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Integrative genomics

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https://www.readbyqxmd.com/read/28531152/genetic-testing-among-children-in-a-complex-care-program
#1
Krista Oei, Robin Z Hayeems, Wendy J Ungar, Ronald D Cohn, Eyal Cohen
Little is known about the pattern of genetic testing and frequency of genetic diagnoses among children enrolled in structured complex care programs (CCPs). Such information may inform the suitability of emerging genome diagnostics for this population. The objectives were to describe the proportion of children with undiagnosed genetic conditions despite genetic testing and measure the testing period, types and costs of genetic tests used. A retrospective analysis of 420 children enrolled in Toronto's Hospital for Sick Children's CCP from January 2010 until June 2014 was conducted...
May 22, 2017: Children
https://www.readbyqxmd.com/read/28530655/a-quantitative-and-multiplexed-approach-to-uncover-the-fitness-landscape-of-tumor-suppression-in-vivo
#2
Zoë N Rogers, Christopher D McFarland, Ian P Winters, Santiago Naranjo, Chen-Hua Chuang, Dmitri Petrov, Monte M Winslow
Cancer growth is a multistage, stochastic evolutionary process. While cancer genome sequencing has been instrumental in identifying the genomic alterations that occur in human tumors, the consequences of these alterations on tumor growth remain largely unexplored. Conventional genetically engineered mouse models enable the study of tumor growth in vivo, but they are neither readily scalable nor sufficiently quantitative to unravel the magnitude and mode of action of many tumor-suppressor genes. Here, we present a method that integrates tumor barcoding with ultradeep barcode sequencing (Tuba-seq) to interrogate tumor-suppressor function in mouse models of human cancer...
May 22, 2017: Nature Methods
https://www.readbyqxmd.com/read/28530652/cd34-cells-from-dental-pulp-stem-cells-with-a-zfn-mediated-and-homology-driven-repair-mediated-locus-specific-knock-in-of-an-artificial-%C3%AE-globin-gene
#3
S Chattong, O Ruangwattanasuk, W Yindeedej, A Setpakdee, K Manotham
In humans, mutations in the β-globin gene (HBB) have two important clinical manifestations: β-thalassemia and sickle cell disease. The progress in genome editing and stem cell research may be relevant to the treatment of β-globin-related diseases. In this work, we employed zinc finger nuclease (ZFN)-mediated gene integration of synthetic β-globin cDNA into HBB loci, thus correcting almost all β-globin mutations. The integration was achieved in both HEK 293 cells and isolated dental pulp stem cell (DPSCs)...
May 22, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28530235/hit-and-go-cas9-delivered-through-a-lentiviral-based-self-limiting-circuit
#4
Gianluca Petris, Antonio Casini, Claudia Montagna, Francesca Lorenzin, Davide Prandi, Alessandro Romanel, Jacopo Zasso, Luciano Conti, Francesca Demichelis, Anna Cereseto
In vivo application of the CRISPR-Cas9 technology is still limited by unwanted Cas9 genomic cleavages. Long-term expression of Cas9 increases the number of genomic loci non-specifically cleaved by the nuclease. Here we develop a Self-Limiting Cas9 circuit for Enhanced Safety and specificity (SLiCES) which consists of an expression unit for Streptococcus pyogenes Cas9 (SpCas9), a self-targeting sgRNA and a second sgRNA targeting a chosen genomic locus. The self-limiting circuit results in increased genome editing specificity by controlling Cas9 levels...
May 22, 2017: Nature Communications
https://www.readbyqxmd.com/read/28529507/a-novel-and-efficient-method-for-bacteria-genome-editing-employing-both-crispr-cas9-and-an-antibiotic-resistance-cassette
#5
Hong Zhang, Qiu-Xiang Cheng, Ai-Min Liu, Guo-Ping Zhao, Jin Wang
As Cas9-mediated cleavage requires both protospacer and protospacer adjacent motif (PAM) sequences, it is impossible to employ the CRISPR/Cas9 system to directly edit genomic sites without available PAM sequences nearby. Here, we optimized the CRISPR/Cas9 system and developed an innovative two-step strategy for efficient genome editing of any sites, which did not rely on the availability of PAM sequences. An antibiotic resistance cassette was employed as both a positive and a negative selection marker. By integrating the optimized two-plasmid CRISPR/Cas system and donor DNA, we achieved gene insertion and point mutation with high efficiency in Escherichia coli, and importantly, obtained clean mutants with no other unwanted mutations...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28529337/dynamic-chromatin-technologies-from-individual-molecules-to-epigenomic-regulation-in-cells
#6
REVIEW
Olivier Cuvier, Beat Fierz
The establishment and maintenance of chromatin states involves multiscale dynamic processes integrating transcription factor and multiprotein effector dynamics, cycles of chemical chromatin modifications, and chromatin structural organization. Recent developments in genomic technologies are emerging that are enabling a view beyond ensemble- and time-averaged properties and are revealing the importance of dynamic chromatin states for cell fate decisions, differentiation and reprogramming at the single-cell level...
May 22, 2017: Nature Reviews. Genetics
https://www.readbyqxmd.com/read/28528868/pleiotropic-effects-of-trait-associated-genetic-variation-on-dna-methylation-utility-for-refining-gwas-loci
#7
Eilis Hannon, Mike Weedon, Nicholas Bray, Michael O'Donovan, Jonathan Mill
Most genetic variants identified in genome-wide association studies (GWASs) of complex traits are thought to act by affecting gene regulation rather than directly altering the protein product. As a consequence, the actual genes involved in disease are not necessarily the most proximal to the associated variants. By integrating data from GWAS analyses with those from genetic studies of regulatory variation, it is possible to identify variants pleiotropically associated with both a complex trait and measures of gene regulation...
May 13, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28528358/dna-topoisomerase-targeting-chemotherapeutics-what-s-new
#8
REVIEW
Selma M Cuya, Mary-Ann Bjornsti, Robert C A M van Waardenburg
To resolve the topological problems that threaten the function and structural integrity of nuclear and mitochondrial genomes and RNA molecules, human cells encode six different DNA topoisomerases including type IB enzymes (TOP1 and TOP1mt), type IIA enzymes (TOP2α and TOP2β) and type IA enzymes (TOP3α and TOP3β). DNA entanglements and the supercoiling of DNA molecules are regulated by topoisomerases through the introduction of transient enzyme-linked DNA breaks. The covalent topoisomerase-DNA complexes are the cellular targets of a diverse group of cancer chemotherapeutics, which reversibly stabilize these reaction intermediates...
May 20, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28527830/crispr-cas9-mediated-precise-targeted-integration-in-vivo-using-a-double-cut-donor-with-short-homology-arms
#9
Xuan Yao, Xing Wang, Junlai Liu, Xinde Hu, Linyu Shi, Xiaowen Shen, Wenqin Ying, Xinyao Sun, Xin Wang, Pengyu Huang, Hui Yang
Precisely targeted genome editing is highly desired for clinical applications. However, the widely used homology-directed repair (HDR)-based genome editing strategies remain inefficient for certain in vivo applications. We here demonstrate a microhomology-mediated end-joining (MMEJ)-based strategy for precisely targeted gene integration in transfected neurons and hepatocytes in vivo with efficiencies up to 20%, much higher (up to 10 fold) than HDR-based strategy in adult mouse tissues. As a proof of concept of its therapeutic potential, we demonstrate the efficacy of MMEJ-based strategy in correction of Fah mutation and rescue of Fah(-/-) liver failure mice, offering an efficient approach for precisely targeted gene therapies...
May 11, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28527571/progesterone-receptor-signaling-in-uterine-myometrial-physiology-and-preterm-birth
#10
San-Pin Wu, Francesco J DeMayo
Myometrium holds the structural integrity for the uterus and generates force for parturition with its primary component, the smooth muscle cells. The progesterone receptor mediates progesterone-dependent signaling and connects to a network of pathways for regulation of contractility and inflammatory responses in myometrium. Dysfunctional progesterone signaling has been linked to pregnancy complications including preterm birth. In the present review, we summarize recent findings on modifiers and effectors of the progesterone receptor signaling...
2017: Current Topics in Developmental Biology
https://www.readbyqxmd.com/read/28527344/harnessing-plant-metabolic-diversity
#11
REVIEW
Charlie Owen, Nicola J Patron, Ancheng Huang, Anne Osbourn
Advances in DNA sequencing and synthesis technologies in the twenty-first century are now making it possible to build large-scale pipelines for engineering plant natural product pathways into heterologous production species using synthetic biology approaches. The ability to decode the chemical potential of plants by sequencing their transcriptomes and/or genomes and to then use this information as an instruction manual to make drugs and other high-value chemicals is opening up new routes to harness the vast chemical diversity of the Plant Kingdom...
May 17, 2017: Current Opinion in Chemical Biology
https://www.readbyqxmd.com/read/28526842/revealing-genome-scale-transcriptional-regulatory-landscape-of-ompr-highlights-its-expanded-regulatory-roles-under-osmotic-stress-in-escherichia-coli-k-12-mg1655
#12
Sang Woo Seo, Ye Gao, Donghyuk Kim, Richard Szubin, Jina Yang, Byung-Kwan Cho, Bernhard O Palsson
A transcription factor (TF), OmpR, plays a critical role in transcriptional regulation of the osmotic stress response in bacteria. Here, we reveal a genome-scale OmpR regulon in Escherichia coli K-12 MG1655. Integrative data analysis reveals that a total of 37 genes in 24 transcription units (TUs) belong to OmpR regulon. Among them, 26 genes show more than two-fold changes in expression level in an OmpR knock-out strain. Specifically, we find that: 1) OmpR regulates mostly membrane-located gene products involved in diverse fundamental biological processes, such as narU (encoding nitrate/nitrite transporter), ompX (encoding outer membrane protein X), and nuoN (encoding NADH:ubiquinone oxidoreductase); 2) by investigating co-regulation of entire sets of genes regulated by other stress-response TFs, stresses are surprisingly independently regulated among each other; and, 3) a detailed investigation of the physiological roles of the newly discovered OmpR regulon genes reveals that activation of narU represents a novel strategy to significantly improve osmotic stress tolerance of E...
May 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28526061/photosynthesis-at-the-far-red-region-of-the-spectrum-in-acaryochloris-marina
#13
REVIEW
Syed Lal Badshah, Yahia Mabkhot, Salim S Al-Showiman
Acaryochloris marina is an oxygenic cyanobacterium that utilizes far-red light for photosynthesis. It has an expanded genome, which helps in its adaptability to the environment, where it can survive on low energy photons. Its major light absorbing pigment is chlorophyll d and it has α-carotene as a major carotenoid. Light harvesting antenna includes the external phycobilin binding proteins, which are hexameric rods made of phycocyanin and allophycocyanins, while the small integral membrane bound chlorophyll binding proteins are also present...
May 19, 2017: Biological Research
https://www.readbyqxmd.com/read/28525986/the-lspc3-41i-restriction-modification-system-is-the-major-determinant-for-genetic-manipulations-of-lysinibacillus-sphaericus-c3-41
#14
Pan Fu, Yong Ge, Yiming Wu, Ni Zhao, Zhiming Yuan, Xiaomin Hu
BACKGROUND: Lysinibacillus sphaericus has been widely used in integrated mosquito control program and it is one of the minority bacterial species unable to metabolize carbohydrates. In consideration of the high genetic conservation at genomic level and difficulty of genetic horizontal transfer, it is hypothesized that effective restriction-modification (R-M) systems existed in mosquitocidal L. sphaericus. RESULTS: In this study, six type II R-M systems including LspC3-41I were predicted in L...
May 19, 2017: BMC Microbiology
https://www.readbyqxmd.com/read/28525650/detection-of-damage-on-single-or-double-stranded-dna-in-a-population-exposed-to-arsenic-in-drinking-water
#15
J Jiménez-Villarreal, D I Rivas-Armendariz, C P Pineda-Belmontes, N D Betancourt-Martínez, M A Macías-Corral, A J Guerra-Alanis, M S Niño-Castañeda, J Morán-Martínez
Different studies have suggested an association between arsenic (As) exposure and damage to single-stranded DNA by reactive oxygen species derived from the biotransformation of arsenic. The single strand damages are converted to double strand damage upon interaction with ultraviolet radiation. Analysis of genomic integrity is important for assessing the genotoxicity caused by environmental pollutants. In this study, we compared the concentration of As in drinking water, nutritional status, lifestyle variables, and the level of genotoxicity in an exposed population and a control group...
May 18, 2017: Genetics and Molecular Research: GMR
https://www.readbyqxmd.com/read/28525563/omics-biomarkers-in-ophthalmology
#16
Susette Lauwen, Eiko K de Jong, Dirk J Lefeber, Anneke I den Hollander
"Omics" refers to high-throughput analyses of genes, proteins, or metabolites in a biological system, and is increasingly used for ophthalmic research. These system-based approaches can unravel disease-related processes and are valuable for biomarker discovery. Furthermore, potential therapeutic targets can be identified based on omics results, and targeted follow-up experiments can be designed to gain molecular understanding of the disease and to test new therapies. Here, we review the application of omics techniques in eye diseases, focusing on age-related macular degeneration (AMD), diabetic retinopathy (DR), retinal detachment (RD), myopia, glaucoma, Fuchs' corneal dystrophy (FCD), cataract, keratoconus, and dry eyes...
May 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28525538/chimeraviz-a-tool-for-visualizing-chimeric-rna
#17
Stian Lågstad, Sen Zhao, Andreas M Hoff, Bjarne Johannessen, Ole Christian Lingjærde, Rolf I Skotheim
Summary: Advances in high-throughput RNA sequencing have enabled more efficient detection of fusion transcripts, but the technology and associated software used for fusion detection from sequencing data often yield a high false discovery rate. Good prioritization of the results is important, and this can be helped by a visualization framework that automatically integrates RNA data with known genomic features. Here we present chimeraviz , a Bioconductor package that automates the creation of chimeric RNA visualizations...
May 19, 2017: Bioinformatics
https://www.readbyqxmd.com/read/28524652/optical-characteristics-and-tumor-imaging-capabilities-of-near-infrared-dyes-in-free-and-nano-encapsulated-formulations-comprised-of-viral-capsids
#18
Yadir Guerrero, Sheela Singh, Turong Mai, Ravoori Murali, Leela Tanikella, Atta Zahedi, Vikas Kundra, Bahman Anvari
Near infrared (NIR) fluorescent molecules and nano-sized structures can serve as potential optical probes for image-guided removal of small tumor nodules (≈ < 1 mm diameter). While indocyanine green (ICG) remains as the only FDA-approved NIR dye, other organic dyes are under extensive development for enhanced imaging capabilities. One such dye is BrCy106-NHS where bromine is substituted for aromatic structures in cyanine dyes. Herein, we investigate the absorption and fluorescence characteristics of ICG and BrCy106-NHS, and quantitatively assess their tumor imaging capabilities in free (non-encapsulated) and a nano-encapsulated form that utilizes the capsid protein (CP) from genome-depleted plant-infecting brome mosaic virus as the encapsulating shell...
May 19, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/28524624/pulmonary-arterial-hypertension-progress-in-understanding-the-disease-and-prioritizing-strategies-for-drug-development
#19
REVIEW
P Ghataorhe, C J Rhodes, L Harbaum, M Attard, J Wharton, M R Wilkins
Pulmonary arterial hypertension (PAH), at one time a largely overlooked disease, is now the subject of intense study in many academic and biotech groups. The availability of new treatments has increased awareness of the condition. This in turn has driven a change in the demographics of PAH, with an increase in the mean age at diagnosis. The diagnosis of PAH in more elderly patients has highlighted the need for careful phenotyping of patients and for further studies to understand how best to manage pulmonary hypertension associated with, for example, left heart disease...
May 19, 2017: Journal of Internal Medicine
https://www.readbyqxmd.com/read/28524166/homology-mediated-end-joining-based-targeted-integration-using-crispr-cas9
#20
Xuan Yao, Xing Wang, Xinde Hu, Zhen Liu, Junlai Liu, Haibo Zhou, Xiaowen Shen, Yu Wei, Zijian Huang, Wenqin Ying, Yan Wang, Yan-Hong Nie, Chen-Chen Zhang, Sanlan Li, Leping Cheng, Qifang Wang, Yan Wu, Pengyu Huang, Qiang Sun, Linyu Shi, Hui Yang
Targeted integration of transgenes can be achieved by strategies based on homologous recombination (HR), microhomology-mediated end joining (MMEJ) or non-homologous end joining (NHEJ). The more generally used HR is inefficient for achieving gene integration in animal embryos and tissues, because it occurs only during cell division, although MMEJ and NHEJ can elevate the efficiency in some systems. Here we devise a homology-mediated end joining (HMEJ)-based strategy, using CRISPR/Cas9-mediated cleavage of both transgene donor vector that contains guide RNA target sites and ∼800 bp of homology arms, and the targeted genome...
May 19, 2017: Cell Research
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