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https://www.readbyqxmd.com/read/29467500/a-tomato-mads-box-protein-slcmb1-regulates-ethylene-biosynthesis-and-carotenoid-accumulation-during-fruit-ripening
#1
Jianling Zhang, Zongli Hu, Qiyuan Yao, Xuhu Guo, Vanluc Nguyen, Fenfen Li, Guoping Chen
The MADS-box transcription factors play essential roles in many physiological and biochemical processes of plants, especially in fruit ripening. Here, a tomato MADS-box gene, SlCMB1, was isolated. SlCMB1 expression declined with the fruit ripening from immature green to B + 7 (7 days after Breaker) fruits in the wild type (WT) and was lower in Nr and rin mutants fruits. Tomato plants with reduced SlCMB1 mRNA displayed delayed fruit ripening, reduced ethylene production and carotenoid accumulation. The ethylene production in SlCMB1-RNAi fruits decreased by approximately 50% as compared to WT...
February 21, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29402611/structure-activity-studies-of-a-macrocyclic-peptide-inhibitor-of-histone-lysine-demethylase-4a
#2
Toby Passioura, Bhaskar Bhushan, Anthony Tumber, Akane Kawamura, Hiroaki Suga
The combination of genetic code reprogramming and mRNA display is a powerful approach for the identification of macrocyclic peptides with high affinities to a target of interest. We have previously used such an approach to identify a potent inhibitor (CP2) of the human KDM4A and KDM4C lysine demethylases; important regulators of gene expression. In the present study, we have used genetic code reprogramming to synthesise very high diversity focused libraries (>1012 compounds) based on CP2 and, through affinity screening, used these to delineate the structure activity relationship of CP2 binding to KDM4A...
January 31, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29367920/the-pronounced-high-expression-of-discoidin-domain-receptor-2-in-human-interstitial-lung-diseases
#3
Huan Bian, Xiaowei Nie, Xin Bu, Feng Tian, Libo Yao, Jingyu Chen, Jin Su
The most typical structural feature of human interstitial lung diseases (ILDs) is the accumulation of vast amounts of collagens within the lung interstitium. The membrane receptors that are responsible for recognising collagens and then transducing signals into the cells include four members of the integrin family (α1β1, α2β1, α10β1 and α11β1) and two members of the discoidin domain receptor family (DDR1 and DDR2). However, it remains unknown whether these six collagen receptors similarly contribute to the pathogenesis of fibrotic lung diseases...
January 2018: ERJ Open Research
https://www.readbyqxmd.com/read/29311466/-elaboration-of-pseudo-natural-products-using-artificial-in-vitro-biosynthesis-systems
#4
REVIEW
Yuki Goto
 Peptidic natural products often consist of not only proteinogenic building blocks but also unique non-proteinogenic structures such as macrocyclic scaffolds and N-methylated backbones. Since such non-proteinogenic structures are important structural motifs that contribute to diverse bioactivity, we have proposed that peptides with non-proteinogenic structures should be attractive candidates as artificial bioactive peptides mimicking natural products, or so-called pseudo-natural products. We previously devised an engineered translation system for pseudo-natural peptides, referred to as the flexible in vitro translation (FIT) system...
2018: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
https://www.readbyqxmd.com/read/29283243/discovery-of-a-29-amino-acid-reactive-abiotic-peptide-for-selective-cysteine-arylation
#5
Ethan D Evans, Bradley L Pentelute
The regio- and chemoselective modification of proteins or peptides with chemical reagents is often challenging. One approach to overcome this problem involves identifying abiotic polypeptide sequences that react with specific small molecules. Toward this goal, we profiled ∼5 × 1013 randomized 30-mer peptides using mRNA display and high-throughput sequencing in search of polypeptides that can undergo cysteine arylation with a water-soluble perfluoroarene. Within this vast chemical space, we discovered a cysteine-containing sequence with a second-order rate constant of 0...
March 16, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29249238/identification-of-nonstandard-macrocyclic-peptide-ligands-through-display-screening
#6
REVIEW
Rhys Dylan Taylor, Matias Rey-Carrizo, Toby Passioura, Hiroaki Suga
Techniques facilitating the synthesis and screening of very high diversity nonstandard macrocyclic peptide libraries have led to such compounds receiving increasing attention as potential drug candidates. Specifically, approaches which allow the use of non-proteinogenic amino acids are proving to be particularly effective, since they expand the accessible chemical space of the starting library and thus allow the identification of compounds with structural similarity to known drugs. This review focuses on mRNA display screening platforms for drug discovery and their combined use with genetic code reprogramming to identify novel macrocyclic peptides with high affinities for disease-related targets of interest...
December 2017: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/28982308/tumor-shb-gene-expression-affects-disease-characteristics-in-human-acute-myeloid-leukemia
#7
Maria Jamalpour, Xiujuan Li, Lucia Cavelier, Karin Gustafsson, Gustavo Mostoslavsky, Martin Höglund, Michael Welsh
The mouse Shb gene coding for the Src Homology 2-domain containing adapter protein B has recently been placed in context of BCRABL1-induced myeloid leukemia in mice and the current study was performed in order to relate SHB to human acute myeloid leukemia (AML). Publicly available AML databases were mined for SHB gene expression and patient survival. SHB gene expression was determined in the Uppsala cohort of AML patients by qPCR. Cell proliferation was determined after SHB gene knockdown in leukemic cell lines...
October 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28966570/effects-of-environmental-enrichment-on-doublecortin-and-bdnf-expression-along-the-dorso-ventral-axis-of-the-dentate-gyrus
#8
Fabio Gualtieri, Catherine Brégère, Grace C Laws, Elena A Armstrong, Nicholas J Wylie, Theo T Moxham, Raphael Guzman, Timothy Boswell, Tom V Smulders
Adult hippocampal neurogenesis (AHN) in the dentate gyrus is known to respond to environmental enrichment, chronic stress, and many other factors. The function of AHN may vary across the septo-temporal axis of the hippocampus, as different subdivisions are responsible for different functions. The dorsal pole regulates cognitive-related behaviors, while the ventral pole mediates mood-related responses through the hypothalamic-pituitary-adrenal (HPA) axis. In this study, we investigate different methods of quantifying the effect of environmental enrichment on AHN in the dorsal and ventral parts of the dentate gyrus (dDG and vDG)...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28935113/directed-evolution-of-glycopeptides-using-mrna-display
#9
Satoru Horiya, Jennifer K Bailey, Isaac J Krauss
Directed evolution is a useful method for the discovery of nucleic acids, peptides, or proteins that have desired binding abilities or functions. Because of the abundance and importance of glycosylation in nature, directed evolution of glycopeptides and glycoproteins is also highly desirable. However, common directed evolution platforms such as phage-, yeast-, or mammalian-cell display are limited for these applications by several factors. Glycan structure at each glycosylation site is not genetically encoded, and yeast and mammalian cells produce a heterogeneous mixture of glycoforms at each site on the protein...
2017: Methods in Enzymology
https://www.readbyqxmd.com/read/28915003/the-evolution-of-dna-templated-synthesis-as-a-tool-for-materials-discovery
#10
Rachel K O'Reilly, Andrew J Turberfield, Thomas R Wilks
Precise control over reactivity and molecular structure is a fundamental goal of the chemical sciences. Billions of years of evolution by natural selection have resulted in chemical systems capable of information storage, self-replication, catalysis, capture and production of light, and even cognition. In all these cases, control over molecular structure is required to achieve a particular function: without structural control, function may be impaired, unpredictable, or impossible. The search for molecules with a desired function is often achieved by synthesizing a combinatorial library, which contains many or all possible combinations of a set of chemical building blocks (BBs), and then screening this library to identify "successful" structures...
October 17, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28768907/upregulated-heme-biosynthesis-an-exploitable-vulnerability-in-mycn-driven-leukemogenesis
#11
Yu Fukuda, Yao Wang, Shangli Lian, John Lynch, Shinjiro Nagai, Bruce Fanshawe, Ayten Kandilci, Laura J Janke, Geoffrey Neale, Yiping Fan, Brian P Sorrentino, Martine F Roussel, Gerard Grosveld, John D Schuetz
The increased heme biosynthesis long observed in leukemia was previously of unknown significance. Heme, synthesized from porphyrin precursors, plays a central role in oxygen metabolism and mitochondrial function, yet little is known about its role in leukemogenesis. Here, we show increased expression of heme biosynthetic genes, including UROD, only in pediatric AML samples that have high MYCN expression. High expression of both UROD and MYCN predicts poor overall survival and unfavorable outcomes in adult AML...
August 3, 2017: JCI Insight
https://www.readbyqxmd.com/read/28685529/expression-of-cell-mitotic-progression-proteins-and-keratinocyte-markers-in-porcine-buccal-pouch-mucosal-cells-during-short-term-real-time-primary-culture
#12
LETTER
A Bryja, M Dyszkiewicz-Konwińska, J Budna, S Ciesiółka, W Kranc, S Borys, M Jeseta, O Urbaniak, D Bukowska, P Antosik, M Bruska, M Nowicki, M Zabel, B Kempisty
The porcine model is often used in clinical trials. The pig has many fundamental anatomic, physiological and nutritional similarities to humans. Additionally, the European Medicines Agency (EMA) demands the use large animals in clinical studies. Oral mucosa has received special attention due to its regenerative properties. Oral tissue is composed of several types of cells including fibroblasts and keratinocytes. The porcine oral mucosa/buccal pouch mucosa has a cellular structure with defined proliferation and differentiated capability...
April 2017: Journal of Biological Regulators and Homeostatic Agents
https://www.readbyqxmd.com/read/28680090/pan-cancer-emt-signature-identifies-rbm47-down-regulation-during-colorectal-cancer-progression
#13
Matjaz Rokavec, Markus Kaller, David Horst, Heiko Hermeking
Epithelial-mesenchymal transition (EMT) plays an important role in tumor invasion and metastasis. A comprehensive, bioinformatics analysis of CCLE and TCGA datasets of seven tumor types allowed us to identify a novel pan-cancer EMT-associated gene expression signature consisting of 16 epithelial and 4 mesenchymal state-associated mRNAs. Among the identified epithelial cell state-associated factors, down-regulation of the RBM47 (RNA binding motif protein 47) mRNA displayed the most significant association with metastasis and poor survival in multiple cohorts of colorectal cancer (CRC) patients...
July 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28584151/discovery-and-characterization-of-a-novel-cd4-binding-adnectin-with-potent-anti-hiv-activity
#14
David Wensel, Yongnian Sun, Zhufang Li, Sharon Zhang, Caryn Picarillo, Thomas McDonagh, David Fabrizio, Mark Cockett, Mark Krystal, Jonathan Davis
A novel fibronectin-based protein (Adnectin) HIV-1 inhibitor was generated using in vitro selection. This inhibitor binds to human CD4 with a high affinity (3.9 nM) and inhibits viral entry at a step after CD4 engagement and preceding membrane fusion. The progenitor sequence of this novel inhibitor was selected from a library of trillions of Adnectin variants using mRNA display and then further optimized for improved antiviral and physical properties. The final optimized inhibitor exhibited full potency against a panel of 124 envelope (gp160) proteins spanning 11 subtypes, indicating broad-spectrum activity...
August 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28572907/linker-free-incorporation-of-carbohydrates-into-in-vitro-displayed-macrocyclic-peptides
#15
S A K Jongkees, S Umemoto, H Suga
We report a strategy for efficient post-translational modification of a library of ribosomally-translated peptides by activation and elimination of cysteine to dehydroalanine then conjugate addition of a range of exogenous thiols, with an emphasis on carbohydrates. These reactions are selective for cysteine, and do not interfere with amplification of the nucleic acid component of an mRNA-displayed peptide. Furthermore, these reactions are shown to be compatible with two different macrocyclisation chemistries, and when applied to a peptide containing an N-terminal cysteine give a ketone that can be functionalised in an orthogonal manner...
February 1, 2017: Chemical Science
https://www.readbyqxmd.com/read/28522832/the-fragment-hmga2-sh-3p20-from-hmga2-mrna-3-utr-promotes-the-growth-of-hepatoma-cells-by-upregulating-hmga2
#16
Yuan Wang, Fuquan Chen, Zhe Yang, Man Zhao, Shuqin Zhang, Yuen Gao, Jinyan Feng, Guang Yang, Weiying Zhang, Lihong Ye, Xiaodong Zhang
High mobility group A2 (HMGA2) plays a crucial role in the development of cancer. However, the mechanism by which HMGA2 promotes the growth of hepatocellular carcinoma (HCC) remains unclear. Here, we explore the hypothesis that HMGA2 may enhance the growth of hepatoma cells through a fragment based on the secondary structure of HMGA2 mRNA 3'-untranslated region (3'UTR). Bioinformatics analysis showed that HMGA2 mRNA displayed a hairpin structure within its 3'UTR, termed HMGA2-sh. Mechanistically, RNA immunoprecipitation assays showed that the microprocessor Drosha or DGCR8 interacted with HMGA2 mRNA in hepatoma cells...
May 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28368002/macrocycle-peptides-delineate-locked-open-inhibition-mechanism-for-microorganism-phosphoglycerate-mutases
#17
Hao Yu, Patricia Dranchak, Zhiru Li, Ryan MacArthur, Matthew S Munson, Nurjahan Mehzabeen, Nathan J Baird, Kevin P Battalie, David Ross, Scott Lovell, Clotilde K S Carlow, Hiroaki Suga, James Inglese
Glycolytic interconversion of phosphoglycerate isomers is catalysed in numerous pathogenic microorganisms by a cofactor-independent mutase (iPGM) structurally distinct from the mammalian cofactor-dependent (dPGM) isozyme. The iPGM active site dynamically assembles through substrate-triggered movement of phosphatase and transferase domains creating a solvent inaccessible cavity. Here we identify alternate ligand binding regions using nematode iPGM to select and enrich lariat-like ligands from an mRNA-display macrocyclic peptide library containing >10(12) members...
April 3, 2017: Nature Communications
https://www.readbyqxmd.com/read/28358987/highly-selective-targeting-of-hepatic-stellate-cells-for-liver-fibrosis-treatment-using-a-d-enantiomeric-peptide-ligand-of-fn14-identified-by-mirror-image-mrna-display
#18
Luying Huang, Jing Xie, Qiuyan Bi, Zhuoxuan Li, Sha Liu, Qing Shen, Chong Li
Although liver fibrosis is a major public health issue, there is still no effective drug therapy in the clinic. Fibroblast growth factor-inducible 14 (Fn14), a membrane receptor highly specifically expressed in activated hepatic stellate cells (HSCs), is the key driver of liver fibrosis, and thus, it has a great potential as a novel target for the development of effective treatment. Here, we identified a d-enantiomeric peptide ligand of Fn14 through mirror-image mRNA display. This included the chemical synthesis of a d-enantiomer of the target protein (extracellular domain of Fn14), identification of an l-peptide ligand of d-Fn14 using a constructed mRNA peptide library, and identification of a d-enantiomer of the l-peptide, which is a ligand of the natural Fn14 for reasons of symmetry...
April 12, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28319812/exploring-sequence-space-harnessing-chemical-and-biological-diversity-towards-new-peptide-leads
#19
REVIEW
Richard Obexer, Louise J Walport, Hiroaki Suga
From their early roots in natural products, peptides now represent an expanding class of novel drugs. Their modular structures make them ideal candidates for pooled library screening approaches. Key technologies for library generation and screening, such as SICLOPPS, phage display and mRNA display, give unparalleled access to tight binding peptides. Through combination with genetic code reprogramming and chemical modifications, access to more natural product-like libraries, spanning non-canonical peptide space, is readily achievable...
June 2017: Current Opinion in Chemical Biology
https://www.readbyqxmd.com/read/28302013/multicyclic-peptides-as-scaffolds-for-the-development-of-tumor-targeting-agents
#20
REVIEW
Anastasia Loktev, Uwe Haberkorn, Walter Mier
The lack of specificity of traditional cytotoxic drugs triggers the development of anticancer agents with high selectivity to tumor-specific proteins. The unveiling of target structures such as EGFR or Her2 allows the focused development of novel therapies and has strongly advanced tumor treatment. Tumor-specific high-affinity ligands can be identified by using display techniques such as phage, yeast surface, ribosome and mRNA display. These techniques enable the screening of huge libraries, consequently providing a valuable alternative to rational drug development...
2017: Current Medicinal Chemistry
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