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Combinatorial genomics

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https://www.readbyqxmd.com/read/29775471/host-directed-combinatorial-rnai-improves-inhibition-of-diverse-strains-of-influenza-a-virus-in-human-respiratory-epithelial-cells
#1
Michael A Estrin, Islam T M Hussein, Wendy B Puryear, Anne C Kuan, Stephen C Artim, Jonathan A Runstadler
Influenza A virus infections are important causes of morbidity and mortality worldwide, and currently available prevention and treatment methods are suboptimal. In recent years, genome-wide investigations have revealed numerous host factors that are required for influenza to successfully complete its life cycle. However, only a select, small number of influenza strains were evaluated using this platform, and there was considerable variation in the genes identified across different investigations. In an effort to develop a universally efficacious therapeutic strategy with limited potential for the emergence of resistance, this study was performed to investigate the effect of combinatorial RNA interference (RNAi) on inhibiting the replication of diverse influenza A virus subtypes and strains...
2018: PloS One
https://www.readbyqxmd.com/read/29772680/the-crosstalk-of-endoplasmic-reticulum-er-stress-pathways-with-nf-%C3%AE%C2%BAb-complex-mechanisms-relevant-for-cancer-inflammation-and-infection
#2
REVIEW
M Lienhard Schmitz, M Samer Shaban, B Vincent Albert, Anke Gökçen, Michael Kracht
Stressful conditions occuring during cancer, inflammation or infection activate adaptive responses that are controlled by the unfolded protein response (UPR) and the nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-κB) signaling pathway. These systems can be triggered by chemical compounds but also by cytokines, toll-like receptor ligands, nucleic acids, lipids, bacteria and viruses. Despite representing unique signaling cascades, new data indicate that the UPR and NF-κB pathways converge within the nucleus through ten major transcription factors (TFs), namely activating transcription factor (ATF)4, ATF3, CCAAT/enhancer-binding protein (CEBP) homologous protein (CHOP), X-box-binding protein (XBP)1, ATF6α and the five NF-κB subunits...
May 16, 2018: Biomedicines
https://www.readbyqxmd.com/read/29765774/how-shall-we-treat-early-triple-negative-breast-cancer-tnbc-from-the-current-standard-to-upcoming-immuno-molecular-strategies
#3
REVIEW
Ji Hyun Park, Jin-Hee Ahn, Sung-Bae Kim
Triple-negative breast cancer (TNBC) is a long-lasting orphan disease in terms of little therapeutic progress during the past several decades and still the standard of care remains chemotherapy. Experimental discovery of molecular signatures including the 'BRCAness' highlighted the innate heterogeneity of TNBC, generating the diversity of TNBC phenotypes. As it contributes to enhancing genomic instability, it has widened the therapeutic spectrum of TNBC. In particular, unusual sensitivity to DNA damaging agents was denoted in patients with BRCA deficiency, suggesting therapeutic benefit from platinum and poly(ADP-ribose) polymerase inhibitors...
2018: ESMO Open
https://www.readbyqxmd.com/read/29760061/methylglucosylation-of-aromatic-amino-and-phenolic-moieties-of-drug-like-biosynthons-by-combinatorial-biosynthesis
#4
Linan Xie, Liwen Zhang, Chen Wang, Xiaojing Wang, Ya-Ming Xu, Hefen Yu, Ping Wu, Shenglan Li, Lida Han, A A Leslie Gunatilaka, Xiaoyi Wei, Min Lin, István Molnár, Yuquan Xu
Glycosylation is a prominent strategy to optimize the pharmacokinetic and pharmacodynamic properties of drug-like small-molecule scaffolds by modulating their solubility, stability, bioavailability, and bioactivity. Glycosyltransferases applicable for "sugarcoating" various small-molecule acceptors have been isolated and characterized from plants and bacteria, but remained cryptic from filamentous fungi until recently, despite the frequent use of some fungi for whole-cell biocatalytic glycosylations...
May 14, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29754820/interfaces-of-malignant-and-immunologic-clonal-dynamics-in-ovarian-cancer
#5
Allen W Zhang, Andrew McPherson, Katy Milne, David R Kroeger, Phineas T Hamilton, Alex Miranda, Tyler Funnell, Nicole Little, Camila P E de Souza, Sonya Laan, Stacey LeDoux, Dawn R Cochrane, Jamie L P Lim, Winnie Yang, Andrew Roth, Maia A Smith, Julie Ho, Kane Tse, Thomas Zeng, Inna Shlafman, Michael R Mayo, Richard Moore, Henrik Failmezger, Andreas Heindl, Yi Kan Wang, Ali Bashashati, Diljot S Grewal, Scott D Brown, Daniel Lai, Adrian N C Wan, Cydney B Nielsen, Curtis Huebner, Basile Tessier-Cloutier, Michael S Anglesio, Alexandre Bouchard-Côté, Yinyin Yuan, Wyeth W Wasserman, C Blake Gilks, Anthony N Karnezis, Samuel Aparicio, Jessica N McAlpine, David G Huntsman, Robert A Holt, Brad H Nelson, Sohrab P Shah
High-grade serous ovarian cancer (HGSC) exhibits extensive malignant clonal diversity with widespread but non-random patterns of disease dissemination. We investigated whether local immune microenvironment factors shape tumor progression properties at the interface of tumor-infiltrating lymphocytes (TILs) and cancer cells. Through multi-region study of 212 samples from 38 patients with whole-genome sequencing, immunohistochemistry, histologic image analysis, gene expression profiling, and T and B cell receptor sequencing, we identified three immunologic subtypes across samples and extensive within-patient diversity...
May 7, 2018: Cell
https://www.readbyqxmd.com/read/29746690/retrospective-analysis-reproducibility-of-interblastomere-differences-of-mrna-expression-in-2-cell-stage-mouse-embryos-is-remarkably-poor-due-to-combinatorial-mechanisms-of-blastomere-diversification
#6
E Casser, S Israel, S Schlatt, V Nordhoff, M Boiani
STUDY QUESTION: What is the prevalence, reproducibility and biological significance of transcriptomic differences between sister blastomeres of the mouse 2-cell embryo? SUMMARY ANSWER: Sister 2-cell stage blastomeres are distinguishable from each other by mRNA analysis, attesting to the fact that differentiation starts mostly early in the mouse embryo; however, the interblastomere differences are poorly reproducible and invoke the combinatorial effects of known and new mechanisms of blastomere diversification...
May 9, 2018: Molecular Human Reproduction
https://www.readbyqxmd.com/read/29745861/computing-the-family-free-dcj-similarity
#7
Diego P Rubert, Edna A Hoshino, Marília D V Braga, Jens Stoye, Fábio V Martinez
BACKGROUND: The genomic similarity is a large-scale measure for comparing two given genomes. In this work we study the (NP-hard) problem of computing the genomic similarity under the DCJ model in a setting that does not assume that the genes of the compared genomes are grouped into gene families. This problem is called family-free DCJ similarity. RESULTS: We propose an exact ILP algorithm to solve the family-free DCJ similarity problem, then we show its APX-hardness and present four combinatorial heuristics with computational experiments comparing their results to the ILP...
May 8, 2018: BMC Bioinformatics
https://www.readbyqxmd.com/read/29745846/pinning-down-ploidy-in-paleopolyploid-plants
#8
Yue Zhang, Chunfang Zheng, David Sankoff
BACKGROUND: Fractionation is the genome-wide process of losing one gene per duplicate pair following whole genome multiplication (doubling, tripling, …). This is important in the evolution of plants over tens of millions of years, because of their repeated cycles of genome multiplication and fractionation. One type of evidence in the study of these processes is the frequency distribution of similarities between the two genes, over all the duplicate pairs in the genome. RESULTS: We study modeling and inference problems around the processes of fractionation and whole genome multiplication focusing first on the frequency distribution of similarities of duplicate pairs in the genome...
May 8, 2018: BMC Genomics
https://www.readbyqxmd.com/read/29740109/locus-specific-engineering-of-tandem-dna-repeats-in-the-genome-of-saccharomyces-cerevisiae-using-crispr-cas9-and-overlapping-oligonucleotides
#9
Astrid Lancrey, Alexandra Joubert, Jean-Baptiste Boulé
DNA repeats constitute a large part of genomes of multicellular eucaryotes. For a longtime considered as junk DNA, their role in genome organization and tuning of gene expression is being increasingly documented. Synthetic biology has so far largely ignored DNA repeats as regulatory elements to manipulate functions in engineered genomes. The yeast Saccharomyces cerevisiae has been a workhorse of synthetic biology, owing to its genetic tractability. Here we demonstrate the ability to synthetize, in a simple manner, tandem DNA repeats of various size by Cas9-assisted oligonucleotide in vivo assembly in this organism...
May 8, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29739937/networks-of-genetic-similarity-reveal-non-neutral-processes-shape-strain-structure-in-plasmodium-falciparum
#10
Qixin He, Shai Pilosof, Kathryn E Tiedje, Shazia Ruybal-Pesántez, Yael Artzy-Randrup, Edward B Baskerville, Karen P Day, Mercedes Pascual
Pathogens compete for hosts through patterns of cross-protection conferred by immune responses to antigens. In Plasmodium falciparum malaria, the var multigene family encoding for the major blood-stage antigen PfEMP1 has evolved enormous genetic diversity through ectopic recombination and mutation. With 50-60 var genes per genome, it is unclear whether immune selection can act as a dominant force in structuring var repertoires of local populations. The combinatorial complexity of the var system remains beyond the reach of existing strain theory and previous evidence for non-random structure cannot demonstrate immune selection without comparison with neutral models...
May 8, 2018: Nature Communications
https://www.readbyqxmd.com/read/29739269/analytical-validation-of-a-psychiatric-pharmacogenomic-test
#11
Michael R Jablonski, Nina King, Yongbao Wang, Joel G Winner, Lucas R Watterson, Sandra Gunselman, Bryan M Dechairo
AIM: The aim of this study was to validate the analytical performance of a combinatorial pharmacogenomics test designed to aid in the appropriate medication selection for neuropsychiatric conditions. MATERIALS & METHODS: Genomic DNA was isolated from buccal swabs. Twelve genes (65 variants/alleles) associated with psychotropic medication metabolism, side effects, and mechanisms of actions were evaluated by bead array, MALDI-TOF mass spectrometry, and/or capillary electrophoresis methods (GeneSight Psychotropic, Assurex Health, Inc...
February 7, 2018: Personalized Medicine
https://www.readbyqxmd.com/read/29736010/mps1-inhibitors-synergise-with-low-doses-of-taxanes-in-promoting-tumour-cell-death-by-enhancement-of-errors-in-cell-division
#12
Ana Rita R Maia, Simon Linder, Ji-Ying Song, Chantal Vaarting, Ute Boon, Colin E J Pritchard, Arno Velds, Ivo J Huijbers, Olaf van Tellingen, Jos Jonkers, René H Medema
BACKGROUND: Chromosomal instability (CIN) is a common trait of cancer characterised by the continuous gain and loss of chromosomes during mitosis. Excessive levels of CIN can suppress tumour growth, providing a possible therapeutic strategy. The Mps1/TTK kinase has been one of the prime targets to explore this concept, and indeed Mps1 inhibitors synergise with the spindle poison docetaxel in inhibiting the growth of tumours in mice. METHODS: To investigate how the combination of docetaxel and a Mps1 inhibitor (Cpd-5) promote tumour cell death, we treated mice transplanted with BRCA1-/- ;TP53-/- mammary tumours with docetaxel and/or Cpd-5...
May 8, 2018: British Journal of Cancer
https://www.readbyqxmd.com/read/29729128/a-high-throughput-workflow-for-crispr-cas9-mediated-combinatorial-promoter-replacements-and-phenotype-characterization-in-yeast
#13
Joosu Kuivanen, Sami Holmström, Birgitta Lehtinen, Merja Penttilä, Jussi Jäntti
Due to the rapidly increasing sequence information on gene variants generated by evolution and our improved abilities to engineer novel biological activities, microbial cells can be evolved for the production of a growing spectrum of compounds. For high productivity, efficient carbon channeling towards the end product is a key element. In large scale production systems the genetic modifications that ensure optimal performance cannot be dependent on plasmid-based regulators, but need to be engineered stably into the host genome...
May 5, 2018: Biotechnology Journal
https://www.readbyqxmd.com/read/29721088/imaging-myeloid-precursor-immortalization-and-genome-editing-for-defining-mechanisms-of-leukocyte-recruitment-in-vivo
#14
Sandra Gran, Lisa Honold, Olesja Fehler, Stefanie Zenker, Sarah Eligehausen, Michael T Kuhlmann, Edwin Geven, Martijn van den Bosch, Peter van Lent, Christoph Spiekermann, Sven Hermann, Thomas Vogl, Michael Schäfers, Johannes Roth
Recruitment of leukocytes from the blood to sites of inflammation poses a promising target for new diagnostic and therapeutic approaches. We aimed to develop a novel method to non-invasively analyze molecular mechanisms of leukocyte migration in pre-clinical models of inflammation in vivo . Methods: We used the ER-HoxB8 system to transiently immortalize murine myeloid precursors from wildtype and CD18- as well as MRP14-deficient mice. A VLA4α-/- cell line was generated by CRISPR/Cas9-mediated gene editing...
2018: Theranostics
https://www.readbyqxmd.com/read/29719789/biosynthesis-of-antibiotic-chuangxinmycin-from-actinoplanes-tsinanensis
#15
Yuanyuan Shi, Zhibo Jiang, Xingxing Li, Lijie Zuo, Xuan Lei, Liyan Yu, Linzhuan Wu, Jiandong Jiang, Bin Hong
Chuangxinmycin is an antibiotic isolated from Actinoplanes tsinanensis CPCC 200056 in the 1970s with a novel indole-dihydrothiopyran heterocyclic skeleton. Chuangxinmycin showed in vitro antibacterial activity and in vivo efficacy in mouse infection models as well as preliminary clinical trials. But the biosynthetic pathway of chuangxinmycin has been obscure since its discovery. Herein, we report the identification of a stretch of DNA from the genome of A. tsinanensis CPCC 200056 that encodes genes for biosynthesis of chuangxinmycin by bioinformatics analysis...
March 2018: Acta Pharmaceutica Sinica. B
https://www.readbyqxmd.com/read/29717463/highly-efficient-and-reliable-dna-aptamer-selection-using-the-partitioning-capabilities-of-ddpcr-the-hi-fi-selex-method
#16
Aaron Ang, Eric Ouellet, Karen C Cheung, Charles Haynes
In addition to its growing use in detecting and quantifying genes and larger genomic events, the partitioning used in digital PCR can serve as a powerful tool for high-fidelity amplification of synthetic combinatorial libraries of single-stranded DNA. Sequence-diverse libraries of this type are used as a basis for selecting tight-binding aptamers against a specific target. Here we provide a detailed description of the Hi-Fi SELEX protocol for rapid and efficient DNA aptamer selection. As part of that methodology, we describe how Hi-Fi SELEX gains advantages over other aptamer selection methods in part through the use of the massive partitioning capability of digital PCR...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29713375/engineering-global-transcription-to-tune-lipophilic-properties-in-yarrowia-lipolytica
#17
Man Wang, Guan-Nan Liu, Hong Liu, Lu Zhang, Bing-Zhi Li, Xia Li, Duo Liu, Ying-Jin Yuan
Background: Evolution of complex phenotypes in cells requires simultaneously tuning expression of large amounts of genes, which can be achieved by reprograming global transcription. Lipophilicity is an important complex trait in oleaginous yeast Yarrowia lipolytica . It is necessary to explore the changes of which genes' expression levels will tune cellular lipophilic properties via the strategy of global transcription engineering. Results: We achieved a strategy of global transcription engineering in Y...
2018: Biotechnology for Biofuels
https://www.readbyqxmd.com/read/29704438/crispr-interference-mediated-metabolic-engineering-of-corynebacterium-glutamicum-for-homo-butyrate-production
#18
Jinkyung Yoon, Han Min Woo
Combinatorial metabolic engineering enabled the development of efficient microbial cell factories for modulating gene expression to produce desired products. Here, we report the combinatorial metabolic engineering of Corynebacterium glutamicum to produce butyrate by introducing a synthetic butyrate pathway including phosphotransferase and butyrate kinase reactions and repressing the essential acn gene encoding aconitase, which has been targeted for down-regulation in a genome-scale model. An All-in-One CRISPR interference system for C...
April 28, 2018: Biotechnology and Bioengineering
https://www.readbyqxmd.com/read/29702275/recent-advances-in-metabolic-engineering-of-saccharomyces-cerevisiae-new-tools-and-their-applications
#19
REVIEW
Jiazhang Lian, Shekhar Mishra, Huimin Zhao
Metabolic engineering aims to develop efficient cell factories by rewiring cellular metabolism. As one of the most commonly used cell factories, Saccharomyces cerevisiae has been extensively engineered to produce a wide variety of products at high levels from various feedstocks. In this review, we summarize the recent development of metabolic engineering approaches to modulate yeast metabolism with representative examples. Particularly, we highlight new tools for biosynthetic pathway optimization (i.e. combinatorial transcriptional engineering and dynamic metabolic flux control) and genome engineering (i...
April 24, 2018: Metabolic Engineering
https://www.readbyqxmd.com/read/29700043/enhancement-of-red-blood-cell-transfusion-compatibility-using-crispr-mediated-erythroblast-gene-editing
#20
Joseph Hawksworth, Timothy J Satchwell, Marjolein Meinders, Deborah E Daniels, Fiona Regan, Nicole M Thornton, Marieangela C Wilson, Johannes Gg Dobbe, Geert J Streekstra, Kongtana Trakarnsanga, Kate J Heesom, David J Anstee, Jan Frayne, Ashley M Toye
Regular blood transfusion is the cornerstone of care for patients with red blood cell (RBC) disorders such as thalassaemia or sickle-cell disease. With repeated transfusion, alloimmunisation often occurs due to incompatibility at the level of minor blood group antigens. We use CRISPR-mediated genome editing of an immortalised human erythroblast cell line (BEL-A) to generate multiple enucleation competent cell lines deficient in individual blood groups. Edits are combined to generate a single cell line deficient in multiple antigens responsible for the most common transfusion incompatibilities: ABO (Bombay phenotype), Rh (Rhnull ), Kell ( K 0 ), Duffy (Duffynull ), GPB (S- s- U- )...
April 26, 2018: EMBO Molecular Medicine
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