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Affinity maturation

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https://www.readbyqxmd.com/read/28323137/defects-in-chondrocyte-maturation-and-secondary-ossification-in-mouse-knee-joint-epiphyses-due-to-snorc-deficiency
#1
J Heinonen, F-P Zhang, C Surmann-Schmitt, S Honkala, M Stock, M Poutanen, A-M Säämänen
OBJECTIVE: The role of Snorc, a novel cartilage specific transmembrane proteoglycan, was studied during skeletal development using two Snorc knockout mouse models. Hypothesizing that Snorc, like the other transmembrane proteoglycans, may be a coreceptor, we also studied its interaction with growth factors. METHODS: Skeletal development was studied in wild type and Snorc knockout mice during postnatal development by whole mount staining, X-ray imaging, histomorphometry, immunohistochemistry and qRT-PCR...
March 17, 2017: Osteoarthritis and Cartilage
https://www.readbyqxmd.com/read/28322543/titratable-avidity-reduction-enhances-affinity-discrimination-in-mammalian-cellular-selections-of-yeast-displayed-ligands
#2
Lawrence A Stern, Cliff M Csizmar, Daniel R Woldring, Carston R Wagner, Benjamin J Hackel
Yeast surface display selections against mammalian cell monolayers have proven effective in isolating proteins with novel binding activity. Recent advances in this technique allow for recovery of clones with even micromolar binding affinity. However, no efficient method has been shown for affinity based selection in this context. This study demonstrates the effectiveness of titratable avidity reduction using dithiothreitol (DTT) to achieve this goal. A series of epidermal growth factor receptor binding fibronectin domains with a range of affinities are used to quantitatively identify the number of ligands per yeast cell that yield the strongest selectivity between strong, moderate, and weak affinities...
March 21, 2017: ACS Combinatorial Science
https://www.readbyqxmd.com/read/28321219/computational-model-reveals-limited-correlation-between-germinal-center-b-cell-subclone-abundancy-and-affinity-implications-for-repertoire-sequencing
#3
Polina Reshetova, Barbera D C van Schaik, Paul L Klarenbeek, Marieke E Doorenspleet, Rebecca E E Esveldt, Paul-Peter Tak, Jeroen E J Guikema, Niek de Vries, Antoine H C van Kampen
Immunoglobulin repertoire sequencing has successfully been applied to identify expanded antigen-activated B-cell clones that play a role in the pathogenesis of immune disorders. One challenge is the selection of the Ag-specific B cells from the measured repertoire for downstream analyses. A general feature of an immune response is the expansion of specific clones resulting in a set of subclones with common ancestry varying in abundance and in the number of acquired somatic mutations. The expanded subclones are expected to have BCR affinities for the Ag higher than the affinities of the naive B cells in the background population...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28319730/deconstructing-the-germinal-center-one-cell-at-a-time
#4
REVIEW
Chad R Dufaud, Louise J McHeyzer-Williams, Michael G McHeyzer-Williams
Successful vaccination relies on driving the immune response towards high specificity, affinity and longevity. Germinal centers facilitate the evolution of antigen-specific B cells by iterative rounds of diversification, selection, and differentiation to memory and plasma cells. Experimental evidence points to B cell receptor affinity and amount of antigen presented to follicular helper T cells as main drivers of clonal evolution. Concurrent studies suggest that modifiers of cognate contact, temporal mechanisms, and stochastic factors can also shape diversity and influence differentiation to memory and plasma cells, but molecular pathways driving these selection decisions are unresolved...
March 17, 2017: Current Opinion in Immunology
https://www.readbyqxmd.com/read/28298600/dengue-virus-ns2b-ns3-protease-inhibitors-exploiting-the-prime-side
#5
Kuan-Hung Lin, Akbar Ali, Linah Rusere, Djade I Soumana, Nese Kurt Yilmaz, Celia A Schiffer
The mosquito-transmitted dengue virus (DENV) infects millions of people in tropical and sub-tropical regions. Maturation of DENV particles requires proper cleavage of the viral polyprotein, including processing 8 of the 13 substrate cleavage sites by dengue NS2B-S3 protease. With no available direct-acting antiviral targeting DENV, NS2-S3 protease is a promising target for inhibitor design. Current design efforts focus on the nonprime side of the DENV protease active site, resulting in highly hydrophilic and nonspecific scaffolds...
March 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28298420/staged-induction-of-hiv-1-glycan-dependent-broadly-neutralizing-antibodies
#6
Mattia Bonsignori, Edward F Kreider, Daniela Fera, R Ryan Meyerhoff, Todd Bradley, Kevin Wiehe, S Munir Alam, Baptiste Aussedat, William E Walkowicz, Kwan-Ki Hwang, Kevin O Saunders, Ruijun Zhang, Morgan A Gladden, Anthony Monroe, Amit Kumar, Shi-Mao Xia, Melissa Cooper, Mark K Louder, Krisha McKee, Robert T Bailer, Brendan W Pier, Claudia A Jette, Garnett Kelsoe, Wilton B Williams, Lynn Morris, John Kappes, Kshitij Wagh, Gift Kamanga, Myron S Cohen, Peter T Hraber, David C Montefiori, Ashley Trama, Hua-Xin Liao, Thomas B Kepler, M Anthony Moody, Feng Gao, Samuel J Danishefsky, John R Mascola, George M Shaw, Beatrice H Hahn, Stephen C Harrison, Bette T Korber, Barton F Haynes
A preventive HIV-1 vaccine should induce HIV-1-specific broadly neutralizing antibodies (bnAbs). However, bnAbs generally require high levels of somatic hypermutation (SHM) to acquire breadth, and current vaccine strategies have not been successful in inducing bnAbs. Because bnAbs directed against a glycosylated site adjacent to the third variable loop (V3) of the HIV-1 envelope protein require limited SHM, the V3-glycan epitope is an attractive vaccine target. By studying the cooperation among multiple V3-glycan B cell lineages and their coevolution with autologous virus throughout 5 years of infection, we identify key events in the ontogeny of a V3-glycan bnAb...
March 15, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28298303/ampa-receptor-mediated-rapid-epscs-in-vestibular-calyx-afferents
#7
Matthew Edward Kirk, Frances L Meredith, Tim A Benke, Katherine J Rennie
In the vestibular periphery neurotransmission between hair cells and primary afferent nerves occurs via specialized ribbon synapses. Type I vestibular hair cells (HCI) make synaptic contacts with calyx terminals, which enclose most of the HCI basolateral surface. To probe synaptic transmission, whole cell patch clamp recordings were made from calyx afferent terminals isolated together with their mature HCI from gerbil crista. Neurotransmitter release was measured as excitatory postsynaptic currents (EPSCs) in voltage clamp...
March 15, 2017: Journal of Neurophysiology
https://www.readbyqxmd.com/read/28297661/t-follicular-helper-cells-promote-a-beneficial-gut-ecosystem-for-host-metabolic-homeostasis-by-sensing-microbiota-derived-extracellular-atp
#8
Lisa Perruzza, Giorgio Gargari, Michele Proietti, Bruno Fosso, Anna Maria D'Erchia, Caterina Elisa Faliti, Tanja Rezzonico-Jost, Daniela Scribano, Laura Mauri, Diego Colombo, Giovanni Pellegrini, Annalisa Moregola, Catherine Mooser, Graziano Pesole, Mauro Nicoletti, Giuseppe Danilo Norata, Markus B Geuking, Kathy D McCoy, Simone Guglielmetti, Fabio Grassi
The ATP-gated ionotropic P2X7 receptor regulates T follicular helper (Tfh) cell abundance in the Peyer's patches (PPs) of the small intestine; deletion of P2rx7, encoding for P2X7, in Tfh cells results in enhanced IgA secretion and binding to commensal bacteria. Here, we show that Tfh cell activity is important for generating a diverse bacterial community in the gut and that sensing of microbiota-derived extracellular ATP via P2X7 promotes the generation of a proficient gut ecosystem for metabolic homeostasis...
March 14, 2017: Cell Reports
https://www.readbyqxmd.com/read/28295017/antimicrobial-peptide-gramicidin-s-is-accumulated-in-granules-of-producer-cells-for-storage-of-bacterial-phosphagens
#9
Marina Berditsch, Mareike Trapp, Sergii Afonin, Christian Weber, Julia Misiewicz, Joana Turkson, Anne S Ulrich
Many antimicrobial peptides are synthesized non-ribosomally in bacteria, but little is known about their subcellular route of biosynthesis, their mode of intracellular accumulation, or their role in the physiology of the producer cells. Here, we present a comprehensive view on the biosynthesis of gramicidin S (GS) in Aneurinibacillus migulanus, having observed a peripheral membrane localization of its synthetases. The peptide gets accumulated in nano-globules, which mature by fusion into larger granules and end up within vacuolar structures...
March 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28293233/the-soil-bacterium-methylococcus-capsulatus-bath-interacts-with-human-dendritic-cells-to-modulate-immune-function
#10
Stine Indrelid, Charlotte Kleiveland, René Holst, Morten Jacobsen, Tor Lea
The prevalence of inflammatory bowel disease (IBD) has increased in Western countries during the course of the twentieth century, and is evolving to be a global disease. Recently we showed that a bacterial meal of a non-commensal, non-pathogenic methanotrophic soil bacterium, Methylococcus capsulatus Bath prevents experimentally induced colitis in a murine model of IBD. The mechanism behind the effect has this far not been identified. Here, for the first time we show that M. capsulatus, a soil bacterium adheres specifically to human dendritic cells, influencing DC maturation, cytokine production, and subsequent T cell activation, proliferation and differentiation...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28290665/kaplan-meier-meets-chemical-kinetics-intrinsic-rate-of-sod1-amyloidogenesis-decreased-by-subset-of-als-mutations-and-cannot-fully-explain-age-of-disease-onset
#11
Alireza Abdolvahabi, Yunhua Shi, Sanaz Rasouli, Corbin M Croom, Amir Aliyan, Angel A Marti, Bryan F Shaw
Over 150 mutations in SOD1 (superoxide dismutase-1) cause amyotrophic lateral sclerosis (ALS), presumably by accelerating SOD1 amyloidogenesis. Like many nucleation processes, SOD1 fibrillization is stochastic (in vitro), which inhibits determination of aggregation rates (and obscures whether rates correlate with patient phenotypes). Here, we diverged from classical chemical kinetics and used Kaplan-Meier estimators to quantify the probability of apo-SOD1 fibrillization (in vitro) from ~ 10(3) replicate amyloid assays of wild-type (WT) SOD1 and nine ALS variants...
March 14, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28287405/t-cells-control-the-generation-of-nanomolar-affinity-anti-glycan-antibodies
#12
Zinaida Polonskaya, Shenglou Deng, Anita Sarkar, Lisa Kain, Marta Comellas-Aragones, Craig S McKay, Katarzyna Kaczanowska, Marie Holt, Ryan McBride, Valle Palomo, Kevin M Self, Seth Taylor, Adriana Irimia, Sanjay R Mehta, Jennifer M Dan, Matthew Brigger, Shane Crotty, Stephen P Schoenberger, James C Paulson, Ian A Wilson, Paul B Savage, M G Finn, Luc Teyton
Vaccines targeting glycan structures at the surface of pathogenic microbes must overcome the inherent T cell-independent nature of immune responses against glycans. Carbohydrate conjugate vaccines achieve this by coupling bacterial polysaccharides to a carrier protein that recruits heterologous CD4 T cells to help B cell maturation. Yet they most often produce low- to medium-affinity immune responses of limited duration in immunologically fit individuals and disappointing results in the elderly and immunocompromised patients...
March 13, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28283566/human-plasmacytoid-dendritic-cells-display-and-shed-b-cell-maturation-antigen-upon-tlr-engagement
#13
Elisabeth Schuh, Andrea Musumeci, Franziska S Thaler, Sarah Laurent, Joachim W Ellwart, Reinhard Hohlfeld, Anne Krug, Edgar Meinl
The BAFF-APRIL system is best known for its control of B cell homeostasis, and it is a target of therapeutic intervention in autoimmune diseases and lymphoma. By analyzing the expression of the three receptors of this system, B cell maturation Ag (BCMA), transmembrane activator and CAML interactor, and BAFF receptor, in sorted human immune cell subsets, we found that BCMA was transcribed in plasmacytoid dendritic cells (pDCs) in both blood and lymphoid tissue. Circulating human pDCs contained BCMA protein without displaying it on the cell surface...
March 10, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28282252/tobacco-phytaspase-successful-expression-in-a-heterologous-system
#14
Sharmila Narayanan, Pallab Sanpui, Lingaraj Sahoo, Siddhartha Sankar Ghosh
Phytaspase, a plant serine protease, has been demonstrated to play an important role in the programmed cell death of various plants. Phytaspase is synthesized as an inactive proenzyme containing an N-terminal signal peptide followed by a pro-domain and a mature protease catalytic domain. Pre-prophytaspase autocatalytically processes itself into a pro-domain and an active mature phytaspase enzyme. We have recently demonstrated the successful expression of mature phytaspase from tobacco in a bacterial system...
February 28, 2017: Bioengineered
https://www.readbyqxmd.com/read/28270509/in-situ-and-in-silico-kinetic-analyses-of-the-programmed-cell-death-1-programmed-cell-death-ligands-and-b7-1-interaction-network
#15
Kaitao Li, Xiaoxiao Cheng, Andreas Tilevik, Simon J Davis, Cheng Zhu
Programmed cell death-1 (PD-1) is an inhibitory receptor with an essential role in maintaining peripheral tolerance, and among the most promising immunotherapeutic targets for treating cancer, autoimmunity, and infectious diseases. A complete understanding of the consequences of PD-1 engagement by its ligands, PD-L1 and PD-L2, and of PD-L1 binding to B7-1, requires quantitative analysis of their interactions at the cell surface. We present here the first complete in situ kinetic analysis of the PD-1/PD-1 ligands/B7-1 system...
March 6, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28260502/selective-binding-baff-april-by-the-in-and-outside-conservative-region-of-bcma
#16
Chang Zheng, Xiaojuan Zhang, Zhen Zhao, Xiaofei Hao, Jing Wei, Jian Sun
B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) play vital roles in the pathogenesis of autoimmune diseases. B cell maturation antigen (BCMA), a receptor of both BAFF and APRIL shows higher affinity for APRIL than for BAFF. In this study, the conserved region of BCMA was divided into two segments BCMA1 (NEYFDSLLHACIPC) and BCMA2 (QLRCSSNTPPLT) with the aim to investigate their contribution to the ligands binding, BCMA1 contains the conservative DxL domain while BCMA2 is the segment outside the main functional area...
March 1, 2017: Protein and Peptide Letters
https://www.readbyqxmd.com/read/28239035/characterization-of-membrane-progestin-receptor-%C3%AE-mpr%C3%AE-of-the-medaka-and-role-in-the-induction-of-oocyte-maturation
#17
Shimi Rani Roy, Jun Wang, Md Rubel Rana, Mikiko Nakashima, Toshinobu Tokumoto
Oocyte maturation in medaka is induced by the maturation-inducing hormone (MIH) via its membrane receptor. The most likely candidates for the membrane receptor are membrane progestin receptors (mPRs). In order to characterize the mPRα subtype of medaka, a human cell line expressing the mPRα gene of medaka was established and its steroid binding property was assessed. The α subtype exhibited high binding affinity for 17,20β-DHP, the MIH in medaka. Treatment with a morpholino antisense oligonucleotide to mPRα blocked oocyte maturation in vivo...
2017: Biomedical Research
https://www.readbyqxmd.com/read/28236848/the-fibrinolytic-system-a-new-target-for-treatment-of-depression-with-psychedelics
#18
R D Idell, G Florova, A A Komissarov, S Shetty, R B S Girard, S Idell
Current understanding of the neurobiology of depression has grown over the past few years beyond the traditional monoamine theory of depression to include chronic stress, inflammation and disrupted synaptic plasticity. Tissue plasminogen activator (tPA) is a key factor that not only promotes fibrinolysis via the activation of plasminogen, but also contributes to regulation of synaptic plasticity and neurogenesis through plasmin-mediated activation of a probrain derived neurotrophic factor (BDNF) to mature BDNF...
March 2017: Medical Hypotheses
https://www.readbyqxmd.com/read/28236743/direct-binding-of-microrna-21-pre-element-with-regorafenib-an-alternative-mechanism-for-anti-colorectal-cancer-chemotherapy
#19
Xiaobing Chen, Bojian Xie, Liang Cao, Feng Zhu, Beibei Chen, Huifang Lv, Xingxing Fan, Lili Han, Liangyu Bie, Xinguang Cao, Xiaokun Shen, Feilin Cao
The Regorafenib is a broad-spectrum kinase inhibitor that has been approved to treat colorectal cancer (CRC). However, evidences have shown that the agent is also implicated in drug interaction with microRNA-21 (miR-21), an oncogenic miRNA which plays a key role in resisting programmed cell death in CRC cells. Here, we supposed that, instead of kinase inhibition, Regorafenib can directly bind to and then stabilize miR-21 pre-element, thus preventing RNase Dicer-meditated cleavage of the pre-element to mature miR-21...
February 10, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28228685/a-new-species-of-erythrostemon-leguminosae-caesalpinioideae-from-the-western-r%C3%A3-o-balsas-depression-mexico
#20
Solange Sotuyo, José Luis Contreras-Jiménez, Gwilym P Lewis
A new legume species from a seasonally dry forest of the Western Río Balsas Depression, in the states of Guerrero and Michoacán, Mexico, Erythrostemon guevarafeferii, is herein described and illustrated. The new species shows morphological affinities with Erythrostemon hintonii, from which it is distinguished in having fewer leaflets per pinna, mature leaflets disposed toward the upper half of the pinnae rachises, long inflorescences on curved slender peduncles, abundant red glands on its flowers and inflorescences, and its fruit glabrous with red stipitate glands at maturity...
2017: PhytoKeys
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