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Mutational robustness

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https://www.readbyqxmd.com/read/28228528/clinical-genetic-and-structural-basis-of-congenital-adrenal-hyperplasia-due-to-11%C3%AE-hydroxylase-deficiency
#1
Ahmed Khattab, Shozeb Haider, Ameet Kumar, Samarth Dhawan, Dauood Alam, Raquel Romero, James Burns, Di Li, Jessica Estatico, Simran Rahi, Saleel Fatima, Ali Alzahrani, Mona Hafez, Noha Musa, Maryam Razzghy Azar, Najoua Khaloul, Moez Gribaa, Ali Saad, Ilhem Ben Charfeddine, Berenice Bilharinho de Mendonça, Alicia Belgorosky, Katja Dumic, Miroslav Dumic, Javier Aisenberg, Nurgun Kandemir, Ayfer Alikasifoglu, Alev Ozon, Nazli Gonc, Tina Cheng, Ursula Kuhnle-Krahl, Marco Cappa, Paul-Martin Holterhus, Munier A Nour, Daniele Pacaud, Assaf Holtzman, Sun Li, Mone Zaidi, Tony Yuen, Maria I New
Congenital adrenal hyperplasia (CAH), resulting from mutations in CYP11B1, a gene encoding 11β-hydroxylase, represents a rare autosomal recessive Mendelian disorder of aberrant sex steroid production. Unlike CAH caused by 21-hydroxylase deficiency, the disease is far more common in the Middle East and North Africa, where consanguinity is common often resulting in identical mutations. Clinically, affected female newborns are profoundly virilized (Prader score of 4/5), and both genders display significantly advanced bone ages and are oftentimes hypertensive...
February 22, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28220129/no-silver-bullet-canonical-poly-adp-ribose-polymerases-parps-are-no-universal-factors-of-abiotic-and-biotic-stress-resistance-of-arabidopsis-thaliana
#2
Dagmar Rissel, Peter P Heym, Kathrin Thor, Wolfgang Brandt, Ludger A Wessjohann, Edgar Peiter
Abiotic and biotic stress can have a detrimental impact on plant growth and productivity. Hence, there is a substantial demand for key factors of stress responses to improve yield stability of crops. Members of the poly(ADP-ribose)polymerase (PARP) protein family, which post-translationally modify (PARylate) nuclear proteins, have been suggested as such universal determinants of plant stress responses. A role under abiotic stress has been inferred from studies in which a genetic or, more commonly, pharmacological inhibition of PARP activity improved the performance of stressed plants...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/28218960/evolutionary-genetics-of-host-shifts-in-herbivorous-insects-insights-from-the-age-of-genomics
#3
Kim L Vertacnik, Catherine R Linnen
Adaptation to different host taxa is a key driver of insect diversification. Herbivorous insects are classic models for ecological and evolutionary research, but it is recent advances in sequencing, statistics, and molecular technologies that have cleared the way for investigations into the proximate genetic mechanisms underlying host shifts. In this review, we discuss how genome-scale data are revealing-at resolutions previously unimaginable-the genetic architecture of host-use traits, the causal loci underlying host shifts, and the predictability of host-use evolution...
February 2017: Annals of the New York Academy of Sciences
https://www.readbyqxmd.com/read/28217006/mutagenesis-and-tilling-to-dissect-gene-function-in-plants
#4
Zerihun Tadele
Mutagenesis can be random or targeted and occur by nature or artificially by humans. However, the bulk of mutagenesis employed in plants are random and caused by physical agents such as x-ray and gamma-ray or chemicals such as ethyl-methane sulfonate (EMS). Researchers are interested in first identifying these mutations and/or polymorphisms in the genome followed by investigating their effects in the plant function as well as their application in crop improvement. The high-throughput technique called TILLING (Targeting Induced Local Lesion IN Genomes) has been already established and become popular for identifying candidate mutant individuals harboring mutations in the gene of interest...
December 2016: Current Genomics
https://www.readbyqxmd.com/read/28213521/signalling-adaptor-shcd-suppresses-erk-phosphorylation-distal-to-the-ret-and-trk-neurotrophic-receptors
#5
Melanie K B Wills, Ava Keyvani Chahi, Hayley R Lau, Manali Tilak, Brianna Guild, Laura A New, Peihua Lu, Keévin Jacquet, Susan O Meakin, Nicolas Bisson, Nina Jones
Proteins of the Shc family are typically involved in signal transduction events involving Ras/MAPK and PI3K/Akt pathways. In the nervous system, they function proximal to the neurotrophic factors that regulate cell survival, differentiation, and neuron-specific characteristics. The least-characterized homolog, ShcD, is robustly expressed in the developing and mature nervous system, but its contributions to neural cell circuitry are largely uncharted. We now report that ShcD binds to active Ret, TrkA, and TrkB neurotrophic factor receptors predominantly via its phosphotyrosine binding (PTB) domain...
February 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28209611/genetic-manipulation-of-helicobacter-pylori-virulence-function-by-host-carcinogenic-phenotypes
#6
Giovanni Suarez, Judith Romero-Gallo, Johanna C Sierra, M Blanca Piazuelo, Uma Krishna, Martin Alonso Gomez, Keith T Wilson, Richard M Peek
Helicobacter pylori is the strongest risk factor for gastric adenocarcinoma, yet only a minority of infected persons ever develop this malignancy. One cancer-linked locus is the cag type 4 secretion system (cagT4SS), which translocates an oncoprotein into host cells. A structural component of the cagT4SS is CagY, which become rapidly altered during in vivo adaptation in mice and rhesus monkeys, rendering the cagT4SS nonfunctional; however, these models rarely develop gastric cancer. We previously demonstrated that the H...
February 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28204960/sites-and-functional-consequence-of-alkylphenol-anesthetic-binding-to-kv1-2-channels
#7
Weiming Bu, Qiansheng Liang, Lianteng Zhi, Lina Maciunas, Patrick J Loll, Roderic G Eckenhoff, Manuel Covarrubias
Inhalational general anesthetics, such as sevoflurane and isoflurane, modulate a subset of brain Kv1 potassium channels. However, the Kv1.2 channel is resistant to propofol, a commonly used intravenous alkylphenol anesthetic. We hypothesize that propofol binds to a presumed pocket involving the channel's S4-S5 linker, but functional transduction is poor and, therefore, propofol efficacy is low. To test this hypothesis, we used a photoactive propofol analog (meta-aziPropofol = AziPm) to directly probe binding and electrophysiological and mutational analyses in Xenopus oocytes to probe function...
February 15, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28202515/systematic-in-vivo-inactivation-of-chromatin-regulating-enzymes-identifies-setd2-as-a-potent-tumor-suppressor-in-lung-adenocarcinoma
#8
David M Walter, Olivia S Venancio, Elizabeth L Buza, John W Tobias, Charuhas Deshpande, A Andrea Gudiel, Caroline Kim-Kiselak, Michelle Cicchini, Travis J Yates, David M Feldser
Chromatin modifying genes are frequently mutated in human lung adenocarcinoma, but the functional impact of these mutations on disease initiation and progression is not well understood. Using a CRISPR-based approach, we systematically inactivated three of the most commonly mutated chromatin regulatory genes in two KrasG12D-driven mouse models of lung adenocarcinoma to characterize the impact of their loss. Targeted inactivation of SWI/SNF nucleosome remodeling complex members Smarca4 (Brg1) or Arid1a had complex effects on lung adenocarcinoma initiation and progression...
February 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28197780/erratum-to-development-of-a-robust-and-sensitive-pyrosequencing-assay-for-the-detection-of-idh1-2-mutations-in-gliomas
#9
Hideyuki Arita, Yoshitaka Narita, Yuko Matsushita, Shintaro Fukushima, Akihiko Yoshida, Hirokazu Takami, Yasuji Miyakita, Makoto Ohno, Soichiro Shibui, Koichi Ichimura
No abstract text is available yet for this article.
February 14, 2017: Brain Tumor Pathology
https://www.readbyqxmd.com/read/28193729/sequential-divergent-and-cooperative-requirements-of-foxl2a-and-foxl2b-in-ovary-development-and-maintenance-of-zebrafish
#10
Yan-Jing Yang, Yang Wang, Zhi Li, Li Zhou, Jian-Fang Gui
Foxl2 is essential for mammalian ovary maintenance. Although sexually dimorphic expression of foxl2 was observed in many teleost, its role and regulative mechanism in fish remained largely unclear. In this study, we first identified two transcript variants of foxl2a and its homologous gene foxl2b in zebrafish, and revealed their specific expression in follicular layer cells in a sequential and divergent fashion during ovary differentiation, maturation and maintenance. Then, homozygous foxl2a mutants (foxl2a(-/-)) and foxl2b mutants (foxl2b(-/-)) were constructed, and detailed comparisons, such as sex ratio, gonadal histological structure, transcriptome profiling and dynamic expression of gonadal development-related genes, were carried out...
February 13, 2017: Genetics
https://www.readbyqxmd.com/read/28188776/aurora-a-overexpression-aurka-is-driven-by-foxm1-and-mapk-erk-activation-in-melanoma-cells-harbouring-braf-or-nras-mutations-impact-on-melanoma-prognosis-and-therapy
#11
Joan Anton Puig-Butille, Antònia Vinyals, Josep R Ferreres, Paula Aguilera, Eduard Cabré, Gemma Tell-Martí, Joaquim Marcoval, Francesca Mateo, Luís Palomero, Celia Badenas, Josep M Piulats, Josep Malvehy, Miquel A Pujana, Susana Puig, Àngels Fabra
The cell cycle-related genes AURORA A and Forkhead box M1 (FOXM1) are overexpressed in melanoma. We show here that AURKA overexpression is associated with poor prognosis in three independent cohorts of melanoma patients and correlates with the presence of genomic amplification of AURKA locus and BRAF(V600E) mutation. AURKA overexpression may also be driven to increased promoter activation through elements such as ETS and FOXM1 found within the 5' proximal promoter region. Activated MAPK-ERK signalling pathway mediates robust AURKA promoter activation, thereby knockdown of BRAF(V600E) and ERK inhibition results in reduced AURKA transcription and expression...
February 7, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28188264/immortalized-human-myotonic-dystrophy-muscle-cell-lines-to-assess-therapeutic-compounds
#12
Arandel Ludovic, Polay-Espinosa Micaela, Matloka Magdalena, Bazinet Audrey, De Dea Diniz Damily, Naouar Naïra, Rau Frédérique, Jollet Arnaud, Edom-Vovard Frédérique, Mamchaoui Kamel, Tarnopolsky Mark, Puymirat Jack, Battail Christophe, Boland Anne, Deleuze Jean-Francois, Mouly Vincent, Klein F Arnaud, Furling Denis
Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant neuromuscular diseases caused by microsatellite expansions and belong to the family of RNA dominant disorders. Availability of cellular models in which the DM mutation is expressed within its natural context is essential to facilitate efforts to identify new therapeutic compounds. Here we generated immortalized DM1 and DM2 human muscle cell lines that display nuclear RNA-aggregates of expanded repeats, a hallmark of myotonic dystrophy. Selected clones of DM1 and DM2 immortalized myoblasts behave as parental primary myoblasts with a reduced fusion capacity of immortalized DM1 myoblasts when compared to control and DM2 cells...
February 10, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28187176/%C3%AE-synuclein-increases-%C3%AE-amyloid-secretion-by-promoting-%C3%AE-%C3%AE-secretase-processing-of-app
#13
Hazel L Roberts, Bernard L Schneider, David R Brown
α-Synuclein misfolding and aggregation is often accompanied by β-amyloid deposition in some neurodegenerative diseases. We hypothesised that α-synuclein promotes β-amyloid production from APP. β-Amyloid levels and APP amyloidogenic processing were investigated in neuronal cell lines stably overexpressing wildtype and mutant α-synuclein. γ-Secretase activity and β-secretase expression were also measured. We show that α-synuclein expression induces β-amyloid secretion and amyloidogenic processing of APP in neuronal cell lines...
2017: PloS One
https://www.readbyqxmd.com/read/28183979/gene-duplication-can-impart-fragility-not-robustness-in-the-yeast-protein-interaction-network
#14
Guillaume Diss, Isabelle Gagnon-Arsenault, Anne-Marie Dion-Coté, Hélène Vignaud, Diana I Ascencio, Caroline M Berger, Christian R Landry
The maintenance of duplicated genes is thought to protect cells from genetic perturbations, but the molecular basis of this robustness is largely unknown. By measuring the interaction of yeast proteins with their partners in wild-type cells and in cells lacking a paralog, we found that 22 out of 56 paralog pairs compensate for the lost interactions. An equivalent number of pairs exhibit the opposite behavior and require each other's presence for maintaining their interactions. These dependent paralogs generally interact physically, regulate each other's abundance, and derive from ancestral self-interacting proteins...
February 10, 2017: Science
https://www.readbyqxmd.com/read/28181325/recurrent-copy-number-alterations-in-low-grade-and-anaplastic-pleomorphic-xanthoastrocytoma-with-and-without-braf-v600e-mutation
#15
Rachael A Vaubel, Alissa A Caron, Seiji Yamada, Paul A Decker, Jeanette E Eckel Passow, Fausto J Rodriguez, Amulya A Nageswara Rao, Daniel Lachance, Ian Parney, Robert Jenkins, Caterina Giannini
Pleomorphic xanthoastrocytoma (PXA) is a rare localized glioma characterized by frequent BRAF V600E mutation and CDKN2A/B deletion. We explored the association of copy-number variants (CNVs) with BRAF mutations, tumor grade, and patient survival in a cohort of 41 PXA patients using OncoScan chromosomal microarray. Primary resection specimens were available in 38 cases, including 24 PXA and 14 anaplastic PXA (A-PXA), 23 BRAF V600E mutant tumors (61%). CNVs were identified in all cases and most frequently involved chromosome 9 with homozygous CDKN2A/B deletion (n=33, 87%), a higher proportion than previously detected by comparative genomic hybridization (50-60%) (37)...
February 9, 2017: Brain Pathology
https://www.readbyqxmd.com/read/28181072/interactions-of-mitochondria-metabolism-and-calcium-regulation-in-alzheimer-s-disease-a-calcinist-point-of-view
#16
Gary E Gibson, Ankita Thakkar
Decades of research suggest that alterations in calcium are central to the pathophysiology of Alzheimer's Disease (AD). Highly reproducible changes in calcium dynamics occur in cells from patients with both genetic and non-genetic forms of AD relative to controls. The most robust change is an exaggerated release of calcium from internal stores. Detailed analysis of these changes in animal and cell models of the AD-causing presenilin mutations reveal robust changes in ryanodine receptors, inositol tris-phosphate receptors, calcium leak channels and store activated calcium entry...
February 8, 2017: Neurochemical Research
https://www.readbyqxmd.com/read/28176805/motivational-proteostatic-and-transcriptional-deficits-precede-synapse-loss-gliosis-and-neurodegeneration-in-the-b6-htt-q111-model-of-huntington-s-disease
#17
Robert M Bragg, Sydney R Coffey, Rory M Weston, Seth A Ament, Jeffrey P Cantle, Shawn Minnig, Cory C Funk, Dominic D Shuttleworth, Emily L Woods, Bonnie R Sullivan, Lindsey Jones, Anne Glickenhaus, John S Anderson, Michael D Anderson, Stephen B Dunnett, Vanessa C Wheeler, Marcy E MacDonald, Simon P Brooks, Nathan D Price, Jeffrey B Carroll
We investigated the appearance and progression of disease-relevant signs in the B6.Htt(Q111/+) mouse, a genetically precise model of the mutation that causes Huntington's disease (HD). We find that B6.Htt(Q111/+) mice are healthy, show no overt signs of central or peripheral inflammation, and no gross motor impairment as late as 12 months of age. Behaviorally, we find that 4-9 month old B6.Htt(Q111/+) mice have normal activity levels and show no clear signs of anxiety or depression, but do show clear signs of reduced motivation...
February 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28174312/selective-whole-genome-amplification-is-a-robust-method-that-enables-scalable-whole-genome-sequencing-of-plasmodium-vivax-from-unprocessed-clinical-samples
#18
Annie N Cowell, Dorothy E Loy, Sesh A Sundararaman, Hugo Valdivia, Kathleen Fisch, Andres G Lescano, G Christian Baldeviano, Salomon Durand, Vince Gerbasi, Colin J Sutherland, Debbie Nolder, Joseph M Vinetz, Beatrice H Hahn, Elizabeth A Winzeler
: Whole-genome sequencing (WGS) of microbial pathogens from clinical samples is a highly sensitive tool used to gain a deeper understanding of the biology, epidemiology, and drug resistance mechanisms of many infections. However, WGS of organisms which exhibit low densities in their hosts is challenging due to high levels of host genomic DNA (gDNA), which leads to very low coverage of the microbial genome. WGS of Plasmodium vivax, the most widely distributed form of malaria, is especially difficult because of low parasite densities and the lack of an ex vivo culture system...
February 7, 2017: MBio
https://www.readbyqxmd.com/read/28174309/understanding-zika-virus-stability-and-developing-a-chimeric-vaccine-through-functional-analysis
#19
Xuping Xie, Yujiao Yang, Antonio E Muruato, Jing Zou, Chao Shan, Bruno T D Nunes, Daniele B A Medeiros, Pedro F C Vasconcelos, Scott C Weaver, Shannan L Rossi, Pei-Yong Shi
: Compared with other flaviviruses, Zika virus (ZIKV) is uniquely associated with congenital diseases in pregnant women. One recent study reported that (i) ZIKV has higher thermostability than dengue virus (DENV [a flavivirus closely related to ZIKV]), which might contribute to the disease outcome; (ii) the higher thermostability of ZIKV could arise from an extended loop structure in domain III of the viral envelope (E) protein and an extra hydrogen-bond interaction between E molecules (V...
February 7, 2017: MBio
https://www.readbyqxmd.com/read/28168313/expression-of-a-mutated-spt15-gene-in-saccharomyces-cerevisiae-enhances-both-cell-growth-and-ethanol-production-in-microaerobic-batch-fed-batch-and-simultaneous-saccharification-and-fermentations
#20
Yeong-Je Seong, Haeseong Park, Jungwoo Yang, Soo-Jung Kim, Wonja Choi, Kyoung Heon Kim, Yong-Cheol Park
The SPT15 gene encodes a Saccharomyces cerevisiae TATA-binding protein, which is able to globally control the transcription levels of various metabolic and regulatory genes. In this study, a SPT15 gene mutant (S42N, S78R, S163P, and I212N) was expressed in S. cerevisiae BY4741 (BSPT15-M3), of which effects on fermentative yeast properties were evaluated in a series of culture types. By applying different nitrogen sources and air supply conditions in batch culture, organic nitrogen sources and microaerobic condition were decided to be more favorable for both cell growth and ethanol production of the BSPT15-M3 strain than the control S...
February 6, 2017: Applied Microbiology and Biotechnology
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