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Genome scale screen

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https://www.readbyqxmd.com/read/30104661/terminal-uridylyltransferases-target-rna-viruses-as-part-of-the-innate-immune-system
#1
Jérémie Le Pen, Hongbing Jiang, Tomás Di Domenico, Emma Kneuss, Joanna Kosałka, Christian Leung, Marcos Morgan, Christian Much, Konrad L M Rudolph, Anton J Enright, Dónal O'Carroll, David Wang, Eric A Miska
RNA viruses are a major threat to animals and plants. RNA interference (RNAi) and the interferon response provide innate antiviral defense against RNA viruses. Here, we performed a large-scale screen using Caenorhabditis elegans and its natural pathogen the Orsay virus (OrV), and we identified cde-1 as important for antiviral defense. CDE-1 is a homolog of the mammalian TUT4 and TUT7 terminal uridylyltransferases (collectively called TUT4(7)); its catalytic activity is required for its antiviral function. CDE-1 uridylates the 3' end of the OrV RNA genome and promotes its degradation in a manner independent of the RNAi pathway...
August 13, 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/30103702/unsupervised-correction-of-gene-independent-cell-responses-to-crispr-cas9-targeting
#2
Francesco Iorio, Fiona M Behan, Emanuel Gonçalves, Shriram G Bhosle, Elisabeth Chen, Rebecca Shepherd, Charlotte Beaver, Rizwan Ansari, Rachel Pooley, Piers Wilkinson, Sarah Harper, Adam P Butler, Euan A Stronach, Julio Saez-Rodriguez, Kosuke Yusa, Mathew J Garnett
BACKGROUND: Genome editing by CRISPR-Cas9 technology allows large-scale screening of gene essentiality in cancer. A confounding factor when interpreting CRISPR-Cas9 screens is the high false-positive rate in detecting essential genes within copy number amplified regions of the genome. We have developed the computational tool CRISPRcleanR which is capable of identifying and correcting gene-independent responses to CRISPR-Cas9 targeting. CRISPRcleanR uses an unsupervised approach based on the segmentation of single-guide RNA fold change values across the genome, without making any assumption about the copy number status of the targeted genes...
August 13, 2018: BMC Genomics
https://www.readbyqxmd.com/read/30097719/genome-wide-investigation-of-an-id-cohort-reveals-de-novo-3-utr-variants-affecting-gene-expression
#3
Paolo Devanna, Maartje van de Vorst, Rolph Pfundt, Christian Gilissen, Sonja C Vernes
Intellectual disability (ID) is a severe neurodevelopmental disorder with genetically heterogeneous causes. Large-scale sequencing has led to the identification of many gene-disrupting mutations; however, a substantial proportion of cases lack a molecular diagnosis. As such, there remains much to uncover for a complete understanding of the genetic underpinnings of ID. Genetic variants present in non-coding regions of the genome have been highlighted as potential contributors to neurodevelopmental disorders given their role in regulating gene expression...
August 10, 2018: Human Genetics
https://www.readbyqxmd.com/read/30096814/predicting-microrna-mediated-gene-regulation-between-human-and-viruses
#4
Xin Shu, Xinyuan Zang, Xiaoshuang Liu, Jie Yang, Jin Wang
MicroRNAs (miRNAs) mediate various biological processes by actively fine-tuning gene expression at the post-transcriptional level. With the identification of numerous human and viral miRNAs, growing evidence has indicated a common role of miRNAs in mediating the interactions between humans and viruses. However, there is only limited information about Cross-Kingdom miRNA target sites from studies. To facilitate an extensive investigation on the interplay among the gene regulatory networks of humans and viruses, we designed a prediction pipeline, mirTarP, that is suitable for miRNA target screening on the genome scale...
August 8, 2018: Cells
https://www.readbyqxmd.com/read/30089637/a-genome-wide-net-to-catch-and-understand-cancer
#5
REVIEW
Neville E Sanjana
Genome-scale forward genetic screens elucidate the genetic basis of therapeutic resistance, tumor evolution, and metastasis in diverse human cancers.
August 8, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30087856/a-novel-dpyd-variant-associated-with-severe-toxicity-of-fluoropyrimidines-role-of-pre-emptive-dpyd-genotype-screening
#6
Chi C Tong, Ching W Lam, Ka O Lam, Victor H F Lee, Mai-Yee Luk
Background: The fluoropyrimidine anticancer drug, especially 5- fluorouracil (5-FU) and its prodrug capecitabine are still being the backbone of chemotherapeutic regimens for colorectal cancer. Dihydropyrimidine dehydrogenase (DPD) is the crucial enzyme in the catabolism of 5-FU. Over the past 30 years, there is substantial clinical evidence showing that DPD deficiency is strongly associated with severe and fatal fluoropyrimidine-induced toxicity. Patients and methods: A 49-year-old lady with resected stage III carcinoma of sigmoid colon was scheduled to have a course of 5-FU based adjuvant chemotherapy...
2018: Frontiers in Oncology
https://www.readbyqxmd.com/read/30081564/chemical-mutagenesis-and-fluorescence-based-high-throughput-screening-for-enhanced-accumulation-of-carotenoids-in-a-model-marine-diatom-phaeodactylum-tricornutum
#7
Zhiqian Yi, Yixi Su, Maonian Xu, Andreas Bergmann, Saevar Ingthorsson, Ottar Rolfsson, Kourosh Salehi-Ashtiani, Sigurdur Brynjolfsson, Weiqi Fu
Diatoms are a major group of unicellular algae that are rich in lipids and carotenoids. However, sustained research efforts are needed to improve the strain performance for high product yields towards commercialization. In this study, we generated a number of mutants of the model diatom Phaeodactylum tricornutum , a cosmopolitan species that has also been found in Nordic region, using the chemical mutagens ethyl methanesulfonate (EMS) and N -methyl- N '-nitro- N -nitrosoguanidine (NTG). We found that both chlorophyll a and neutral lipids had a significant correlation with carotenoid content and these correlations were better during exponential growth than in the stationary growth phase...
August 4, 2018: Marine Drugs
https://www.readbyqxmd.com/read/30066920/genome%C3%A2-scale-analysis-to-identify-potential-prognostic-microrna-biomarkers-for-predicting-overall-survival-in-patients-with-colon-adenocarcinoma
#8
Hao-Tang Wei, Er-Na Guo, Xi-Wen Liao, Li-Sheng Chen, Jia-Lei Wang, Min Ni, Chi Liang
The aim of the present study was to identify potential prognostic microRNA (miRNA) biomarkers for colon adenocarcinoma (COAD) prognostic prediction using the dataset of The Cancer Genome Atlas (TCGA). The genome‑wide miRNA sequencing dataset and corresponding COAD clinical information were downloaded from TCGA. Prognosis‑related miRNA screening was performed by genome‑wide multivariable Cox regression analysis and used for prognostic signature construction. Ten miRNAs (hsa‑mir‑891a, hsa‑mir‑6854, hsa‑mir‑216a, hsa‑mir‑378d‑1, hsa‑mir‑92a‑1, hsa‑mir‑4709, hsa‑mir‑92a‑2, hsa‑mir‑210, hsa‑mir‑940 and hsa‑mir‑887) were identified as prognostic miRNAs and used for further prognostic signature construction...
July 30, 2018: Oncology Reports
https://www.readbyqxmd.com/read/30065072/use-of-zebrafish-models-to-investigate-rare-human-disease
#9
Kathryn Isabel Adamson, Eamonn Sheridan, Andrew James Grierson
Rare diseases are collectively common and often extremely debilitating. Following the emergence of next-generation sequencing (NGS) technologies, the variants underpinning rare genetic disorders are being unearthed at an accelerating rate. However, many rare conditions lack effective treatments due to their poorly understood pathophysiology. There is therefore a growing demand for the development of novel experimental models of rare genetic diseases, so that potentially causative variants can be validated, pathogenic mechanisms can be investigated and therapeutic targets can be identified...
July 31, 2018: Journal of Medical Genetics
https://www.readbyqxmd.com/read/30059005/an-alternative-splicing-switch-in-flnb-promotes-the-mesenchymal-cell-state-in-human-breast-cancer
#10
Ji Li, Peter S Choi, Christine L Chaffer, Katherine Labella, Justin H Hwang, Andrew O Giacomelli, Jong Wook Kim, Nina Ilic, John G Doench, Seav Huong Ly, Chao Dai, Kimberly Hagel, Andrew L Hong, Ole Gjoerup, Shom Goel, Jennifer Y Ge, David E Root, Jean J Zhao, Angela N Brooks, Robert A Weinberg, William C Hahn
Alternative splicing of mRNA precursors represents a key gene expression regulatory step and permits the generation of distinct protein products with diverse functions. In a genome-scale expression screen for inducers of the epithelial-to-mesenchymal transition (EMT), we found a striking enrichment of RNA-binding proteins. We validated that QKI and RBFOX1 were necessary and sufficient to induce an intermediate mesenchymal cell state and increased tumorigenicity. Using RNA-seq and eCLIP analysis, we found that QKI and RBFOX1 coordinately regulated the splicing and function of the actin-binding protein FLNB, which plays a causal role in the regulation of EMT...
July 30, 2018: ELife
https://www.readbyqxmd.com/read/30053901/integrative-omics-analyses-broaden-treatment-targets-in-human-cancer
#11
Sohini Sengupta, Sam Q Sun, Kuan-Lin Huang, Clara Oh, Matthew H Bailey, Rajees Varghese, Matthew A Wyczalkowski, Jie Ning, Piyush Tripathi, Joshua F McMichael, Kimberly J Johnson, Cyriac Kandoth, John Welch, Cynthia Ma, Michael C Wendl, Samuel H Payne, David Fenyö, Reid R Townsend, John F Dipersio, Feng Chen, Li Ding
BACKGROUND: Although large-scale, next-generation sequencing (NGS) studies of cancers hold promise for enabling precision oncology, challenges remain in integrating NGS with clinically validated biomarkers. METHODS: To overcome such challenges, we utilized the Database of Evidence for Precision Oncology (DEPO) to link druggability to genomic, transcriptomic, and proteomic biomarkers. Using a pan-cancer cohort of 6570 tumors, we identified tumors with potentially druggable biomarkers consisting of drug-associated mutations, mRNA expression outliers, and protein/phosphoprotein expression outliers identified by DEPO...
July 27, 2018: Genome Medicine
https://www.readbyqxmd.com/read/30053271/pharmacodb-an-integrative-database-for-mining-in-vitro-anticancer-drug-screening-studies
#12
Petr Smirnov, Victor Kofia, Alexander Maru, Mark Freeman, Chantal Ho, Nehme El-Hachem, George-Alexandru Adam, Wail Ba-Alawi, Zhaleh Safikhani, Benjamin Haibe-Kains
Recent cancer pharmacogenomic studies profiled large panels of cell lines against hundreds of approved drugs and experimental chemical compounds. The overarching goal of these screens is to measure sensitivity of cell lines to chemical perturbations, correlate these measures to genomic features, and thereby develop novel predictors of drug response. However, leveraging these valuable data is challenging due to the lack of standards for annotating cell lines and chemical compounds, and quantifying drug response...
January 4, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/30045945/genome-scale-crispr-cas9-screen-identifies-druggable-dependencies-in-tp53-wild-type-ewing-sarcoma
#13
Björn Stolte, Amanda Balboni Iniguez, Neekesh V Dharia, Amanda L Robichaud, Amy Saur Conway, Ann M Morgan, Gabriela Alexe, Nathan J Schauer, Xiaoxi Liu, Gregory H Bird, Aviad Tsherniak, Francisca Vazquez, Sara J Buhrlage, Loren D Walensky, Kimberly Stegmaier
Ewing sarcoma is a pediatric cancer driven by EWS-ETS transcription factor fusion oncoproteins in an otherwise stable genomic background. The majority of tumors express wild-type TP53 , and thus, therapies targeting the p53 pathway would benefit most patients. To discover targets specific for TP53 wild-type Ewing sarcoma, we used a genome-scale CRISPR-Cas9 screening approach and identified and validated MDM2 , MDM4 , USP7, and PPM1D as druggable dependencies. The stapled peptide inhibitor of MDM2 and MDM4, ATSP-7041, showed anti-tumor efficacy in vitro and in multiple mouse models...
August 6, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/30043362/application-of-crispr-cas-to-understand-cis-and-trans-regulatory-elements-in-plants
#14
Felix Wolter, Holger Puchta
The recent emergence of the CRISPR/Cas system as a genome editing tool enables simple, fast, and efficient induction of DNA double-strand breaks at precise positions in the genome. This has proven extremely useful for analysis and modification of protein-coding sequences. Regulatory sequences have received much less attention, but can now be quickly and easily disrupted as well. Editing of cis-regulatory elements (CRE) offers considerable potential for crop improvement via fine-tuning of gene expression that cannot be achieved by simple KO mutations, but its widespread application is still hampered by a lack of precise knowledge about functional motifs in CRE...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/30042095/genome-wide-screen-identifies-cullin-ring-ligase-machinery-required-for-lenalidomide-dependent-crl4-crbn-activity
#15
Quinlan L Sievers, Jessica A Gasser, Glenn S Cowley, Eric S Fischer, Benjamin L Ebert
Lenalidomide mediates the ubiquitination and degradation of IKZF1, IKZF3 and CK1α by facilitating their interaction with cereblon (CRBN), the substrate receptor for the CRL4CRBN E3 ubiquitin ligase. Through this mechanism, lenalidomide is a clinically effective treatment for multiple myeloma and myelodysplastic syndrome with deletion of chromosome 5q (del(5q) MDS). To identify the cellular machinery required for lenalidomide-induced CRL4CRBN activity, we performed a positive selection, genome-scale CRISPR-Cas9 screen in a lenalidomide-sensitive myeloma cell line...
July 24, 2018: Blood
https://www.readbyqxmd.com/read/30040834/an-enormous-potential-for-niche-construction-through-bacterial-cross-feeding-in-a-homogeneous-environment
#16
Magdalena San Roman, Andreas Wagner
Microorganisms modify their environment by excreting by-products of metabolism, which can create new ecological niches that can help microbial populations diversify. A striking example comes from experimental evolution of genetically identical Escherichia coli populations that are grown in a homogeneous environment with the single carbon source glucose. In such experiments, stable communities of genetically diverse cross-feeding E. coli cells readily emerge. Some cells that consume the primary carbon source glucose excrete a secondary carbon source, such as acetate, that sustains other community members...
July 2018: PLoS Computational Biology
https://www.readbyqxmd.com/read/30039847/marginal-screening-of-2-%C3%A3-2-tables-in-large-scale-case-control-studies
#17
Ian W McKeague, Min Qian
Assessing the statistical significance of risk factors when screening large numbers of 2×2 tables that cross-classify disease status with each type of exposure poses a challenging multiple testing problem. The problem is especially acute in large-scale genomic case-control studies. We develop a potentially more powerful and computationally efficient approach (compared with existing methods, including Bonferroni and permutation testing) by taking into account the presence of complex dependencies between the 2×2 tables...
July 24, 2018: Biometrics
https://www.readbyqxmd.com/read/30039311/genome-shuffling-and-high-throughput-screening-of-brevibacterium-flavum-mdv1-for-enhanced-l-valine-production
#18
Qin-Geng Huang, Bang-Ding Zeng, Ling Liang, Song-Gang Wu, Jian-Zhong Huang
L-valine is an essential branched-amino acid that is widely used in multiple areas such as pharmaceuticals and special dietary products and its use is increasing. As the world market for L-valine grows rapidly, there is an increasing interest to develop an efficient L-valine-producing strain. In this study, a simple, sensitive, efficient, and consistent screening procedure termed 96 well plate-PC-HPLC (96-PH) was developed for the rapid identification of high-yield L-valine strains to replace the traditional L-valine assay...
July 23, 2018: World Journal of Microbiology & Biotechnology
https://www.readbyqxmd.com/read/30026574/a-genome-scale-crispr-cas9-screening-in-myeloma-cells-identifies-regulators-of-immunomodulatory-drug-sensitivity
#19
Jiye Liu, Tianyu Song, Wenrong Zhou, Lijie Xing, Su Wang, Matthew Ho, Zhengang Peng, Yu-Tzu Tai, Teru Hideshima, Kenneth C Anderson, Yong Cang
Immunomodulatory drugs (IMiDs) including lenalidomide and pomalidomide bind cereblon (CRBN) and activate the CRL4CRBN ubiquitin ligase to trigger proteasomal degradation of the essential transcription factors IKZF1 and IKZF3 and multiple myeloma (MM) cytotoxicity. We have shown that CRBN is also targeted for degradation by SCFFbxo7 ubiquitin ligase. In the current study, we explored the mechanisms underlying sensitivity of MM cells to IMiDs using genome-wide CRISPR-Cas9 screening. We validate that CSN9 signalosome complex, a deactivator of Cullin-RING ubiquitin ligase, inhibits SCFFbxo7 E3 ligase-mediated CRBN degradation, thereby conferring sensitivity to IMiDs; conversely, loss of function of CSN9 signalosome activates SCFFbxo7 complex, thereby enhancing degradation of CRBN and conferring IMiD resistance...
July 19, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/30023898/extracting-compound-profiling-matrices-from-screening-data
#20
Martin Vogt, Swarit Jasial, Jürgen Bajorath
Compound profiling matrices record assay results for compound libraries tested against panels of targets. In addition to their relevance for exploring structure-activity relationships, such matrices are of considerable interest for chemoinformatic and chemogenomic applications. For example, profiling matrices provide a valuable data resource for the development and evaluation of machine learning approaches for multitask activity prediction. However, experimental compound profiling matrices are rare in the public domain...
April 30, 2018: ACS Omega
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