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https://www.readbyqxmd.com/read/28078645/parp-inhibitors-in-reproductive-system-cancers-current-use-and-developments
#1
REVIEW
Geraldine O'Sullivan Coyne, Alice P Chen, Robert Meehan, James H Doroshow
The repair of DNA damage is a critical cellular process governed by multiple biochemical pathways that are often found to be defective in cancer cells. The poly(ADP-ribose) polymerase (PARP) family of proteins controls response to single-strand DNA breaks by detecting these damaged sites and recruiting the proper factors for repair. Blocking this pathway forces cells to utilize complementary mechanisms to repair DNA damage. While PARP inhibition may not, in itself, be sufficient to cause tumor cell death, inhibition of DNA repair with PARP inhibitors is an effective cytotoxic strategy when it is used in patients who carry other defective DNA-repair mechanisms, such as mutations in the genes BRCA 1 and 2...
January 11, 2017: Drugs
https://www.readbyqxmd.com/read/28069867/the-carboxyl-terminal-region-of-dok-7-plays-a-key-but-not-essential-role-in-activation-of-muscle-specific-receptor-kinase-musk-and-neuromuscular-synapse-formation
#2
Ryo Ueta, Tohru Tezuka, Yosuke Izawa, Sadanori Miyoshi, Satoru Nagatoishi, Kouhei Tsumoto, Yuji Yamanashi
As the synapse between a motor neuron and skeletal muscle, the neuromuscular junction (NMJ) is required for muscle contraction. The formation and maintenance of NMJs are controlled by the muscle-specific receptor kinase MuSK. Dok-7 is the essential cytoplasmic activator of MuSK, and indeed mice lacking Dok-7 form no NMJs. Moreover, DOK7 gene mutations underlie DOK7 myasthenia, an NMJ synaptopathy. Previously, we failed to detect MuSK activation in myotubes by Dok-7 mutated in the N-terminal pleckstrin homology (PH) or phosphotyrosine binding (PTB) domain or that lacked the C-terminal region (Dok-7-ΔC)...
January 7, 2017: Journal of Biochemistry
https://www.readbyqxmd.com/read/28052327/tissue-disruption-increases-stochastic-gene-expression-thus-producing-tumours-cancer-initiation-without-driver-mutation
#3
REVIEW
Jean-Pascal Capp
Cancer research produced many paradoxical results in recent years. The reductionist approach now shows its limits. Considering the origin of the disease at the tissue level and increased stochastic gene expression (SGE) as a driving force, while admitting a role for genetic alterations in cancer progression, might solve these contradictions. Undifferentiated cells are characterized by open and accessible chromatin generating global and highly SGE (high expression noise) which is a hallmark of pluripotency, while differentiation is associated with progressive chromatin closing and decreased noise...
January 4, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28043510/effects-of-sorbitol-and-glycerol-on-the-structure-dynamics-and-stability-of-mycobacterium-tuberculosis-pyrazinamidase
#4
Mehrnoosh Khajehzadeh, Faramarz Mehrnejad, Mohammad Pazhang, Farahnoosh Doustdar
OBJECTIVE/BACKGROUND: Mycobacterium tuberculosis pyrazinamidase (PZase) is known an enzyme that is involved in degradation of pyrazinamide to ammonia and pyrazinoic acid. Pyrazinamide is an important first-line drug used in the short-course treatment of tuberculosis. Previous investigations have indicated that the pyrazinamide (PZA)-resistant M. tuberculosis strains are caused by point mutations in the PZase enzyme which is the activator of the prodrug PZA. Although the general fold of PZase was determined, the structural and functional properties of the enzyme in solution were not understood very well...
December 2016: International Journal of Mycobacteriology
https://www.readbyqxmd.com/read/28041892/an-alternative-derivation-of-the-stationary-distribution-of-the-multivariate-neutral-wright-fisher-model-for-low-mutation-rates-with-a-view-to-mutation-rate-estimation-from-site-frequency-data
#5
Dominik Schrempf, Asger Hobolth
Recently, Burden and Tang (2016) provided an analytical expression for the stationary distribution of the multivariate neutral Wright-Fisher model with low mutation rates. In this paper we present a simple, alternative derivation that illustrates the approximation. Our proof is based on the discrete multivariate boundary mutation model which has three key ingredients. First, the decoupled Moran model is used to describe genetic drift. Second, low mutation rates are assumed by limiting mutations to monomorphic states...
December 29, 2016: Theoretical Population Biology
https://www.readbyqxmd.com/read/28030585/organ-of-corti-and-stria-vascularis-is-there-an-interdependence-for-survival
#6
Huizhan Liu, Yi Li, Lei Chen, Qian Zhang, Ning Pan, David H Nichols, Weiping J Zhang, Bernd Fritzsch, David Z Z He
Cochlear hair cells and the stria vascularis are critical for normal hearing. Hair cells transduce mechanical stimuli into electrical signals, whereas the stria is responsible for generating the endocochlear potential (EP), which is the driving force for hair cell mechanotransduction. We questioned whether hair cells and the stria interdepend for survival by using two mouse models. Atoh1 conditional knockout mice, which lose all hair cells within four weeks after birth, were used to determine whether the absence of hair cells would affect function and survival of stria...
2016: PloS One
https://www.readbyqxmd.com/read/28025742/loss-of-function-of-ptpr-%C3%AE-and-%C3%AE-observed-in-sporadic-schizophrenia-causes-brain-region-specific-deregulation-of-monoamine-levels-and-altered-behavior-in-mice
#7
Arnaud Cressant, Veronique Dubreuil, Jing Kong, Thorsten Manfred Kranz, Francoise Lazarini, Jean-Marie Launay, Jacques Callebert, Jan Sap, Dolores Malaspina, Sylvie Granon, Sheila Harroch
RATIONALE: The receptor protein tyrosine phosphatase PTPRG has been genetically associated with psychiatric disorders and is a ligand for members of the contactin family, which are themselves linked to autism spectrum disorders. OBJECTIVE: Based on our finding of a phosphatase-null de novo mutation in PTPRG associated with a case of sporadic schizophrenia, we used PTPRG knockout (KO) mice to model the effect of a loss-of-function mutation. We compared the results with loss-of-function in its close paralogue PTPRZ, previously associated with schizophrenia...
December 26, 2016: Psychopharmacology
https://www.readbyqxmd.com/read/28017821/identification-of-a-p-arg708gln-variant-in-col1a2-in-atypical-femoral-fractures
#8
Funck-Brentano Thomas, Ostertag Agnes, Debiais Francoise, Fardellone Patrice, Corinne Collet, Mornet Etienne, Cohen-Solal Martine
OBJECTIVES: Long-term bisphosphonates exposure is a proven risk factor for atypical femoral fractures (AFF) but several cases occur in untreated patients. The identification of other risk factors for AFF is critical for the management of osteoporosis. We here assessed the genetic factors associated with AFF regardless of the treatment. METHODS: Cases were identified through ICD-10 codes in 3 academic centers. Medical records were analyzed by 2 investigators that adjudicated X-rays for typical or atypical fractures...
December 22, 2016: Joint, Bone, Spine: Revue du Rhumatisme
https://www.readbyqxmd.com/read/27999589/empirical-validation-of-a-hypothesis-of-the-hormetic-selective-forces-driving-the-evolution-of-longevity-regulation-mechanisms
#9
Alejandra Gomez-Perez, Pavlo Kyryakov, Michelle T Burstein, Nimara Asbah, Forough Noohi, Tania Iouk, Vladimir I Titorenko
Exogenously added lithocholic bile acid and some other bile acids slow down yeast chronological aging by eliciting a hormetic stress response and altering mitochondrial functionality. Unlike animals, yeast cells do not synthesize bile acids. We therefore hypothesized that bile acids released into an ecosystem by animals may act as interspecies chemical signals that generate selective pressure for the evolution of longevity regulation mechanisms in yeast within this ecosystem. To empirically verify our hypothesis, in this study we carried out a three-step process for the selection of long-lived yeast species by a long-term exposure to exogenous lithocholic bile acid...
2016: Frontiers in Genetics
https://www.readbyqxmd.com/read/27994558/epigallocatechin-3-gallate-accelerates-relaxation-and-ca-2-transient-decay-and-desensitizes-myofilaments-in-healthy-and-mybpc3-targeted-knock-in-cardiomyopathic-mice
#10
Felix W Friedrich, Frederik Flenner, Mahtab Nasib, Thomas Eschenhagen, Lucie Carrier
Background: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac muscle disease with left ventricular hypertrophy, interstitial fibrosis and diastolic dysfunction. Increased myofilament Ca(2+) sensitivity could be the underlying cause of diastolic dysfunction. Epigallocatechin-3-gallate (EGCg), a catechin found in green tea, has been reported to decrease myofilament Ca(2+) sensitivity in HCM models with troponin mutations. However, whether this is also the case for HCM-associated thick filament mutations is not known...
2016: Frontiers in Physiology
https://www.readbyqxmd.com/read/27994045/effects-of-activation-on-the-elastic-properties-of-intact-soleus-muscles-with-a-deletion-in-titin
#11
Jenna A Monroy, Krysta L Powers, Cinnamon M Pace, Theodore Uyeno, Kiisa C Nishikawa
Titin has long been known to contribute to muscle passive tension. Recently, it was also demonstrated that titin-based stiffness increases upon Ca(2+)-activation of wildtype mouse psoas myofibrils stretched beyond overlap of the thick and thin filaments. In addition, this increase in titin-based stiffness upon activation was impaired in single psoas myofibrils from mdm mice with a deletion in titin. Here, we investigate the effects of muscle activation on elastic properties of intact soleus muscles from wildtype and mdm mice to determine whether titin may contribute to active muscle stiffness...
December 19, 2016: Journal of Experimental Biology
https://www.readbyqxmd.com/read/27990849/investigation-of-t-cell-immunoglobulin-and-mucin-domain-containing-molecule-3-tim-3-polymorphisms-in-essential-thrombocythaemia-et
#12
Fuyan Han, Guanghai Wang, Yuantang Li, Wenjun Tian, Zhenfang Dong, Shiqing Cheng, Yiqing Liu, Teng Qu, Xiaoying Wang, Yong Wang, Bingchang Zhang, Ying Ju
OBJECTIVES: T-cell immunoglobulin- and mucin-domain-containing molecule-3 (TIM-3) is preferentially expressed on terminally differentiated Th1 cells and inhibits their IFN-γ production. It has been reported that chronic inflammation may be an important driving force for myeloproliferative neoplasms (MPNs). Therefore, we hypothesized that as an important inflammation regulator, TIM-3 may be involved in essential thrombocythaemia (ET). The goal of this study was to investigate whether the -1516G > T, -574G > T and +4259T > G single-nucleotide polymorphisms (SNPs) within the TIM-3 gene contribute to the genetic susceptibility of individuals to ET...
December 17, 2016: Hematology (Amsterdam, Netherlands)
https://www.readbyqxmd.com/read/27941758/single-molecule-analysis-reveals-multi-state-folding-of-a-guanine-riboswitch
#13
Vishnu Chandra, Zain Hannan, Huizhong Xu, Maumita Mandal
Guanine-responsive riboswitches undergo ligand-dependent structural rearrangements to control gene expression by transcription termination. While the molecular basis for ligand recognition is well established, the associated structural rearrangements and the kinetics involved in the formation of the aptamer domain are less well understood. Using high-resolution optical tweezers, we followed the folding trajectories of a single molecule of the xpt-pbuX guanine aptamer from Bacillus subtilis. We report a rapid six-state conformational rearrangement, in which three of the states are guanine dependent, during the transition from the linear to the native receptor conformation...
December 12, 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/27936050/gene-targeted-mice-with-the-human-troponin-t-r141w-mutation-develop-dilated-cardiomyopathy-with-calcium-desensitization
#14
Mohun Ramratnam, Guy Salama, Ravi K Sharma, David Wen Rui Wang, Stephen H Smith, Sanjay K Banerjee, Xueyin N Huang, Lindsey M Gifford, Michele L Pruce, Bethann E Gabris, Samir Saba, Sanjeev G Shroff, Ferhaan Ahmad
Most studies of the mechanisms leading to hereditary dilated cardiomyopathy (DCM) have been performed in reconstituted in vitro systems. Genetically engineered murine models offer the opportunity to dissect these mechanisms in vivo. We generated a gene-targeted knock-in murine model of the autosomal dominant Arg141Trp (R141W) mutation in Tnnt2, which was first described in a human family with DCM. Mice heterozygous for the mutation (Tnnt2R141W/+) recapitulated the human phenotype, developing left ventricular dilation and reduced contractility...
2016: PloS One
https://www.readbyqxmd.com/read/27935748/atf4-targets-ret-for-degradation-and-is-a-candidate-tumor-suppressor-gene-in-medullary-thyroid-cancer
#15
Rozita Bagheri-Yarmand, Michelle D Williams, Elizabeth G Grubbs, Robert F Gagel
CONTEXT: Medullary thyroid cancer (MTC) is an aggressive tumor that harbors activating mutations of the RET proto-oncogene. We previously reported that RET inhibits transcriptional activity of ATF4, the master regulator of the stress response pathway, to prevent cell death. OBJECTIVE: We hypothesized that loss of function of ATF4 play a role in initiation of MTC. DESIGN: Targeted deletion of ATF4 in mice was used to assess ATF4 function in the thyroid gland...
December 9, 2016: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/27933179/associations-between-genetics-medical-status-physical-exercise-and-psychological-well-being-in-adults-with-cystic-fibrosis
#16
Lena Backström-Eriksson, Agneta Bergsten-Brucefors, Lena Hjelte, Bo Melin, Kimmo Sorjonen
BACKGROUND: Cystic fibrosis (CF) is the most common autosomal recessive, life-shortening disease among people of European origin. Type of genetic mutation and regular physical exercise has an impact on clinical outcome. This cross-sectional study explores the associations between genetics, medical status, physical exercise and psychological well-being in adult patients with CF. METHODS: Adult patients with CF (N=68; mean age: 32.2; range 18-67 years; 46% women) completed the Cystic Fibrosis Questionnaire-Revised and Hospital Anxiety Depression Scale...
2016: BMJ Open Respiratory Research
https://www.readbyqxmd.com/read/27919846/nucleos-t-ide-analogues-causes-hbv-s-gene-mutations-and-carcinogenesis
#17
Meng-Lan Wang, Hong Tang
BACKGROUND: The long-term use of nucleos(t)ide analogues causes drug resistance and mutations in the HBV reverse transcriptase (RT) region of the polymerase gene. The RT region overlaps the HBV surface gene (S gene) and therefore, the mutations in the RT region simultaneously modify S gene sequence. Certain mutations in the RT region bring about truncated S proteins because the corresponding changed S gene encodes a stop codon which results in the loss of a large portion of the C-terminal hydrophobic region of HBV surface protein...
December 2016: Hepatobiliary & Pancreatic Diseases International: HBPD INT
https://www.readbyqxmd.com/read/27910033/cytogenetic-resources-and-information
#18
Etienne De Braekeleer, Jean-Loup Huret, Hossain Mossafa, Philippe Dessen
The main databases devoted stricto sensu to cancer cytogenetics are the "Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer" ( http://cgap.nci.nih.gov/Chromosomes/Mitelman ), the "Atlas of Genetics and Cytogenetics in Oncology and Haematology" ( http://atlasgeneticsoncology.org ), and COSMIC ( http://cancer.sanger.ac.uk/cosmic ).However, being a complex multistep process, cancer cytogenetics are broadened to "cytogenomics," with complementary resources on: general databases (nucleic acid and protein sequences databases; cartography browsers: GenBank, RefSeq, UCSC, Ensembl, UniProtKB, and Entrez Gene), cancer genomic portals associated with recent international integrated programs, such as TCGA or ICGC, other fusion genes databases, array CGH databases, copy number variation databases, and mutation databases...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27899282/bindprofx-assessing-mutation-induced-binding-affinity-change-by-protein-interface-profiles-with-pseudo-counts
#19
Peng Xiong, Chengxin Zhang, Wei Zheng, Yang Zhang
Understanding how gene-level mutations affect the binding affinity of protein-protein interactions is a key issue of protein engineering. Due to the complexity of the problem, using physical force field to predict the mutation-induced binding free-energy change remains challenging. In this work, we present a renewed approach to calculate the impact of gene mutations on the binding affinity through the structure-based profiling of protein-protein interfaces, where the binding free-energy change (ΔΔG) is counted as the logarithm of relative probability of mutant amino acids over wild-type ones in the interface alignment matrix; three pseudo-counts are introduced to alleviate the limit of the current interface library...
November 27, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27897175/accelerated-pseudogenization-on-the-neo-x-chromosome-in-drosophila-miranda
#20
Masafumi Nozawa, Kanako Onizuka, Mai Fujimi, Kazuho Ikeo, Takashi Gojobori
Y chromosomes often degenerate via the accumulation of pseudogenes and transposable elements. By contrast, little is known about X-chromosome degeneration. Here we compare the pseudogenization process between genes on the neo-sex chromosomes in Drosophila miranda and their autosomal orthologues in closely related species. The pseudogenization rate on the neo-X is much lower than the rate on the neo-Y, but appears to be higher than the rate on the orthologous autosome in D. pseudoobscura. Genes under less functional constraint and/or genes with male-biased expression tend to become pseudogenes on the neo-X, indicating the accumulation of slightly deleterious mutations and the feminization of the neo-X...
November 29, 2016: Nature Communications
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