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Affinity maturation

Lining Ju, James D McFadyen, Saheb Al-Daher, Imala Alwis, Yunfeng Chen, Lotte L Tønnesen, Sophie Maiocchi, Brianna Coulter, Anna C Calkin, Eric I Felner, Neale Cohen, Yuping Yuan, Simone M Schoenwaelder, Mark E Cooper, Cheng Zhu, Shaun P Jackson
Diabetes is associated with an exaggerated platelet thrombotic response at sites of vascular injury. Biomechanical forces regulate platelet activation, although the impact of diabetes on this process remains ill-defined. Using a biomembrane force probe (BFP), we demonstrate that compressive force activates integrin αIIb β3 on discoid diabetic platelets, increasing its association rate with immobilized fibrinogen. This compressive force-induced integrin activation is calcium and PI 3-kinase dependent, resulting in enhanced integrin affinity maturation and exaggerated shear-dependent platelet adhesion...
March 14, 2018: Nature Communications
Laurie G Sherlock, Ashley Trumpie, Laura Hernandez-Lagunas, Sarah McKenna, Susan Fisher, Russell Bowler, Clyde J Wright, Cassidy Delaney, Eva Nozik-Grayck
BACKGROUND: A naturally occurring single nucleotide polymorphism (SNP), (R213 G), in extracellular superoxide dismutase (SOD3), decreases SOD3 matrix binding affinity. Humans and mature mice expressing the R213 G SNP exhibit increased cardiovascular disease but decreased lung disease. The impact of this SNP on the neonatal lung at baseline or with injury is unknown. METHODS: Wild type and homozygous R213 G mice were injected with intraperitoneal bleomycin or phosphate buffered saline (PBS) three times weekly for three weeks and tissue harvested at 22 days of life...
March 14, 2018: Antioxidants (Basel, Switzerland)
Emily C Sheppard, Rikke Brandstrup Morrish, Michael J Dillon, Rebecca Leyland, Richard Chahwan
Epigenetic modifications, such as histone modifications, DNA methylation status, and non-coding RNAs (ncRNA), all contribute to antibody maturation during somatic hypermutation (SHM) and class-switch recombination (CSR). Histone modifications alter the chromatin landscape and, together with DNA primary and tertiary structures, they help recruit Activation-Induced Cytidine Deaminase (AID) to the immunoglobulin (Ig) locus. AID is a potent DNA mutator, which catalyzes cytosine-to-uracil deamination on single-stranded DNA to create U:G mismatches...
2018: Frontiers in Immunology
Peng Zhang, Yu Liu, Min Wang, Miren Dong, Zhaoqun Liu, Zhihao Jia, Weilin Wang, Anguo Zhang, Lingling Wang, Linsheng Song
Iron-sulphur clusters (ISCs), one of the oldest and most versatile cofactors of proteins, are involved in catalysis reactions, electron transport reactions, regulation processes as well as sensing of ambient conditions. Iron-sulphur cluster assembly protein (IscA) is a scaffold protein member of ISC formation system, which plays a significant role in the assembly and maturation process of ISC proteins. In the present study, the cDNA sequence of iron-sulphur cluster assembly protein 2 (designated as EsIscA2) was cloned from Eriocheir sinensis...
March 9, 2018: Developmental and Comparative Immunology
Jacques Robert
Although the amphibian Xenopus laevis produces antibodies as diversified as those from mammals in the primary repertoire, antibody affinity maturation after immunization is relatively poor and has been associated with a poor B cell selection of AID-mediated hypermutations and lack of germinal centers in the spleen, the only secondary lymphoid organ of this amphibian. In this issue of the European Journal of Immunology, Neely et al., [Eur. J. Immunol. 2018. 48: 430-440] have unveiled the role of distinctive dendritic cell (DC) subset, XL cells, which have the capacity to acquire and retain native antigens for B cell maturation...
March 2018: European Journal of Immunology
Jiraprapa Wipasa, Romanee Chaiwarith, Kriangkrai Chawansuntati, Jutarat Praparattanapan, Kritsadee Rattanathammethee, Khuanchai Supparatpinyo
A major characteristic of immunodeficiency associated with life-threatening intracellular infection in adults is the presence of anti-interferon-γ antibodies. Although little is known about the mechanism underlying this syndrome, it is believed that the antibodies inhibit the activity of downstream signaling pathway of interferon-γ. In this study, the characteristics of these antibodies in patients who presented, or have a history of, intracellular infection and were positive to anti-interferon-γ antibodies were investigated...
January 1, 2018: Experimental Biology and Medicine
Pradipta Chakraborty, Laura Acquasaliente, Leslie A Pelc, Enrico Di Cera
Trypsin-like proteases are synthesized as zymogens and activated through a mechanism that folds the active site for efficient binding and catalysis. Ligand binding to the active site is therefore a valuable source of information on the changes that accompany zymogen activation. Using the physiologically relevant transition of the clotting zymogen prothrombin to the mature protease thrombin, we show that the mechanism of ligand recognition follows selection within a pre-existing ensemble of conformations with the active site accessible (E) or inaccessible (E*) to binding...
March 6, 2018: Scientific Reports
Damien Bonnard, Erwann Le Rouzic, Sylvia Eiler, Céline Amadori, Igor Orlov, Jean-Michel Bruneau, Julie Brias, Julien Barbion, Francis Chevreuil, Danièle Spehner, Sophie Chasset, Benoit Ledoussal, François Moreau, Ali Saïb, Bruno P Klaholz, Stéphane Emiliani, Marc Ruff, Alessia Zamborlini, Richard Benarous
Recently, a new class of HIV-1 integrase (IN) inhibitors with a dual mode of action, called IN-LEDGF/p75 allosteric inhibitors (INLAIs), was described. Designed to interfere with the INLEDGF/p75 interaction during viral integration, unexpectedly, their major impact was on virus maturation. This activity has been linked to induction of aberrant IN multimerization, while inhibition of the IN-LEDGF/p75 interaction accounts for weaker antiretroviral effect at integration. Since these dual activities result from INLAI binding to IN at a single binding site, we expected that these activities co-evolved together, driven by the affinity for IN...
March 5, 2018: Journal of Biological Chemistry
Dongfang Tang, Zhen Xiao, Yan Xu, Jiao Zeng, Dezheng Peng, Songping Liang, Cheng Tang, Zhonghua Liu
Spider venom is rich in peptide toxins that could be used to explore the structure and function of voltage-gated sodium channels (NaV s). This study has characterized a 44-amino acid peptide toxin, δ-hexatoxin-MrIX (δ-HXTX-MrIX), from the venom of the spider Macrothele raveni. δ-hexatoxin-MrIX potently inhibited the fast inactivation of NaV s in mouse cerebellar granule cells (CGCs) with an EC50 of 35.3 ± 5.9 nM. The toxin shifted both the steady-state activation and the steady-state inactivation curves of CGC NaV s to the hyperpolarized direction...
February 28, 2018: Peptides
Kyung-Ho Roh, Hannah W Song, Pallab Pradhan, Kevin Bai, Caitlin D Bohannon, Gordon Dale, Jardin Leleux, Joshy Jacob, Krishnendu Roy
B cells play a major role in the adaptive immune response by producing antigen-specific antibodies against pathogens and imparting immunological memory. Following infection or vaccination, antibody-secreting B cells and memory B cells are generated in specialized regions of lymph nodes and spleens, called germinal centers. Here, we report a fully synthetic ex-vivo system that recapitulates the generation of antigen-specific germinal-center (GC) like B cells using material-surface driven polyvalent signaling...
February 21, 2018: Biomaterials
Chen-Hao Yeh, Takuya Nojima, Masayuki Kuraoka, Garnett Kelsoe
B cells expressing high affinity antigen receptors are advantaged in germinal centers (GC), perhaps by increased acquisition of antigen for presentation to follicular helper T cells and improved T-cell help. In this model for affinity-dependent selection, the density of peptide/MHCII (pMHCII) complexes on GC B cells is the primary determinant of selection. Here we show in chimeric mice populated by B cells differing only in their capacity to express MHCII (MHCII+/+ and MHCII+/- ) that GC selection is insensitive to halving pMHCII density...
March 2, 2018: Nature Communications
Zhiheng Wang, Yan Li, Wenbin Liang, Junsong Zheng, Shuhui Li, Chuanmin Hu, An Chen
The hepatitis B virus (HBV) infection is a critical health problem worldwide, and HBV preS1 is an important biomarker for monitoring HBV infection. Previously, we found that a murine monoclonal antibody, mAb-D8, targets the preS1 (aa91-107) fragment of HBV. To improve its performance, we prepared the single-chain variable region of mAb-D8 (scFvD8) and constructed the three-dimensional structure of the scFvD8-preS1 (aa91-107) complex by computer modelling. The affinity of scFvD8 was markedly increased by the introduction of mutations L96Tyr to Ser and H98Asp to Ser...
March 1, 2018: Scientific Reports
Andrew C Phillips, Erwin R Boghaert, Kedar S Vaidya, Hugh D Falls, Michael J Mitten, Peter J DeVries, Lorenzo Benatuil, Chung-Ming Hsieh, Jonathan A Meulbroek, Sanjay C Panchal, Fritz G Buchanan, Kenneth R Durbin, Martin J Voorbach, David R Reuter, Sarah R Mudd, Lise I Loberg, Sherry L Ralston, Diana Cao, Hui K Gan, Andrew M Scott, Edward B Reilly
Depatuxizumab mafodotin (depatux-m, ABT-414) is a tumor-selective antibody drug conjugate (ADC) comprised of the anti-EGFR antibody ABT-806 and the monomethyl auristatin F (MMAF) warhead. Depatux-m has demonstrated promising clinical activity in glioblastoma multiforme (GBM) patients and is currently being evaluated in clinical trials in first-line and recurrent GBM disease settings. Depatux-m responses have been restricted to patients with amplified EGFR highlighting the need for therapies with activity against tumors with non-amplified EGFR overexpression...
February 26, 2018: Molecular Cancer Therapeutics
Giovanna Liguori, Caterina Squillacioti, Loredana Assisi, Alessandra Pelagalli, Alfredo Vittoria, Anna Costagliola, Nicola Mirabella
BACKGROUND: Cryptorchidism is one of the most common birth disorders of the male reproductive system identified in dogs and other mammals. This condition is characterised by the absence of one (unilateral) or both (bilateral) gonads from the scrotum. The peptides orexin A (OxA) and B (OxB) were obtained by post-transcriptional proteolytic cleavage of a precursor molecule, called prepro-orexin. These substances bind two types of G-coupled receptors called receptor 1 (OX1R) and 2 (OX2R) for orexins...
February 27, 2018: BMC Veterinary Research
Elodie Choque, Claudia Schneider, Olivier Gadal, Christophe Dez
Ribosome biogenesis requires more than 200 trans-acting factors to achieve the correct production of the two mature ribosomal subunits. Here, we have identified Efg1 as a novel, nucleolar ribosome biogenesis factor in Saccharomyces cerevisiae that is directly linked to the surveillance of pre-40S particles. Depletion of Efg1 impairs early pre-rRNA processing, leading to a strong decrease in 18S rRNA and 40S subunit levels and an accumulation of the aberrant 23S rRNA. Using Efg1 as bait, we revealed a novel degradation pathway of the 23S rRNA...
February 22, 2018: Nucleic Acids Research
Wenshuai Liu, Haipeng Song, Quan Chen, Jianli Yu, Mo Xian, Rui Nian, Dongxiao Feng
Nanobodies represent the next-generation antibody-derived biologics with significant advances over conventional antibodies. Several rapid and robust techniques for isolating highly specific nanobodies have been developed. Antigen specific nanobodies are selected from constructed nanobody libraries, which can be classified into 3 main types: immune library, naïve library, and semisynthetic/synthetic library. The immune library is the most widely used strategy for nanobody screening. Target specific nanobodies are highly enriched in immune libraries than in non-immune libraries; however, it is largely limited by the natural antigenicity of antigens...
February 22, 2018: Molecular Immunology
Lloyd Fricker
Peptidomic techniques are powerful tools to identify peptides in a biological sample. This protocol describes a targeted peptidomic approach that uses affinity chromatography to purify peptides that are substrates of carboxypeptidase E (CPE), an enzyme present in the secretory pathway of neuroendocrine cells. Many CPE products function as neuropeptides and/or peptide hormones, and therefore represent an important subset of the peptidome. Because CPE removes C-terminal Lys and Arg residues from peptide-processing intermediates, organisms lacking CPE show a large decrease in the levels of the mature forms of most neuropeptides and peptide hormones, and a very large increase in the levels of the processing intermediates that contain C-terminal Lys and/or Arg (i...
2018: Methods in Molecular Biology
Munir Akkaya, Billur Akkaya, Ann S Kim, Pietro Miozzo, Haewon Sohn, Mirna Pena, Alexander S Roesler, Brandon P Theall, Travis Henke, Juraj Kabat, Jinghua Lu, David W Dorward, Eric Dahlstrom, Jeff Skinner, Louis H Miller, Susan K Pierce
Key events in T cell-dependent antibody responses, including affinity maturation, are dependent on the B cell's presentation of antigen to helper T cells at critical checkpoints in germinal-center formation in secondary lymphoid organs. Here we found that signaling via Toll-like receptor 9 (TLR9) blocked the ability of antigen-specific B cells to capture, process and present antigen and to activate antigen-specific helper T cells in vitro. In a mouse model in vivo and in a human clinical trial, the TLR9 agonist CpG enhanced the magnitude of the antibody response to a protein vaccine but failed to promote affinity maturation...
February 23, 2018: Nature Immunology
Zhuo Yang, Mingjuan Du, Wei Wang, Xiu Xin, Peixiang Ma, Hongkai Zhang, Richard A Lerner
It has been observed that converting scFv formatted antibodies to full-length IgG often associates with loss of affinity. We aim to address this issue in this paper by establishing an integrated affinity maturation method applying yeast display technology platform. To demonstrate that, we employed a human thrombopoietin receptor targeting antibody named 3D9 which was identified previously from a combinational antibody library in scFv-Fc fusion protein form. We have observed that significant potency loss happened when 3D9 was transformed to full-length IgG form...
February 21, 2018: Protein Engineering, Design & Selection: PEDS
William S DeWitt, Luka Mesin, Gabriel D Victora, Vladimir N Minin, Frederick A Matsen
Modern biological techniques enable very dense genetic sampling of unfolding evolutionary histories, and thus frequently sample some genotypes multiple times. This motivates strategies to incorporate genotype abundance information in phylogenetic inference. In this paper, we synthesize a stochastic process model with standard sequence-based phylogenetic optimality, and show that tree estimation is substantially improved by doing so. Our method is validated with extensive simulations and an experimental single-cell lineage tracing study of germinal center B cell receptor affinity maturation...
February 20, 2018: Molecular Biology and Evolution
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