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Mutational robustness

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https://www.readbyqxmd.com/read/29679929/a-phylogenetic-framework-facilitates-y-str-variant-discovery-and-classification-via-massively-parallel-sequencing
#1
Tunde I Huszar, Mark A Jobling, Jon H Wetton
Short tandem repeats on the male-specific region of the Y chromosome (Y-STRs) are permanently linked as haplotypes, and therefore Y-STR sequence diversity can be considered within the robust framework of a phylogeny of haplogroups defined by single nucleotide polymorphisms (SNPs). Here we use massively parallel sequencing (MPS) to analyse the 23 Y-STRs in Promega's prototype PowerSeq™ Auto/Mito/Y System kit (containing the markers of the PowerPlex® Y23 [PPY23] System) in a set of 100 diverse Y chromosomes whose phylogenetic relationships are known from previous megabase-scale resequencing...
April 12, 2018: Forensic Science International. Genetics
https://www.readbyqxmd.com/read/29675036/ps-fw-a-hybrid-algorithm-based-on-particle-swarm-and-fireworks-for-global-optimization
#2
Shuangqing Chen, Yang Liu, Lixin Wei, Bing Guan
Particle swarm optimization (PSO) and fireworks algorithm (FWA) are two recently developed optimization methods which have been applied in various areas due to their simplicity and efficiency. However, when being applied to high-dimensional optimization problems, PSO algorithm may be trapped in the local optima owing to the lack of powerful global exploration capability, and fireworks algorithm is difficult to converge in some cases because of its relatively low local exploitation efficiency for noncore fireworks...
2018: Computational Intelligence and Neuroscience
https://www.readbyqxmd.com/read/29670616/overactivity-of-alternative-pathway-convertases-in-patients-with-complement-mediated-renal-diseases
#3
Marloes A H M Michels, Nicole C A J van de Kar, Marcin Okrój, Anna M Blom, Sanne A W van Kraaij, Elena B Volokhina, Lambertus P W J van den Heuvel
Overactivation of the alternative pathway of the complement system is associated with the renal diseases atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G). C3 nephritic factors (C3NeF) play an important role in C3G pathogenesis by stabilizing the key enzymatic complex of complement, the C3 convertase. However, the reliability of assays detecting these autoantibodies is limited. Therefore, in this study, we validated and optimized a prototype hemolytic method for robust detection and characterization of factors causing convertase overactivity in large patient cohorts...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29669262/dna-mismatch-repair-in-cancer
#4
REVIEW
Marina Baretti, Dung T Le
Microsatellite instability (MSI) refers to the hypermutator phenotype secondary to frequent polymorphism in short repetitive DNA sequences and single nucleotide substitution, as consequence of DNA mismatch repair (MMR) deficiency. MSI secondary to germline mutation in DNA MMR proteins is the molecular fingerprint of Lynch Syndrome (LS), while epigenetic inactivation of these genes is more commonly found in sporadic MSI tumors. MSI occurs at different frequencies across malignancies, although original methods to assess MSI or MMR deficiency have been developed mostly in LS related cancers...
April 15, 2018: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/29668270/mapping-the-plasticity-of-the-e-coli-genetic-code-with-orthogonal-pair-directed-sense-codon-reassignment
#5
Margaret A Schmitt, Wil Biddle, John Domenic Fisk
The relative quantitative importance of the factors that determine the fidelity of translation is largely unknown, which makes predicting the extent to which the degeneracy of the genetic code can be broken challenging. Our strategy of using orthogonal tRNA/aminoacyl tRNA synthetase pairs to precisely direct the incorporation of a single amino acid in response to individual sense and nonsense codons provides a suite of related data with which to examine the plasticity of the code. Each directed sense codon reassignment measurement is an in vivo competition experiment between the introduced orthogonal translation machinery and the natural machinery in E...
April 18, 2018: Biochemistry
https://www.readbyqxmd.com/read/29665400/tolerant-industrial-yeast-saccharomyces-cerevisiae-posses-a-more-robust-cell-wall-integrity-signaling-pathway-against-2-furaldehyde-and-5-hydroxymethyl-2-furaldehyde
#6
Z Lewis Liu, Xu Wang, Scott A Weber
Cell wall integrity signaling pathway in Saccharomyces cerevisiae is a conserved function for detecting and responding to cell stress conditions but less understood for industrial yeast. We examined gene expression dynamics for a tolerant industrial yeast strain NRRL Y-50049 in response to challenges of furfural and HMF through comparative quantitative gene expression analysis using pathway-based qRT-PCR array assays. All tested genes from Y-50049, except for MLP2, demonstrated more resistant and significantly increased gene expression than that from a laboratory strain BY4741...
April 14, 2018: Journal of Biotechnology
https://www.readbyqxmd.com/read/29665313/refinement-of-the-endogenous-epitope-tagging-eet-technology-allows-the-identification-of-a-novel-nras-binding-partner-in-melanoma
#7
Michal Alon, Rafi Emmanuel, Nouar Qutob, Anna Bakhman, Victoria Peshti, Alexandra Brodezki, David Bassan, Mickey Kosloff, Yardena Samuels
The NRAS oncoprotein is highly mutated in melanoma. However, to date, no comprehensive proteomic study has been reported for NRAS. Here we utilized the Endogenous Epitope Tagging (EET) approach for the identification of novel NRAS binding partners. Using EET, an epitope tag is added to the endogenously expressed protein, via modification of its genomic coding sequence. Existing EET systems are not robust, suffer from high background and are labor-intensive. To this end, we present a polyadenylation signal-trap construct for N'-tagging, that generates a polycistronic mRNA with the gene of interest...
April 17, 2018: Pigment Cell & Melanoma Research
https://www.readbyqxmd.com/read/29662203/potent-antitumor-efficacy-of-anti-gd2-car-t-cells-in-h3-k27m-diffuse-midline-gliomas
#8
Christopher W Mount, Robbie G Majzner, Shree Sundaresh, Evan P Arnold, Meena Kadapakkam, Samuel Haile, Louai Labanieh, Esther Hulleman, Pamelyn J Woo, Skyler P Rietberg, Hannes Vogel, Michelle Monje, Crystal L Mackall
Diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMGs) with mutated histone H3 K27M (H3-K27M)1-5 are aggressive and universally fatal pediatric brain cancers 6 . Chimeric antigen receptor (CAR)-expressing T cells have mediated impressive clinical activity in B cell malignancies7-10 , and recent results suggest benefit in central nervous system malignancies11-13 . Here, we report that patient-derived H3-K27M-mutant glioma cell cultures exhibit uniform, high expression of the disialoganglioside GD2...
April 16, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29662124/stag2-deficiency-induces-interferon-responses-via-cgas-sting-pathway-and-restricts-virus-infection
#9
Siyuan Ding, Jonathan Diep, Ningguo Feng, Lili Ren, Bin Li, Yaw Shin Ooi, Xin Wang, Kevin F Brulois, Linda L Yasukawa, Xingnan Li, Calvin J Kuo, David A Solomon, Jan E Carette, Harry B Greenberg
Cohesin is a multi-subunit nuclear protein complex that coordinates sister chromatid separation during cell division. Highly frequent somatic mutations in genes encoding core cohesin subunits have been reported in multiple cancer types. Here, using a genome-wide CRISPR-Cas9 screening approach to identify host dependency factors and novel innate immune regulators of rotavirus (RV) infection, we demonstrate that the loss of STAG2, an important component of the cohesin complex, confers resistance to RV replication in cell culture and human intestinal enteroids...
April 16, 2018: Nature Communications
https://www.readbyqxmd.com/read/29661159/active-dna-end-processing-in-micronuclei-of-ovarian-cancer-cells
#10
Zizhi Tang, Juan Yang, Xin Wang, Ming Zeng, Jing Wang, Ao Wang, Mingcai Zhao, Liandi Guo, Cong Liu, Dehua Li, Jie Chen
BACKGROUND: Ovarian cancer is one of the most deadly gynecological malignancies and inclined to recurrence and drug resistance. Previous studies showed that the tumorigenesis of ovarian cancers and their major histotypes are associated with genomic instability caused by defined sets of pathogenic mutations. In contrast, the mechanism that influences the development of drug resistance and disease recurrence is not well elucidated. Solid tumors are prone to chromosomal instability (CIN) and micronuclei formation (MN)...
April 16, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29658163/a-novel-oncolytic-herpes-capable-of-cell-specific-transcriptional-targeting-of-cd133%C3%A2-cancer-cells-induces-significant-tumor-regression
#11
Kaoru Terai, Danse Bi, Zhengian Liu, Emma Borrego-Diaz, Kyle Kimura, Zohreh Sanaat, Roya Dolatkhah, Mina Soleimani, Christopher Jones, Judith Larson, Allison Bright, Tuba Esfandyari, Faris Farassati
The topic of cancer stem cells is of significant importance due to its implications in our understanding of the tumor biology, as well as the development of novel cancer therapeutics. However, the question of whether targeting cancer stem cells can hamper the growth of tumors remains mainly unanswered due to the lack of specific agents for this purpose. In order to address this issue, we have developed the first mutated version of herpes simplex virus-1 (HSV-1) that is transcriptionally targeted against CD133+ cells...
April 15, 2018: Stem Cells
https://www.readbyqxmd.com/read/29651426/4-hydroxy-2-nonenal-alkylated-and-peroxynitrite-nitrated-proteins-localize-to-the-fused-mitochondria-in-malpighian-epithelial-cells-of-type-iv-collagen-drosophila-mutants
#12
András A Kiss, Nikoletta Popovics, Zsolt Boldogkői, Katalin Csiszár, Mátyás Mink
Background . Human type IV collagenopathy is associated with mutations within the COL4A1 and to a less extent the COL4A2 genes. The proteins encoded by these genes form heterotrimers and are the highest molar ratio components of the ubiquitous basement membrane. The clinical manifestations of the COL4A1/A2 mutations are systemic affecting many tissues and organs among these kidneys. In order to uncover the cellular and biochemical alterations associated with aberrant type IV collagen, we have explored the phenotype of the Malpighian tubules, the secretory organ and insect kidney model, in col4a1 collagen gene mutants of the fruit fly Drosophila melanogaster ...
2018: BioMed Research International
https://www.readbyqxmd.com/read/29649263/validation-of-czecanca-czech-cancer-panel-for-clinical-application-for-targeted-ngs-based-analysis-of-hereditary-cancer-syndromes
#13
Jana Soukupova, Petra Zemankova, Klara Lhotova, Marketa Janatova, Marianna Borecka, Lenka Stolarova, Filip Lhota, Lenka Foretova, Eva Machackova, Viktor Stranecky, Spiros Tavandzis, Petra Kleiblova, Michal Vocka, Hana Hartmannova, Katerina Hodanova, Stanislav Kmoch, Zdenek Kleibl
BACKGROUND: Carriers of mutations in hereditary cancer predisposition genes represent a small but clinically important subgroup of oncology patients. The identification of causal germline mutations determines follow-up management, treatment options and genetic counselling in patients' families. Targeted next-generation sequencing-based analyses using cancer-specific panels in high-risk individuals have been rapidly adopted by diagnostic laboratories. While the use of diagnosis-specific panels is straightforward in typical cases, individuals with unusual phenotypes from families with overlapping criteria require multiple panel testing...
2018: PloS One
https://www.readbyqxmd.com/read/29648537/the-conformation-of-the-histone-h3-tail-inhibits-association-of-the-bptf-phd-finger-with-the-nucleosome
#14
Emma A Morrison, Samuel Bowerman, Kelli L Sylvers, Jeff Wereszczynski, Catherine A Musselman
Histone tails harbor a plethora of post-translational modifications that direct the function of chromatin regulators, which recognize them through effector domains. Effector domain/histone interactions have been broadly studied, but largely using peptide fragments of histone tails. Here, we extend these studies into the nucleosome context and find that the conformation adopted by the histone H3 tails is inhibitory to BPTF PHD finger binding. Using NMR spectroscopy and MD simulations, we show that the H3 tails interact robustly but dynamically with nucleosomal DNA, substantially reducing PHD finger association...
April 12, 2018: ELife
https://www.readbyqxmd.com/read/29622805/generation-and-customization-of-biosynthetic-excitable-tissues-for-electrophysiological-studies-and-cell-based-therapies
#15
Hung X Nguyen, Robert D Kirkton, Nenad Bursac
We describe a two-stage protocol to generate electrically excitable and actively conducting cell networks with stable and customizable electrophysiological phenotypes. Using this method, we have engineered monoclonally derived excitable tissues as a robust and reproducible platform to investigate how specific ion channels and mutations affect action potential (AP) shape and conduction. In the first stage of the protocol, we combine computational modeling, site-directed mutagenesis, and electrophysiological techniques to derive optimal sets of mammalian and/or prokaryotic ion channels that produce specific AP shape and conduction characteristics...
May 2018: Nature Protocols
https://www.readbyqxmd.com/read/29622782/multiple-sgrnas-with-overlapping-sequences-enhance-crispr-cas9-mediated-knock-in-efficiency
#16
Da Eun Jang, Jae Young Lee, Jae Hoon Lee, Ok Jae Koo, Hee Sook Bae, Min Hee Jung, Ji Hyun Bae, Woo Sung Hwang, Yoo Jin Chang, Yoon Hoo Lee, Han Woong Lee, Su Cheong Yeom
The CRISPR/Cas9 system is widely applied in genome engineering due to its simplicity and versatility. Although this has revolutionized genome-editing technology, knockin animal generation via homology directed repair (HDR) is not as efficient as nonhomologous end-joining DNA-repair-dependent knockout. Although its double-strand break activity may vary, Cas9 derived from Streptococcus pyogenens allows robust design of single-guide RNAs (sgRNAs) within the target sequence; However, prescreening for different sgRNA activities delays the process of transgenic animal generation...
April 6, 2018: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/29619162/crispr-cas9-induced-shank3b-mutant-zebrafish-display-autism-like-behaviors
#17
Chun-Xue Liu, Chun-Yang Li, Chun-Chun Hu, Yi Wang, Jia Lin, Yong-Hui Jiang, Qiang Li, Xiu Xu
Background: Human genetic and genomic studies have supported a strong causal role of SHANK3 deficiency in autism spectrum disorder (ASD). However, the molecular mechanism underlying SHANK3 deficiency resulting in ASD is not fully understood. Recently, the zebrafish has become an attractive organism to model ASD because of its high efficiency of genetic manipulation and robust behavioral phenotypes. The orthologous gene to human SHANK3 is duplicated in the zebrafish genome and has two homologs, shank3a and shank3b ...
2018: Molecular Autism
https://www.readbyqxmd.com/read/29618815/distributed-hepatocytes-expressing-telomerase-repopulate-the-liver-in-homeostasis-and-injury
#18
Shengda Lin, Elisabete M Nascimento, Chandresh R Gajera, Lu Chen, Patrick Neuhöfer, Alina Garbuzov, Sui Wang, Steven E Artandi
Hepatocytes are replenished gradually during homeostasis and robustly after liver injury1, 2 . In adults, new hepatocytes originate from the existing hepatocyte pool3-8 , but the cellular source of renewing hepatocytes remains unclear. Telomerase is expressed in many stem cell populations, and mutations in telomerase pathway genes have been linked to liver diseases9-11 . Here we identify a subset of hepatocytes that expresses high levels of telomerase and show that this hepatocyte subset repopulates the liver during homeostasis and injury...
April 4, 2018: Nature
https://www.readbyqxmd.com/read/29614781/exploiting-a-phage-bacterium-interaction-system-as-a-molecular-switch-to-decipher-macromolecular-interactions-in-the-living-cell
#19
Éva Viola Surányi, Rita Hírmondó, Kinga Nyíri, Szilvia Tarjányi, Bianka Kőhegyi, Judit Tóth, Beáta G Vértessy
Pathogenicity islands of Staphylococcus aureus are under the strong control of helper phages, where regulation is communicated at the gene expression level via a family of specific repressor proteins. The repressor proteins are crucial to phage-host interactions and, based on their protein characteristics, may also be exploited as versatile molecular tools. The Stl repressor from this protein family has been recently investigated and although the binding site of Stl on DNA was recently discovered, there is a lack of knowledge on the specific protein segments involved in this interaction...
April 1, 2018: Viruses
https://www.readbyqxmd.com/read/29610332/accurate-and-sensitive-quantification-of-protein-dna-binding-affinity
#20
Chaitanya Rastogi, H Tomas Rube, Judith F Kribelbauer, Justin Crocker, Ryan E Loker, Gabriella D Martini, Oleg Laptenko, William A Freed-Pastor, Carol Prives, David L Stern, Richard S Mann, Harmen J Bussemaker
Transcription factors (TFs) control gene expression by binding to genomic DNA in a sequence-specific manner. Mutations in TF binding sites are increasingly found to be associated with human disease, yet we currently lack robust methods to predict these sites. Here, we developed a versatile maximum likelihood framework named No Read Left Behind (NRLB) that infers a biophysical model of protein-DNA recognition across the full affinity range from a library of in vitro selected DNA binding sites. NRLB predicts human Max homodimer binding in near-perfect agreement with existing low-throughput measurements...
April 2, 2018: Proceedings of the National Academy of Sciences of the United States of America
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