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Mutational robustness

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https://www.readbyqxmd.com/read/28535375/morc-1-integrates-nuclear-rnai-and-transgenerational-chromatin-architecture-to-promote-germline-immortality
#1
Natasha E Weiser, Danny X Yang, Suhua Feng, Natallia Kalinava, Kristen C Brown, Jayshree Khanikar, Mallory A Freeberg, Martha J Snyder, Györgyi Csankovszki, Raymond C Chan, Sam G Gu, Taiowa A Montgomery, Steven E Jacobsen, John K Kim
Germline-expressed endogenous small interfering RNAs (endo-siRNAs) transmit multigenerational epigenetic information to ensure fertility in subsequent generations. In Caenorhabditis elegans, nuclear RNAi ensures robust inheritance of endo-siRNAs and deposition of repressive H3K9me3 marks at target loci. How target silencing is maintained in subsequent generations is poorly understood. We discovered that morc-1 is essential for transgenerational fertility and acts as an effector of endo-siRNAs. Unexpectedly, morc-1 is dispensable for siRNA inheritance but is required for target silencing and maintenance of siRNA-dependent chromatin organization...
May 22, 2017: Developmental Cell
https://www.readbyqxmd.com/read/28533123/molecular-characterization-of-caulobacter-crescentus-mutator-strains
#2
Marinalva Martins-Pinheiro, Alice R Oliveira, Alexy O Valencia, Frank S Fernandez-Silva, Larissa G Silva, Carina O Lopes-Kulishev, Valeria C S Italiani, Marilis V Marques, Carlos F Menck, Rodrigo S Galhardo
Mutator strains were identified by screening random Tn5 insertion clones of Caulobacter crescentus. We identified clones with robust increases in mutation rates with Tn5 insertions in the mutY, mutS, mutL and uvrD genes, known to act in mutation-preventing pathways in Escherichia coli. Analysis of mutations in the rpoB gene revealed that in both the parental strain and mismatch repair-deficient mutants, A:T→G:C transitions predominate by a large margin over C:G→T:A. We have also investigated the role of the error-prone polymerase encoded by imuC (dnaE2) in spontaneous mutagenesis, and found that a imuC mutant strain shows mutation rates and sequences comparable to the parental strain...
May 19, 2017: Gene
https://www.readbyqxmd.com/read/28527722/crispr-cas9-mediated-ccr5-ablation-in-human-hematopoietic-stem-progenitor-cells-confers-hiv-1-resistance-in%C3%A2-vivo
#3
Lei Xu, Huan Yang, Yang Gao, Zeyu Chen, Liangfu Xie, Yulin Liu, Ying Liu, Xiaobao Wang, Hanwei Li, Weifeng Lai, Yuan He, Anzhi Yao, Liying Ma, Yiming Shao, Bin Zhang, Chengyan Wang, Hu Chen, Hongkui Deng
Transplantation of hematopoietic stem cells (HSCs) with a naturally occurring CCR5 mutation confers a loss of detectable HIV-1 in the patient, making ablation of the CCR5 gene in HSCs an ideal therapy for an HIV-1 cure. Although CCR5 disruption has been attempted in CD4(+) T cells and hematopoietic stem/progenitor cells (HSPCs), efficient gene editing with high specificity and long-term therapeutic potential remains a major challenge for clinical translation. Here, we established a CRISPR/Cas9 gene editing system in human CD34(+) HSPCs and achieved efficient CCR5 ablation evaluated in long-term reconstituted NOD/Prkdc(scid)/IL-2Rγ(null) mice...
May 17, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28527117/non-viral-and-viral-delivery-systems-for-crispr-cas9-technology-in-the-biomedical-field
#4
REVIEW
Zhi-Yao He, Ke Men, Zhou Qin, Yang Yang, Ting Xu, Yu-Quan Wei
The clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (CRISPR-Cas9) system provides a novel genome editing technology that can precisely target a genomic site to disrupt or repair a specific gene. Some CRISPR-Cas9 systems from different bacteria or artificial variants have been discovered or constructed by biologists, and Cas9 nucleases and single guide RNAs (sgRNA) are the major components of the CRISPR-Cas9 system. These Cas9 systems have been extensively applied for identifying therapeutic targets, identifying gene functions, generating animal models, and developing gene therapies...
May 2, 2017: Science China. Life Sciences
https://www.readbyqxmd.com/read/28525897/a-cellular-platform-for-the-evaluation-of-immune-checkpoint-molecules
#5
Sabrina Jutz, Annika Hennig, Wolfgang Paster, Ömer Asrak, Dejana Dijanovic, Florian Kellner, Winfried F Pickl, Johannes B Huppa, Judith Leitner, Peter Steinberger
Blockade of the T cell coinhibitory molecules CTLA-4 and PD-1 has clinical utility to strengthen T cell responses. In addition to these immune checkpoints an ever-growing number of molecules has been implicated in generating coinhibitory signals in T cells. However, investigating coinhibitory molecules in primary human cells is complicated by the restricted expression and promiscuity of both coinhibitory receptors and their ligands. Here we have evaluated the potential of fluorescence-based transcriptional reporters based on the human Jurkat T cell line in conjunction with engineered T cell stimulator cell lines for investigating coinhibitory pathways...
May 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28525762/minimal-residual-disease-monitoring-of-acute-myeloid-leukemia-by-massively-multiplex-digital-pcr-in-patients-with-npm1-mutations
#6
Nuria Mencia-Trinchant, Yang Hu, Maria Antonina Alas, Fatima Ali, Bas J Wouters, Sangmin Lee, Ellen K Ritchie, Pinkal Desai, Monica L Guzman, Gail J Roboz, Duane C Hassane
The presence of minimal residual disease (MRD) is widely recognized as a powerful predictor of therapeutic outcome in acute myeloid leukemia (AML), but methods of measurement and quantification of MRD in AML are not yet standardized in clinical practice. There is an urgent, unmet need for robust and sensitive assays that can be readily adopted as real-time tools for disease monitoring. NPM1 frameshift mutations are an established MRD marker present in half of patients with cytogenetically normal AML. However, detection is complicated by the existence of hundreds of potential frameshift insertions, clonal heterogeneity, and absence of sequence information when the NPM1 mutation is identified using capillary electrophoresis...
May 16, 2017: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/28524730/recent-advances-in-genetic-testing-for-familial-hypercholesterolemia
#7
Michael A Iacocca, Robert A Hegele
Familial hypercholesterolemia (FH) is a common genetic cause of premature coronary heart disease that is widely underdiagnosed and undertreated. To improve the identification of FH and initiate timely and appropriate treatment strategies, genetic testing is becoming increasingly offered worldwide as a central part of diagnosis. Areas covered: Recent advances have been propelled by an improved understanding of the genetic determinants of FH together with substantially reduced costs of appropriate screening strategies...
May 19, 2017: Expert Review of Molecular Diagnostics
https://www.readbyqxmd.com/read/28523104/3-aroyl-1-4-diarylpyrroles-inhibit-chronic-myeloid-leukemia-cell-growth-through-an-interaction-with-tubulin
#8
Giuseppe La Regina, Ruoli Bai, Antonio Coluccia, Valeria Famiglini, Sara Passacantilli, Valentina Naccarato, Giorgio Ortar, Carmela Mazzoccoli, Vitalba Ruggieri, Francesca Agriesti, Claudia Piccoli, Tiziana Tataranni, Marianna Nalli, Andrea Brancale, Stefania Vultaggio, Ciro Mercurio, Mario Varasi, Concetta Saponaro, Sara Sergio, Michele Maffia, Addolorata Maria Luce Coluccia, Ernest Hamel, Romano Silvestri
We designed 3-aroyl-1,4-diarylpyrrole (ARDAP) derivatives as potential anticancer agents having different substituents at the 1- or 4-phenyl ring. ARDAP compounds exhibited potent inhibition of tubulin polymerization, binding of colchicine to tubulin, and cancer cell growth. ARDAP derivative 10 inhibited the proliferation of BCR/ABL-expressing KU812 and LAMA84 cells from chronic myeloid leukemia (CML) patients in blast crisis and of hematopoietic cells ectopically expressing the imatinib mesylate (IM)-sensitive KBM5-WT or its IM-resistant KBM5-T315I mutation...
May 11, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28520872/glucocerebrosidase-deficiency-in-dopaminergic-neurons-induces-microglial-activation-without-neurodegeneration
#9
Federico N Soria, Michel Engeln, Marta Martinez-Vicente, Christelle Glangetas, María José López-González, Sandra Dovero, Benjamin Dehay, Elisabeth Normand, Miquel Vila, Alexandre Favereaux, François Georges, Christophe Lo Bianco, Erwan Bezard, Pierre-Olivier Fernagut
Mutations in the GBA1 gene encoding the lysosomal enzyme glucocerebrosidase (GBA1) are important risk factors for Parkinson's disease (PD). In vitro, altered GBA1 activity promotes alpha-synuclein accumulation while elevated levels of alpha-synuclein compromise GBA1 function, thus supporting a pathogenic mechanism in PD. However, the mechanisms by which GBA1 deficiency is linked to increased risk of PD remains elusive, partially because of lack of aged models of GBA1 deficiency. Since knocking-out GBA1 in the entire brain induces massive neurodegeneration and early death, we generated a mouse model of GBA1 deficiency amenable to investigate the long-term consequences of compromised GBA1 function in dopaminergic neurons...
May 17, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28515174/functional-assessment-of-sodium-chloride-co-transporter-ncc-mutants-in-polarized-mammalian-epithelial-cells
#10
Lena Lindtoft Rosenbaek, Federica Rizzo, Nanna MacAulay, Olivier Staub, Robert A Fenton
The thiazide-sensitive sodium chloride co-transporter, NCC, is important for maintaining serum sodium (Na+) and, indirectly, serum potassium (K+) levels. Functional studies on NCC have used cell lines with native NCC expression, transiently transfected non-polarized cell lines or Xenopus laevis oocytes. Here, we developed polarized Madin-Darby canine kidney type I (MDCKI) mammalian epithelial cell lines with tetracycline-inducible human NCC expression to study NCC activity and membrane abundance in the same system...
May 17, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/28515047/centrosome-amplification-a-suspect-in-breast-cancer-and-racial-disparities
#11
Angela Ogden, Padmashree C G Rida, Ritu Aneja
The multifaceted involvement of centrosome amplification (CA) in tumorigenesis is coming into focus following years of meticulous experimentation, which have elucidated the powerful abilities of CA to promote cellular invasion, disrupt stem cell division, drive chromosomal instability (CIN), and perturb tissue architecture, activities that can accelerate tumor progression. Integration of the extant in vitro, in vivo, and clinical data suggests that in some tissues CA may be a tumor-initiating event, in others a consequential "hit" in multistep tumorigenesis, and in still others non-tumorigenic...
May 17, 2017: Endocrine-related Cancer
https://www.readbyqxmd.com/read/28512244/engineering-and-functional-characterization-of-fusion-genes-identifies-novel-oncogenic-drivers-of-cancer
#12
Hengyu Lu, Nicole Villafane, Turgut Dogruluk, Caitlin L Grzeskowiak, Kathleen Kong, Yiu Huen Tsang, Oksana Zagorodna, Angeliki Pantazi, Lixing Yang, Nicholas J Neill, Young Won Kim, Chad J Creighton, Roel G Verhaak, Gordon B Mills, Peter Park, Raju S Kucherlapati, Kenneth L Scott
Oncogenic gene fusions drive many human cancers, but tools to more quickly unravel their functional contributions are needed. Here we describe methodology permitting fusion gene construction for functional evaluation. Using this strategy, we engineered the known fusion oncogenes, BCR-ABL1, EML4-ALK, and ETV6-NTRK3, as well as 20 previously uncharacterized fusion genes identified in TCGA datasets. In addition to confirming oncogenic activity of the known fusion oncogenes engineered by our construction strategy, we validated five novel fusion genes involving MET, NTRK2, and BRAF kinases that exhibited potent transforming activity and conferred sensitivity to FDA-approved kinase inhibitors...
May 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28511096/improved-amplification-results-following-episodes-of-failure-to-amplify-at-the-amelogenin-locus-using-powerplex-%C3%A2-esi-16-fast-system
#13
Sigal Berlyne, Carla Oz, Naftaly Einot, Shlomit Avraham, Tanya Ram, Miri D Goldberg, Ron Gafny
In 2012 the Israel Police DNA Casework laboratory adopted the 16 STR PowerPlex(®) ESI kit for routine use. The Promega Company updated this kit and developed the PowerPlex(®) ESI 16 Fast System in which all autosomal primer pairs remained identical to the original set, except at the amelogenin site. The master mix was improved and optimized which allowed for direct, faster and more robust amplification. Prior to implementing the PowerPlex(®) ESI 16 Fast System in our lab, we conducted a preliminary assay where 213 casework samples were amplified using the new kit...
April 29, 2017: Forensic Science International. Genetics
https://www.readbyqxmd.com/read/28507080/divergent-roles-of-a-peripheral-transmembrane-segment-in-ampa-and-nmda-receptors
#14
Johansen B Amin, Catherine L Salussolia, Kelvin Chan, Michael C Regan, Jian Dai, Huan-Xiang Zhou, Hiro Furukawa, Mark E Bowen, Lonnie P Wollmuth
Ionotropic glutamate receptors (iGluRs), including AMPA receptor (AMPAR) and NMDA receptor (NMDAR) subtypes, are ligand-gated ion channels that mediate signaling at the majority of excitatory synapses in the nervous system. The iGluR pore domain is structurally and evolutionarily related to an inverted two-transmembrane K(+) channel. Peripheral to the pore domain in eukaryotic iGluRs is an additional transmembrane helix, the M4 segment, which interacts with the pore domain of a neighboring subunit. In AMPARs, the integrity of the alignment of a specific face of M4 with the adjacent pore domain is essential for receptor oligomerization...
May 15, 2017: Journal of General Physiology
https://www.readbyqxmd.com/read/28502728/technical-validation-of-a-next-generation-sequencing-assay-for-detecting-clinically-relevant-levels-of-breast-cancer-related-single-nucleotide-variants-and-copy-number-variants-using-simulated-cell-free-dna
#15
Xin Yang, Yuxing Chu, Rui Zhang, Yanxi Han, Lucheng Zhang, Yu Fu, Dan Li, Rongxue Peng, Dongdong Li, Jiansheng Ding, Ziyang Li, Meiru Zhao, Kuo Zhang, Tian Lu, Lang Yi, Qisheng Wu, Guigao Lin, Jiehong Xie, Tao Liu, Ling Yang, Xin Yi, Jinming Li
Next-generation sequencing (NGS) is commonly used in a clinical setting for diagnostic and prognostic testing of genetic mutations to select optimal targeted therapies. Herein, we describe the development of a custom NGS assay for detecting single-nucleotide variants (SNVs) and copy number variations (CNVs) in a panel of 51 genes related to breast cancer. We designed and implemented a validation strategy in accordance with principles and guidelines developed by the Next-Generation Sequencing: Standardization of Clinical Testing work group using artificial, cell-free DNA (cfDNA) with mutant fragments prepared in a simple, rapid, and cost-effective manner...
May 11, 2017: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/28500657/modulation-of-herg-channels-by-5-1h-indazol-5-yl-oxy-methyl-n-4-trifluoromethoxy-phenyl-pyrimidin-2-amine-itp-2-a-novel-small-molecule-activator
#16
Harinath Sale, Samrat Roy, Jayakumar Warrier, Srinivasan Thangathirupathy, Yoganand Vadari, Shruthi K Gopal, Prasad Krishnamurthy, Manjunath Ramarao
BACKGROUND AND PURPOSE: hERG channel activators have potential utility in the treatment of acquired and congenital long QT syndrome. In this article, we describe a new hERG activator, 5-(((1H-indazol-5-yl)oxy)methyl)-N-(4-(trifluoromethoxy)phenyl)pyrimidin-2-amine (ITP-2), with a chemical structure distinct from the previously reported compounds. EXPERIMENTAL APPROACH: We investigated the effect of ITP-2 on hERG1a and hERG1a/1b channels expressed heterologously in HEK-293 cells using conventional electrophysiological methods...
May 12, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28499489/neuronal-pas-domain-proteins-1-and-3-are-master-regulators-of-neuropsychiatric-risk-genes
#17
Jacob J Michaelson, Min-Kyoo Shin, Jin-Young Koh, Leo Brueggeman, Angela Zhang, Aaron Katzman, Latisha McDaniel, Mimi Fang, Miles Pufall, Andrew A Pieper
BACKGROUND: NPAS3 has been established as a robust genetic risk factor in major mental illness. In mice, loss of neuronal PAS domain protein 3 (NPAS3) impairs postnatal hippocampal neurogenesis, while loss of the related protein NPAS1 promotes it. These and other findings suggest a critical role for NPAS proteins in neuropsychiatric functioning, prompting interest in the molecular pathways under their control. METHODS: We used RNA sequencing coupled with chromatin immunoprecipitation sequencing to identify genes directly regulated by NPAS1 and NPAS3 in the hippocampus of wild-type, Npas1(-/-), and Npas3(-/-) mice...
April 6, 2017: Biological Psychiatry
https://www.readbyqxmd.com/read/28499063/high-efficient-multi-sites-genome-editing-in-allotetraploid-cotton-gossypium-hirsutum-using-crispr-cas9-system
#18
Pengcheng Wang, Jun Zhang, Lin Sun, Yizan Ma, Jiao Xu, Sijia Liang, Jinwu Deng, Jiafu Tan, Qinghua Zhang, Lili Tu, Henry Daniell, Shuangxia Jin, Xianlong Zhang
Gossypium hirsutum is an allotetraploid with a complex genome. Most genes have multiple copies that belong to At and Dt subgenomes. Sequence similarity is also very high between gene homologs. To efficiently achieve site/gene-specific mutation is quite needed. Due to its high efficiency and robustness, the CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas9 system has exerted broad site-specific genome editing from prokaryotes to eukaryotes. In this study, we utilized a CRISPR/Cas9 system to generate two sgRNAs in a single vector to conduct multiple sites genome editing in allotetraploid cotton...
May 12, 2017: Plant Biotechnology Journal
https://www.readbyqxmd.com/read/28498365/inhibition-of-twist1-mediated-invasion-by-chk2-promotes-premature-senescence-in-p53-defective-cancer-cells
#19
Debasis Nayak, Anmol Kumar, Souneek Chakraborty, Reyaz Ur Rasool, Hina Amin, Archana Katoch, Veena Gopinath, Vidushi Mahajan, Mahesh K Zilla, Bilal Rah, Sumit G Gandhi, Asif Ali, Lekha Dinesh Kumar, Anindya Goswami
Twist1, a basic helix-loop-helix transcription factor is implicated as a key mediator of epithelial-mesenchymal transition (EMT) and metastatic dissemination in p53-deficient cancer cells. On the other hand, checkpoint kinase 2 (Chk2), a major cell cycle regulatory protein provides a barrier to tumorigenesis due to DNA damage response by preserving genomic stability of the cells. Here we demonstrate that Chk2 induction proficiently abrogates invasion, cell scattering and invadopodia formation ability of p53-mutated invasive cells by suppressing Twist1, indicating Chk2 confers vital role in metastasis prevention...
May 12, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28495971/cilia-and-flagella-associated-protein-69-regulates-olfactory-transduction-kinetics-in-mice
#20
Anna K Talaga, Frederick N Dong, Johannes Reisert, Haiqing Zhao
Animals detect odorous chemicals through specialized olfactory sensory neurons (OSNs) that transduce odorants into neural electrical signals. We identify a novel and evolutionarily conserved protein, CFAP69, in mice that regulates olfactory transduction kinetics. In the olfactory epithelium CFAP69 is enriched in OSN cilia, where olfactory transduction occurs. Bioinformatic analysis suggests that a large portion of CFAP69 can form Armadillo-type α-helical repeats, which may mediate protein-protein interaction...
May 11, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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