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https://www.readbyqxmd.com/read/28818832/b-cell-ox40l-supports-t-follicular-helper-cell-development-and-contributes-to-sle-pathogenesis
#1
Andrea Cortini, Ursula Ellinghaus, Talat H Malik, Deborah S Cunningham Grahman, Marina Botto, Timothy James Vyse
OBJECTIVES: TNFSF4 (encodes OX40L) is a susceptibility locus for systemic lupus erythematosus (SLE). Risk alleles increase TNFSF4 expression in cell lines, but the mechanism linking this effect to disease is unclear, and the OX40L-expressing cell types mediating the risk are not clearly established. Blockade of OX40L has been demonstrated to reduce disease severity in several models of autoimmunity, but not in SLE. We sought to investigate its potential therapeutic role in lupus. METHODS: We used a conditional knockout mouse system to investigate the function of OX40L on B and T lymphocytes in systemic autoimmunity...
August 17, 2017: Annals of the Rheumatic Diseases
https://www.readbyqxmd.com/read/28801913/design-of-synthetic-promoters-for-gene-circuits-in-mammalian-cells
#2
Pratik Saxena, Daniel Bojar, Martin Fussenegger
Synthetic biology, the synthesis of engineering and biology, has rapidly matured and has dramatically increased the complexity of artificial gene circuits in recent years. The deployment of intricate synthetic gene circuits in mammalian cells requires the establishment of very precise and orthogonal control of transgene expression. In this chapter, we describe methods of modulating the expression of transgenes at the transcriptional level. Using cAMP-response element-binding protein (CREB)-dependent promoters as examples, a tool for the precise tuning of gene expression by using different core promoters and by varying the binding affinity of transcription factor operator sites is described...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28799584/molecular-determinants-involved-in-differential-behaviour-between-soluble-tissue-factor-and-full-length-tissue-factor-towards-factor-viia
#3
Ramesh Prasad, Prosenjit Sen
During blood-coagulation, the transmembrane protein tissue factor (TF) binds to its ligand, factor (F)VII, activating and allosterically modifying it to form a mature active binary complex (TF-FVIIa). Although the extracellular domain of TF (sTF) can bind to FVII, it fails to activate it. Binding of TF with FVIIa only partially enhances FVIIa proteolytic activity. Our previous kinetic study revealed that sTF has a lower binding capacity with FVIIa compared to membrane bound full-length (fl)TF. The reason behind this incapability of FVII activation and reduced catalytic activity remains unexplored due to the lack of an flTF crystal structure...
August 11, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28796568/contribution-of-human-smooth-muscle-cells-to-amyloid-angiopathy-in-al-light-chain-amyloidosis
#4
Moiz Vora, Christopher G Kevil, Guillermo A Herrera
OBJECTIVE: Amyloid light-chain (AL) amyloidosis is a disease process that often compromises the peripheral vascular system and leads to systemic end-organ dysfunction. Although amyloid formation in vessel walls is a multifaceted process, the assembly of the native light chains (LCs) into amyloid fibrils is central to its pathogenesis. Recent evidence suggests that endocytosis and endolysosomal processing of immunoglobin LCs by host cells is essential to the formation of amyloid fibrils that are deposited in at least some tissues...
August 10, 2017: Ultrastructural Pathology
https://www.readbyqxmd.com/read/28792244/a-novel-%C3%AE-v%C3%AE-3-ligand-modified-hpma-copolymers-for-anticancer-drug-delivery
#5
Fengling Wang, Lian Li, Wei Sun, Lijia Li, Yuanyuan Liu, Yuan Huang, Zhou Zhou
The integrin αVβ3 receptor emerged as one of the most promising targets owing to its high expression on the surface of various malignant tumor cells and tumor angiogenesis endothelial cells, but with little expression in mature endothelial cells and the majority of normal cells. Here we report a new targeting ligand FQSIYPpIK (FQS) with high affinity to integrin αVβ3 receptor. To take the advantage of the particular interaction between FQS and integrin αVβ3 receptor, FQS was linked to N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers...
August 9, 2017: Journal of Drug Targeting
https://www.readbyqxmd.com/read/28789584/monoclonal-antibodies-technologies-for-early-discovery-and-engineering
#6
Patrick J Kennedy, Carla Oliveira, Pedro L Granja, Bruno Sarmento
Antibodies are essential in modern life sciences biotechnology. Their architecture and diversity allow for high specificity and affinity to a wide array of biochemicals. Combining monoclonal antibody (mAb) technology with recombinant DNA and protein expression links antibody genotype with phenotype. Yet, the ability to select and screen for high affinity binders from recombinantly-displayed, combinatorial libraries unleashes the true power of mAbs and a flood of clinical applications. The identification of novel antibodies can be accomplished by a myriad of in vitro display technologies from the proven (e...
August 8, 2017: Critical Reviews in Biotechnology
https://www.readbyqxmd.com/read/28781232/multivalent-recruitment-of-human-argonaute-by-gw182
#7
Elad Elkayam, Christopher R Faehnle, Marjorie Morales, Jingchuan Sun, Huilin Li, Leemor Joshua-Tor
In miRNA-mediated gene silencing, the physical interaction between human Argonaute (hAgo) and GW182 (hGW182) is essential for facilitating the downstream silencing of the targeted mRNA. GW182 can interact with hAgo via three of the GW/WG repeats in its Argonaute-binding domain: motif-1, motif-2, and the hook motif. The structure of hAgo1 in complex with the hook motif of hGW182 reveals a "gate"-like interaction that is critical for GW182 docking into one of hAgo1's tryptophan-binding pockets. We show that hAgo1 and hAgo2 have a single GW182-binding site and that miRNA binding increases hAgo's affinity to GW182...
August 17, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28759640/t-dependent-b-cell-responses-to-plasmodium-induce-antibodies-that-form-a-high-avidity-multivalent-complex-with-the-circumsporozoite-protein
#8
Camilla R Fisher, Henry J Sutton, Joe A Kaczmarski, Hayley A McNamara, Ben Clifton, Joshua Mitchell, Yeping Cai, Johanna N Dups, Nicholas J D'Arcy, Mandeep Singh, Aaron Chuah, Thomas S Peat, Colin J Jackson, Ian A Cockburn
The repeat region of the Plasmodium falciparum circumsporozoite protein (CSP) is a major vaccine antigen because it can be targeted by parasite neutralizing antibodies; however, little is known about this interaction. We used isothermal titration calorimetry, X-ray crystallography and mutagenesis-validated modeling to analyze the binding of a murine neutralizing antibody to Plasmodium falciparum CSP. Strikingly, we found that the repeat region of CSP is bound by multiple antibodies. This repeating pattern allows multiple weak interactions of single FAB domains to accumulate and yield a complex with a dissociation constant in the low nM range...
July 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28759213/design-and-evolution-of-a-macrocyclic-peptide-inhibitor-of-the-sonic-hedgehog-patched-interaction
#9
Andrew E Owens, Ivan de Paola, William A Hansen, Yi-Wen Liu, Sagar D Khare, Rudi Fasan
The Hedgehog (Hh) signaling pathway plays a central role during embryonic development and its aber-rant activation has been implicated in the development and progression of several human cancers. Ma-jor efforts toward the identification of chemical modulators of the Hedgehog pathway has yielded sev-eral antagonists of the GPCR-like Smoothened receptor. In contrast, potent inhibitors of the Sonic Hedgehog/Patched interaction, the most upstream event in ligand-induced activation of this signaling pathway, have been elusive...
July 31, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28750813/methods-for-the-development-of-in-silico-gpcr-models
#10
Paula Morales, Dow P Hurst, Patricia H Reggio
The Reggio group has constructed computer models of the inactive and G-protein-activated states of the cannabinoid CB1 and CB2 receptors, as well as, several orphan receptors that recognize a subset of cannabinoid compounds, including GPR55 and GPR18. These models have been used to design ligands, mutations, and covalent labeling studies. The resultant second-generation models have been used to design ligands with improved affinity, efficacy, and subtype selectivity. Herein, we provide a guide for the development of GPCR models using the most recent orphan receptor studied in our lab, GPR3...
2017: Methods in Enzymology
https://www.readbyqxmd.com/read/28747530/sequence-intrinsic-somatic-mutation-mechanisms-contribute-to-affinity-maturation-of-vrc01-class-hiv-1-broadly-neutralizing-antibodies
#11
Joyce K Hwang, Chong Wang, Zhou Du, Robin M Meyers, Thomas B Kepler, Donna Neuberg, Peter D Kwong, John R Mascola, M Gordon Joyce, Mattia Bonsignori, Barton F Haynes, Leng-Siew Yeap, Frederick W Alt
Variable regions of Ig chains provide the antigen recognition portion of B-cell receptors and derivative antibodies. Ig heavy-chain variable region exons are assembled developmentally from V, D, J gene segments. Each variable region contains three antigen-contacting complementarity-determining regions (CDRs), with CDR1 and CDR2 encoded by the V segment and CDR3 encoded by the V(D)J junction region. Antigen-stimulated germinal center (GC) B cells undergo somatic hypermutation (SHM) of V(D)J exons followed by selection for SHMs that increase antigen-binding affinity...
July 26, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28744287/ccr6-deficiency-impairs-iga-production-and-dysregulates-antimicrobial-peptide-production-altering-the-intestinal-flora
#12
Ya-Lin Lin, Peng-Peng Ip, Fang Liao
Intestinal immunity exists as a complex relationship among immune cells, epithelial cells, and microbiota. CCR6 and its ligand-CCL20 are highly expressed in intestinal mucosal tissues, such as Peyer's patches (PPs) and isolated lymphoid follicles (ILFs). In this study, we investigated the role of the CCR6-CCL20 axis in intestinal immunity under homeostatic conditions. CCR6 deficiency intrinsically affects germinal center reactions in PPs, leading to impairments in IgA class switching, IgA affinity, and IgA memory B cell production and positioning in PPs, suggesting an important role for CCR6 in T-cell-dependent IgA generation...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28743631/molecular-characterization-and-functional-analysis-of-the-hepcidin-gene-from-roughskin-sculpin-trachidermus-fasciatus
#13
Yingying Liu, Xiaodi Han, Xuezhao Chen, Shanshan Yu, Yingmei Chai, Tongjie Zhai, Qian Zhu
Hepcidin is a kind of cysteine-rich antimicrobial peptide that plays a vital role in host innate immune activity and iron regulation. Here, we report the molecular characterization and functional analysis of a novel hamp1 hepcidin isoforms Tf-Hep from roughskin sculpin, Trachidermus fasciatus. A cDNA fragment of 988 bp with an ORF of 273 bp was obtained. The coding sequence encodes for a signal peptide of 24 amino acids coupled with a prodomain of 40 amino acids and a mature peptide of 26 amino acids. Tissue distribution analysis indicated that Tf-Hep was most abundant in the liver...
July 22, 2017: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/28738289/germinal-center-enhancement-by-extended-antigen-availability
#14
REVIEW
Kimberly M Cirelli, Shane Crotty
Vaccine elicitation of protective antibody responses has proved difficult for a number of important human pathogens, including HIV-1. The amount of somatic hypermutation associated with the development of broadly neutralizing antibodies against HIV has not been achieved using conventional immunization strategies. An underexplored aspect of vaccine design is modulation of antigen kinetics. Immunization strategies with extended antigen availability have recently been shown to enhance humoral responses. In this review, we explore the mechanisms through which sustained antigen availability can enhance germinal center responses and the potency of antibody responses...
July 21, 2017: Current Opinion in Immunology
https://www.readbyqxmd.com/read/28713775/salivary-tick-cystatin-omc2-targets-lysosomal-cathepsins-s-and-c-in-human-dendritic-cells
#15
Tina Zavašnik-Bergant, Robert Vidmar, Andreja Sekirnik, Marko Fonović, Jiří Salát, Lenka Grunclová, Petr Kopáček, Boris Turk
To ensure successful feeding tick saliva contains a number of inhibitory proteins that interfere with the host immune response and help to create a permissive environment for pathogen transmission. Among the potential targets of the salivary cystatins are two host cysteine proteases, cathepsin S, which is essential for antigen- and invariant chain-processing, and cathepsin C (dipeptidyl peptidase 1, DPP1), which plays a critical role in processing and activation of the granule serine proteases. Here, the effect of salivary cystatin OmC2 from Ornithodoros moubata was studied using differentiated MUTZ-3 cells as a model of immature dendritic cells of the host skin...
2017: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/28710641/a-ligand-binding-assay-to-measure-the-affinity-and-specificity-of-sterol-binding-proteins-in-vitro
#16
Rabih Darwiche, Roger Schneiter
Sterols are major constituents of the plasma membrane of eukaryotic cells and serve as a precursor for several classes of signaling molecules, including steroids and hydroxy sterols. They maintain the functionality and permeability barrier of the plasma membrane through lipid-lipid and lipid-protein interactions. The S. cerevisiae pathogen-related yeast proteins 1, 2, and 3 (Pry) belong to a large protein superfamily known as CAP/SCP/TAPS. Members of this superfamily have been implicated in a wide variety of processes, including immune defense in mammals and plants, pathogen virulence, sperm maturation and fertilization, venom toxicity, and prostate and brain cancer...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28701402/increased-durable-b-cell-and-adcc-responses-associated-with-t-helper-responses-to-hiv-1-envelope-in-macaques-vaccinated-with-gp140-occluded-at-the-cd4-receptor-binding-site
#17
Willy M J M Bogers, Susan W Barnett, Herman Oostermeijer, Ivonne G Nieuwenhuis, Niels Beenhakker, Daniella Mortier, Petra Mooij, Gerrit Koopman, Edmund Remarque, Gregoire Martin, Rachel Pei-Jen Lai, Antu K Dey, Yide Sun, Brian Burke, Guido Ferrari, David Montefiori, Loic Martin, David Davis, Indresh Srivastava, Jonathan L Heeney
Strategies are needed to improve the immunogenicity of HIV-1 envelope (Env) antigens for more long lived, efficacious HIV-1 vaccine induced B-cell responses. HIV-1 Env gp140 (native or un-cleaved molecules) or gp120 monomeric proteins elicit relatively poor B-cell responses which are short-lived. We hypothesized that Env engagement of the CD4 receptor on T-helper cells may result in anergic effects on T-cell recruitment and consequently a lack of strong robust and durable B-memory responses. To test this hypothesis we occluded the CD4 binding site (CD4bs) of gp140 by stable cross-linking with a 3kD CD4 miniprotein mimetic serving to block ligation of gp140 on CD4+T-cells while preserving CD4 inducible (CDi) neutralizing and epitopes targeted by antibody dependent cellular cytotoxic (ADCC) effector responses...
July 12, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28698213/gene-expression-profiles-of-brain-endothelial-cells-during-embryonic-development-at-bulk-and-single-cell-levels
#18
Mike Hupe, Minerva Xueting Li, Susanne Kneitz, Daria Davydova, Chika Yokota, Julianna Kele-Olovsson, Belma Hot, Jan M Stenman, Manfred Gessler
The blood-brain barrier is a dynamic interface that separates the brain from the circulatory system, and it is formed by highly specialized endothelial cells. To explore the molecular mechanisms defining the unique nature of vascular development and differentiation in the brain, we generated high-resolution gene expression profiles of mouse embryonic brain endothelial cells using translating ribosome affinity purification and single-cell RNA sequencing. We compared the brain vascular translatome with the vascular translatomes of other organs and analyzed the vascular translatomes of the brain at different time points during embryonic development...
July 11, 2017: Science Signaling
https://www.readbyqxmd.com/read/28696509/an-l-rna-aptamer-with-expanded-chemical-functionality-that-inhibits-microrna-biogenesis
#19
Adam Michael Kabza, Jonathan Thomas Sczepanski
In order to facilitate isolation of L-aptamers with novel RNA-binding properties, we have employed a cationic nucleotide, 5-aminoallyl-uridine, during the mirror image in vitro selection process. In this effort, we identified a modified L-RNA aptamer (MLRA) capable of binding oncogenic pre-miR-19a with exceptional affinity, and we show that the cationic modification is absolutely critical for binding. Furthermore, formation of the MLRA-pre-miR-19a complex inhibits Dicer-mediated cleavage of the pre-miR, thus blocking formation of the mature functional microRNA...
July 11, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28696260/biophysical-analysis-of-arabidopsis-protein-only-rnase-p-alone-and-in-complex-with-trna-provides-a-refined-model-of-trna-binding
#20
Franziska Pinker, Cédric Schelcher, Pablo Fernández-Millán, Anthony Gobert, Catherine Birck, Aurélien Thureau, Pierre Roblin, Philippe Giegé, Claude Sauter
RNase P is a universal enzyme that removes 5' leader sequences from tRNA precursors. The enzyme is therefore essential for maturation of functional tRNAs and mRNA translation. RNase P represents a unique example of an enzyme that can occur either as ribonucleoprotein or as protein alone. The latter form of the enzyme called PRORP (PRotein-Only RNase P) is widespread in eukaryotes, in which it can provide organellar or nuclear RNase P activities. Here, we have focused on Arabidopsis nuclear PRORP2 and its interaction with tRNA substrates...
July 10, 2017: Journal of Biological Chemistry
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