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Mutational robustness

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https://www.readbyqxmd.com/read/29456549/global-dna-methylation-in-the-chestnut-blight-fungus-cryphonectria-parasitica-and-genome-wide-changes-in-dna-methylation-accompanied-with-sectorization
#1
Kum-Kang So, Yo-Han Ko, Jeesun Chun, Jyotiranjan Bal, Junhyun Jeon, Jung-Mi Kim, Jaeyoung Choi, Yong-Hwan Lee, Jin Hoe Huh, Dae-Hyuk Kim
Mutation in CpBck1 , an ortholog of the cell wall integrity mitogen-activated protein kinase kinase kinase (MAPKKK) of Saccharomyces cerevisiae , in the chestnut blight fungus Cryphonectria parasitica resulted in a sporadic sectorization as culture proceeded. The progeny from the sectored area maintained the characteristics of the sector, showing a massive morphogenetic change, including robust mycelial growth without differentiation. Epigenetic changes were investigated as the genetic mechanism underlying this sectorization...
2018: Frontiers in Plant Science
https://www.readbyqxmd.com/read/29456136/a-sex-chromosome-pirna-promotes-robust-dosage-compensation-and-sex-determination-in-c-elegans
#2
Wen Tang, Meetu Seth, Shikui Tu, En-Zhi Shen, Qian Li, Masaki Shirayama, Zhiping Weng, Craig C Mello
In metazoans, Piwi-related Argonaute proteins engage piRNAs (Piwi-interacting small RNAs) to defend the genome against invasive nucleic acids, such as transposable elements. Yet many organisms-including worms and humans-express thousands of piRNAs that do not target transposons, suggesting that piRNA function extends beyond genome defense. Here, we show that the X chromosome-derived piRNA 21ux-1 downregulates XOL-1 (XO Lethal), a master regulator of X chromosome dosage compensation and sex determination in Caenorhabditis elegans...
February 13, 2018: Developmental Cell
https://www.readbyqxmd.com/read/29453278/molecular-signatures-of-circulating-melanoma-cells-for-monitoring-early-response-to-immune-checkpoint-therapy
#3
Xin Hong, Ryan J Sullivan, Mark Kalinich, Tanya Todorova Kwan, Anita Giobbie-Hurder, Shiwei Pan, Joseph A LiCausi, John D Milner, Linda T Nieman, Ben S Wittner, Uyen Ho, Tianqi Chen, Ravi Kapur, Donald P Lawrence, Keith T Flaherty, Lecia V Sequist, Sridhar Ramaswamy, David T Miyamoto, Michael Lawrence, Mehmet Toner, Kurt J Isselbacher, Shyamala Maheswaran, Daniel A Haber
A subset of patients with metastatic melanoma have sustained remissions following treatment with immune checkpoint inhibitors. However, analyses of pretreatment tumor biopsies for markers predictive of response, including PD-1 ligand (PD-L1) expression and mutational burden, are insufficiently precise to guide treatment selection, and clinical radiographic evidence of response on therapy may be delayed, leading to some patients receiving potentially ineffective but toxic therapy. Here, we developed a molecular signature of melanoma circulating tumor cells (CTCs) to quantify early tumor response using blood-based monitoring...
February 16, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29449275/circulating-tumor-dna-reveals-genetics-clonal-evolution-and-residual-disease-in-classical-hodgkin-lymphoma
#4
Valeria Spina, Alessio Bruscaggin, Annarosa Cuccaro, Maurizio Martini, Martina Di Trani, Gabriela Forestieri, Martina Manzoni, Adalgisa Condoluci, Alberto Arribas, Lodovico Terzi-Di-Bergamo, Silvia Laura Locatelli, Elisa Cupelli, Luca Ceriani, Alden A Moccia, Anastasios Stathis, Luca Nassi, Clara Deambrogi, Fary Diop, Francesca Guidetti, Alessandra Cocomazzi, Salvatore Annunziata, Vittoria Rufini, Alessandro Giordano, Antonino Neri, Renzo Boldorini, Bernhard Gerber, Francesco Bertoni, Michele Ghielmini, Georg Stüssi, Armando Santoro, Franco Cavalli, Emanuele Zucca, Luigi Maria Larocca, Gianluca Gaidano, Stefan Hohaus, Carmelo Carlo-Stella, Davide Rossi
The rarity of neoplastic cells in the biopsy imposes major technical hurdles that have so far limited genomic studies in classical Hodgkin lymphoma (cHL). By using a highly sensitive and robust deep-next-generation-sequencing approach for circulating tumor DNA (ctDNA), here we aimed at tracking the genetics of cHL in different clinical phases, and its modifications upon treatment. The analysis was based on specimens collected from 80 newly diagnosed and 32 refractory cHL patients, including longitudinal samples collected under ABVD chemotherapy and longitudinal samples from relapsing patients treated with chemotherapy and immunotherapy...
February 15, 2018: Blood
https://www.readbyqxmd.com/read/29443056/primordial-germ-cell-transplantation-for-crispr-cas9-based-leapfrogging-in-xenopus
#5
Ira L Blitz
The creation of mutant lines by genome editing is accelerating genetic analysis in many organisms. CRISPR/Cas9 methods have been adapted for use in the African clawed frog, Xenopus, a longstanding model organism for biomedical research. Traditional breeding schemes for creating homozygous mutant lines with CRISPR/Cas9-targeted mutagenesis have several time-consuming and laborious steps. To facilitate the creation of mutant embryos, particularly to overcome the obstacles associated with knocking out genes that are essential for embryogenesis, a new method called leapfrogging was developed...
February 1, 2018: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/29441510/translating-the-combination-of-gene-therapy-and-tissue-engineering-for-treating-recessive-dystrophic-epidermolysis-bullosa
#6
A Dakiw Piaceski, D Larouche, K Ghani, F Bisson, S Cortez Ghio, S Larochelle, M J Moulin, M Caruso, L Germain
The combination of gene therapy and tissue engineering is one of the most promising strategies for the treatment of recessive dystrophic epidermolysis bullosa (RDEB). RDEB is a rare genetic disease characterised by mutations in the COL7A1 gene, encoding type VII collagen (COLVII), which forms anchoring fibrils at the dermal-epidermal junction of the skin. This disease causes severe blistering and only palliative treatments are offered. In this study, the base of a strategy combining gene therapy and a tissue-engineered skin substitute (TES), which would be suitable for the permanent closure of skin wounds, was set-up...
February 14, 2018: European Cells & Materials
https://www.readbyqxmd.com/read/29435161/nonlinear-mixed-effects-dose-response-modeling-in-high-throughput-drug-screens-application-to-melanoma-cell-line-analysis
#7
Kuan-Fu Ding, Emanuel F Petricoin, Darren Finlay, Hongwei Yin, William P D Hendricks, Chris Sereduk, Jeffrey Kiefer, Aleksandar Sekulic, Patricia M LoRusso, Kristiina Vuori, Jeffrey M Trent, Nicholas J Schork
Cancer cell lines are often used in high throughput drug screens (HTS) to explore the relationship between cell line characteristics and responsiveness to different therapies. Many current analysis methods infer relationships by focusing on one aspect of cell line drug-specific dose-response curves (DRCs), the concentration causing 50% inhibition of a phenotypic endpoint (IC50). Such methods may overlook DRC features and do not simultaneously leverage information about drug response patterns across cell lines, potentially increasing false positive and negative rates in drug response associations...
January 12, 2018: Oncotarget
https://www.readbyqxmd.com/read/29426712/getting-momentum-from-biocatalysis-to-advanced-synthetic-biology
#8
REVIEW
Christoffel P S Badenhorst, Uwe T Bornscheuer
Applied biocatalysis is driven by environmental and economic incentives for using enzymes in the synthesis of various pharmaceutical and industrially important chemicals. Protein engineering is used to tailor the properties of enzymes to catalyze desired chemical transformations, and some engineered enzymes now outperform the best chemocatalytic alternatives by orders of magnitude. Unfortunately, custom engineering of a robust biocatalyst is still a time-consuming process, but an understanding of how enzyme function depends on amino acid sequence will speed up the process...
February 6, 2018: Trends in Biochemical Sciences
https://www.readbyqxmd.com/read/29423038/suppression-of-fgfr3-and-myc-dependent-oncogenesis-by-tubacin-association-with-hdac6-dependent-and-independent-activities
#9
Sara Ota, Zi-Qiang Zhou, Peter J Hurlin
Fibroblast growth factor receptor 3 (FGFR3) is amplified, translocated or mutated in a number of different human cancer types, but most commonly in bladder cancers. We previously found that the accumulation of FGFR3 is dependent on histone deacetylase 6 (HDAC6). Here we show that HDAC6 loss or inhibition reduces FGFR3 accumulation in cells made tumorigenic by ectopic expression of a mutant activated version of FGFR3 together with the MYC oncoprotein and in a bladder cancer cell line whose tumorigenicity is dependent on expression of a translocated version of FGFR3...
January 9, 2018: Oncotarget
https://www.readbyqxmd.com/read/29422527/regulation-of-mutant-tert-by-braf-v600e-map-kinase-pathway-through-fos-gabp-in-human-cancer
#10
Rengyun Liu, Tao Zhang, Guangwu Zhu, Mingzhao Xing
The unique oncogene duet of coexisting BRAF V600E and TERT promoter mutations are widely found to be a robust genetic background promoting human cancer aggressiveness, but the mechanism is unclear. Here, we demonstrate that the BRAF V600E/MAP kinase pathway phosphorylates and activates FOS, which in turn acts as a transcription factor to bind and activate the GABPB promoter, increasing GABPB expression and driving formation of GABPA-GABPB complex; the latter selectively binds and activates mutant TERT promoter, upregulating TERT expression...
February 8, 2018: Nature Communications
https://www.readbyqxmd.com/read/29420474/enhancer-redundancy-provides-phenotypic-robustness-in-mammalian-development
#11
Marco Osterwalder, Iros Barozzi, Virginie Tissières, Yoko Fukuda-Yuzawa, Brandon J Mannion, Sarah Y Afzal, Elizabeth A Lee, Yiwen Zhu, Ingrid Plajzer-Frick, Catherine S Pickle, Momoe Kato, Tyler H Garvin, Quan T Pham, Anne N Harrington, Jennifer A Akiyama, Veena Afzal, Javier Lopez-Rios, Diane E Dickel, Axel Visel, Len A Pennacchio
Distant-acting tissue-specific enhancers, which regulate gene expression, vastly outnumber protein-coding genes in mammalian genomes, but the functional importance of this regulatory complexity remains unclear. Here we show that the pervasive presence of multiple enhancers with similar activities near the same gene confers phenotypic robustness to loss-of-function mutations in individual enhancers. We used genome editing to create 23 mouse deletion lines and inter-crosses, including both single and combinatorial enhancer deletions at seven distinct loci required for limb development...
February 8, 2018: Nature
https://www.readbyqxmd.com/read/29417219/robust-identification-of-mosaic-variants-in-congenital-heart-disease
#12
Kathryn B Manheimer, Felix Richter, Lisa J Edelmann, Sunita L D'Souza, Lisong Shi, Yufeng Shen, Jason Homsy, Marko T Boskovski, Angela C Tai, Joshua Gorham, Christopher Yasso, Elizabeth Goldmuntz, Martina Brueckner, Richard P Lifton, Wendy K Chung, Christine E Seidman, J G Seidman, Bruce D Gelb
Mosaicism due to somatic mutations can cause multiple diseases including cancer, developmental and overgrowth syndromes, neurodevelopmental disorders, autoinflammatory diseases, and atrial fibrillation. With the increased use of next generation sequencing technology, multiple tools have been developed to identify low-frequency variants, specifically from matched tumor-normal tissues in cancer studies. To investigate whether mosaic variants are implicated in congenital heart disease (CHD), we developed a pipeline using the cancer somatic variant caller MuTect to identify mosaic variants in whole-exome sequencing (WES) data from a cohort of parent/affected child trios (n = 715) and a cohort of healthy individuals (n = 416)...
February 7, 2018: Human Genetics
https://www.readbyqxmd.com/read/29416618/preclinical-efficacy-and-biological-effects-of-the-oral-proteasome-inhibitor-ixazomib-in-diffuse-large-b-cell-lymphoma
#13
Wei Liu, Juan Chen, Archito T Tamayo, Changgeng Ruan, Li Li, Shouhao Zhou, Chan Shen, Ken H Young, Jason Westin, Richard E Davis, Shimin Hu, Leonard J Medeiros, Richard J Ford, Lan V Pham
Despite advances in deciphering the molecular pathogenesis of diffuse large B-cell lymphoma (DLBCL), patients with relapsed/refractory disease, particularly those with adverse genetic features (e.g., mutated p53 or double hit lymphoma (DHL)) have very poor prognoses, and effective therapies are lacking. In this study we examined the preclinical efficacy and associated biological effects of the first oral proteasome inhibitor, ixazomib, in DLBCL in vitro and in vivo models. We demonstrated that ixazomib exhibited anti-tumor activities in 28 representative DLBCL cell lines, 10 primary DLBCL samples, and a DHL xenotransplant mouse model, at clinically achievable drug concentrations...
January 2, 2018: Oncotarget
https://www.readbyqxmd.com/read/29414698/fret-image-correlation-spectroscopy-reveals-rnapii-independent-p-tefb-recruitment-on-chromatin
#14
Gabriel Bidaux, Corentin Le Nézet, Mariano Gonzalez Pisfil, Mélanie Henry, Alessandro Furlan, Oliver Bensaude, Bernard Vandenbunder, Laurent Héliot
Biochemical studies have revealed that the RNA Polymerase II (RNAPII) pause release is triggered by phosphorylation of the transcription machinery by the positive transcription elongation factor b (P-TEFb). However, there are no direct report that P-TEFb and RNA polymerase II interact in single living cells and the biophysical mechanisms mediating this association are still unclear. Förster resonance energy transfer (FRET) detects molecular interactions at the subcellular level. Time domain fluorescence lifetime imaging provides an accurate quantification of FRET efficiency, EFRET, because it is fluorochrome concentration-independent and insensitive to fluorescence bleed-through...
February 6, 2018: Biophysical Journal
https://www.readbyqxmd.com/read/29414186/substantial-variation-in-the-hepatitis-b-surface-antigen-hbsag-in-hepatitis-b-virus-hbv-positive-patients-from-south-africa-reliable-detection-of-hbv-by-the-elecsys-hbsag-ii-assay
#15
Mikael Gencay, Marion Vermeulen, Dionysis Neofytos, Gaston Westergaard, Stephan Pabinger, Albert Kriegner, Anja Seffner, Peter Gohl, Kirsten Huebner, Markus Nauck, Wolfgang E Kaminski
BACKGROUND: It is essential that hepatitis B surface antigen (HBsAg) diagnostic assays reliably detect genetic diversity in the major hydrophilic region (MHR) of HBsAg to avoid false-negative results. Mutations in this domain display marked ethno-geographic variation and may lead to failure to diagnose hepatitis B virus (HBV) infection. OBJECTIVES: Evaluate diagnostic performance of the Elecsys® HBsAg II Qualitative assay in a cohort of South African HBV-positive blood donors...
January 30, 2018: Journal of Clinical Virology: the Official Publication of the Pan American Society for Clinical Virology
https://www.readbyqxmd.com/read/29403014/deaminase-mediated-multiplex-genome-editing-in-escherichia-coli
#16
Satomi Banno, Keiji Nishida, Takayuki Arazoe, Hitoshi Mitsunobu, Akihiko Kondo
In eukaryotes, the CRISPR-Cas9 system has now been widely used as a revolutionary genome engineering tool1, 2. However, in prokaryotes, the use of nuclease-mediated genome editing tools has been limited to negative selection for the already modified cells because of its lethality3, 4. Here, we report on deaminase-mediated targeted nucleotide editing (Target-AID) 5 adopted in Escherichia coli. Cytidine deaminase PmCDA1 fused to the nuclease-deficient CRISPR-Cas9 system achieved specific point mutagenesis at the target sites in E...
February 5, 2018: Nature Microbiology
https://www.readbyqxmd.com/read/29402979/human-neurospheroid-arrays-for-in-vitro-studies-of-alzheimer-s-disease
#17
Mehdi Jorfi, Carla D'Avanzo, Rudolph E Tanzi, Doo Yeon Kim, Daniel Irimia
Neurospheroids are commonly used for in vitro disease modeling and drug screening. However, the heterogeneity in size of the neurospheroids mixtures available through current methods limits their utility when employed for basic mechanistic studies of neurodegenerative diseases or screening for new interventions. Here, we generate neurospheroids from immortalized neural progenitor cells and human induced pluripotent stem cells that are uniform in size, into large-scale arrays. In proof of concept experiments, we validate the neurospheroids array as a sensitive and robust tool for screening compounds over extended time...
February 5, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29402297/cos-7-based-model-methodological-approach-to-study-john-cunningham-virus-replication-cycle
#18
C Prezioso, D Scribano, D M Rodio, C Ambrosi, M Trancassini, A T Palamara, V Pietropaolo
John Cunningham virus (JCV) is a human neurotropic polyomavirus whose replication in the Central Nervous System (SNC) induces the fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML). JCV propagation and PML investigation have been severely hampered by the lack of an animal model and cell culture systems to propagate JCV have been very limited in their availability and robustness. We previously confirmed that JCV CY strain efficiently replicated in COS-7 cells as demonstrated by the progressive increase of viral load by quantitative PCR (Q-PCR) during the time of transfection and that archetypal regulatory structure was maintained, although two characteristic point mutations were detected during the viral cycle...
February 5, 2018: Virology Journal
https://www.readbyqxmd.com/read/29402231/the-first-international-conference-on-syngap1-related-brain-disorders-a-stakeholder-meeting-of-families-researchers-clinicians-and-regulators
#19
REVIEW
Monica Weldon, Murat Kilinc, J Lloyd Holder, Gavin Rumbaugh
BACKGROUND: Pathologic mutations in SYNGAP1 cause a genetically defined form of intellectual disability (ID) with comorbid epilepsy and autistic features. While only recently discovered, pathogenicity of this gene is a relatively frequent genetic cause of classically undefined developmental delay that progresses to ID with commonly occurring comorbidities. MAIN BODY: A meeting of 150 people was held that included affected individuals and their caregivers, clinicians that treat this and related brain disorders, neuroscientists that study SYNGAP1 biology or the function of related genes, and representatives from government agencies that fund science and approve new medical treatments...
February 5, 2018: Journal of Neurodevelopmental Disorders
https://www.readbyqxmd.com/read/29396495/structure-guided-design-of-serratia-marcescens-short-chain-dehydrogenase-reductase-for-stereoselective-synthesis-of-r-phenylephrine
#20
Jai-Shin Liu, Yi-Chia Kuan, Yu Tsou, Tung-Yueh Lin, Wen-Hwei Hsu, Ming-Te Yang, Jong-Yih Lin, Wen-Ching Wang
Bioconversion is useful to produce optically pure enantiomers in the pharmaceutical industry, thereby avoiding problems with side reactions during organic synthesis processes. A short-chain dehydrogenase/reductase from Serratia marcescens BCRC 10948 (SmSDR) can stereoselectively convert 1-(3-hydroxyphenyl)-2-(methylamino) ethanone (HPMAE) into (R)-phenylephrine [(R)-PE], which is marketed medically as a nasal decongestant agent. The whole-cell conversion process for the synthesis of (R)-PE using SmSDR was reported to have an unexpectedly low conversion rate...
February 2, 2018: Scientific Reports
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