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Inducible crispr

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https://www.readbyqxmd.com/read/27906098/direct-reprogramming-of-urine-derived-cells-with-inducible-myod-for-modeling-human-muscle-disease
#1
Ellis Y Kim, Patrick Page, Lisa M Dellefave-Castillo, Elizabeth M McNally, Eugene J Wyatt
BACKGROUND: Cellular models of muscle disease are taking on increasing importance with the large number of genes and mutations implicated in causing myopathies and the concomitant need to test personalized therapies. Developing cell models relies on having an easily obtained source of cells, and if the cells are not derived from muscle itself, a robust reprogramming process is needed. Fibroblasts are a human cell source that works well for the generation of induced pluripotent stem cells, which can then be differentiated into cardiomyocyte lineages, and with less efficiency, skeletal muscle-like lineages...
September 15, 2016: Skeletal Muscle
https://www.readbyqxmd.com/read/27902686/genomic-characterization-of-metformin-hepatic-response
#2
Marcelo R Luizon, Walter L Eckalbar, Yao Wang, Stacy L Jones, Robin P Smith, Megan Laurance, Lawrence Lin, Paul J Gallins, Amy S Etheridge, Fred Wright, Yihui Zhou, Cliona Molony, Federico Innocenti, Sook Wah Yee, Kathleen M Giacomini, Nadav Ahituv
Metformin is used as a first-line therapy for type 2 diabetes (T2D) and prescribed for numerous other diseases. However, its mechanism of action in the liver has yet to be characterized in a systematic manner. To comprehensively identify genes and regulatory elements associated with metformin treatment, we carried out RNA-seq and ChIP-seq (H3K27ac, H3K27me3) on primary human hepatocytes from the same donor treated with vehicle control, metformin or metformin and compound C, an AMP-activated protein kinase (AMPK) inhibitor (allowing to identify AMPK-independent pathways)...
November 2016: PLoS Genetics
https://www.readbyqxmd.com/read/27899566/asymmetric-positioning-of-cas1-2-complex-and-integration-host-factor-induced-dna-bending-guide-the-unidirectional-homing-of-protospacer-in-crispr-cas-type-i-e-system
#3
K N R Yoganand, R Sivathanu, Siddharth Nimkar, B Anand
CRISPR-Cas system epitomizes prokaryote-specific quintessential adaptive defense machinery that limits the genome invasion of mobile genetic elements. It confers adaptive immunity to bacteria by capturing a protospacer fragment from invading foreign DNA, which is later inserted into the leader proximal end of CRIPSR array and serves as immunological memory to recognize recurrent invasions. The universally conserved Cas1 and Cas2 form an integration complex that is known to mediate the protospacer invasion into the CRISPR array...
November 29, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27899508/optimized-inducible-shrna-and-crispr-cas9-platforms-for-in-vitro-studies-of-human-development-using-hpscs
#4
Alessandro Bertero, Matthias Pawlowski, Daniel Ortmann, Kirsten Snijders, Loukia Yiangou, Miguel Cardoso de Brito, Stephanie Brown, William G Bernard, James D Cooper, Elisa Giacomelli, Laure Gambardella, Nicholas R F Hannan, Dharini Iyer, Fotios Sampaziotis, Felipe Serrano, Mariëlle C F Zonneveld, Sanjay Sinha, Mark Kotter, Ludovic Vallier
Inducible loss of gene function experiments are necessary to uncover mechanisms underlying development, physiology and disease. However, current methods are complex, lack robustness and do not work in multiple cell types. Here we address these limitations by developing single-step optimized inducible gene knockdown or knockout (sOPTiKD or sOPTiKO) platforms. These are based on genetic engineering of human genomic safe harbors combined with an improved tetracycline-inducible system and CRISPR/Cas9 technology...
December 1, 2016: Development
https://www.readbyqxmd.com/read/27899159/p53-signaling-modulation-of-cell-cycle-arrest-and-viral-replication-in-porcine-circovirus-type-2-infection-cells
#5
Dan Xu, Qian Du, Cong Han, Zengguo Wang, Xiujuan Zhang, Tongtong Wang, Xiaomin Zhao, Yong Huang, Dewen Tong
Porcine circovirus type 2 (PCV2) is a ubiquitous pathogen in the swine industry worldwide. Previous studies have shown that PCV2 infection induces host cell apoptosis through up-regulation of p53. To further identify the regulatory roles of p53 signaling in the process of PCV2 infection, we established p53 gene knockout PK15 cell lines using the genomic editor tool CRISPR/Cas9, and further investigated the roles of p53 in modulating the cell cycle and viral replication in this study. The results show that PCV2 infection induced obvious S phase accumulation in wild-type PK15 cells and a compromised S phase accumulation in the p53 gene mutation cells (813PK15 (p53m/m) ), but did not induce obvious S phase accumulation in the p53 gene knockout cells (148PK15 (p53-/-)) compared with the respective mock infection...
November 29, 2016: Veterinary Research
https://www.readbyqxmd.com/read/27898262/characterization-of-genetic-loss-of-function-of-fus-in-zebrafish
#6
Svetlana Lebedeva, António M de Jesus Domingues, Falk Butter, René F Ketting
The RNA-binding protein FUS is implicated in transcription, alternative splicing of neuronal genes and DNA repair. Mutations in FUS have been linked to human neurodegenerative diseases such as ALS (amyotrophic lateral sclerosis). We genetically disrupted fus in zebrafish (Danio rerio) using the CRISPR-Cas9 system. The fus knockout animals are fertile and did not show any distinctive phenotype. Mutation of fus induces mild changes in gene expression on the transcriptome and proteome level in the adult brain...
November 29, 2016: RNA Biology
https://www.readbyqxmd.com/read/27898094/crispr-cas9-aav-mediated-knock-in-at-nrl-locus-in-human-embryonic-stem-cells
#7
Xianglian Ge, Haitao Xi, Fayu Yang, Xiao Zhi, Yanghua Fu, Ding Chen, Ren-He Xu, Ge Lin, Jia Qu, Junzhao Zhao, Feng Gu
Clustered interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-mediated genome engineering technologies are sparking a new revolution in biological research. This technology efficiently induces DNA double strand breaks at the targeted genomic sequence and results in indel mutations by the error-prone process of nonhomologous end joining DNA repair or homologous recombination with a DNA repair template. The efficiency of genome editing with CRISPR/Cas9 alone in human embryonic stem cells is still low...
November 29, 2016: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/27898091/restoring-ureagenesis-in-hepatocytes-by-crispr-cas9-mediated-genomic-addition-to-arginase-deficient-induced-pluripotent-stem-cells
#8
Patrick C Lee, Brian Truong, Agustin Vega-Crespo, W Blake Gilmore, Kip Hermann, Stephanie Ak Angarita, Jonathan K Tang, Katherine M Chang, Austin E Wininger, Alex K Lam, Benjamen E Schoenberg, Stephen D Cederbaum, April D Pyle, James A Byrne, Gerald S Lipshutz
Urea cycle disorders are incurable enzymopathies that affect nitrogen metabolism and typically lead to hyperammonemia. Arginase deficiency results from a mutation in Arg1, the enzyme regulating the final step of ureagenesis and typically results in developmental disabilities, seizures, spastic diplegia, and sometimes death. Current medical treatments for urea cycle disorders are only marginally effective, and for proximal disorders, liver transplantation is effective but limited by graft availability. Advances in human induced pluripotent stem cell research has allowed for the genetic modification of stem cells for potential cellular replacement therapies...
November 29, 2016: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/27895652/rapid-evolution-of-manifold-crispr-systems-for-plant-genome-editing
#9
REVIEW
Levi Lowder, Aimee Malzahn, Yiping Qi
Advanced CRISPR-Cas9 based technologies first validated in mammalian cell systems are quickly being adapted for use in plants. These new technologies increase CRISPR-Cas9's utility and effectiveness by diversifying cellular capabilities through expression construct system evolution and enzyme orthogonality, as well as enhanced efficiency through delivery and expression mechanisms. Here, we review the current state of advanced CRISPR-Cas9 and Cpf1 capabilities in plants and cover the rapid evolution of these tools from first generation inducers of double strand breaks for basic genetic manipulations to second and third generation multiplexed systems with myriad functionalities, capabilities, and specialized applications...
2016: Frontiers in Plant Science
https://www.readbyqxmd.com/read/27893734/an-ipsc-derived-vascular-model-of-marfan-syndrome-identifies-key-mediators-of-smooth-muscle-cell-death
#10
Alessandra Granata, Felipe Serrano, William George Bernard, Madeline McNamara, Lucinda Low, Priya Sastry, Sanjay Sinha
Marfan syndrome (MFS) is a heritable connective tissue disorder caused by mutations in FBN1, which encodes the extracellular matrix protein fibrillin-1. To investigate the pathogenesis of aortic aneurysms in MFS, we generated a vascular model derived from human induced pluripotent stem cells (MFS-hiPSCs). Our MFS-hiPSC-derived smooth muscle cells (SMCs) recapitulated the pathology seen in Marfan aortas, including defects in fibrillin-1 accumulation, extracellular matrix degradation, transforming growth factor-β (TGF-β) signaling, contraction and apoptosis; abnormalities were corrected by CRISPR-based editing of the FBN1 mutation...
November 28, 2016: Nature Genetics
https://www.readbyqxmd.com/read/27892925/a-mouse-model-for-mers-coronavirus-induced-acute-respiratory-distress-syndrome
#11
Adam S Cockrell, Boyd L Yount, Trevor Scobey, Kara Jensen, Madeline Douglas, Anne Beall, Xian-Chun Tang, Wayne A Marasco, Mark T Heise, Ralph S Baric
Middle East respiratory syndrome coronavirus (MERS-CoV) is a novel virus that emerged in 2012, causing acute respiratory distress syndrome (ARDS), severe pneumonia-like symptoms and multi-organ failure, with a case fatality rate of ∼36%. Limited clinical studies indicate that humans infected with MERS-CoV exhibit pathology consistent with the late stages of ARDS, which is reminiscent of the disease observed in patients infected with severe acute respiratory syndrome coronavirus. Models of MERS-CoV-induced severe respiratory disease have been difficult to achieve, and small-animal models traditionally used to investigate viral pathogenesis (mouse, hamster, guinea-pig and ferret) are naturally resistant to MERS-CoV...
November 28, 2016: Nature Microbiology
https://www.readbyqxmd.com/read/27890641/specific-point-mutations-in-key-redox-enzymes-are-associated-with-chemoresistance-in-epithelial-ovarian-cancer
#12
Nicole M Fletcher, Jimmy Belotte, Mohammed G Saed, Ira Memaj, Michael P Diamond, Robert T Morris, Ghassan M Saed
Oxidative stress plays an important role in the pathophysiology of ovarian cancer. Resistance to chemotherapy presents a significant challenge for ovarian cancer treatment. Specific single nucleotide polymorphisms (SNPs) in key redox enzymes have been associated with ovarian cancer survival and progression. The objective of this study was to determine whether chemotherapy induces point mutations in key redox enzymes that lead to the acquisition of chemoresistance in epithelial ovarian cancer (EOC). Human EOC cell lines and their chemoresistant counterpart were utilized for this study...
November 24, 2016: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/27888625/trim11-a-direct-target-of-mir-24-3p-promotes-cell-proliferation-and-inhibits-apoptosis-in-colon-cancer
#13
Yan Yin, Jun Zhong, Si-Wei Li, Jian-Zhe Li, Min Zhou, Yin Chen, Yi Sang, Lijuan Liu
TRIM11 (tripartite motif-containing protein 11) is an E3 ubiquitin ligase recently identified as an oncogene in malignant glioma and lung cancer. In the present study, we report that expression of TRIM11 was increased in colon cancer (CC) tissue relative to paired normal tissues and that higher TRIM11 levels predicted poor overall survival (OS) and disease-free survival (DFS) in CC patients. Mechanistically, we showed that miR-24-3p downregulation contributes to TRIM11 upregulation in CC. We also demonstrated that TRIM11 overexpression promotes cell proliferation and colony formation and inhibits apoptosis in CC, while knocking down TRIM11 using CRISPR/Cas9-mediated genome editing inhibited cell proliferation and induced apoptosis...
November 24, 2016: Oncotarget
https://www.readbyqxmd.com/read/27883055/gapmer-cellular-internalization-by-macropinocytosis-induces-sequence-specific-gene-silencing-in-human-primary-t-cells
#14
Mobashar Hussain Urf Turabe Fazil, Seow Theng Ong, Madhavi Latha Somaraju Chalasani, Jian Hui Low, Atish Kizhakeyil, Akshay Mamidi, Carey Fang Hui Lim, Graham D Wright, Rajamani Lakshminarayanan, Dermot Kelleher, Navin Kumar Verma
Post-transcriptional gene silencing holds great promise in discovery research for addressing intricate biological questions and as therapeutics. While various gene silencing approaches, such as siRNA and CRISPR-Cas9 techniques, are available, these cannot be effectively applied to "hard-to-transfect" primary T-lymphocytes. The locked nucleic acid-conjugated chimeric antisense oligonucleotide, called "GapmeR", is an emerging new class of gene silencing molecule. Here, we show that GapmeR internalizes into human primary T-cells through macropinocytosis...
November 24, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27881733/lysosomal-trafficking-regulator-lyst-links-membrane-trafficking-to-toll-like-receptor-mediated-inflammatory-responses
#15
Andreas Westphal, Weijia Cheng, Jinbo Yu, Guntram Grassl, Martina Krautkrämer, Otto Holst, Niko Föger, Kyeong-Hee Lee
Subcellular compartmentalization of receptor signaling is an emerging principle in innate immunity. However, the functional integration of receptor signaling pathways into membrane trafficking routes and its physiological relevance for immune responses is still largely unclear. In this study, using Lyst-mutant beige mice, we show that lysosomal trafficking regulator Lyst links endolysosomal organization to the selective control of toll-like receptor 3 (TLR3)- and TLR4-mediated proinflammatory responses. Consequently, Lyst-mutant mice showed increased susceptibility to bacterial infection and were largely resistant to endotoxin-induced septic shock...
November 23, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27881681/a-novel-regulatory-mechanism-of-type-ii-collagen-expression-via-a-sox9-dependent-enhancer-in-intron-6
#16
Hideyo Yasuda, Chun-Do Oh, Di Chen, Benoit de Crombrugghe, Jin-Hoi Kim
Type II collagen α1 is specific for cartilaginous tissues, and mutations in its gene are associated with skeletal diseases. Its expression has been shown to be dependent on SOX9, a master transcription factor required for chondrogenesis that binds to an enhancer region in intron 1. However, ChIP-sequencing revealed that SOX9 does not strongly bind to intron 1, but rather it binds to intron 6 and a site 30 kb upstream of the transcription start site. Here, we aimed to determine the role of the novel SOX9-binding site in intron 6...
November 23, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27875524/microrna-137-promotes-apoptosis-in-ovarian-cancer-cells-via-the-regulation-of-xiap
#17
Xiaodi Li, Wei Chen, Wenshu Zeng, Chunling Wan, Shiwei Duan, Songshan Jiang
BACKGROUND: microRNAs (miRNAs) have regulatory roles in various cellular processes, including apoptosis. Recently, X-linked inhibitor of apoptosis protein (XIAP) has been reported to be dysregulated in epithelial ovarian cancer (EOC). However, the mechanism underlying this dysregulation is largely unknown. METHODS: Using bioinformatics and a literature analysis, a panel of miRNAs dysregulated in EOC was chosen for further experimental confirmation from hundreds of miRNAs that were predicted to interact with the XIAP 3'UTR...
November 22, 2016: British Journal of Cancer
https://www.readbyqxmd.com/read/27875093/autolysosome-biogenesis-and-developmental-senescence-are-regulated-by-both-spns1-and-v-atpase
#18
Tomoyuki Sasaki, Shanshan Lian, Alam Khan, Jesse R Llop, Andrew V Samuelson, Wenbiao Chen, Daniel J Klionsky, Shuji Kishi
Spns1 (Spinster homolog 1 [Drosophila]) in vertebrates, as well as Spin (Spinster) in Drosophila, is a hypothetical lysosomal H(+)-carbohydrate transporter, which functions at a late stage of macroautophagy (hereafter autophagy). The Spin/Spns1 defect induces aberrant autolysosome formation that leads to developmental senescence in the embryonic stage and premature aging symptoms in adulthood. However, the molecular mechanism by which loss of Spin/Spns1 leads to the specific pathogenesis remains to be elucidated...
November 22, 2016: Autophagy
https://www.readbyqxmd.com/read/27875019/generation-of-targeted-mutant-rice-using-a-crispr-cpf1-system
#19
Rongfang Xu, Ruiying Qin, Hao Li, Dongdong Li, Li Li, Pengcheng Wei, Jianbo Yang
CRISPR-Cpf1 is a newly identified CRISPR-Cas system, and Cpf1 was recently engineered as a molecular tool for targeted genome editing in mammalian cells. To test whether the engineered CRISPR-Cpf1 system could induce the production of rice mutants, we selected two genome targets in the OsPDS and OsBEL genes. Our results show that both targets could be efficiently mutated in transgenic rice plants using CRISPR-Cpf1. We found that pre-crRNAs with a full-length direct repeat sequence exhibited considerably increased efficiencies compared with mature crRNAs...
November 22, 2016: Plant Biotechnology Journal
https://www.readbyqxmd.com/read/27874856/in-vivo-editing-of-the-human-mutant-rhodopsin-gene-by-electroporation-of-plasmid-based-crispr-cas9-in-the-mouse-retina
#20
Maria Carmela Latella, Maria Teresa Di Salvo, Fabienne Cocchiarella, Daniela Benati, Giulia Grisendi, Antonella Comitato, Valeria Marigo, Alessandra Recchia
The bacterial CRISPR/Cas system has proven to be an efficient tool for genetic manipulation in various organisms. Here we show the application of CRISPR-Cas9 technology to edit the human Rhodopsin (RHO) gene in a mouse model for autosomal dominant Retinitis Pigmentosa. We designed single or double sgRNAs to knock-down mutant RHO expression by targeting exon 1 of the RHO gene carrying the P23H dominant mutation. By delivering Cas9 and sgRNAs in a single plasmid we induced an efficient gene editing in vitro, in HeLa cells engineered to constitutively express the P23H mutant RHO allele...
November 22, 2016: Molecular Therapy. Nucleic Acids
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