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https://www.readbyqxmd.com/read/29786095/high-throughput-creation-and-functional-profiling-of-dna-sequence-variant-libraries-using-crispr-cas9-in-yeast
#1
Xiaoge Guo, Alejandro Chavez, Angela Tung, Yingleong Chan, Christian Kaas, Yi Yin, Ryan Cecchi, Santiago Lopez Garnier, Eric D Kelsic, Max Schubert, James E DiCarlo, James J Collins, George M Church
Construction and characterization of large genetic variant libraries is essential for understanding genome function, but remains challenging. Here, we introduce a Cas9-based approach for generating pools of mutants with defined genetic alterations (deletions, substitutions, and insertions) with an efficiency of 80-100% in yeast, along with methods for tracking their fitness en masse. We demonstrate the utility of our approach by characterizing the DNA helicase SGS1 with small tiling deletion mutants that span the length of the protein and a series of point mutations against highly conserved residues in the protein...
May 21, 2018: Nature Biotechnology
https://www.readbyqxmd.com/read/29785947/-n-wasp-regulates-cortical-neuron-migration-through-its-polypro-and-vca-domains
#2
Xiu Lian Shen, Yi Chao Lu, Zhi Lian Jia, Qiang Wu
Cortical neuron migration in the developing mouse forebrain is a complex process, which contains several steps related to cytoskeleton dynamics and remodeling. Neural Wiskott-Aldrich syndrome protein (N-WASP), a member of the WASP-WAVE family, regulates actin cytoskeleton reorganization through the binding of its VCA domain to the Arp2/3 complex. Here we report expression patterns of N-WASP gene in the mouse developing embryonic cortex (E12.5~ E18.5) and find its expression levels are decreased during embryonic development...
May 20, 2018: Yi Chuan, Hereditas
https://www.readbyqxmd.com/read/29785143/pilot-study-of-the-antifibrotic-effects-of-the-multikinase-inhibitor-pacritinib-in-a-mouse-model-of-liver-fibrosis
#3
Suliman Al-Fayoumi, Taishi Hashiguchi, Yuka Shirakata, John Mascarenhas, Jack W Singer
Background: Fibrotic diseases result from an exuberant response to chronic inflammation. Myelofibrosis is the end result of inflammation in bone, caused by an inflammatory process triggered by production of abnormal myeloid cells driven by mutations affecting the JAK-STAT pathway. Inflammatory cytokine overproduction leads to increased mesenchymal cell proliferation, culminating in fibrosis. Although JAK2 inhibitors, such as the JAK1/2 inhibitor ruxolitinib and the JAK2/FLT3/CSF1R/IRAK1 inhibitor pacritinib suppress abnormal clone expansion in myelofibrosis, ruxolitinib does not appear to prevent or reverse bone-marrow fibrosis in most patients...
2018: Journal of Experimental Pharmacology
https://www.readbyqxmd.com/read/29785026/resetting-the-epigenetic-balance-of-polycomb-and-compass-function-at-enhancers-for-cancer-therapy
#4
Lu Wang, Zibo Zhao, Patrick A Ozark, Damiano Fantini, Stacy A Marshall, Emily J Rendleman, Kira A Cozzolino, Nundia Louis, Xingyao He, Marc A Morgan, Yoh-Hei Takahashi, Clayton K Collings, Edwin R Smith, Panagiotis Ntziachristos, Jeffrey N Savas, Lihua Zou, Rintaro Hashizume, Joshua J Meeks, Ali Shilatifard
The lysine methyltransferase KMT2C (also known as MLL3), a subunit of the COMPASS complex, implements monomethylation of Lys4 on histone H3 (H3K4) at gene enhancers. KMT2C (hereafter referred to as MLL3) frequently incurs point mutations across a range of human tumor types, but precisely how these lesions alter MLL3 function and contribute to oncogenesis is unclear. Here we report a cancer mutational hotspot in MLL3 within the region encoding its plant homeodomain (PHD) repeats and demonstrate that this domain mediates association of MLL3 with the histone H2A deubiquitinase and tumor suppressor BAP1...
May 21, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29784826/deletion-of-lrrtm1-and-lrrtm2-in-adult-mice-impairs-basal-ampa-receptor-transmission-and-ltp-in-hippocampal-ca1-pyramidal-neurons
#5
Mehdi Bhouri, Wade Morishita, Paul Temkin, Debanjan Goswami, Hiroshi Kawabe, Nils Brose, Thomas C Südhof, Ann Marie Craig, Tabrez J Siddiqui, Robert Malenka
Leucine-rich repeat transmembrane (LRRTM) proteins are synaptic cell adhesion molecules that influence synapse formation and function. They are genetically associated with neuropsychiatric disorders, and via their synaptic actions likely regulate the establishment and function of neural circuits in the mammalian brain. Here, we take advantage of the generation of a LRRTM1 and LRRTM2 double conditional knockout mouse ( LRRTM1,2 cKO) to examine the role of LRRTM1,2 at mature excitatory synapses in hippocampal CA1 pyramidal neurons...
May 21, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29784605/code-seq-an-augmented-whole-exome-sequencing-enables-the-accurate-detection-of-cnvs-and-mutations-in-mendelian-obesity-and-intellectual-disability
#6
Louise Montagne, Mehdi Derhourhi, Amélie Piton, Bénédicte Toussaint, Emmanuelle Durand, Emmanuel Vaillant, Dorothée Thuillier, Stefan Gaget, Franck De Graeve, Iandry Rabearivelo, Amélie Lansiaux, Bruno Lenne, Sylvie Sukno, Rachel Desailloud, Miriam Cnop, Ramona Nicolescu, Lior Cohen, Jean-François Zagury, Mélanie Amouyal, Jacques Weill, Jean Muller, Olivier Sand, Bruno Delobel, Philippe Froguel, Amélie Bonnefond
OBJECTIVE: The molecular diagnosis of extreme forms of obesity, in which accurate detection of both copy number variations (CNVs) and point mutations, is crucial for an optimal care of the patients and genetic counseling for their families. Whole-exome sequencing (WES) has benefited considerably this molecular diagnosis, but its poor ability to detect CNVs remains a major limitation. We aimed to develop a method (CoDE-seq) enabling the accurate detection of both CNVs and point mutations in one step...
May 16, 2018: Molecular Metabolism
https://www.readbyqxmd.com/read/29782825/characterization-of-an-n-terminal-mutant-of-%C3%AE-a-crystallin-%C3%AE-a-r21q-associated-with-congenital-cataract
#7
Ashutosh S Phadte, Puttur Santhoshkumar, K Krishna Sharma
Several mutations associated with congenital cataracts in human beings target conserved arginine residues in αA-crystallin. The N-terminal region of αA-crystallin is a "mutational hotspot," with multiple cataract-related mutations reported in this region. Two mutations at arginine 21 in the N-terminal domain of αA-crystallin - αA-R21L and αA-R21W have been associated with congenital cataract. A third mutant of R21, αA-R21Q, was recently identified to be associated with congenital cataract in a South Australian family...
May 18, 2018: Experimental Eye Research
https://www.readbyqxmd.com/read/29782346/claudins-and-nephrolithiasis
#8
Allein Plain, R Todd Alexander
PURPOSE OF REVIEW: The greatest risk factor for kidney stone formation is increased urinary calcium excretion. Most filtered calcium is reabsorbed from the proximal tubule and the thick ascending limb (TAL) of Henle's loop via a paracellular pathway. Claudins are tight junction proteins that confer the permeability properties of an epithelium. We review the contribution of renal claudins to nephron calcium permeability and how perturbations in these pathways cause alterations in tubular calcium transport, hypercalciuria, nephrocalcinosis, or nephrolithiasis...
May 17, 2018: Current Opinion in Nephrology and Hypertension
https://www.readbyqxmd.com/read/29780457/highly-efficient-base-editing-in-staphylococcus-aureus-using-an-engineered-crispr-rna-guided-cytidine-deaminase
#9
Tongnian Gu, Siqi Zhao, Yishuang Pi, Weizhong Chen, Chuanyuan Chen, Qian Liu, Min Li, Dali Han, Quanjiang Ji
Novel therapeutic means against Staphylococcus aureus infections are urgently needed due to the emergence of drug-resistant S. aureus . We report the development of a CRISPR RNA-guided cytidine deaminase (pnCasSA-BEC), enabling highly efficient gene inactivation and point mutations in S. aureus . We engineered a fusion of a Cas9 nickase (Cas9D10A) and a cytidine deaminase (APOBEC1) that can be guided to a target genomic locus for gene inactivation via generating a premature stop codon. The pnCasSA-BEC system nicks the non-edited strand of the genomic DNA, directly catalyzes the conversion of cytidine (C) to uridine (U), and relies on DNA replication to achieve C → T (G → A) conversion without using donor repair templates...
March 28, 2018: Chemical Science
https://www.readbyqxmd.com/read/29780391/concepts-collide-genomic-immune-and-microbial-influences-on-the-tumor-microenvironment-and-response-to-cancer-therapy
#10
REVIEW
Miles C Andrews, Alexandre Reuben, Vancheswaran Gopalakrishnan, Jennifer A Wargo
Cancer research has seen unprecedented advances over the past several years, with tremendous insights gained into mechanisms of response and resistance to cancer therapy. Central to this has been our understanding of crosstalk between the tumor and the microenvironment, with the recognition that complex interactions exist between tumor cells, stromal cells, overall host immunity, and the environment surrounding the host. This is perhaps best exemplified in cancer immunotherapy, where numerous studies across cancer types have illuminated our understanding of the genomic and immune factors that shape responses to therapy...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29780379/point-mutation-of-a-non-elastase-binding-site-in-human-%C3%AE-1-antitrypsin-alters-its-anti-inflammatory-properties
#11
Yotam Lior, Mariana Zaretsky, David E Ochayon, Diana Lotysh, Boris M Baranovski, Ronen Schuster, Ofer Guttman, Amir Aharoni, Eli C Lewis
Introduction: Human α1-antitrypsin (hAAT) is a 394-amino acid long anti-inflammatory, neutrophil elastase inhibitor, which binds elastase via a sequence-specific molecular protrusion (reactive center loop, RCL; positions 357-366). hAAT formulations that lack protease inhibition were shown to maintain their anti-inflammatory activities, suggesting that some attributes of the molecule may reside in extra-RCL segments. Here, we compare the protease-inhibitory and anti-inflammatory profiles of an extra-RCL mutation (cys232pro) and two intra-RCL mutations (pro357cys, pro357ala), to naïve [wild-type (WT)] recombinant hAAT, in vitro , and in vivo ...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29779772/dissecting-whole-genome-sequencing-based-online-tools-for-predicting-resistance-in-mycobacterium-tuberculosis-can-we-use-them-for-clinical-decision-guidance
#12
Rita Macedo, Alexandra Nunes, Isabel Portugal, Sílvia Duarte, Luís Vieira, João Paulo Gomes
Whole-genome sequencing (WGS)-based bioinformatics platforms for the rapid prediction of resistance will soon be implemented in the Tuberculosis (TB) laboratory, but their accuracy assessment still needs to be strengthened. Here, we fully-sequenced a total of 54 multidrug-resistant (MDR) and five susceptible TB strains and performed, for the first time, a simultaneous evaluation of the major four free online platforms (TB Profiler, PhyResSE, Mykrobe Predictor and TGS-TB). Overall, the sensitivity of resistance prediction ranged from 84...
May 2018: Tuberculosis
https://www.readbyqxmd.com/read/29778643/inheritance-of-co-edited-genes-by-crispr-based-targeted-nucleotide-substitutions-in-rice
#13
Zenpei Shimatani, Ushio Fujikura, Hisaki Ishii, Yusuke Matsui, Minoru Suzuki, Yuki Ueke, Ken-Ichiro Taoka, Rie Terada, Keiji Nishida, Akihiko Kondo
The CRISPR/Cas9 system is a revolutionary genome-editing tool for directed gene editing in various organisms. Cas9 variants can be applied as molecular homing devices when combined with various functional effectors such as transcriptional activators or DNA modification enzymes. Target-AID is a synthetic complex of nuclease deficient Cas9 fused to an activation-induced cytidine deaminase (AID) that enables targeted nucleotide substitution (C to T or G to A). We previously demonstrated that the introduction of desired point mutations into target genes by Target-AID confers herbicide tolerance to rice callus...
April 25, 2018: Plant Physiology and Biochemistry: PPB
https://www.readbyqxmd.com/read/29777197/the-transition-state-structure-for-binding-between-taz1-of-cbp-and-the-disordered-hif-1%C3%AE-cad
#14
Ida Lindström, Eva Andersson, Jakob Dogan
Intrinsically disordered proteins (IDPs) are common in eukaryotes. However, relatively few experimental studies have addressed the nature of the rate-limiting transition state for the coupled binding and folding reactions involving IDPs. By using site-directed mutagenesis in combination with kinetics measurements we have here characterized the transition state for binding between the globular TAZ1 domain of CREB binding protein and the intrinsically disordered C-terminal activation domain of Hif-1α (Hif-1α CAD)...
May 18, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29776930/modifying-the-lantibiotic-mutacin-1140-for-increased-yield-activity-and-stability
#15
Mengxin Geng, Leif Smith
Mutacin 1140 belongs to the epidermin family of type AI lantibiotics. This family has a broad spectrum of activity against Gram-positive bacteria. The binding of mutacin 1140 to lipid II leads to the inhibition of cell wall synthesis. Pharmacokinetic experiments on type AI lantibiotics are generally discouraging for clinical applications due to their short half-life. The unprotected dehydrated and protease susceptible residues outside of the lanthionine rings may play a role in their short half-life in physiological settings...
May 18, 2018: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/29776628/molecular-pathology-techniques-advances-in-2018
#16
REVIEW
Mark J Bluth, Martin H Bluth
Molecular pathology techniques continue to evolve. Although polymerase chain reaction (PCR) remains the cornerstone methodology for nucleic acid amplification, improvements in nucleic acid detection methodologies (i.e. PCR) have increased the detection sensitivity by using fluorescent and bead based array technologies. Single base pair lesions can be detected via sequencing and related techniques to discern point mutations in disease pathogenesis. Novel technologies, such as high- resolution melting analysis, provide fast high throughput post PCR analysis of genetic mutations or variance in nucleic acid sequences...
June 2018: Clinics in Laboratory Medicine
https://www.readbyqxmd.com/read/29776379/development-of-a-rapid-field-applicable-molecular-diagnostic-for-knockdown-resistance-kdr-markers-in-an-gambiae
#17
Vera T Unwin, Shaun Ainsworth, Emily J Rippon, El Hadji Amadou Niang, Mark J I Paine, David Weetman, Emily R Adams
BACKGROUND: The spread of insecticide resistance (IR) is a major threat to vector control programmes for mosquito-borne diseases. Early detection of IR using diagnostic markers could help inform these programmes, especially in remote locations where gathering reliable bioassay data is challenging. Most current molecular tests for genetic IR markers are only suitable for use in well-equipped laboratory settings. There is an unmet need for field-applicable diagnostics. METHODS: A single-cartridge test was designed to detect key IR mutations in the major African vector of malaria, Anopheles gambiae...
May 18, 2018: Parasites & Vectors
https://www.readbyqxmd.com/read/29776361/emergence-of-knock-down-resistance-in-the-anopheles-gambiae-complex-in-the-upper-river-region-the-gambia-and-its-relationship-with-malaria-infection-in-children
#18
Anne L Wilson, Margaret Pinder, John Bradley, Martin J Donnelly, Majidah Hamid-Adiamoh, Lamin B S Jarju, Musa Jawara, David Jeffries, Ballah Kandeh, Emily J Rippon, Kolawole Salami, Umberto D'Alessandro, Steven W Lindsay
BACKGROUND: Insecticide resistance threatens malaria control in sub-Saharan Africa. Knockdown resistance to pyrethroids and organochlorines in Anopheles gambiae sensu lato (s.l.) is commonly caused by mutations in the gene encoding a voltage-gated sodium channel which is the target site for the insecticide. The study aimed to examine risk factors for knockdown resistance in An. gambiae s.l. and its relationship with malaria infection in children in rural Gambia. Point mutations at the Vgsc-1014 locus, were measured in An...
May 18, 2018: Malaria Journal
https://www.readbyqxmd.com/read/29775787/genomic-insights-of-reduced-teicoplanin-susceptible-community-acquired-methicillin-resistant-staphylococcus-aureus-mrsa-case-of-necrotizing-fasciitis
#19
Yamuna Devi Bakthavatchalam, Boopalan Ramaswamy, Rajinikanth Janakiraman, Runal John Steve, Balaji Veeraraghavan
OBJECTIVE: Glycopeptides are being increasingly used to multi-resistant MRSA infections. We report MRSA with low level teicoplanin resistance recovered from a patient treated with teicoplanin for fatal necrotizing fasciitis. PATIENT AND METHODS: MRSA recovered from a patient with necrotizing fasciitis was treated with teicoplanin. The minimum inhibitory concentration (MIC) for vancomycin and teicoplanin was determined using E-test. Reduced glycopeptide susceptibility was screened using GRD E-test and population analysis profile (PAP) method...
May 15, 2018: Journal of Global Antimicrobial Resistance
https://www.readbyqxmd.com/read/29775073/diffuse-gliomas-for-nonneuropathologists-the-new-integrated-molecular-diagnostics
#20
Sunhee C Lee
Diffuse gliomas comprise the bulk of "brain cancer" in adults. The recent update to the 4th edition of the World Health Organization's classification of tumors of the central nervous system reflects an unprecedented change in the landscape of the diagnosis and management of diffuse gliomas that will affect all those involved in the management and care of patients. Of the recently discovered gene alterations, mutations in the Krebs cycle enzymes isocitrate dehydrogenases (IDHs) 1 and 2 have fundamentally changed the way the gliomas are understood and classified...
May 18, 2018: Archives of Pathology & Laboratory Medicine
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