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https://www.readbyqxmd.com/read/28655168/bmp4-uses-several-different-effector-pathways-to-regulate-proliferation-and-differentiation-in-the-epithelial-and-mesenchymal-tissue-compartments-of-the-developing-mouse-ureter
#1
Tamrat M Mamo, Anna B Wittern, Marc-Jens Kleppa, Tobias Bohnenpoll, Anna-Carina Weiss, Andreas Kispert
Heterozygous loss of Bmp4 results both in humans and mice in severe malformation of the urinary tract. These defects have at least partially been attributed to loss of expression of Bmp4 in the ureteric mesenchyme, yet the cellular and molecular function of this signal as well as its effector pathways in this tissue have remained incompletely resolved. Here, we show that mice with a conditional deletion of Bmp4 in the ureteric mesenchyme exhibited hydroureter and hydronephrosis at newborn stages due to functional and physical ureter obstruction...
June 26, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28654259/a-new-inhibitor-targeting-signal-transducer-and-activator-of-transcription-5-stat5-signaling-in-myeloid-leukemias
#2
Ludovic Juen, Marie Brachet-Botineau, Cécile Parmenon, Jérôme Bourgeais, Olivier Hérault, Fabrice Gouilleux, Marie-Claude Viaud-Massuard, Gildas Prié
Signal Transducer and Activator of Transcription 5 (STAT5) are crucial effectors of tyrosine kinase oncogenes in myeloid leukemias. Inhibition of STAT5 would contribute to reducing the survival of leukemic cells and also tackling their chemoresistance. In a first screening experiment, we identified hit 13 as able to inhibit STAT5 phosphorylation and leukemic cell growth. The synthesis of 18 analogs of 13 allowed us to identify one compound, 17f, as having the most potent antileukemic effect. 17f inhibited the growth of acute and chronic myeloid leukemia cells and phosphorylation and transcriptional activity of STAT5...
June 27, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28654216/mechanistic-sharing-between-nk-cells-in-abmr-and-effector-t-cells-in-tcmr
#3
Michael D Parkes, Philip F Halloran, Luis G Hidalgo
Human organ allograft rejection depends on effector lymphocytes: NK cells in antibody-mediated rejection (ABMR) and effector T cells in T cell-mediated rejection (TCMR). We hypothesized that NK cell CD16a stimulation and CD8 T cell TCR/CD3 stimulation represent highly similar effector systems, and should lead to shared molecular changes between ABMR and TCMR. We studied similarity between soluble proteins and the transcripts induced in CD16a stimulated NK cells and TCR/CD3-stimulated T cells in vitro. Of 30 soluble mediators tested, CD16a-activated NK cells and CD3/TCR activated T cells produced the same limited set of five mediators-CCL3, CCL4, CSF2, IFNG, and TNF-and failed to produce 25 others...
June 27, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28654074/a-chronic-autoimmune-dry-eye-rat-model-with-increase-in-effector-memory-t-cells-in-eyeball-tissue
#4
Aihua Hou, Tanima Bose, K George Chandy, Louis Tong
Dry eye disease is a very common condition that causes morbidity and healthcare burden and decreases the quality of life. There is a need for a suitable dry eye animal model to test novel therapeutics to treat autoimmune dry eye conditions. This protocol describes a chronic autoimmune dry eye rat model. Lewis rats were immunized with an emulsion containing lacrimal gland extract, ovalbumin, and complete Freund's adjuvant. A second immunization with the same antigens in incomplete Freund's adjuvant was administered two weeks later...
June 7, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28653862/optimal-response-to-dimethyl-fumarate-associates-in-ms-with-a-shift-from-an-inflammatory-to-a-tolerogenic-blood-cell-profile
#5
Silvia Medina, Noelia Villarrubia, Susana Sainz de la Maza, José Lifante, Lucienne Costa-Frossard, Ernesto Roldán, Carmen Picón, José C Álvarez-Cermeño, Luisa M Villar
BACKGROUND: The precise mechanism of action of dimethyl fumarate (DMF) treatment in MS remains unknown. OBJECTIVE: To identify the changes in the blood lymphocyte profile of MS patients predicting no evidence of disease activity (NEDA) status after DMF treatment. METHODS: We studied blood lymphocyte subsets of 64 MS patients treated with DMF at baseline and after 6 months of treatment by flow cytometry. NEDA (41 patients) or ongoing disease activity (ODA, 23 patients) were monitored after a year of follow-up...
June 1, 2017: Multiple Sclerosis: Clinical and Laboratory Research
https://www.readbyqxmd.com/read/28653671/a-dynamic-and-adaptive-network-of-cytosolic-interactions-governs-protein-export-by-the-t3ss-injectisome
#6
Andreas Diepold, Erdinc Sezgin, Miles Huseyin, Thomas Mortimer, Christian Eggeling, Judith P Armitage
Many bacteria use a type III secretion system (T3SS) to inject effector proteins into host cells. Selection and export of the effectors is controlled by a set of soluble proteins at the cytosolic interface of the membrane spanning type III secretion 'injectisome'. Combining fluorescence microscopy, biochemical interaction studies and fluorescence correlation spectroscopy, we show that in live Yersinia enterocolitica bacteria these soluble proteins form complexes both at the injectisome and in the cytosol. Binding to the injectisome stabilizes these cytosolic complexes, whereas the free cytosolic complexes, which include the type III secretion ATPase, constitute a highly dynamic and adaptive network...
June 27, 2017: Nature Communications
https://www.readbyqxmd.com/read/28652577/human-in-vitro-induced-regulatory-t-cells-display-dlgh1dependent-and-pkc-%C3%AE-restrained-suppressive-activity
#7
Alexandra Zanin-Zhorov, Sudha Kumari, Keli L Hippen, Sarah C Merkel, Margaret L MacMillan, Bruce R Blazar, Michael L Dustin
In vitro induced human regulatory T cells (iTregs) have demonstrated in vivo therapeutic utility, but pathways regulating their function have not been elucidated. Here, we report that human iTregs generated in vitro from naïve cord blood cells preferentially recruit Disc large homolog 1 (Dlgh1) and exclude protein kinase C (PKC)-θ from immunological synapses formed on supported lipid bilayers with laterally mobile ICAM-1 and anti-CD3 mAb. Also, iTregs display elevated Dlgh1 overall and Dlgh1-dependent p38 phosphorylation, higher levels of phosphatase and tensin homolog (PTEN), and diminished Akt phosphorylation...
June 26, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28652399/c-rel-and-i%C3%AE%C2%BAbns-govern-common-and-independent-steps-of-regulatory-t-cell-development-from-novel-cd122-expressing-pre-precursors
#8
Marc Schuster, Carlos Plaza-Sirvent, Anne-Marie Matthies, Ulrike Heise, Andreas Jeron, Dunja Bruder, Alexander Visekruna, Jochen Huehn, Ingo Schmitz
Foxp3-expressing regulatory T cells (Tregs) are essential regulators of immune homeostasis and, thus, are prime targets for therapeutic interventions of diseases such as cancer and autoimmunity. c-REL and IκBNS are important regulators of Foxp3 induction in Treg precursors upon γ-chain cytokine stimulation. In c-REL/IκBNS double-deficient mice, Treg numbers were dramatically reduced, indicating that together, c-REL and IκBNS are pivotal for Treg development. However, despite the highly reduced Treg compartment, double-deficient mice did not develop autoimmunity even when aged to more than 1 y, suggesting that c-REL and IκBNS are required for T cell effector function as well...
June 26, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28652395/differential-requirements-for-tcf1-long-isoforms-in-cd8-and-cd4-t-cell-responses-to-acute-viral-infection
#9
Jodi A Gullicksrud, Fengyin Li, Shaojun Xing, Zhouhao Zeng, Weiqun Peng, Vladimir P Badovinac, John T Harty, Hai-Hui Xue
In response to acute viral infection, activated naive T cells give rise to effector T cells that clear the pathogen and memory T cells that persist long-term and provide heightened protection. T cell factor 1 (Tcf1) is essential for several of these differentiation processes. Tcf1 is expressed in multiple isoforms, with all isoforms sharing the same HDAC and DNA-binding domains and the long isoforms containing a unique N-terminal β-catenin-interacting domain. In this study, we specifically ablated Tcf1 long isoforms in mice, while retaining expression of Tcf1 short isoforms...
June 26, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28652364/cide-domains-form-functionally-important-higher-order-assemblies-for-dna-fragmentation
#10
Jae Young Choi, Qi Qiao, Se-Hoon Hong, Chang Min Kim, Jae-Hee Jeong, Yeon-Gil Kim, Yong-Keun Jung, Hao Wu, Hyun Ho Park
Cell death-inducing DFF45-like effector (CIDE) domains, initially identified in apoptotic nucleases, form a family with diverse functions ranging from cell death to lipid homeostasis. Here we show that the CIDE domains of Drosophila and human apoptotic nucleases Drep2, Drep4, and DFF40 all form head-to-tail helical filaments. Opposing positively and negatively charged interfaces mediate the helical structures, and mutations on these surfaces abolish nuclease activation for apoptotic DNA fragmentation. Conserved filamentous structures are observed in CIDE family members involved in lipid homeostasis, and mutations on the charged interfaces compromise lipid droplet fusion, suggesting that CIDE domains represent a scaffold for higher-order assembly in DNA fragmentation and other biological processes such as lipid homeostasis...
June 26, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28652358/targeting-cancer-cell-integrins-using-gold-nanorods-in-photothermal-therapy-inhibits-migration-through-affecting-cytoskeletal-proteins
#11
Moustafa R K Ali, Yue Wu, Yan Tang, Haopeng Xiao, Kuangcai Chen, Tiegang Han, Ning Fang, Ronghu Wu, Mostafa A El-Sayed
Metastasis is responsible for most cancer-related deaths, but the current clinical treatments are not effective. Recently, gold nanoparticles (AuNPs) were discovered to inhibit cancer cell migration and prevent metastasis. Rationally designed AuNPs could greatly benefit their antimigration property, but the molecular mechanisms need to be explored. Cytoskeletons are cell structural proteins that closely relate to migration, and surface receptor integrins play critical roles in controlling the organization of cytoskeletons...
June 26, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28652328/pathogen-exploitation-of-an-abscisic-acid-and-jasmonate-inducible-mapk-phosphatase-and-its-interception-by-arabidopsis-immunity
#12
Akira Mine, Matthias L Berens, Tatsuya Nobori, Shajahan Anver, Kaori Fukumoto, Thomas M Winkelmüller, Atsushi Takeda, Dieter Becker, Kenichi Tsuda
Phytopathogens promote virulence by, for example, exploiting signaling pathways mediated by phytohormones such as abscisic acid (ABA) and jasmonate (JA). Some plants can counteract pathogen virulence by invoking a potent form of immunity called effector-triggered immunity (ETI). Here, we report that ABA and JA mediate inactivation of the immune-associated MAP kinases (MAPKs), MPK3 and MPK6, in Arabidopsis thaliana ABA induced expression of genes encoding the protein phosphatases 2C (PP2Cs), HAI1, HAI2, and HAI3 through ABF/AREB transcription factors...
June 26, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28652310/bacterial-nucleotidyl-cyclase-inhibits-host-innate-immune-response-through-suppressing-tak1-activation
#13
Chenxi He, Yilong Zhou, Feng Liu, Haipeng Liu, Hao Tan, Shouguang Jin, Weihui Wu, Baoxue Ge
Exoenzyme Y (ExoY) is a type III secretion system effector found in 90% of the Pseudomonas aeruginosa isolates. Although it is known that ExoY is a soluble nucleotidyl cyclase that increases the cytoplasmic levels of nucleoside 3' , 5' -cyclic monophosphates (cNMPs) to mediate endothelial Tau phosphorylation and permeability, its functional role in the innate immune response is still poorly understood. Transforming growth factor β activated kinase-1 (TAK1) is critical for mediating Toll-like receptor (TLR) signaling and subsequent activation of NF-κB and AP-1, which are transcriptional activators of innate immunity...
June 26, 2017: Infection and Immunity
https://www.readbyqxmd.com/read/28652264/analysis-of-the-zar1-immune-complex-reveals-determinants-for-immunity-and-molecular-interactions
#14
Maël Baudin, Jana A Hassan, Karl Schreiber, Jennifer D Lewis
Plants depend on innate immunity to prevent disease. Plant pathogenic bacteria, like Pseudomonas syringae and Xanthomonas campestris, use the type III secretion system as a molecular syringe to inject type III secreted effector (T3SE) proteins in plants. The primary function of most T3SEs is to suppress immunity, however the plant can evolve NBD-LRR domain-containing (NLR) proteins to recognize specific T3SEs. The AtZAR1 NLR induces strong defense responses against P. syringae and X. campestris. The P. syringae T3SE HopZ1a is an acetyltransferase that acetylates the pseudokinase AtZED1, and triggers recognition by AtZAR1...
June 26, 2017: Plant Physiology
https://www.readbyqxmd.com/read/28652236/synthetic-cyclic-peptomers-as-type-iii-secretion-system-inhibitors
#15
Hanh Lam, Joshua Schwochert, Yongtong Lao, Tannia Lau, Cameron Lloyd, Justin Luu, Olivia Kooner, Jessica Morgan, Scott Lokey, Victoria Auerbuch
Antibiotic resistant bacteria are an emerging threat to global public health. New classes of antibiotics and tools for antimicrobial discovery are urgently needed. The type III secretion system (T3SS), which is required by dozens of Gram-negative bacteria for virulence but largely absent from non-pathogenic bacteria, is a promising virulence blocker target. The ability of mammalian cells to recognize the presence of a functional T3SS and trigger NFκB activation provides a rapid and sensitive method to identify chemical inhibitors of T3SS activity...
June 26, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28651813/magnetic-oculomotor-prosthetics-for-acquired-nystagmus
#16
Parashkev Nachev, Geoff E Rose, David H Verity, Sanjay G Manohar, Kelly MacKenzie, Gill Adams, Maria Theodorou, Quentin A Pankhurst, Christopher Kennard
PURPOSE: Acquired nystagmus, a highly symptomatic consequence of damage to the substrates of oculomotor control, often is resistant to pharmacotherapy. Although heterogeneous in its neural cause, its expression is unified at the effector-the eye muscles themselves-where physical damping of the oscillation offers an alternative approach. Because direct surgical fixation would immobilize the globe, action at a distance is required to damp the oscillation at the point of fixation, allowing unhindered gaze shifts at other times...
June 23, 2017: Ophthalmology
https://www.readbyqxmd.com/read/28651788/mechanistic-target-of-rapamycin-independent-antidepressant-effects-of-r-ketamine-in-a-social-defeat-stress-model
#17
Chun Yang, Qian Ren, Youge Qu, Ji-Chun Zhang, Min Ma, Chao Dong, Kenji Hashimoto
BACKGROUND: The role of the mechanistic target of rapamycin (mTOR) signaling in the antidepressant effects of ketamine is controversial. In addition to mTOR, extracellular signal-regulated kinase (ERK) is a key signaling molecule in prominent pathways that regulate protein synthesis. (R)-Ketamine has a greater potency and longer-lasting antidepressant effects than (S)-ketamine. Here we investigated whether mTOR signaling and ERK signaling play a role in the antidepressant effects of two enantiomers...
May 31, 2017: Biological Psychiatry
https://www.readbyqxmd.com/read/28651743/the-combination-of-nk-and-cd8-t-cells-with-ccl20-il15-armed-oncolytic-adenoviruses-enhances-the-growth-suppression-of-tert-positive-tumor-cells
#18
Jun-Feng Ye, Wen-Xi Qi, Ming-Yuan Liu, Yang Li
Adoptive immunotherapy and targeted gene therapy have been extensively used to eliminate tumor cells. The combination treatment is capable of efficiently generating an effective antitumor immune response and disrupting tumor-induced tolerance. Moreover, effective antitumor immune responses are dependent on coordinate interaction among various effector cells. This study focused on whether the combination of cytotoxic effector cell-based adoptive immunotherapy and CCL20/IL15-armed oncolytic adenoviruses could induce enhanced antitumor activity...
June 7, 2017: Cellular Immunology
https://www.readbyqxmd.com/read/28651594/the-cd4-t-cell-regulatory-network-mediates-inflammatory-responses-during-acute-hyperinsulinemia-a-simulation-study
#19
Mariana E Martinez-Sanchez, Marcia Hiriart, Elena R Alvarez-Buylla
BACKGROUND: Obesity is frequently linked to insulin resistance, high insulin levels, chronic inflammation, and alterations in the behaviour of CD4+ T cells. Despite the biomedical importance of this condition, the system-level mechanisms that alter CD4+ T cell differentiation and plasticity are not well understood. RESULTS: We model how hyperinsulinemia alters the dynamics of the CD4+ T regulatory network, and this, in turn, modulates cell differentiation and plasticity...
June 26, 2017: BMC Systems Biology
https://www.readbyqxmd.com/read/28651566/arginine-kinase-from-haemonchus-contortus-decreased-the-proliferation-and-increased-the-apoptosis-of-goat-pbmcs-in-vitro
#20
Muhammad Ehsan, WenXiang Gao, Javaid Ali Gadahi, MingMin Lu, XinChao Liu, YuJian Wang, RuoFeng Yan, LiXin Xu, XiaoKai Song, XiangRui Li
BACKGROUND: Arginine kinase (AK), an important member of phosphagen kinase family has been extensively studied in various vertebrates and invertebrates. Immunologically, AKs are important constituents of different body parts, involved in various biological and cellular functions, and considered as immune-modulator and effector for pro-inflammatory cytokines. However, immunoregulatory changes of host cells triggered by AK protein of Haemonchus contortus, a parasitic nematode of ruminants, are still unknown...
June 26, 2017: Parasites & Vectors
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