://dx.doi.org/10.1139/g87-030.
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Cytogenic studies were conducted on self-pollinated progenies from two monosomic lines of Brassica napus to ascertain the mode of transmission of the monosomic chromosome. An approximately 1:1 ratio of disomic to monosomic plants was obtained. Only one nullisomic plant was found among a total of 71 plants analyzed. The 1:1 ratio and the anaphase I disjunction (19–18) suggest that the gametes (n) were twice as competitive or functional as their counterpart (n − 1). Since quadrivalents were observed in the disomic plants and only trivalents in the monosomics, the monosomic chromosomes were believed to be the ones that were involved in the formation of multivalents. The percentage of multivalent association in monosomic plants was almost double that in disomic plants. In the disomic plants, an average of 11.96% of pollen mother cells had one to two quadri-valents. The average frequency of trivalents in the monosomics was 23.63%. It was suggested that pairing of these homologs was genetically controlled with a dosage effect. The absence of one chromosome increased the frequency of multivalents. Key words: monosomic, Brassica, rapeseed, aneuploid.
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White, J., G. Jenkins, and J. S. Parker. "Elimination of multivalents during meiotic prophase in Scilla autumnalis. I. Diploid and triploid." Genome 30, no. 6 (December 1, 1988): 930–39. http://dx.doi.org/10.1139/g88-149.
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The ultrastructure and pairing behaviour of the chromosomes of two diploid cytotypes and a triploid of Scilla autumnalis were investigated using the techniques of three-dimensional reconstruction from serial electron micrographs and whole-mount surface spreading of synaptonemal complexes. The diploids, designated AA and B7B7, have karyotypes that are virtually identical in appearance at mitotic metaphase but differ in length by 47% and in DNA content by 66%. All the chromosomes were identified during meiotic prophase in both diploids, enabling construction of accurate karyotypes, which were the same as those derived from root tip metaphases. Chromosome pairing was largely regular with very few structural chromosome rearrangements. These two observations permitted confident interpretations of multivalent configurations observed in polyploids containing multiples of the A and B7 genomes. In the triploid (AB7B7) during meiotic prophase lateral components are associated in groups of three, either as trivalents with several exchanges of pairing partners, or as bivalents and univalents in close alignment. The overall difference in length between A and B7 chromosomes is close to expected, but varies to some degree depending on the extent of pairing between the two chromosome types. Most of the synaptonemal complexes between A and B7 homoeologues are ineffective in terms of chiasma formation, as revealed by the low frequency of multivalents and heteromorphic bivalents at metaphase I. In other words, there is an elimination of multivalents during meiotic prophase in the triploid.Key words: Scilla autumnalis, synaptonemal complex, multivalents, elimination.
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Kostiainen, Mauri A, David K Smith, and Olli Ikkala. "Optically Triggered Release of DNA from Multivalent Dendrons by Degrading and Charge-Switching Multivalency." Angewandte Chemie 119, no. 40 (October 8, 2007): 7744–48. http://dx.doi.org/10.1002/ange.200701200.
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Kostiainen, Mauri A, David K Smith, and Olli Ikkala. "Optically Triggered Release of DNA from Multivalent Dendrons by Degrading and Charge-Switching Multivalency." Angewandte Chemie International Edition 46, no. 40 (October 8, 2007): 7600–7604. http://dx.doi.org/10.1002/anie.200701200.
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Helmer, Christine. "Trust and the Spirit: The Canon's Anticipated Unity." Journal of Theological Interpretation 1, no. 1 (2007): 61–77. http://dx.doi.org/10.2307/26421378.
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Abstract How can one talk responsibly and theologically about the biblical canon's unity in a pluralist age? In this article I explore a number of ways in which theological practice both appeals to and constructs the canon's unity. The argument of section one addresses biblical, not canonical, unity. I distinguish between the Bible as a given text composed of multivalent layers, individual texts, genres, and a plurality of content; and the canon as a theological concept, which is analytic with unity. The theological arguments of sections two and three situate the theological construction of the canon's unity in view of biblical multivalence. Some theological issues are at stake in this relation. Biblical multivalence opens up theological, philosophical, and ethical questions concerning how different proposals of the canon's unity can coexist, while each making claims to truth. Truth criteria—for example, coherence and comprehensiveness—can be worked out in order to determine the validity and viability of different theological proposals. A proposal must also be evaluated on the basis of its adequacy to contemporary concerns. The complex process of forming theological judgments about the canon's unity contextualizes the selection of one proposal of unity, among others, in a particular matrix of contemporary concerns. Hence, the unity of the canon is anticipatory in view of the process of articulating theological judgments in various contexts. I conclude by proposing that unity and multivalence can be grasped together in the intersubjective orientation to truth that takes place in trust, established by the Holy Spirit.
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Helmer, Christine. "Trust and the Spirit: The Canon's Anticipated Unity." Journal of Theological Interpretation 1, no. 1 (2007): 61–77. http://dx.doi.org/10.2307/jtheointe.1.1.0061.
Full textAbstract:
Abstract How can one talk responsibly and theologically about the biblical canon's unity in a pluralist age? In this article I explore a number of ways in which theological practice both appeals to and constructs the canon's unity. The argument of section one addresses biblical, not canonical, unity. I distinguish between the Bible as a given text composed of multivalent layers, individual texts, genres, and a plurality of content; and the canon as a theological concept, which is analytic with unity. The theological arguments of sections two and three situate the theological construction of the canon's unity in view of biblical multivalence. Some theological issues are at stake in this relation. Biblical multivalence opens up theological, philosophical, and ethical questions concerning how different proposals of the canon's unity can coexist, while each making claims to truth. Truth criteria—for example, coherence and comprehensiveness—can be worked out in order to determine the validity and viability of different theological proposals. A proposal must also be evaluated on the basis of its adequacy to contemporary concerns. The complex process of forming theological judgments about the canon's unity contextualizes the selection of one proposal of unity, among others, in a particular matrix of contemporary concerns. Hence, the unity of the canon is anticipatory in view of the process of articulating theological judgments in various contexts. I conclude by proposing that unity and multivalence can be grasped together in the intersubjective orientation to truth that takes place in trust, established by the Holy Spirit.
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Lukhtanov, Vladimir, and Alexander Dantchenko. "Karyotype of Polyommatus (Agrodiaetus) eriwanensis Forster, 1960 and taxonomic position of P. (A.) interjectus de Lesse, 1960 (Lepidoptera, Lycaenidae)." Comparative Cytogenetics 13, no. 4 (November 12, 2019): 359–66. http://dx.doi.org/10.3897/compcytogen.v13i4.46897.
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The karyotype of Polyommatus (Agrodiaetus) eriwanensis Forster, 1960 from the type locality (“Eriwan” [Yerevan, Armenia]) and other localities in Armenia was investigated. The number of chromosomal elements (bivalents+ multivalents) observed in male meiosis I was found to vary from 29 to 34. In individuals with n = 34, all observed elements were represented by bivalents. In other specimens, heterozygosity for different number of chromosomal fusions resulted in multivalent formation at MI stage and consequently in a lower number of recognizable chromosomal elements. We show that all karyotype peculiarities of P. (A.) interjectus de Lesse, 1960 (n = 29–32) from Turkey are similar to those in A. eriwanensis. The butterflies of these taxa have allopatric distribution and can be considered as conspecific.
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Staiber, Wolfgang. "Multivalent formation and pairing behavior of germ line limited chromosomes in male meiosis of Acricotopus lucidus (Diptera, Chironomidae)." Genome 32, no. 6 (December 1, 1989): 941–45. http://dx.doi.org/10.1139/g89-535.
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The pairing behavior of the germ line limited chromosomes of Acricotopus lucidus was investigated in male meiosis using G-banding. Each of the nine different types of limited chromosomes can be absent or can be present in metaphase I with two or four homologous chromosomes, one type even with up to 10. Usually the homologues form bivalents, but frequently quadrivalents and also hexavalents consisting of the same chromosome type were observed. In some cases multivalents composed of different limited chromosomes occurred. This resulted probably from pairing and crossing-over between hom(oe)ologous segments in otherwise nonhomologous chromosomes. The observations are discussed in relation to origin and diversity of the germ line limited chromosomes.Key words: germ line limited chromosomes, multivalent formation, male meiosis, Acricotopus lucidus.
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Kumar, P. S., and P. D. Walton. "Introgression of genes from Canada wildrye to slender wheatgrass: cytology and fertility of backcross progeny." Genome 35, no. 5 (October 1, 1992): 894–96. http://dx.doi.org/10.1139/g92-136.
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Partially fertile synthetic amphiploids (2n = 8x = 56) of Canada wildrye × slender wheatgrass F1 hybrid were crossed to slender wheatgrass and tetraploid lines resembling slender wheatgrass were recovered after four backcrosses. The BC1 progeny was hexaploid, while the BC2 and BC3 progenies were aneuploids with chromosome numbers ranging from 31 to 38. Tetraploid lines were recovered in the BC4 generation along with 29- and 30-chromosome types. Multivalents (mostly trivalents) resulting from intergenomic pairing were fequently encountered in BC1 and BC2 plants. The multivalent frequencies declined with each succeeding backcross. Pairing in the 28-chromosome BC4 plants was completely regular with 14 bivalents. Intergenomic pairing in the backcross progeny promoted introgression from Canada wildrye to slender wheatgrass.Key words: Elymus, intergenomic pairing, trivalents, recombination.
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Wallace, A. J., and R. S. Callow. "Meiotic variation in an intergenomic autopolyploid series. II. Pairing behaviour." Genome 38, no. 1 (February 1, 1995): 133–39. http://dx.doi.org/10.1139/g95-016.
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Pairing behaviour has been studied in PMCs of C0 autotetraploids of seven Lathyrus species exhibiting a range of genome size (10.8–19.9 pg DNA/2C). Each tetrasome within a C0 autotetraploid is equally likely to form a quadrivalent and the great majority of metaphase multivalents (96%) gave evidence of only a single synaptic exchange. Four components of variance in bivalent frequency were detected in the tetraploids. Both chiasma-dependent (0.5%) and chiasma-independent (4.2%) interspecific components were observed, whereas the only intraspecific component between plants (2.8%) was independent of variation in chiasma frequency. The only nonresidual component of variance in minimal incidence of synaptic exchange was interspecific (3.9%) and independent of variation in multivalent frequency.Key words: meiosis, chiasma frequency, autopolyploid, Lathyrus.
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Perumal, Suguna, Raji Atchudan, Eckart Rühl, and Christina Graf. "Controlled Synthesis of Platinum and Silver Nanoparticles Using Multivalent Ligands." Nanomaterials 12, no. 13 (July 4, 2022): 2294. http://dx.doi.org/10.3390/nano12132294.
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Here, the controlled formation of platinum nanoparticles (PtNPs) and silver nanoparticles (AgNPs) using amine-functionalized multivalent ligands are reported. The effects of reaction temperature and ligand multivalency on the growth kinetics, size, and shape of PtNPs and AgNPs were systematically studied by performing a stepwise and a one-step process. PtNPs and AgNPs were prepared in the presence of amine ligands using platinum (II) acetylacetonate and silver (I) acetylacetonate, respectively. The effects of ligands and temperature on the formation of PtNPs were studied using a transmission electron microscope (TEM). For the characterization of AgNPs, additionally, ultraviolet-visible (UV-Vis) absorption was employed. The TEM measurements revealed that PtNPs prepared at different temperatures (160–200 °C, in a stepwise process) are monodispersed and of spherical shape regardless of the ligand multivalency or reaction temperature. In the preparation of PtNPs by the one-step process, ligands affect the shape of the PtNPs, which can be explained by the affinity of the ligands. The TEM and UV-Vis absorption studies on the formation of AgNPs with mono-, di-, and trivalent ligands showed narrower size distributions, while increasing the temperature from 80 °C to 120 °C and with a trivalent ligand in a one-step process.
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Choudhary, Anushree, Liam Wright, Olga Ponce, Jing Chen, Ankush Prashar, Eugenio Sanchez-Moran, Zewei Luo, and Lindsey Compton. "Varietal variation and chromosome behaviour during meiosis in Solanum tuberosum." Heredity 125, no. 4 (June 10, 2020): 212–26. http://dx.doi.org/10.1038/s41437-020-0328-6.
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Abstract Naturally occurring autopolyploid species, such as the autotetraploid potato Solanum tuberosum, face a variety of challenges during meiosis. These include proper pairing, recombination and correct segregation of multiple homologous chromosomes, which can form complex multivalent configurations at metaphase I, and in turn alter allelic segregation ratios through double reduction. Here, we present a reference map of meiotic stages in diploid and tetraploid S. tuberosum using fluorescence in situ hybridisation (FISH) to differentiate individual meiotic chromosomes 1 and 2. A diploid-like behaviour at metaphase I involving bivalent configurations was predominant in all three tetraploid varieties. The crossover frequency per bivalent was significantly reduced in the tetraploids compared with a diploid variety, which likely indicates meiotic adaptation to the autotetraploid state. Nevertheless, bivalents were accompanied by a substantial frequency of multivalents, which varied by variety and by chromosome (7–48%). We identified possible sites of synaptic partner switching, leading to multivalent formation, and found potential defects in the polymerisation and/or maintenance of the synaptonemal complex in tetraploids. These findings demonstrate the rise of S. tuberosum as a model for autotetraploid meiotic recombination research and highlight constraints on meiotic chromosome configurations and chiasma frequencies as an important feature of an evolved autotetraploid meiosis.
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Jong, J. H. de, A. M. A. Wolters, J. M. Kok, H. Verhaar, and J. van Eden. "Chromosome pairing and potential for intergeneric recombination in some hypotetraploid somatic hybrids of Lycopersicon esculentum (+) Solanum tuberosum." Genome 36, no. 6 (December 1, 1993): 1032–41. http://dx.doi.org/10.1139/g93-138.
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Three somatic hybrids resulting from protoplast fusions of a diploid kanamycin-resistant line of tomato (Lycopersicon esculentum) and a dihaploid hygromycin-resistant transformant of a monohaploid potato (Solanum tuberosum) line were used for a cytogenetic study on chromosome pairing and meiotic recombination. Chromosome counts in root-tip meristem cells revealed two hypotetraploids with chromosome complements of 2n = 46 and one with 2n = 47. Electron microscope analyses of synaptonemal complex spreads of hypotonically burst protoplasts at mid prophase I showed abundant exchanges of pairing partners in multivalents involving as many as eight chromosomes. In the cells at late pachytene recombination nodules were found in multivalents on both sides of pairing partner exchanges, indicating recombination at both homologous and homoeologous sites. Light microscope observations of pollen mother cells at late diakinesis and metaphase I also revealed multivalents, though their occurrence in low frequencies betrays the reduction of multivalent number and complexity. Precocious separation of half bivalents at metaphase I and lagging of univalents at anaphase I were observed frequently. Bridges, which may result from an apparent inversion loop found in the synaptonemal complexes of a mid prophase I nucleus, were also quite common at anaphase I, though the expected accompanying fragments could be detected in only a few cells. Most striking were the high frequencies of first division restitution in preparations at metaphase II/anaphase II, giving rise to unreduced gametes. In spite of the expected high numbers of balanced haploid and diploid gametes, male fertility, as revealed by pollen staining, was found to be negligible.Key words: synaptonemal complex, recombination, chromosome pairing, somatic hybrid, Lycopersicon esculentum (+) Solanum tuberosum.
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Thomas, Huw M., and Barry J. Thomas. "Meiosis in triploid Lolium. I. Synaptonemal complex formation and chromosome configurations at metaphase I in aneuploid autotriploid L. multiflorum." Genome 37, no. 2 (April 1, 1994): 181–89. http://dx.doi.org/10.1139/g94-025.
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A spreading technique for synaptonemal complexes (SCs) was applied to pollen mother cells of two aneuploid genotypes of autotriploid Lolium multiflorum (2n = 3x + 1 = 22). In the earliest nuclei analyzed the axial elements are in six groups of 3 and one group of 4. Most groups have formed multivalents with from one to five pairing partner exchanges, but there are also groups that have formed bivalents and univalents. Some axial elements have formed triple associations, in one case for the length of the trivalent. Unsynapsed axial elements remain aligned with their homologous SCs into pachytene, but this alignment is abolished as these axes pair heterologously among themselves until the entire axial element complement is synapsed. At metaphase I most chromosomes are associated as trivalents and quadrivalents.Key words: Lolium, triploid, pairing partner exchange, chiasma, multivalent.
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Biswas, Koushik, Stephan Lany, and Alex Zunger. "The electronic consequences of multivalent elements in inorganic solar absorbers: Multivalency of Sn in Cu2ZnSnS4." Applied Physics Letters 96, no. 20 (May 17, 2010): 201902. http://dx.doi.org/10.1063/1.3427433.
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Dam, Tarun K., René Roy, Daniel Pagé, and C. Fred Brewer. "Negative Cooperativity Associated with Binding of Multivalent Carbohydrates to Lectins. Thermodynamic Analysis of the “Multivalency Effect”†." Biochemistry 41, no. 4 (January 2002): 1351–58. http://dx.doi.org/10.1021/bi015830j.
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Cecioni, Samy, Sophie Faure, Ulrich Darbost, Isabelle Bonnamour, Hélène Parrot-Lopez, Olivier Roy, Claude Taillefumier, et al. "Selectivity among Two Lectins: Probing the Effect of Topology, Multivalency and Flexibility of “Clicked” Multivalent Glycoclusters." Chemistry - A European Journal 17, no. 7 (January 5, 2011): 2146–59. http://dx.doi.org/10.1002/chem.201002635.
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Divine, Robby, Ha V. Dang, George Ueda, Jorge A. Fallas, Ivan Vulovic, William Sheffler, Shally Saini, et al. "Designed proteins assemble antibodies into modular nanocages." Science 372, no. 6537 (April 1, 2021): eabd9994. http://dx.doi.org/10.1126/science.abd9994.
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Multivalent display of receptor-engaging antibodies or ligands can enhance their activity. Instead of achieving multivalency by attachment to preexisting scaffolds, here we unite form and function by the computational design of nanocages in which one structural component is an antibody or Fc-ligand fusion and the second is a designed antibody-binding homo-oligomer that drives nanocage assembly. Structures of eight nanocages determined by electron microscopy spanning dihedral, tetrahedral, octahedral, and icosahedral architectures with 2, 6, 12, and 30 antibodies per nanocage, respectively, closely match the corresponding computational models. Antibody nanocages targeting cell surface receptors enhance signaling compared with free antibodies or Fc-fusions in death receptor 5 (DR5)–mediated apoptosis, angiopoietin-1 receptor (Tie2)–mediated angiogenesis, CD40 activation, and T cell proliferation. Nanocage assembly also increases severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pseudovirus neutralization by α-SARS-CoV-2 monoclonal antibodies and Fc–angiotensin-converting enzyme 2 (ACE2) fusion proteins.
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Tüű-Szabó, B., L. T. Kóczy, and M. Fuxreiter. "Simulations of Higher-Order Protein Organizations Using a Fuzzy Framework." Complexity 2018 (December 2, 2018): 1–10. http://dx.doi.org/10.1155/2018/6360846.
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Spatiotemporal regulation of the biochemical information is often linked to supramolecular organizations proteins and nucleic acids, the driving forces of which have yet to be elucidated. Although the critical role of multivalency in phase transition has been recognized, the organization principles of higher-order structures need to be understood. Here, we present a fuzzy mathematical framework to handle the heterogeneity of interactions patterns and the resultant multiplicity of conformational states in protein assemblies. In this model, redundant binding motifs can establish simultaneous and partial interactions with multiple targets. We demonstrate that these multivalent, weak contacts facilitate polymer formation, while recapitulating the observed valency-dependence. In addition, the impact of linker dynamics and motif binding affinity, as well as the interplay between the two effects was studied. Our results support that fuzziness is a critical factor in driving higher-order protein organizations, and this could be used as a general framework to simulate different kinds of supramolecular assemblies.
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Zhao, Jisi, Shuang Li, Yingying Jin, Jessica Wang, Wenjing Li, Wenjie Wu, and Zhangyong Hong. "Multimerization Increases Tumor Enrichment of Peptide–Photosensitizer Conjugates." Molecules 24, no. 4 (February 25, 2019): 817. http://dx.doi.org/10.3390/molecules24040817.
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Photodynamic therapy (PDT) is an established therapeutic modality for the management of cancers. Conjugation with tumor-specific small molecule ligands (e.g., short peptides or peptidomimetics) could increase the tumor targeting of PDT agents, which is very important for improving the outcome of PDT. However, compared with antibody molecules, small molecule ligands have a much weaker affinity to their receptors, which means that their tumor enrichment is not always ideal. In this work, we synthesized multimeric RGD ligand-coupled conjugates of pyropheophorbide-a (Pyro) to increase the affinity through multivalent and cluster effects to improve the tumor enrichment of the conjugates. Thus, the dimeric and trimeric RGD peptide-coupled Pyro conjugates and the monomeric one for comparison were efficiently synthesized via a convergent strategy. A short polyethylene glycol spacer was introduced between two RGD motifs to increase the distance required for multivalence. A subsequent binding affinity assay verified the improvement of the binding towards integrin αvβ3 receptors after the increase in the valence, with an approximately 20-fold improvement in the binding affinity of the trimeric conjugate compared with that of the monomeric conjugate. In vivo experiments performed in tumor-bearing mice also confirmed a significant increase in the distribution of the conjugates in the tumor site via multimerization, in which the trimeric conjugate had the best tumor enrichment compared with the other two conjugates. These results indicated that the multivalence interaction can obviously increase the tumor enrichment of RGD peptide-conjugated Pyro photosensitizers, and the prepared trimeric conjugate can be used as a novel antitumor photodynamic agent with high tumor enrichment.
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Aung, Taing, and P. D. Walton. "Cytology of triploid and pentaploid hybrids of Elymus trachycaulus × Pseudoroegneria spicata and P. spicata ssp. inermis." Genome 29, no. 3 (June 1, 1987): 470–80. http://dx.doi.org/10.1139/g87-082.
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Emasculated clones of tetraploid and octaploid Elymus trachycaulus crossed with Pseudoroegneria spicata yielded 69 triploids and 13 pentaploid hybrids. The triploid hybrids were morphologically intermediate between the parental species but the pentaploid hybrids resembled E. trachycaulus more closely than P. spicata. A very high degree of plant size variability (very weak to very vigorous) was observed among the 50 triploids that survived to maturity. The variability among the pentaploids, though apparent, was not high. Mean chromosome associations among the selected eight triploids varied from low multivalent formation at meiosis (7.60 I + 6.18 II + 0.24 III + 0.08 IV) to high multivalent-forming meiosis (7.28 I + 5.66 II + 0.32 III + 0.36 IV). The bivalent configurations in these triploids were attributed to homoeologous pairing between the S1 genome of P. spicata and S genomes of E. trachycaulus and the multivalents indicated intergenomal and intragenomal pairings. Mean chromosome associations of 5.22 I + 11.94 II + 1.97 III in 78.7% and 7 I + 14 II in 21.3% of the 150 cells were distributed among the three pentaploid hybrids. The low frequency of trivalents and the absence of multivalents higher than trivalent configurations suggest that homoeologous pairing was substantially reduced and there was no intergenomal and intragenomal pairing in these 2n = 35 x hybrids. Fourteen triploids and three pentaploid hybrids were produced from 4x and 8x forms of E. trachycaulus and P. spicata spp. inermis crosses. The triploids were intermediate between the parents but the pentaploids were more similar to E. trachycaulus. Mean chromosome associations in the triploids (6.020 I + 5.315 II + 0.554 III + 0.235 IV + 0.250 V + 0.048 VI + 0.03 VII) and in the pentaploids (3.50 I + 10.18 II + 3.54 III + 0.13 IV) indicated a very high degree of intergenomal and intragenomal pairing in the triploids; nevertheless, it was greatly reduced in the pentaploids. The Pseudoroegneria spicata ssp. inermis genome may have gene(s) that affect a high degree of intergenomal and intragenomal pairing in triploid hybrids with E. trachycaulus. However, in pentaploid hybrids (SS HH S2) the S and H genomes of E. trachycaulus in double dose seem to have restored its regular meiotic bahaviour, at least partially, and reduced homoeologous pairing as well as intergenomal and intragenomal pairing. Key words: Elymus trachycaulus, Pseudoroegneria spicata, regular meiotic behaviour, double dose, intergenomal pairing, intragenomal pairing.
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Singh, Ajay N., Wei Liu, Guiyang Hao, Amit Kumar, Anjali Gupta, Orhan K. Öz, Jer-Tsong Hsieh, and Xiankai Sun. "Multivalent Bifunctional Chelator Scaffolds for Gallium-68 Based Positron Emission Tomography Imaging Probe Design: Signal Amplification via Multivalency." Bioconjugate Chemistry 22, no. 8 (August 17, 2011): 1650–62. http://dx.doi.org/10.1021/bc200227d.
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Nelissen, Frank H. T., Wenny J. M. Peeters, Timo P. Roelofs, Anika Nagelkerke, Paul N. Span, and Hans A. Heus. "Improving Breast Cancer Treatment Specificity Using Aptamers Obtained by 3D Cell-SELEX." Pharmaceuticals 14, no. 4 (April 9, 2021): 349. http://dx.doi.org/10.3390/ph14040349.
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Three-dimensional spheroids of non-malignant MCF10A and malignant SKBR3 breast cells were used for subsequent 3D Cell-SELEX to generate aptamers for specific binding and treatment of breast cancer cells. Using 3D Cell-SELEX combined with Next-Generation Sequencing and bioinformatics, ten abundant aptamer families with specific structures were identified that selectively bind to SKBR3, and not to MCF10A cells. Multivalent aptamer polymers were synthesized by co-polymerization and analyzed for binding performance as well as therapeutic efficacy. Binding performance was determined by confocal fluorescence imaging and revealed specific binding and efficient internalization of aptamer polymers into SKBR3 spheroids. For therapeutic purposes, DNA sequences that intercalate the cytotoxic drug doxorubicin were co-polymerized into the aptamer polymers. Viability tests show that the drug-loaded polymers are specific and effective in killing SKBR3 breast cancer cells. Thus, the 3D-selected aptamers enhanced the specificity of doxorubicin against malignant over non-malignant breast cells. The innovative modular DNA aptamer platform based on 3D Cell SELEX and polymer multivalency holds great promise for diagnostics and treatment of breast cancer.
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Zhou, Shujun, Lei Zhong, Lu Zhang, Zhenghua Xu, Xuxin Liu, Kehu Li, and Guixue Zhou. "Study on the homology of the genomes of tetraploid Asiatic lilies (Lilium) using FISH." Genome 58, no. 11 (November 2015): 453–61. http://dx.doi.org/10.1139/gen-2015-0057.
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Asiatic lily cultivars, bred by hybridization and (or) chromosome doubling of species of section Sinomartagon of Lilium, are diploid, triploid, or tetraploid, but the homology of the genomes among species of section Sinomartagon and Asiatic lilies remains unclear. In the present research, two tetraploid Asiatic cultivars were analyzed, using 45S rDNA as probe, for their FISH karyotypes and their chromosomal association, anaphase I, telophase II, and pollen viability were surveyed to assess the multivalent segregation. Chromosomal assortment of six progenies of the two tetraploid cultivars were also investigated. The results showed that the tetraploid cultivars had similar FISH karyotypes, they predominantly formed multivalents, and these were equally separated because their anaphase I, telophase II, and pollen viability were similar to those of diploid species. Apart from minor variations, FISH karyotypes of progenies were similar to each other and to their parents. Based on these results and considering the high crossability among species of section Sinomartagon and (or) Asiatic lilies, we concluded that species of section Sinomartagon and their resulting cultivars share a common genome; thus, polyploidy Asiatic lilies are autopolyploid.