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https://www.readbyqxmd.com/read/29146598/structural-analyses-unravel-the-molecular-mechanism-of-cyclic-di-gmp-regulation-of-bacterial-chemotaxis-via-a-pilz-adaptor-protein
#1
Xin-Fu Yan, Lingyi Xin, Jackie Tan Yen, Yukai Zeng, Shengyang Jin, Qing Wei Cheang, Rachel Andrea Chea Yuen Fong, Keng-Hwee Chiam, Zhao-Xun Liang, Yong-Gui Gao
The bacterial second messenger cyclic di-GMP (c-di-GMP) has emerged as a prominent mediator of bacterial physiology, motility and pathogenicity. Cdi-GMP often regulates the function of its protein targets through a unique mechanism that involves a discrete PilZ adaptor protein. However, the molecular mechanism in c-di-GMP-mediated protein regulation is unclear. Here, we present the structure of the PilZ adaptor protein MapZ co-crystallized in complex with c-di-GMP and its protein target CheR1, a chemotaxis-regulating methyltransferase in Pseudomonas aeruginosa This co-crystal structure, together with the structure of free CheR1, revealed that the binding of c-di-GMP induces dramatic structural changes in MapZ that are crucial for CheR1 binding...
November 16, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29133940/stimulators-and-activators-of-soluble-guanylate-cyclase-for-urogenital-disorders
#2
REVIEW
Fabiola Z Mónica, Edson Antunes
Lower urinary tract symptoms (LUTS), comprising storage (such as urinary incontinence and urinary frequency), voiding, and postmicturition symptoms, are highly prevalent conditions that affect millions of people worldwide. LUTS have a profound effect on quality of life and are a considerable cost to health care systems. In men specifically, BPH commonly leads to LUTS. Clinical studies also show an association of LUTS with erectile dysfunction (ED). Nitric oxide (NO) has long been recognized as an important nonadrenergic, noncholinergic (NANC) transmitter in bladder, urethra, prostate, and corpus cavernosum smooth muscle...
November 14, 2017: Nature Reviews. Urology
https://www.readbyqxmd.com/read/29124970/a-review-on-the-nucleic-acid-constituents-in-mushrooms-nucleobases-nucleosides-and-nucleotides
#3
Chia-Wei Phan, Joon-Keong Wang, Shiau-Chuen Cheah, Murali Naidu, Pamela David, Vikineswary Sabaratnam
Mushrooms have become increasingly important as a reliable food source. They have also been recognized as an important source of bioactive compounds of high nutritional and medicinal values. The nucleobases, nucleosides and nucleotides found in mushrooms play important roles in the regulation of various physiological processes in the human body via the purinergic and/or pyrimidine receptors. Cordycepin, a 3'-deoxyadenosine found in Cordyceps sinensis has received much attention as it possesses many medicinal values including anticancer properties...
November 10, 2017: Critical Reviews in Biotechnology
https://www.readbyqxmd.com/read/29123521/good-manufacturing-practice-compliant-production-and-lot-release-of-ex-vivo-expanded-regulatory-t-cells-as-basis-for-treatment-of-patients-with-autoimmune-and-inflammatory-disorders
#4
Manuel Wiesinger, Diane Stoica, Susanne Roessner, Carmen Lorenz, Anika Fischer, Raja Atreya, Clemens F Neufert, Imke Atreya, Alexander Scheffold, Beatrice Schuler-Thurner, Markus F Neurath, Gerold Schuler, Caroline J Voskens
In recent years, the exploration of regulatory T cell (Treg)-based cellular therapy has become an attractive strategy to ameliorate inflammation and autoimmunity in various clinical settings. The main obstacle to the clinical application of Treg in human is their low number circulating in peripheral blood. Therefore, ex vivo expansion is inevitable. Moreover, isolation of Treg bears the risk of concurrent isolation of unwanted effector cells, which may trigger or deteriorate inflammation upon adoptive Treg transfer...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29115976/gmp-production-of-purified-human-b-lymphocytes-for-the-adoptive-transfer-in-patients-after-allogeneic-hematopoietic-stem-cell-transplantation
#5
Hannes Tittlbach, Andrea Schneider, Julian Strobel, Robert Zimmermann, Stefanie Maas, Bernd Gebhardt, Georg Rauser, Michael Mach, Andreas Mackensen, Thomas H Winkler, Julia Winkler
BACKGROUND: We have recently shown that memory B cells from murine CMV immune donor animals adoptively transferred into immunodeficient mice were highly effective in protecting from a viral infection indicating a therapeutic potential of virus specific memory B cells. These preclinical data provided evidence that a cell-based strategy supporting the humoral immune response might be effective in a clinical setting of immunodeficiency after allogeneic hematopoietic stem cell transplantation...
November 7, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/29115906/challenges-of-running-a-gmp-facility-for-regenerative-medicine-in-a-public-hospital
#6
Mariele Viganò, Rosaria Giordano, Lorenza Lazzari
Advanced therapy medicinal products represent a new generation of medicinal products for regenerative medicine. Since the implementation of the EU regulation for this innovative class of drugs, the academic and hospital institutions have played a central role in their development and manufacture. For these institutions that are not familiar with the industrial context, being in compliance with the pharmaceutical standards is extremely challenging. This report describes how we dealt with some specific issues during our hospital-based GMP experience...
November 8, 2017: Regenerative Medicine
https://www.readbyqxmd.com/read/29113319/comparative-proteomic-analysis-of-virulent-and-avirulent-strains-of-toxoplasma-gondii-reveals-strain-specific-patterns
#7
Dong-Hui Zhou, Ze-Xiang Wang, Chun-Xue Zhou, Shuai He, Hany M Elsheikha, Xing-Quan Zhu
Research exploring the proteome of Toxoplasma gondii oocysts has gained momentum over the past few years. However, little is known about the oocyst's protein repertoires that contribute to differential virulence among T. gondii strains. Here, we used isobaric tag for relative and absolute quantitation-based proteomic analysis of oocysts of two T. gondii strains exhibiting the virulent PYS (ToxoDB#9) phenotype versus the less virulent PRU (Type II, ToxoDB#1) phenotype. Our aim was to determine protein expression patterns that contribute to the virulence of a particular phenotype...
October 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/29109530/a-clinical-scale-bioartificial-liver-developed-for-gmp-improved-clinical-parameters-of-liver-function-in-porcine-liver-failure
#8
Clare Selden, James Bundy, Eloy Erro, Eva Puschmann, Malcolm Miller, Delawir Kahn, Humphrey Hodgson, Barry Fuller, Jordi Gonzalez-Molina, Aurelie Le Lay, Stephanie Gibbons, Sherri Chalmers, Sunil Modi, Amy Thomas, Peter Kilbride, Agnes Isaacs, Richard Ginsburg, Helen Ilsley, David Thomson, Galya Chinnery, Ncedile Mankahla, Lizel Loo, C Wendy Spearman
Liver failure, whether arising directly from acute liver failure or from decompensated chronic liver disease is an increasing problem worldwide and results in many deaths. In the UK only 10% of individuals requiring a liver transplant receive one. Thus the need for alternative treatments is paramount. A BioArtificial Liver machine could temporarily replace the functions of the liver, buying time for the patient's liver to repair and regenerate. We have designed, implemented and tested a clinical-scale BioArtificial Liver machine containing a biomass derived from a hepatoblastoma cell-line cultured as three dimensional organoids, using a fluidised bed bioreactor, together with single-use bioprocessing equipment, with complete control of nutrient provision with feedback BioXpert recipe processes, and yielding good phenotypic liver functions...
November 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29109186/insights-into-biofilm-dispersal-regulation-from-the-crystal-structure-of-the-pas-ggdef-eal-region-of-rbda-from-pseudomonas-aeruginosa
#9
Chong Liu, Chong Wai Liew, Yee Hwa Wong, Siok Thing Tan, Wee Han Poh, Sony M S Manimekalai, Sreekanth Rajan, Lingyi Xin, Zhao-Xun Liang, Gerhard Grüber, Scott A Rice, Julien Lescar
RbdA is a positive Regulator of biofilm dispersal of Pseudomonas aeruginosa Its cytoplasmic region (cRbdA) comprises a N-terminal PAS domain followed by a diguanylate cyclase (GGDEF) and an EAL domain, whose phosphodiesterase activity is allosterically stimulated by GTP binding to the GGDEF domain. We report crystal structures of cRbdA and of two binary complexes: with GTP/Mg(2+) bound to the GGDEF active site and with the EAL domain bound to the c-di-GMP substrate. These structures unveil a 2-fold symmetric dimer, stabilized by a closely packed N-terminal PAS domain and a non-canonical EAL dimer...
November 6, 2017: Journal of Bacteriology
https://www.readbyqxmd.com/read/29106401/irf3-and-type-i-interferons-fuel-a-fatal-response-to-myocardial-infarction
#10
Kevin R King, Aaron D Aguirre, Yu-Xiang Ye, Yuan Sun, Jason D Roh, Richard P Ng, Rainer H Kohler, Sean P Arlauckas, Yoshiko Iwamoto, Andrej Savol, Ruslan I Sadreyev, Mark Kelly, Timothy P Fitzgibbons, Katherine A Fitzgerald, Timothy Mitchison, Peter Libby, Matthias Nahrendorf, Ralph Weissleder
Interferon regulatory factor 3 (IRF3) and type I interferons (IFNs) protect against infections and cancer, but excessive IRF3 activation and type I IFN production cause autoinflammatory conditions such as Aicardi-Goutières syndrome and STING-associated vasculopathy of infancy (SAVI). Myocardial infarction (MI) elicits inflammation, but the dominant molecular drivers of MI-associated inflammation remain unclear. Here we show that ischemic cell death and uptake of cell debris by macrophages in the heart fuel a fatal response to MI by activating IRF3 and type I IFN production...
November 6, 2017: Nature Medicine
https://www.readbyqxmd.com/read/29103969/differentiation-of-human-induced-pluripotent-or-embryonic-stem-cells-decreases-the-dna-damage-repair-by-homologous-recombination
#11
Kalpana Mujoo, Raj K Pandita, Anjana Tiwari, Vijay Charaka, Sharmistha Chakraborty, Dharmendra Kumar Singh, Shashank Hambarde, Walter N Hittelman, Nobuo Horikoshi, Clayton R Hunt, Kum Kum Khanna, Alexander Y Kots, E Brian Butler, Ferid Murad, Tej K Pandita
The nitric oxide (NO)-cyclic GMP pathway contributes to human stem cell differentiation, but NO free radical production can also damage DNA, necessitating a robust DNA damage response (DDR) to ensure cell survival. How the DDR is affected by differentiation is unclear. Differentiation of stem cells, either inducible pluripotent or embryonic derived, increased residual DNA damage as determined by γ-H2AX and 53BP1 foci, with increased S-phase-specific chromosomal aberration after exposure to DNA-damaging agents, suggesting reduced homologous recombination (HR) repair as supported by the observation of decreased HR-related repair factor foci formation (RAD51 and BRCA1)...
November 14, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/29100010/human-trials-of-stem-cell-derived-dopamine-neurons-for-parkinson-s-disease-dawn-of-a-new-era
#12
Roger A Barker, Malin Parmar, Lorenz Studer, Jun Takahashi
Stem cell-based therapies for Parkinson's disease are moving into a new and exciting era, with several groups pursuing clinical trials with pluripotent stem cell (PSC)-derived dopamine neurons. As many groups have ongoing or completed GMP-level cell manufacturing, we highlight key clinical translation considerations from our recent fourth GForce-PD meeting.
November 2, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/29096714/isolation-and-prolonged-expansion-of-oral-mesenchymal-stem-cells-under-clinical-grade-gmp-compliant-conditions-differentially-affects-stemness-properties
#13
Athina Bakopoulou, Danae Apatzidou, Eleni Aggelidou, Evangelia Gousopoulou, Gabriele Leyhausen, Joachim Volk, Aristeidis Kritis, Petros Koidis, Werner Geurtsen
BACKGROUND: Development of clinical-grade cell preparations is central to meeting the regulatory requirements for cellular therapies under good manufacturing practice-compliant (cGMP) conditions. Since addition of animal serum in culture media may compromise safe and efficient expansion of mesenchymal stem cells (MSCs) for clinical use, this study aimed to investigate the potential of two serum/xeno-free, cGMP culture systems to maintain long-term "stemness" of oral MSCs (dental pulp stem cells (DPSCs) and alveolar bone marrow MSCs (aBMMSCs)), compared to conventional serum-based expansion...
November 2, 2017: Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/29091392/thiol-benzo-triazolo-quinazolinone-covalently-modifies-alg44-to-inhibit-c-di-gmp-binding-and-reduces-alginate-production-by-pseudomonas-aeruginosa
#14
Eric Zhou, Anna B Seminara, Soo-Kyoung Kim, Cherisse L Hall, Yan Wang, Vincent T Lee
Pseudomonas aeruginosa is an opportunistic pathogen that affects a large proportion of cystic fibrosis (CF) patients. CF patients have dehydrated mucus within the airways that leads to the inability of the mucociliary escalator to expel inhaled microbes. Once inhaled, P. aeruginosa can persist in the lungs of the CF patients for the remainder of their lives. During this chronic infection, a phenomenon called mucoid conversion can occur in which P. aeruginosa can mutate and inactivate their mucA gene. As a consequence, transcription of the alg operon is highly expressed leading to the copious secretion of the alginate exopolysaccharide, which is associated with decreased lung function and increased CF patient morbidity and mortality...
November 1, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29091032/cyclic-di-gmp-differentially-tunes-a-bacterial-flagellar-motor-through-a-novel-class-of-chey-like-regulators
#15
Jutta Nesper, Isabelle Hug, Setsu Kato, Chee-Seng Hee, Judith Maria Habazettl, Pablo Manfredi, Stephan Grzesiek, Tilman Schirmer, Thierry Emonet, Urs Jenal
The flagellar motor is a sophisticated rotary machine facilitating locomotion and signal transduction. Owing to its important role in bacterial behavior, its assembly and activity are tightly regulated. For example, chemotaxis relies on a sensory pathway coupling chemical information to rotational bias of the motor through phosphorylation of the motor switch protein CheY. Using a chemical proteomics approach, we identified a novel family of CheY-like (Cle) proteins in Caulobacter crescentus, which tune flagellar activity in response to binding of the second messenger c-di-GMP to a C-terminal extension...
November 1, 2017: ELife
https://www.readbyqxmd.com/read/29090193/reduced-intracellular-c-di-gmp-content-increases-expression-of-quorum-sensing-regulated-genes-in-pseudomonas-aeruginosa
#16
Song Lin Chua, Yang Liu, Yingying Li, Hui Jun Ting, Gurjeet S Kohli, Zhao Cai, Pipob Suwanchaikasem, Kelvin Kau Kit Goh, Sean Pin Ng, Tim Tolker-Nielsen, Liang Yang, Michael Givskov
Cyclic-di-GMP (c-di-GMP) is an intracellular secondary messenger which controls the biofilm life cycle in many bacterial species. High intracellular c-di-GMP content enhances biofilm formation via the reduction of motility and production of biofilm matrix, while low c-di-GMP content in biofilm cells leads to increased motility and biofilm dispersal. While the effect of high c-di-GMP levels on bacterial lifestyles is well studied, the physiology of cells at low c-di-GMP levels remains unclear. Here, we showed that Pseudomonas aeruginosa cells with high and low intracellular c-di-GMP contents possessed distinct transcriptome profiles...
2017: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/29084181/altered-synaptic-membrane-retrieval-after-strong-stimulation-of-cerebellar-granule-neurons-in-cyclic-gmp-dependent-protein-kinase-ii-cgkii-knockout-mice
#17
Andrea Collado-Alsina, Franz Hofmann, José Sánchez-Prieto, Magdalena Torres
The nitric oxide (NO)/cyclic guanosine monophosphate (cGMP)/cGMP-dependent protein kinase (cGK) signaling pathway regulates the clustering and the recruitment of proteins and vesicles to the synapse, thereby adjusting the exoendocytic cycle to the intensity of activity. Accordingly, this pathway can accelerate endocytosis following large-scale exocytosis, and pre-synaptic cGK type II (cGKII) plays a major role in this process, controlling the homeostatic balance of vesicle exocytosis and endocytosis. We have studied synaptic vesicle recycling in cerebellar granule cells from mice lacking cGKII under strong and sustained stimulation, combining imaging techniques and ultrastructural analyses...
October 30, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29077161/expression-and-significance-of-vwf-gmp-140-and-adamts13-in-patients-with-aneurysmal-subarachnoid-hemorrhage
#18
W-H Li, C-J Hui, H Ju
OBJECTIVE: The aim of this study was to investigate the role of the von Willebrand factor (vWF) in patients with aneurysmal subarachnoid hemorrhage (aSAH), platelet membrane glycoprotein-140 (GMP-140). The aim is also to discover the expression and clinical significance of von Willebrand factor (vWF) cleaving protease (ADAMTS13). PATIENTS AND METHODS: 83 patients with aSAH were selected from January 2014 to December 2016. The patients were divided into cerebral vasospasm group (CVS group) (n = 37) and no convulsion group (non-CVS group) (n = 46); delayed cerebral ischemia group (DCI group) (n = 31) and non-delayed cerebral ischemia group (non-DCI group) (n = 52)...
October 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/29077065/glycomacropeptide-reduces-intestinal-epithelial-cell-barrier-dysfunction-and-adhesion-of-entero-hemorrhagic-and-entero-pathogenic-escherichia-coli-in-vitro
#19
Shane Feeney, Joseph Thomas Ryan, Michelle Kilcoyne, Lokesh Joshi, Rita Hickey
In recent years, the potential of glycosylated food components to positively influence health has received considerable attention. Milk is a rich source of biologically active glycoconjugates which are associated with antimicrobial, immunomodulatory, anti-adhesion, anti-inflammatory and prebiotic properties. Glycomacropeptide (GMP) is the C-terminal portion of kappa-casein that is released from whey during cheese-making by the action of chymosin. Many of the biological properties associated with GMP, such as anti-adhesion, have been linked with the carbohydrate portion of the protein...
October 27, 2017: Foods (Basel, Switzerland)
https://www.readbyqxmd.com/read/29076098/good-manufacturing-practice-gmp-translation-of-advanced-cellular-therapeutics-lessons-for-the-manufacture-of-erythrocytes-as-medicinal-products
#20
Neil W A McGowan, John D M Campbell, Joanne C Mountford
Blood transfusion is a mainstay of modern medical practice. In many parts of the world the use of this life-saving therapy is hampered by issues of supply and the potential for transfusion transmitted infections. Accordingly, there are many studies seeking to find an alternative to donated red blood cells (RBCs) for transfusion, including large-scale production from adult and pluripotent stem cells, or erythroid cell lines. Translating basic studies, using any cell lineage, into protocols that are suitable for the generation of cellular therapies requires a wide range of biological and regulatory procedures to be put in place...
2018: Methods in Molecular Biology
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