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https://www.readbyqxmd.com/read/28218845/phosphinophosphonates-and-their-tris-pivaloyloxymethyl-prodrugs-reveal-a-negatively-cooperative-butyrophilin-activation-mechanism
#1
Rebekah R Shippy, Xiaochen Lin, Sherry S Agabiti, Jin Li, Brendan M Zangari, Benjamin J Foust, Michael M Poe, Chia-Hung Christine Hsiao, Olga Vinogradova, David F Wiemer, Andrew Joseph Wiemer
Butyrophilin 3A1 (BTN3A1) binds small phosphorous-containing molecules, which initiates transmembrane signaling and activates butyrophilin-responsive cells. We synthesized several phosphinophosphonates and their corresponding tris-pivaloyloxymethyl prodrugs and examined their effects on BTN3A1. An analog of (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP) bound to BTN3A1 with intermediate affinity, which was enthalpy-driven. Docking studies revealed binding to the basic surface pocket and interactions between the allylic hydroxyl group and the BTN3A1 backbone...
February 20, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28216098/potential-influences-of-complement-factor-h-in-autoimmune-inflammatory-and-thrombotic-disorders
#2
Janez Ferluga, Lubna Kouser, Valarmathy Murugaiah, Robert B Sim, Uday Kishore
Complement system homeostasis is important for host self-protection and anti-microbial immune surveillance, and recent research indicates roles in tissue development and remodelling. Complement also appears to have several points of interaction with the blood coagulation system. Deficiency and altered function due to gene mutations and polymorphisms in complement effectors and regulators, including Factor H, have been associated with familial and sporadic autoimmune inflammatory - thrombotic disorders, in which autoantibodies play a part...
February 16, 2017: Molecular Immunology
https://www.readbyqxmd.com/read/28209616/octn1-is-a-high-affinity-carrier-of-nucleoside-analogs
#3
Christina Drenberg, Alice A Gibson, Stanley Pounds, Lei Shi, Dena Rhinehart, Lie Li, Shuiying Hu, Guoqing Du, Anne T Nies, Matthias Schwab, Navjotsingh Pabla, William Blum, Tanja A Gruber, Sharyn D Baker, Alex Sparreboom
Resistance to xenobiotic nucleosides used to treat acute myeloid leukemia (AML) and other cancers remains a major obstacle to clinical management. One process suggested to participate in resistance is reduced uptake into tumor cells via nucleoside transporters, although precise mechanisms are not understood. Through transcriptomic profiling, we determined that low expression of the ergothioneine transporter OCTN1 (SLC22A4; ETT) strongly predicts poor event-free survival and overall survival in multiple cohorts of AML patients receiving treatment with the cytidine nucleoside analog cytarabine...
February 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28208397/impact-of-lipid-rafts-on-the-t-cell-receptor-and-peptide-major-histocompatibility-complex-interactions-under-different-measurement-conditions
#4
Long Li, Guang-Kui Xu, Fan Song
The interactions between T-cell receptor (TCR) and peptide-major-histocompatibility complex (pMHC), which enable T-cell development and initiate adaptive immune responses, have been intensively studied. However, a central issue of how lipid rafts affect the TCR-pMHC interactions remains unclear. Here, by using a statistical-mechanical membrane model, we show that the binding affinity of TCR and pMHC anchored on two apposing cell membranes is significantly enhanced because of the lipid raft-induced signaling protein aggregation...
January 2017: Physical Review. E
https://www.readbyqxmd.com/read/28202756/a-glycosylation-benchmark-profile-for-hiv-1-envelope-glycoprotein-production-based-on-eleven-env-trimers
#5
Eden P Go, Haitao Ding, Shijian Zhang, Rajesh P Ringe, Nathan Nicely, David Hua, Robert T Steinbock, Michael Golabek, James Alin, S Munir Alam, Albert Cupo, Barton F Haynes, John C Kappes, John P Moore, Joseph G Sodroski, Heather Desaire
HIV-1 envelope glycoprotein (Env) glycosylation is important because individual glycans are components of multiple broadly neutralizing antibody epitopes, while shielding other sites that might otherwise be immunogenic. The glycosylation on Env is influenced by a variety of factors, including the genotype of the protein, the cell line used for its expression, and the details of the construct design. Here, we used a mass spectrometry-based approach to map the complete glycosylation profile at every site in multiple HIV-1 Env trimers, accomplishing two goals: 1) We determined which glycosylation sites contain conserved glycan profiles across many trimeric Envs...
February 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28202026/an-indirect-enzyme-linked-immunosorbent-assay-for-the-identification-of-antibodies-to-senecavirus-a-in-swine
#6
Cheryl M T Dvorak, Zeynep Akkutay-Yoldar, Suzanne R Stone, Steven J P Tousignant, Fabio A Vannucci, Michael P Murtaugh
BACKGROUND: Senecavirus A (SVA), a member of the family Picornaviridae, genus Senecavirus, is a recently identified single-stranded RNA virus closely related to members of the Cardiovirus genus. SVA was originally identified as a cell culture contaminant and was not associated with disease until 2007 when it was first observed in pigs with Idiopathic Vesicular Disease (IVD). Vesicular disease is sporadically observed in swine, is not debilitating, but is significant due to its resemblance to foreign animal diseases, such as foot-and-mouth disease (FMD), whose presence would be economically devastating to the United States...
February 15, 2017: BMC Veterinary Research
https://www.readbyqxmd.com/read/28198394/cockroach-protease-allergen-induces-allergic-airway-inflammation-via-epithelial-cell-activation
#7
Sagar L Kale, Komal Agrawal, Shailendra Nath Gaur, Naveen Arora
Protease allergens are known to enhance allergic inflammation but their exact role in initiation of allergic reactions at mucosal surfaces still remains elusive. This study was aimed at deciphering the role of serine protease activity of Per a 10, a major cockroach allergen in initiation of allergic inflammation at mucosal surfaces. We demonstrate that Per a 10 increases epithelial permeability by disruption of tight junction proteins, ZO-1 and occludin, and enhances the migration of Monocyte derived dendritic cell precursors towards epithelial layer as exhibited by trans-well studies...
February 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28197404/using-global-analysis-to-extend-the-accuracy-and-precision-of-binding-measurements-with-t-cell-receptors-and-their-peptide-mhc-ligands
#8
Sydney J Blevins, Brian M Baker
In cellular immunity, clonally distributed T cell receptors (TCRs) engage complexes of peptides bound to major histocompatibility complex proteins (pMHCs). In the interactions of TCRs with pMHCs, regions of restricted and variable diversity align in a structurally complex fashion. Many studies have used mutagenesis to attempt to understand the "roles" played by various interface components in determining TCR recognition properties such as specificity and cross-reactivity. However, these measurements are often complicated or even compromised by the weak affinities TCRs maintain toward pMHC...
2017: Frontiers in Molecular Biosciences
https://www.readbyqxmd.com/read/28197315/affinity-based-selectivity-profiling-of-an-in-class-selective-competitive-inhibitor-of-acyl-protein-thioesterase-2
#9
Sang Joon Won, Joseph D Eschweiler, Jaimeen D Majmudar, Fei San Chong, Sin Ye Hwang, Brandon T Ruotolo, Brent R Martin
Activity-based protein profiling (ABPP) has revolutionized the discovery and optimization of active-site ligands across distinct enzyme families, providing a robust platform for in-class selectivity profiling. Nonetheless, this approach is less straightforward for profiling reversible inhibitors and does not access proteins outside the ABPP probe's target profile. While the active-site competitive acyl protein thioesterase 2 inhibitor ML349 (Ki = 120 nM) is highly selective within the serine hydrolase enzyme family, it could still interact with other cellular targets...
February 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28195200/dynamical-footprint-of-cross-reactivity-in-a-human-autoimmune-t-cell-receptor
#10
Amit Kumar, Francesco Delogu
The present work focuses on the dynamical aspects of cross-reactivity between myelin based protein (MBP) self-peptide and two microbial peptides (UL15, PMM) for Hy.1B11 T-cell receptor (TCR). This same TCR was isolated from a patient suffering from multiple sclerosis (MS). The study aims at highlighting the chemical interactions underlying recognition mechanisms between TCR and the peptides presented by Major Histocompatibility Complex (MHC) proteins, which form a crucial component in adaptive immune response against foreign antigens...
February 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28194013/potent-single-domain-antibodies-that-arrest-respiratory-syncytial-virus-fusion-protein-in-its-prefusion-state
#11
Iebe Rossey, Morgan S A Gilman, Stephanie C Kabeche, Koen Sedeyn, Daniel Wrapp, Masaru Kanekiyo, Man Chen, Vicente Mas, Jan Spitaels, José A Melero, Barney S Graham, Bert Schepens, Jason S McLellan, Xavier Saelens
Human respiratory syncytial virus (RSV) is the main cause of lower respiratory tract infections in young children. The RSV fusion protein (F) is highly conserved and is the only viral membrane protein that is essential for infection. The prefusion conformation of RSV F is considered the most relevant target for antiviral strategies because it is the fusion-competent form of the protein and the primary target of neutralizing activity present in human serum. Here, we describe two llama-derived single-domain antibodies (VHHs) that have potent RSV-neutralizing activity and bind selectively to prefusion RSV F with picomolar affinity...
February 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/28193829/soluble-cd83-inhibits-t-cell-activation-by-binding-to-the-tlr4-md-2-complex-on-cd14-monocytes
#12
Joe M Horvatinovich, Elizabeth W Grogan, Marcus Norris, Alexander Steinkasserer, Henrique Lemos, Andrew L Mellor, Irina Y Tcherepanova, Charles A Nicolette, Mark A DeBenedette
The transmembrane protein CD83, expressed on APCs, B cells, and T cells, can be expressed as a soluble form generated by alternative splice variants and/or by shedding. Soluble CD83 (sCD83) was shown to be involved in negatively regulating the immune response. sCD83 inhibits T cell proliferation in vitro, supports allograft survival in vivo, prevents corneal transplant rejection, and attenuates the progression and severity of autoimmune diseases and experimental colitis. Although sCD83 binds to human PBMCs, the specific molecules that bind sCD83 have not been identified...
February 13, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28193538/multifunctional-luv-liposomes-decorated-for-bbb-and-amyloid-targeting-a-in-vitro-proof-of-concept
#13
Konstantina Papadia, Eleni Markoutsa, Spyridon Mourtas, Anastassios D Giannou, Barabara La Ferla, Fransesco Nicotra, Mario Salmona, Pavlos Klepetsanis, Georgios T Stathopoulos, Sophia G Antimisiaris
Multifunctional LUV liposomes (mf-LIPs) were developed, having a curcumin-lipid ligand (TREG) with affinity towards amyloid species, together with ligands to target the transferrin and the LDL receptors of the blood-brain-barrier (BBB), on their surface. mf-LIPs were evaluated for their brain targeting, on hCMEC/D3 monolayers, and for their ability to inhibit Aβ-peptide aggregation. The transport of mf-LIP across hCMEC/D3 monolayers was similar to that of BBB-LIPs, indicating that the presence of TREG on their surface does not reduce their brain targeting potential...
February 11, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28192940/analysis-of-tertiary-interactions-between-sart3-and-u6-small-nuclear-rna-using-modified-nanocapillaries
#14
Choongman Lee, Joon Kyu Park, Yeoan Youn, Joo Hyoung Kim, Kyo-Seok Lee, Nak-Kyoon Kim, Eunji Kim, Eunice Eunkyeong Kim, Kyung-Hwa Yoo
We employed modified glass nanocapillaries to investigate interactions between the RNA-binding protein, known as cell carcinoma antigen recognized by T cells-3 (SART3), and the noncoding spliceosome component, U6 small nuclear RNA (snRNA), at the single-molecule level. We functionalized the nanocapillaries with U6 snRNA fragments, which were hybridized to DNA molecules and then covalently attached to the nanocapillary surface. When transported through the modified nanocapillaries, two different SART3-derived constructs, HAT-RRM1-RRM2 and RRM1-RRM2, exhibited resistive ionic current pulses with different dwell times, which represented their different binding affinities to tethered U6 snRNAs...
February 9, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28190767/an-interaction-landscape-of-ubiquitin-signaling
#15
Xiaofei Zhang, Arne H Smits, Gabrielle B A van Tilburg, Pascal W T C Jansen, Matthew M Makowski, Huib Ovaa, Michiel Vermeulen
Intracellular signaling via the covalent attachment of different ubiquitin linkages to protein substrates is fundamental to many cellular processes. Although linkage-selective ubiquitin interactors have been studied on a case-by-case basis, proteome-wide analyses have not been conducted yet. Here, we present ubiquitin interactor affinity enrichment-mass spectrometry (UbIA-MS), a quantitative interaction proteomics method that makes use of chemically synthesized diubiquitin to enrich and identify ubiquitin linkage interactors from crude cell lysates...
January 25, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28188662/population-genetics-of-reef-coral-endosymbionts-symbiodinium-dinophyceae
#16
D J Thornhill, E J Howells, D C Wham, T D Steury, S R Santos
Symbiodinium is a diverse genus of unicellular dinoflagellate symbionts associating with various marine protists and invertebrates. Although the broad-scale diversity and phylogenetics of the Symbiodinium complex is well established, there have been surprisingly few data on fine-scale population structure and biogeography of these dinoflagellates. Yet population level processes contribute strongly to the biology of Symbiodinium, including how anthropogenic-driven global climate change impacts these symbionts and their host associations...
February 11, 2017: Molecular Ecology
https://www.readbyqxmd.com/read/28187261/sorption-of-cationic-surfactants-to-artificial-cell-membranes-comparing-phospholipid-bilayers-with-monolayer-coatings-and-molecular-simulations
#17
Niels Timmer, Steven T J Droge
This study reports the distribution coefficient between phospholipid bilayer membranes and PBS medium (DMW,PBS) for 19 cationic surfactants. The method used a sorbent dilution series with solid supported lipid membranes (SSLMs). The existing SSLM protocol, applying a 96 well plate set-up, was adapted to use 1.5 mL glass autosampler vials instead, which facilitated sampling and circumvented several confounding loss processes for some of the cationic surfactants. About 1% of the phospholipids were found to be detached from the SSLM beads, resulting in nonlinear sorption isotherms for compounds with logDMW values above 4...
February 10, 2017: Environmental Science & Technology
https://www.readbyqxmd.com/read/28186846/in-vitro-mouse-and-human-serum-stability-of-a-heterobivalent-dual-target-probe-that-has-strong-affinity-to-gastrin-releasing-peptide-and-neuropeptide-y1-receptors-on-tumor-cells
#18
Arijit Ghosh, Natarajan Raju, Michael Tweedle, Krishan Kumar
Receptor-targeting radiolabeled molecular probes with high affinity and specificity are useful in studying and monitoring biological processes and responses. Dual- or multiple-targeting probes, using radiolabeled metal chelates conjugated to peptides, have potential advantages over single-targeting probes as they can recognize multiple targets leading to better sensitivity for imaging and radiotherapy when target heterogeneity is present. Two natural hormone peptide receptors, gastrin-releasing peptide (GRP) and Y1, are specifically interesting as their expression is upregulated in most breast and prostate cancers...
February 2017: Cancer Biotherapy & Radiopharmaceuticals
https://www.readbyqxmd.com/read/28184223/fc-engineering-for-developing-therapeutic-bispecific-antibodies-and-novel-scaffolds
#19
REVIEW
Hongyan Liu, Abhishek Saxena, Sachdev S Sidhu, Donghui Wu
Therapeutic monoclonal antibodies have become molecules of choice to treat autoimmune disorders, inflammatory diseases, and cancer. Moreover, bispecific/multispecific antibodies that target more than one antigen or epitope on a target cell or recruit effector cells (T cell, natural killer cell, or macrophage cell) toward target cells have shown great potential to maximize the benefits of antibody therapy. In the past decade, many novel concepts to generate bispecific and multispecific antibodies have evolved successfully into a range of formats from full bispecific immunoglobulin gammas to antibody fragments...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28181907/the-role-of-interleukin-15-in-neoplasia
#20
Małgorzata Chłopek, Artur Kowalik, Stanisław Góźdź, Katarzyna Koziak
Interleukin 15 is a pleiotropic cytokine of the four α helix bundle family. Binding to a heterotrimeric receptor complex, which consists of a unique, high affinity IL‑15Rα‑chain and IL-2/IL-15Rβ and IL‑2Rγ chains, IL‑15 activates signaling pathways leading to activation and proliferation of T and B cells, as well as natural killer cells. At the same time, IL‑15 protects effector cells from T regulatory cells and does not induce immune tolerance. The significant regulatory action of IL‑15 on the immune system provides new opportunities for development of anti‑cancer therapies...
January 10, 2017: Postȩpy Higieny i Medycyny Doświadczalnej
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