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Artykuły w czasopismach na temat "PTC mutation"
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Liu, Xiaoli, Justin Bishop, Yuan Shan, Sara Pai, Dingxie Liu, Avaniyapuram Kannan Murugan, Hui Sun, Adel K. El-Naggar i Mingzhao Xing. "Highly prevalent TERT promoter mutations in aggressive thyroid cancers". Endocrine-Related Cancer 20, nr 4 (13.06.2013): 603–10. http://dx.doi.org/10.1530/erc-13-0210.
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Mutations 1 295 228 C>T and 1 295 250 C>T (termed C228T and C250T respectively), corresponding to −124 C>T and −146 C>T from the translation start site in the promoter of the telomerase reverse transcriptase (TERT) gene, have recently been reported in human cancers, but not in thyroid cancers yet. We explored these mutations in thyroid cancers by genomic sequencing of a large number of primary tumor samples. We found the C228T mutation in 0 of 85 (0.0%) benign thyroid tumors, 30 of 257 (11.7%) papillary thyroid cancers (PTC), 9 of 79 (11.4%) follicular thyroid cancers (FTC), 3 of 8 (37.5%) poorly differentiated thyroid cancers (PDTC), 23 of 54 (42.6%) anaplastic thyroid cancers (ATC), and 8 of 12 (66.7%) thyroid cancer cell lines. The C250T mutation was uncommon, but mutually exclusive with the C228T mutation, and the two mutations were collectively found in 11 of 79 (13.9%) FTC, 25 of 54 (46.3%) ATC, and 11 of 12 (91.7%) thyroid cancer cell lines. Among PTC variants, the C228T mutation was found in 4 of 13 (30.8%) tall-cell PTC (TCPTC), 23 of 187 (12.3%) conventional PTC, and 2 of 56 (3.6%) follicular variant PTC samples. No TERT mutation was found in 16 medullary thyroid cancer samples. The C228T mutation was associated with the BRAF V600E mutation in PTC, being present in 19 of 104 (18.3%) BRAF mutation-positive PTC vs 11 of 153 (7.2%) the BRAF mutation-negative PTC samples (P=0.0094). Conversely, BRAF mutation was found in 19 of 30 (63.3%) C228T mutation-positive PTC vs 85 of 227 (37.4%) C228T mutation-negative PTC samples (P=0.0094). We thus for the first time, to our knowledge, demonstrate TERT promoter mutations in thyroid cancers, that are particularly prevalent in the aggressive thyroid cancers TCPTC, PDTC, ATC and BRAF mutation-positive PTC, revealing a novel genetic background for thyroid cancers.
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Rusinek, Dagmara, Aleksandra Pfeifer, Jolanta Krajewska, Malgorzata Oczko-Wojciechowska, Daria Handkiewicz-Junak, Agnieszka Pawlaczek, Jadwiga Zebracka-Gala i in. "Coexistence of TERT Promoter Mutations and the BRAF V600E Alteration and Its Impact on Histopathological Features of Papillary Thyroid Carcinoma in a Selected Series of Polish Patients". International Journal of Molecular Sciences 19, nr 9 (6.09.2018): 2647. http://dx.doi.org/10.3390/ijms19092647.
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TERT promoter (TERTp) mutations are important factors in papillary thyroid carcinomas (PTCs). They are associated with tumor aggressiveness, recurrence, and disease-specific mortality and their use in risk stratification of PTC patients has been proposed. In this study we investigated the prevalence of TERTp mutations in a cohort of Polish patients with PTCs and the association of these mutations with histopathological factors, particularly in coexistence with the BRAF V600E mutation. A total of 189 consecutive PTC specimens with known BRAF mutational status were evaluated. TERTp mutations were detected in 8.5% of cases (16/189) with the C228T mutation being the most frequent. In six of the PTC specimens (3.2%), four additional TERTp alterations were found, which included one known polymorphism (rs2735943) and three previously unreported alterations. The association analysis revealed that the TERTp hotspot mutations were highly correlated with the presence of the BRAF V600E mutation and their coexistence was significantly associated with gender, advanced patient age, advanced disease stage, presence of lymph node metastases, larger tumor size, and tumor-capsule infiltration. While correlations were identified, the possibility of TERTp mutations being key molecular modulators responsible for PTC aggressiveness requires further studies.
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Clarke, Luka A., Vanessa C. C. Luz, Szymon Targowski, Sofia S. Ramalho, Carlos M. Farinha i Margarida D. Amaral. "Integrity and Stability of PTC Bearing CFTR mRNA and Relevance to Future Modulator Therapies in Cystic Fibrosis". Genes 12, nr 11 (18.11.2021): 1810. http://dx.doi.org/10.3390/genes12111810.
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Major advances have recently been made in the development and application of CFTR (cystic fibrosis transmembrane conductance regulator) mutation class-specific modulator therapies, but to date, there are no approved modulators for Class I mutations, i.e., those introducing a premature termination codon (PTC) into the CFTR mRNA. Such mutations induce nonsense-mediated decay (NMD), a cellular quality control mechanism that reduces the quantity of PTC bearing mRNAs, presumably to avoid translation of potentially deleterious truncated CFTR proteins. The NMD-mediated reduction of PTC-CFTR mRNA molecules reduces the efficacy of one of the most promising approaches to treatment of such mutations, namely, PTC readthrough therapy, using molecules that induce the incorporation of near-cognate amino acids at the PTC codon, thereby enabling translation of a full-length protein. In this study, we measure the effect of three different PTC mutations on the abundance, integrity, and stability of respective CFTR mRNAs, using CFTR specific RT-qPCR-based assays. Altogether, our data suggest that optimized rescue of PTC mutations has to take into account (1) the different steady-state levels of the CFTR mRNA associated with each specific PTC mutation; (2) differences in abundance between the 3′ and 5′ regions of CFTR mRNA, even following PTC readthrough or NMD inhibition; and (3) variable effects on CFTR mRNA stability for each specific PTC mutation.
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Henke, Lauren E., John D. Pfeifer, Thomas J. Baranski, Todd DeWees i Perry W. Grigsby. "Long-term outcomes of follicular variant vs classic papillary thyroid carcinoma". Endocrine Connections 7, nr 12 (grudzień 2018): 1226–35. http://dx.doi.org/10.1530/ec-18-0264.
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The majority of papillary thyroid carcinoma (PTC) cases comprise classic papillary (C-PTC) and follicular variant (FV-PTC) histologic sub-types. Historically, clinical equivalency was assumed, but recent data suggest C-PTC may have poorer outcomes. However, large single-institution series with long-term outcomes of C-PTC and FV-PTC, using modern pathologic criteria for FV-PTC, are needed. Our objective was to compare prevalence and impact of clinicopathologic factors, including BRAF mutation status, on long-term outcomes of C-PTC and FV-PTC. We hypothesized that patients with C-PTC would have higher risk disease features and worse survival outcomes. This retrospective study included 1293 patients treated at a single, US academic institution between 1943 and 2009 with mean follow-up of 8.6 years. All patients underwent either partial or total thyroidectomy and had invasive C-PTC or FV-PTC per modern pathology criteria. Primary study measurements included differences in recurrence-free survival (RFS), disease-specific survival (DSS) and associations with clinicopathologic factors including the BRAF mutation. Compared to FV-PTC, C-PTC was associated with multiple features of high-risk disease (P < 0.05) and significantly reduced RFS and DSS. Survival differences were consistent across univariate, multivariate and Kaplan–Meier analyses. BRAF mutations were more common in C-PTC (P = 0.002). However, on Kaplan–Meier analysis, mutational status did not significantly impact RFS or DSS for patients with either histologic sub-type. C-PTC therefore indicates higher-risk disease and predicts for significantly poorer long-term outcomes when compared to FV-PTC. The nature of this difference in outcome is not explained by traditional histopathologic findings or by the BRAF mutation.
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Choi, Yun-Suk, Seong-Woon Choi i Jin-Wook Yi. "Prospective Analysis of TERT Promoter Mutations in Papillary Thyroid Carcinoma at a Single Institution". Journal of Clinical Medicine 10, nr 10 (18.05.2021): 2179. http://dx.doi.org/10.3390/jcm10102179.
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Background: Papillary thyroid cancer (PTC) has the highest cancer incidence in Korea. It is known that some thyroid cancers have aggressive clinical behavior and a poor prognosis. Genomic studies have described some somatic mutations that are related to the aggressive features of thyroid cancer, such as the BRAFV600E mutation. Recently, TERT promoter mutations were identified and reported as poor prognostic factors in PTC. Our aim was to identify the frequency and clinical impact of TERT promoter mutation in PTC. Methods: Analysis of both BRAFV600E and TERT promoter mutations in thyroidectomy specimens began in February 2019. As of December 2020, 622 patients had been tested. Data were prospectively collected and retrospectively reviewed to ascertain clinical and pathologic variables. Results: TERT promoter mutations were identified in 13 patients (2.09%); 12 had the C228T mutation, and one had the C216T mutation. In total, ten patients had the BRAFV600E mutation. TERT promoter mutation was significantly associated with advanced age (46.795 ± 12.616 versus 65.692 ± 13.628 years, p < 0.001), large tumor size (1.006 ± 0.829 versus 2.285 ± 1.938 cm, p = 0.035), extrathyroidal extension, surgical margin involvement, angioinvasion, BRAFV600E mutation and advanced TNM stage, a higher MACIS score and a high proportion of radioactive iodine therapy application. Logistic regression showed that lymphatic and angioinvasion and BRAFV600E mutation were predictive of TERT promoter mutation. Conclusions: Our study is the first to report the prospective results of TERT promoter mutations at a single tertiary hospital in Incheon, Korea. PTC with TERT promoter mutation was associated with more aggressive behavior than PTC with wild-type TERT gene status.
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Liu, Jie, Huizheng Li, Rong Du, Nan Fang, Jingbo Zhang, Yu Tang, Jianwei Wang i Qixi Wu. "Targeted next-generation sequencing in papillary thyroid carcinoma of Chinese Han population." Journal of Clinical Oncology 37, nr 15_suppl (20.05.2019): e17574-e17574. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e17574.
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e17574 Background: Papillary Thyroid Carcinoma (PTC) is the most common type of thyroid cancer. Developments in next-generation sequencing (NGS) technology can help to disclose the genotype of PTC in the Chinese Han population. Methods: A total of 50 patients with PTC who underwent thyroidectomy in 2015-2018 at the Affiliated Dalian Friendship Hospital of Medical University were enrolled. Total DNA was extracted from formalin-fixed, paraffin-embedded tissue sections and quantified. Targeted regions of 57 thyroid cancer-associated genes were amplified, barcoded and sequenced using an Illumina MiSeq 500 platform. Results: A total of 591 mutations were detected in 50 samples, including 514 missense mutations (87%), 39 frameshift mutations (6.6%), 22 stop-gain (3.7%) and 16 indel (2.7%) variants. Among them, only 64 mutations have been studied with cancer clinical relevance. The BRAF V600E mutation was present in 42 of 50 (84%) patients, and was the most common mutation. The CHEK2 mutation was present in 27 of 50 (54%) patients. The 10 most important genes with mutations included AKT1 (34%), EIF1AX( 30%), ATM (20%) , MED12 (18%) , NF1 (18%), RET (18%), RBM10 (16%) and TERT (12%). Among them, the CHEK2, AKT1 and EIF1AX mutations were always concomitant with the BRAF V600E mutation, which is controversial to previous studies. Only two samples had no mutation tested. The medium mutation is 11 muts/sample. Six samples had more than 10 occurrences of gene mutations. However, the mutation burden has no relevance to lymph node metastasis or other pathological prognostic factors. Conclusions: BRAF V600E is the most common and important mutation in PTC, but there are also many other genes that mutate in this disease. The gene mutation in PTC varies in different patients, but no relevance between pathological factors and gene mutations have been founded . However, the discovery of the gene mutation spectrum in the Han Chinese population with PTC could enhance the understanding of this disease’s clinical behavior.
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Chakraborty, Dhritiman, Sunil Shakya, Sanjana Ballal, Shipra Agarwal i Chandrasekhar Bal. "BRAFV600E and TERT promoter mutations in paediatric and young adult papillary thyroid cancer and clinicopathological correlation". Journal of Pediatric Endocrinology and Metabolism 33, nr 11 (26.11.2020): 1465–74. http://dx.doi.org/10.1515/jpem-2020-0174.
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AbstractObjectivesThe primary objective of this study was to determine the prevalence of BRAFV600E and TERTpromoter mutations in paediatric and young adult patients with papillary thyroid carcinoma (PTC) and the secondary objective, to assess their association with clinicopathological features.MethodsPatients ≤20 years who underwent surgery for differentiated thyroid cancer (DTC) from 2005 to 2018 were consecutively enrolled for BRAFV600E and TERTpromoter mutations analysis and records analysed for the association of aggressive features. Univariate analysis and multivariate logistic regression were used to identify the independent predictors of BRAFV600E mutations.ResultsAmong 100 patients with DTC, 68 patients were ≤18 years and the remaining 30 patients were >18 years of age with a median age of 17 years (IQR 14–19 years) 98 patients had PTC and 2 had FTC. BRAFV600E mutation was present in 14/98 (14.3%) PTC and TERTpromoter mutation noted in none. Multivariate analysis identified RAI refractoriness (OR:10.57, 95% CI: 2.6 to 41.6, P-0.0008) as an independent factor associated with BRAFV600E mutation. 17 patients with distant metastases were negative for both BRAFV600E or TERTpromoter mutation. No significant association was observed between age, gender, PTC variants, extra-thyroidal extension, lymphovascular invasion, multifocality, RAI administration and event rate with BRAFV600E mutation. Irrespective of BRAFV600E mutation, radioiodine refractory status (p-0.0001) had a reduced EFS probability.ConclusionIn paediatric & young adult PTC, TERTpromoter mutation is absent and BRAFV600E mutation is not associated with distant metastasis. The prevalence rate of the BRAFV600E mutation is much lower compared to adult PTC patients.
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Barzon, Luisa, Giulia Masi, Isabella Merante Boschin, Enrico Lavezzo, Monia Pacenti, Eric Casal Ide, Antonio Toniato, Stefano Toppo, Giorgio Palù i Maria Rosa Pelizzo. "Characterization of a novel complex BRAF mutation in a follicular variant papillary thyroid carcinoma." European Journal of Endocrinology 159, nr 1 (lipiec 2008): 77–80. http://dx.doi.org/10.1530/eje-08-0239.
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IntroductionActivating mutations of the BRAF oncogene are frequently detected in papillary thyroid carcinoma (PTC) and have been associated with a worse prognosis. The amino acid substitution V600E accounts for 90% of all oncogenic BRAF mutations and is typically detected in classic PTCs, whereas other less frequent BRAF mutations seem to be associated with other PTC histotypes.CaseScreening for activating BRAF mutations in a series of 83 PTCs identified the most common V600E mutation in 39 cases (histologically, 38 classic PTCs and 1 sclerosing variant PTC) and a complex in-frame mutation involving amino acids V600–S605 in a stage III multicentric follicular variant PTC, occurring in a 50-year-old female patient, who was affected by hypothyroidism in autoimmune thyroiditis and had a family history of PTC and autoimmune thyroiditis. Since the identified BRAF mutation was novel in the literature, bioinformatic modeling was performed to predict its impact on BRAF activity. Although the mutation resulted in loss of a phosphorylation site in the activation loop of BRAF, it was predicted to increase BRAF kinase activity by mimicking an activating phosphorylation.ConclusionsThis study, which reports a new BRAF mutation, highlights the usefulness of bioinformatic modeling in the prediction of functional effects of new mutations and indicates that mutation-specific screening tests might miss some rare BRAF mutations. These facts should be taken into consideration in the molecular diagnosis of thyroid cancer and in the design of therapeutic protocols based on inhibitors of the BRAF pathway.
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Siraj, Sarah, Tariq Masoodi, Abdul K. Siraj, Saud Azam, Zeeshan Qadri, Sandeep K. Parvathareddy, Rong Bu i in. "APOBEC SBS13 Mutational Signature—A Novel Predictor of Radioactive Iodine Refractory Papillary Thyroid Carcinoma". Cancers 14, nr 6 (21.03.2022): 1584. http://dx.doi.org/10.3390/cancers14061584.
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Standard surgery followed by radioactive iodine (131I, RAI) therapy are not curative for 5–20% of papillary thyroid carcinoma (PTC) patients with RAI refractory disease. Early predictors indicating therapeutic response to RAI therapy in PTC are yet to be elucidated. Whole-exome sequencing was performed (at median depth 198x) on 66 RAI-refractory and 92 RAI-avid PTCs with patient-matched germline. RAI-refractory tumors were significantly associated with distinct aggressive clinicopathological features, including positive surgical margins (p = 0.016) and the presence of lymph node metastases at primary diagnosis (p = 0.012); higher nonsilent tumor mutation burden (p = 0.011); TERT promoter (TERTp) mutation (p < 0.0001); and the enrichment of the APOBEC-related single-base substitution (SBS) COSMIC mutational signatures 2 (p = 0.030) and 13 (p < 0.001). Notably, SBS13 (odds ratio [OR] 30.4, 95% confidence intervals [CI] 1.43–647.22) and TERTp mutation (OR 41.3, 95% CI 4.35–391.60) were revealed to be independent predictors of RAI refractoriness in PTC (p = 0.029 and 0.001, respectively). Although SBS13 and TERTp mutations alone highly predicted RAI refractoriness, when combined, they significantly increased the likelihood of predicting RAI refractoriness in PTC. This study highlights the APOBEC SBS13 mutational signature as a novel independent predictor of RAI refractoriness in a distinct subgroup of PTC.
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Durand, Stéphanie, Carole Ferraro-Peyret, Mireille Joufre, Annie Chave, Françoise Borson-Chazot, Samia Selmi-Ruby i Bernard Rousset. "Molecular characteristics of papillary thyroid carcinomas without BRAF mutation or RET/PTC rearrangement: relationship with clinico-pathological features". Endocrine-Related Cancer 16, nr 2 (czerwiec 2009): 467–81. http://dx.doi.org/10.1677/erc-08-0081.
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About 60–70% of papillary thyroid carcinomas (PTC) present a BRAFT1799A gene mutation or a rearrangement of RET gene (RET/PTC). In this study, we examined whether PTC without BRAFT1799A mutation and without RET/PTC rearrangement named PTC-ga(−) were distinguishable from PTC-ga(+) (with one or the other gene alteration) on the basis of gene expression characteristics. We analyzed the mutational state of 116 PTC and we compared gene expression profiles of PTC-ga(+) and PTC-ga(−) from data of a 200 gene macroarray and quantitative PCR. Seventy five PTC were PTC-ga(+) and 41 were PTC-ga(−). Unsupervised analyses of macroarray data by hierarchical clustering led to a complete segregation of PTC-ga(+) and PTC-ga(−). In a series of 42 genes previously recognized as PTC ‘marker’ genes, 22 were found to be expressed at a comparable level in PTC-ga(−) and normal tissue. Thyroid-specific genes, TPO, TG, DIO1, and DIO2 were under-expressed in PTC-ga(+) but expressed at a normal level in PTC-ga(−). A few genes including DUOX1 and DUOX2 were selectively dys-regulated in PTC-ga(−). Tumor grade of PTC-ga(−) was lower than that of PTC-ga(+). There was a strong association between the mutational state and histiotype of PTC; 81% of PTC follicular variants were corresponded to PTC-ga(−), whereas 84% of PTC of classical form were PTC-ga(+). In conclusion, we show that PTC without BRAFT1799A mutation or RET/PTC rearrangement, mainly corresponding to follicular variants, maintain a thyroid differentiation expression level close to that of normal tissue and should be of better prognosis than PTC with one or the other gene alteration.
Rozprawy doktorskie na temat "PTC mutation"
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Maxwell, Megan Amanda, i n/a. "PEX1 Mutations in Australasian Patients with Disorders of Peroxisome Biogenesis". Griffith University. School of Biomolecular and Biomedical Science, 2004. http://www4.gu.edu.au:8080/adt-root/public/adt-QGU20040219.100649.
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The peroxisome is a subcellular organelle that carries out a diverse range of metabolic functions, including the b-oxidation of very long chain fatty acids, the breakdown of peroxide and the a-oxidation of fatty acids. Disruption of peroxisome metabolic functions leads to severe disease in humans. These diseases can be broadly grouped into two categories: those in which a single enzyme is defective, and those known as the peroxisome biogenesis disorders (PBDs), which result from a generalised failure to import peroxisomal matrix proteins (and consequently result in disruption of multiple metabolic pathways). The PBDs result from mutations in PEX genes, which encode protein products called peroxins, required for the normal biogenesis of the peroxisome. PEX1 encodes an AAA ATPase that is essential for peroxisome biogenesis, and mutations in PEX1 are the most common cause of PBDs worldwide. This study focused on the identification of mutations in PEX1 in an Australasian cohort of PBD patients, and the impact of these mutations on PEX1 function. As a result of the studies presented in this thesis, twelve mutations in PEX1 were identified in the Australasian cohort of patients. The identified mutations can be broadly grouped into three categories: missense mutations, mutations directly introducing a premature termination codon (PTC) and mutations that interrupt the reading frame of PEX1. The missense mutations that were identified were R798G, G843D, I989T and R998Q; all of these mutations affect amino acid residues located in the AAA domains of the PEX1 protein. Two mutations that directly introduce PTCs into the PEX1 transcript (R790X and R998X), and four frameshift mutations (A302fs, I370fs, I700fs and S797fs) were identified. There was also one mutation found in an intronic region (IVS22-19A>G) that is presumed to affect splicing of the PEX1 mRNA. Three of these mutations, G843D, I700fs and G973fs, were found at high frequency in this patient cohort. At the commencement of these studies, it was hypothesised that missense mutations would result in attenuation of PEX1 function, but mutations that introduced PTCs, either directly or indirectly, would have a deleterious effect on PEX1 function. Mutations introducing PTCs are thought to cause mRNA to be degraded by the nonsense-mediated decay of mRNA (NMD) pathway, and thus result in a decrease in PEX1 protein levels. The studies on the cellular impact of the identified PEX1 mutations were consistent with these hypotheses. Missense mutations were found to reduce peroxisomal protein import and PEX1 protein levels, but a residual level of function remained. PTC-generating mutations were found to have a major impact on PEX1 function, with PEX1 mRNA and protein levels being drastically reduced, and peroxisomal protein import capability abolished. Patients with two missense mutations showed the least impact on PEX1 function, patients with two PTC-generating mutations had a severe defect in PEX1 function, and patients carrying a combination of a missense mutation and a PTC-generating mutation showed levels of PEX1 function that were intermediate between these extremes. Thus, a correlation between PEX1 genotype and phenotype was defined for the Australasian cohort of patients investigated in these studies. For a number of patients, mutations in the coding sequence of one PEX1 allele could not be identified. Analysis of the 5' UTR of this gene was therefore pursued for potential novel mutations. The initial analyses demonstrated that the 5' end of PEX1 extended further than previously reported. Two co-segregating polymorphisms were also identified, termed 137 T>C and 53C>G. The -137T>C polymorphism resided in an upstream, in-frame ATG (termed ATG1), and the possibility that the additional sequence represented PEX1 coding sequence was examined. While both ATGs were found to be functional by virtue of in vitro and in vivo expression investigations, Western blot analysis of the PEX1 protein in patient and control cell extracts indicated that physiological translation of PEX1 was from the second ATG only. Using a luciferase reporter approach, the additional sequence was found to exhibit promoter activity. When examined alone the -137T>C polymorphism exerted a detrimental effect on PEX1 promoter activity, reducing activity to half that of wild-type levels, and the -53C>G polymorphism increased PEX1 promoter activity by 25%. When co-expressed (mimicking the physiological condition) these polymorphisms compensated for each other to bring PEX1 promoter activity to near wild-type levels. The PEX1 mutations identified in this study have been utilised by collaborators at the National Referral Laboratory for Lysosomal, Peroxisomal and Related Genetic Disorders (based at the Women's and Children's Hospital, Adelaide), in prenatal diagnosis of the PBDs. In addition, the identification of three common mutations in Australasian PBD patients has led to the implementation of screening for these mutations in newly referred patients, often enabling a precise diagnosis of a PBD to be made. Finally, the strong correlation between genotype and phenotype for the patient cohort investigated as part of these studies has generated a basis for the assessment of newly identified mutations in PEX1.
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Maxwell, Megan Amanda. "PEX1 Mutations in Australasian Patients with Disorders of Peroxisome Biogenesis". Thesis, Griffith University, 2004. http://hdl.handle.net/10072/366184.
Pełny tekst źródłaStreszczenie:
The peroxisome is a subcellular organelle that carries out a diverse range of metabolic functions, including the b-oxidation of very long chain fatty acids, the breakdown of peroxide and the a-oxidation of fatty acids. Disruption of peroxisome metabolic functions leads to severe disease in humans. These diseases can be broadly grouped into two categories: those in which a single enzyme is defective, and those known as the peroxisome biogenesis disorders (PBDs), which result from a generalised failure to import peroxisomal matrix proteins (and consequently result in disruption of multiple metabolic pathways). The PBDs result from mutations in PEX genes, which encode protein products called peroxins, required for the normal biogenesis of the peroxisome. PEX1 encodes an AAA ATPase that is essential for peroxisome biogenesis, and mutations in PEX1 are the most common cause of PBDs worldwide. This study focused on the identification of mutations in PEX1 in an Australasian cohort of PBD patients, and the impact of these mutations on PEX1 function. As a result of the studies presented in this thesis, twelve mutations in PEX1 were identified in the Australasian cohort of patients. The identified mutations can be broadly grouped into three categories: missense mutations, mutations directly introducing a premature termination codon (PTC) and mutations that interrupt the reading frame of PEX1. The missense mutations that were identified were R798G, G843D, I989T and R998Q; all of these mutations affect amino acid residues located in the AAA domains of the PEX1 protein. Two mutations that directly introduce PTCs into the PEX1 transcript (R790X and R998X), and four frameshift mutations (A302fs, I370fs, I700fs and S797fs) were identified. There was also one mutation found in an intronic region (IVS22-19A>G) that is presumed to affect splicing of the PEX1 mRNA. Three of these mutations, G843D, I700fs and G973fs, were found at high frequency in this patient cohort. At the commencement of these studies, it was hypothesised that missense mutations would result in attenuation of PEX1 function, but mutations that introduced PTCs, either directly or indirectly, would have a deleterious effect on PEX1 function. Mutations introducing PTCs are thought to cause mRNA to be degraded by the nonsense-mediated decay of mRNA (NMD) pathway, and thus result in a decrease in PEX1 protein levels. The studies on the cellular impact of the identified PEX1 mutations were consistent with these hypotheses. Missense mutations were found to reduce peroxisomal protein import and PEX1 protein levels, but a residual level of function remained. PTC-generating mutations were found to have a major impact on PEX1 function, with PEX1 mRNA and protein levels being drastically reduced, and peroxisomal protein import capability abolished. Patients with two missense mutations showed the least impact on PEX1 function, patients with two PTC-generating mutations had a severe defect in PEX1 function, and patients carrying a combination of a missense mutation and a PTC-generating mutation showed levels of PEX1 function that were intermediate between these extremes. Thus, a correlation between PEX1 genotype and phenotype was defined for the Australasian cohort of patients investigated in these studies. For a number of patients, mutations in the coding sequence of one PEX1 allele could not be identified. Analysis of the 5' UTR of this gene was therefore pursued for potential novel mutations. The initial analyses demonstrated that the 5' end of PEX1 extended further than previously reported. Two co-segregating polymorphisms were also identified, termed –137 T>C and –53C>G. The -137T>C polymorphism resided in an upstream, in-frame ATG (termed ATG1), and the possibility that the additional sequence represented PEX1 coding sequence was examined. While both ATGs were found to be functional by virtue of in vitro and in vivo expression investigations, Western blot analysis of the PEX1 protein in patient and control cell extracts indicated that physiological translation of PEX1 was from the second ATG only. Using a luciferase reporter approach, the additional sequence was found to exhibit promoter activity. When examined alone the -137T>C polymorphism exerted a detrimental effect on PEX1 promoter activity, reducing activity to half that of wild-type levels, and the -53C>G polymorphism increased PEX1 promoter activity by 25%. When co-expressed (mimicking the physiological condition) these polymorphisms compensated for each other to bring PEX1 promoter activity to near wild-type levels. The PEX1 mutations identified in this study have been utilised by collaborators at the National Referral Laboratory for Lysosomal, Peroxisomal and Related Genetic Disorders (based at the Women's and Children's Hospital, Adelaide), in prenatal diagnosis of the PBDs. In addition, the identification of three common mutations in Australasian PBD patients has led to the implementation of screening for these mutations in newly referred patients, often enabling a precise diagnosis of a PBD to be made. Finally, the strong correlation between genotype and phenotype for the patient cohort investigated as part of these studies has generated a basis for the assessment of newly identified mutations in PEX1.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Biomolecular and Biomedical Sciences
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Panton, Nicola. "Mutation analysis of four genes implicated in iron homeostasis in porphyria cutanea tarda (PCT) patients". Thesis, Link to the online version, 2008. http://hdl.handle.net/10019/888.
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Ajlani, Ghada. "Détermination des sites de mutation responsables de résistance aux herbicides chez des mutants de la cyanobactérie Synechocystis PCC 6714 : étude de l'effet de ces mutations sur le transfert d’électrons du photosystème II". Paris 11, 1989. http://www.theses.fr/1989PA112130.
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Mohamed-Uvaize, Musfira. "The Effects of Dilated Cardiomyopathy and Atrial Fibrillation Lamin A/C Mutations on Phosphorylated Kinase C Alpha Cellular Distribution and Activity". Thesis, Université d'Ottawa / University of Ottawa, 2014. http://hdl.handle.net/10393/30545.
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Dilated Cardiomyopathy (DCM) with conduction disease and Atrial Fibrillation (AF) are the two cardiac-specific diseases associated with lamin A/C gene (LMNA) mutations. Protein Kinase C Alpha, (PKCα) functions as a nodal integrator of cardiac contractility by “sensing” intracellular calcium and signal transduction. PKCα has been implicated in heart failure and cardiac hypertrophy. Moreover, abnormal PKCα function results in irregular atrial potassium channel activity associated with chronic AF PKCα is a lamin A/C binding partner. Thus, the deregulation of PKCα signaling can contribute to the development of DCM and AF.
Our hypothesis is that the AF (Thr528Met), DCM-associated (Arg541Cys) and (Arg541Gly) and DCM/AF-associated (Tyr481Stop) LMNA variants will disrupt the cellular distribution of PKCα therefore resulting in impaired PKCα function.
The first objective was to phenotypically characterise Arg541Cys LMNA variant in murine skeletal myoblasts cell line (C2C12) in comparison to cellular phenotypes induced by LMNA variants associated with AF, DCM and DCM with AF. Arg541Cys lamin A and C variants formed circular and sickle-shaped lamin A/C in the nucleus of C2C12 cells.
The second objective was to determine the effect of these lamin variants on cellular distribution of PKCα in C2C12 cells. PKCα mislocalized into the nucleus of C2C12 cells transfected with AF and DCM-associated variants (Thr528Met and Arg541Cys). Colocalization analysis showed significant increase in PKCα in the nucleus of AF (Thr528Met) and DCM (Arg541Cys) variants when lamin A and C, were co-transfected compared to wild-type, DCM (Arg541Gly) and DCM/AF (Tyr481Stop) variants. Densitometry analysis showed statistically significant increase in phosphorylated PKCα, the active form of PKCα, in nuclear and cytoplasmic extracts of C2C12 cells expressing Arg541Cys variant. Densitometry analysis also showed statistically significant increase in non-phosphorylated PKCα in the nuclear extract of Thr528Met variant expressing cells.
The third objective was to determine the effect of AF and DCM-associated variants on the activity of PKCα. PKCα activity is quantified by measuring the phosphorylation of a known phosphorylated PKCα substrate. Alpha-6-tubulin phospho (Ser165) is phosphorylated by PKCα. Hence, this was used to quantify PKCα activity. No statistical significance was observed in the level of phosphorylated alpha-6-tubulin at (Ser165) in the C2C12 cells that were transfected with lamin A and C variants compared to wild type. Furthermore, PKCα phosphorylation state is cyclic in nature and this could have had an impact on the phosphorylation state of the chosen substrate in this study.
The functional consequence of nuclear translocation of PKCα with respect to laminopathies is unknown. Abnormal activation of the Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK1/2) which are branches of the mitogen-activated protein kinase (MAPK) signalling cascade in hearts of mice, and humans prior to the onset of cardiomyopathy. These findings have been associated to cardiac disease-causing lamin A/C alteration to signal transduction pathways implicated in heart function and cardiomyopathy. Human LMNA cardiomyopathy, could lead to abnormal activation of MAPK signalling pathways via abnormal PKCα activation in cardiomyocytes.
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Lemonnier, François. "Mutations d'IDH2, TET2 et DNMT3A dans les lymphomes T périphériques : de la biologie à la clinique". Thesis, Paris Est, 2016. http://www.theses.fr/2016PESC0082.
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Les mutations de TET2, IDH2 et DNMT3A, 3 gènes impliqués dans la régulation de la méthylation de l'ADN, sont fréquentes dans les lymphomes T périphériques (PTCL), mais leurs conséquences sont mal connues. Nous avons montré que les mutations d'IDH2 dans les lymphomes angioimmunoblastiques (AITL) sont restreintes aux cellules T tumorales et que l'enzyme mutée, exprimée dans des lymphocytes T, produit bien l'oncometabolite D-2 hydroxyglutarate (D-2HG). Utilisant des modèles de souris transgéniques, nous avons montré que, dans un lymphocyte T, seule la mutation IDH2R172K produit suffisamment de D-2HG pour inhiber les protéines TET et altérer la différentiation lymphoïde. Ceci peut expliquer qu'IDH2R172 soit la seule mutation d'IDH retrouvée dans les AITL. Les mutations d'IDH2 inhibant les protéines TET, ce qui conduit à une baisse de la 5 hydroxyméthylcytosine (5hmC), nous avons évalué le niveau de 5hmC dans des PTCL mutés ou non pour TET2, IDH2 et/ou DNMT3A. Par rapport aux lymphocytes T normaux, nous avons vu une perte de 5hmC dans les cellules tumorales des PTCL, qui de façon intéressante était présente dans toutes les entités étudiées, quel que soit le statut mutationnel, à l'exception des lymphomes T hépatospléniques. Dans une démarche plus transversale, nous avons montré que la fréquence élevée de mutations de TET2, IDH2 et DNMT3A dans des PTCL présentant des caractéristiques TFH permet d'apporter un argument moléculaire, qui s'ajoute aux similitudes histologiques et phénotypiques pour regrouper ces lymphomes avec les AITL. Enfin, la description de l'efficacité d'un traitement par 5 azacytidine chez une patiente atteinte de AITL mutée pour TET2, suggère que les traitements ciblant l'épigénétique pourraient être efficaces dans ces maladiesTET2, IDH2 and DNMT3A, 3 genes involved in the regulation of DNA methylation, are frequently mutated in Peripheral T Cell Lymphomas (PTCL). However, the consequences of these mutations are poorly understood. Focusing on IDH2 mutation, we demonstrated that this mutation is restricted to tumor T cells within angioimmunoblastic lymphoma (AITL) tumor tissue. We also demonstrated that, in AITL, IDH2 mutated T cells had the ability to produce D-2 hydroxyglutarate (D-2HG), a metabolite that has oncogenic effect. Using transgenic mouse models, we showed that IDH2R172K was the only IDH mutation that, when expressed in T cells, produced enough D-2HG to inhibit TET proteins and impairing lymphoid differentiation. This likely explains why IDH2R172 is the only IDH mutation found in AITL. As IDH2 mutation results in TET2 inhibition, which impairs 5hmC formation, we assessed the level of 5hmC in AITL, and described 5hmC loss, compared to normal TFH, in all AITL, regardless of the TET2, IDH2 and DNMT3A mutational status. We extended these finding to main nodal and extranodal PTCL entities, showing that 5hmC loss was a general mechanism present in all PTCL, with the exception of hepatosplenic T cell lymphoma. In a translational approach, we saw that the high frequency of TET2, DNMT3A and RHOA mutations in TFH like PTCL suggest a common molecular basis shared with AITL that could argue, in addition to phenotypic and histological similarities, to group these 2 entities into a single category. Finally, we described the first complete remission of a patient with a TET2 mutated AITL with 5 azacytidine, suggesting that hypomethylating agents could be active in PTCL
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Kallassy-Awad, Mireille. "Étude de gènes impliqués dans la cancerogénèse de la peau chez l'homme : implications des gènes p21WAF1, ptch, smoh et cdc27HS/h-nuc". Lyon 1, 1998. http://www.theses.fr/1998LYO1T051.
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Russo, Chantal. "De l'assurance de responsabilité à l'assurance directe : contribution à l'étude d'une mutation de la couverture des risques". Nice, 1999. http://buadistant.univ-angers.fr/login?url=https://www.dalloz-bibliotheque.fr/pvurl.php?r=http%3A%2F%2Fdallozbndpro-pvgpsla.dalloz-bibliotheque.fr%2Ffr%2Fpvpage2.asp%3Fpuc%3D5442%26nu%3D48.
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Le droit de la responsabilité a évolué selon deux grandes orientations : le développement des responsabilités sans faute - l'objectivation - et la dilution de la charge des dommages reportée sur une collectivité, par le biais de la technique de l'assurance - la collectivisation -. Cette dynamique incessante entre l'assurance et la responsabilité constitue actuellement le point central du débat engage par les assureurs, selon lesquels l'extension ininterrompue du champ de la responsabilité civile grâce à l'assurance mettrait en péril conjointement ces deux institutions. Ils préconisent des lors de dissocier la responsabilité et l'indemnisation en vue d'indemniser les victimes sans étendre le domaine de la responsabilité. Concrètement, il s'agirait d'abandonner le recours à l'assurance de responsabilité pour lui substituer l'assurance directe des victimes potentielles. Or, cette technique mise à l'épreuve de l'expérience acquise en assurance construction - ou elle a été consacrée par le législateur - ainsi qu'en assurance automobile - ou elle a été spontanément imposée par le réseau conventionnel des assureurs -, laisse présager un certain nombre de bouleversements, particulièrement à propos du droit des victimes à être indemnisées et plus généralement à propos du droit de la responsabilité et de l'évolution que l'on peut craindre. Cette étude se divise en deux étapes. Dans un premier temps, l'évolution de l'assurance de responsabilité - de sa consécration a son rejet actuel - sera retracée afin de préciser les raisons structurelles (liées à la technique de l'assurance) et conjoncturelles (liées à la "crise" de la responsabilité) qui entretiennent ce débat. Cette recherche accomplie, le fonctionnement de l'assurance directe sera analysé, notamment à partir des expériences déjà acquises. Les fruits de cette analyse imposeront inévitablement une approche critique de l'assurance directe, confortée par notre réflexion sur la recherche de sa légitimité, ainsi que par nos interrogations sur l'avenir de la responsabilité dans l'hypothèse de la généralisation d'un tel système.
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Karimi, Gilda. "Etude de l'assemblage de la NADPH oxydase du phagocyte". Thesis, Paris 11, 2014. http://www.theses.fr/2014PA112025.
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La NADPH oxydase du phagocyte est une enzyme impliquée dans la défense immunitaire contre les pathogènes. Après activation du phagocyte, cette enzyme produit des ions superoxyde par réduction du dioxygène par le NADPH. Elle est constituée de quatre sous- unités cytosolubles (p47phox ; p67phox ; p40phox et Rac), et deux membranaires (gp91 ; p22phox). Son activation fait intervenir un processus complexe qui met en jeu des changements d’interaction entre les protéines la constituant et qui permet l’assemblage des six sous- unités. Afin d’obtenir des informations sur les processus d’assemblage et d’activation, j’ai reconstitué le complexe dans un système cell free à l’aide de protéines recombinantes pour pouvoir contrôler tous les paramètres. Dans ce travail nous avons comparé les modes d’activation de p47phox par phosphorylation, par mutation substitutionelle sérine - aspartate en position S303,S304 et S328 pour mimer la phosphorylation et enfin par addition d’acide arachidonique (AA) activateur connu de l’enzyme in vitro mais aussi in vivo. Bien qu’il ai été montré que ces trois méthodes ouvrent la protéine vers une conformation ayant des propriétés similaires, nous avons trouvé que les effets de ces méthodes d’activation sont significativement différents. Ainsi, les changement de conformation observés par dichroisme circulaire, sont dissemblables. Pour p47phox, l’addition de AA déstructure la protéine. La phosphorylation induit un déplacement bathochrome des bandes de CD qualitativement similaire, alors que les mutations S-D de p47phox provoquent un déplacement opposé. Pour le complexe p47phox-p67phox l’addition d’AA destructure le mélange tandis que la mutation induit relativement peu de changement. Nous avons mesuré les constantes de dissociation Kd du complexe p47phox-p67phox. Alors que pour les protéines « sauvages », le Kd est faible (4±2 nM), les mutations de p47phox ainsi que l’addition d’AA augmentent cette valeur jusqu’à environ 50 nM, montrant une diminution de l’affinité entre p47phox-p67phox. De même, sur le complexe entier, l’effet de la phosphorylation de p47phox est différent de la mutation. Nous avons mesuré les valeurs de EC50 relatives à p67phox pour les différentes formes de p47phox. L’activation de p47phox par phosphorylation diminue l’EC₅₀, alors que les doubles ou triple mutations augmentent sa valeur. Nous avons confirmé que la phosphorylation et la mutation sont insuffisantes pour activer l’enzyme. La présence de AA est indispensable pour le fonctionnement du complexe. L’ordre de fixation des sous unités cytosoliques semble indifférent mais il faut que tous les composants soient présents lors de l’ajout de AA. Enfin, la délétion de p47phox dans la partie C-terminale (aa 343 à 390, domaine d’interaction avec p67phox) il n’y a plus de formation du dimère mais l’enzyme fonctionne normalement. Ces résultats apportent des éléments nouveaux sur le rôle de la dimérisation p47 phox-p67 phox, non indispensable à l’activité du système et sur le rôle mineur de la phosphorylation dans l’activation de la NADPH oxydase in vitroThe NADPH oxidase of phagocytes is an enzyme involved in the innate defense of organisms against pathogens. After phagocyte activation, this enzyme produces superoxide ions by reduction of dioxygen by NADPH. It is constituted of four cytosolic sub-units (p47phox ; p67phox ; p40phox et Rac) and two membrane proteins (gp91 ; p22phox). Its activation takes place through a complex process that involves protein-protein interaction changes leading to assembly and functionning of the catalytic core. In order to obtain information on this process, I have reconstituted the enzyme in a cell free systeme using recombinant proteins, to be able to fully control all the measurement conditions. In this work, we have compared different activation modes of p47phox i) phosphorylation; ii) substitution serine - aspartate by mutations at positions S303, S304 and S328 to mimic phosphorylation; iii) addition of arachidonic acid (AA), a well known activator molecule in vitro. It has been shown that these three activating methods transform p47phox to an open configuration with similar characteristics. However, we have found that the effects of these methods are significantly different. Indeed, the conformational changes observed by circular dichroism are different. For p47phox, the addition of AA destructures the protein. Its phosphorylation induces a bathochromic displacement of the bands, whereas the mutations S-D lead to an opposite displacement. For the dimer p47phox-p67phox , the addition of AA destructures the proteins while mutations induce hardly no changes. We have measured the dissociation constant Kd of the complex p47phox-p67phox. For wild type proteins, Kd value is low (4±2 nM), while mutations of p47phox as well as addition of AA increase its value up to 50 nM, showing a decrease of affinity between p47phox and p67phox. Moreover, on the whole complex, the effect of phosphorylation of p47phox is different from mutations. We have shown that the EC50 values relative to p67phox are sensitive to the various modifications of p47phox. Phosphorylation of p47phox decreases EC₅₀, while double or triple mutations increase its value. We have confirmed that phosphorylation and mutation are not sufficient to activate the enzyme. The presence of AA is a prerequisite for the functionning of the complex, i.e. production of superoxide. The binding order of the cytosolic proteins seems random but it is necessary that all the components be present during the activation by AA. Finally, deletion of the C terminal part of p47phox (aa 343 to 390, interaction domain with p67phox) leads to the absence of dimer formation but does not affect the enzyme activity. These results bring new information on the role of dimerisation of p47-p67 and on that of phosphorylation in the activation of NADPH oxidase in vitro
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Bettignies, Geoffroy de. "Analyse fonctionnelle de la Rho GAP codée par le gène RGD1 chez la levure Saccharomyces cerevisiae : mise en évidence de relations avec la "voie PKC"". Bordeaux 2, 2000. http://www.theses.fr/2000BOR28740.
Pełny tekst źródłaKsiążki na temat "PTC mutation"
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Derks, Allen Kimbell. Synechococcus sp. PCC 7002 CpcB lyase null mutations alter phycocyanin chromophore function and, consequently, affect the redistribution of excitation energy via the light state transition. St. Catharines, Ont: Brock University, Dept. of Biological Sciences, 2007.
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Matthew Kynes, J. Hemophilia (Presentation in Emergency Surgery). Redaktorzy Matthew D. McEvoy i Cory M. Furse. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780190226459.003.0085.
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Hemophilia is a complex disease of variable severity that affects clotting function and has significant implications in perioperative and emergency care. Hereditary or de novo mutations cause deficiencies in factor VIII or IX production, which may manifest as spontaneous bleeding into joint spaces, muscles, or other sites in severe forms of the disease. Intracranial bleeding is one of the most serious and often fatal complications. In a patient with abnormal bleeding, laboratory results indicative of hemophilia include an increased partial prothromboplastin time (PT), with normal prothrombin time/international normalized ratio (PTT/INR) and normal platelet count. The diagnosis is confirmed with specific factor assays. Advances in prophylaxis with factor replacement have improved outcomes and reduced bleeding episodes in hemophilia. However, patients with hemophilia may present emergently for operation and require factor replacement. In patients that have developed antibodies to factor replacement, clotting factor bypass agents may be required to control bleeding.
Części książek na temat "PTC mutation"
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Enoiu, Eduard P., Daniel Sundmark, Adnan Čaušević, Robert Feldt i Paul Pettersson. "Mutation-Based Test Generation for PLC Embedded Software Using Model Checking". W Testing Software and Systems, 155–71. Cham: Springer International Publishing, 2016. http://dx.doi.org/10.1007/978-3-319-47443-4_10.
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Buzby, J. S., R. O. Mumma, D. A. Bryant, J. Gingrich, R. H. Hamilton, R. D. Porter, C. A. Mullin i S. E. Stevens. "Genes with Mutations Causing Herbicide Resistance from the Cyanobacterium Synechococcus PCC 7002". W Progress in Photosynthesis Research, 757–60. Dordrecht: Springer Netherlands, 1987. http://dx.doi.org/10.1007/978-94-017-0519-6_157.
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Shari, Ummi Syuhada Halmi, Azlin Suhaida Azmi i Azura Amid. "Chemical Mutation Method for High CO2-Requiring-Mutants of the Cyanobacterium Synechococcus sp. PCC 7002". W Multifaceted Protocol in Biotechnology, 53–62. Singapore: Springer Singapore, 2018. http://dx.doi.org/10.1007/978-981-13-2257-0_5.
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Gingrich, Jeffrey C., Jeffrey S. Buzby, Veronica L. Stirewalt i Donald A. Bryant. "Genetic analysis of two new mutations resulting in herbicide resistance in the cyanobacterium Synechococcus sp. PCC 7002". W Molecular Biology of Photosynthesis, 353–69. Dordrecht: Springer Netherlands, 1988. http://dx.doi.org/10.1007/978-94-009-2269-3_16.
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Schulz, R., L. B. Smart, J. Yu i L. McIntosh. "A New Set of Site-Directed Mutations in Photosystem I Core Reaction Center from Synechocystis sp. PCC 6803". W Photosynthesis: from Light to Biosphere, 1097–100. Dordrecht: Springer Netherlands, 1995. http://dx.doi.org/10.1007/978-94-009-0173-5_259.
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Zeng, Mingtao, Irit Sagi, Michael C. W. Evans, Nathan Nelson i Chanoch Carmeli. "Site Directed and Suppressor Mutations of Ex Ligands in Psab of Photosystem I in Synechocystis SP PCC 6803". W Photosynthesis: Mechanisms and Effects, 643–46. Dordrecht: Springer Netherlands, 1998. http://dx.doi.org/10.1007/978-94-011-3953-3_152.
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Meng, Xiangxiu, Xuejun Zhu, Yunpeng Ding i Dengrong Qi. "Application of Image Recognition in Precise Inoculation Control System of Pleurotus Eryngii". W Proceeding of 2021 International Conference on Wireless Communications, Networking and Applications, 988–1005. Singapore: Springer Nature Singapore, 2022. http://dx.doi.org/10.1007/978-981-19-2456-9_100.
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AbstractThe traditional inoculation technology of Pleurotus eryngii is artificial inoculation, which has the disadvantages of low efficiency and high failure rate. In order to solve this problem, it is necessary to put forward the automatic control system of Pleurotus eryngii inoculation. In this paper, based on the system of high reliability, high efficiency, flexible configuration and other performance requirements, PLC is used as the core components of the control system and control the operation of the whole system. In order to improve the efficiency of the control system, the particle swarm optimization algorithm was used to optimize the interpolation time of the trajectory of the manipulator. Through simulation, it was found that the joint acceleration curve was smooth without mutation, and the running time was short. Because the position deviation of the Culture medium of Pleurotus eryngii to be inoculated will inevitably occur when it is transferred on the conveyor belt, the image recognition technology is used to accurately locate them. In order to improve the efficiency of image recognition, the genetic algorithm (GA) is used to improve Otsu to find the target region of Culture medium of Pleurotus eryngii to be inoculated, and the simulation results showed that the computational efficiency could be increased by 70%. In order to locate the center of the target region, the mean value method is used to find their centroid coordinates. At last, it is found by simulation that the centroid coordinates could be accurately calculated for a basket of 12 Pleuroides eryngii medium to be inoculated.
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Astier, C., G. Ajlani, I. Perewoska, M. Picaud i C. Vernotte. "Expected and Unexpected Effects of Mutations Conferring Herbicide Resistance on Photosystem II Activity in Synechocystis PCC 6714 and 6803". W Research in Photosynthesis, 575–78. Dordrecht: Springer Netherlands, 1992. http://dx.doi.org/10.1007/978-94-009-0383-8_126.
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Chu, Hsiu-An, Anh P. Nguyen i Richard J. Debus. "An Improved Host Strain of Synechocystis sp. PCC 6803 for Introducing Site-Directed Mutations into the D1 Protein of Photosystem II". W Photosynthesis: from Light to Biosphere, 1417–20. Dordrecht: Springer Netherlands, 1995. http://dx.doi.org/10.1007/978-94-009-0173-5_334.
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Ermakova-Gerdes, Svetlana, Sergey Shestakov i Wim Vermaas. "Development of a Photosystem I-Less Strain of Synechocystis sp. PCC 6803 for Analysis of Mutations in the Photosystem II Proteins D2 and CP43". W Photosynthesis: from Light to Biosphere, 483–86. Dordrecht: Springer Netherlands, 1995. http://dx.doi.org/10.1007/978-94-009-0173-5_111.
Pełny tekst źródłaStreszczenia konferencji na temat "PTC mutation"
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Sawa, T. "Radial network reconfiguration method in distribution system using mutation Particle Swarm Optimization". W 2009 IEEE Bucharest PowerTech (POWERTECH). IEEE, 2009. http://dx.doi.org/10.1109/ptc.2009.5281827.
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Danysh, Brian P., Maria E. Cabanillas i Marie-Claude Hofmann. "Abstract 2933: Long-term BRAF(V600E) inhibition results in a spontaneous KRAS(G12D) mutation and increased epithelial to mesenchymal transition (EMT) in papillary thyroid cancer cells (PTC)". W Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-2933.
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Wu, Xiaoxue, Wei Zheng, Zhao Shi, Zehai Wang, Lixin Cao i Dejun Mu. "Concurrency Bug-Oriented Mutation Operators Design for Java". W 2018 IEEE International Conference on Progress in Informatics and Computing (PIC). IEEE, 2018. http://dx.doi.org/10.1109/pic.2018.8706335.
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Muhovic, D., B. Smolovic, A. Hodzic i B. Peterlin. "CAROLI'S DISEASE (CD) CAUSED BY VERY RARE GENETIC MUTATION, MISDIAGNOSED WITH ERCP AND MRCP AS PRIMARY SCLEROSING CHOLANGITIS (PSC)". W ESGE Days 2019. Georg Thieme Verlag KG, 2019. http://dx.doi.org/10.1055/s-0039-1681852.
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Leeman-Neill, Rebecca J., Alina V. Brenner, Mark P. Little, Andre C. Bouville, Tetyana I. Bogdanova, Maureen Hatch, Kiyohiko Mabuchi, Mykola D. Tronko i Yuri E. Nikiforov. "Abstract 2544: Associations between RET/PTC rearrangements, BRAF and RAS mutations and radiation dose, age at exposure, and latency in post-Chernobyl thyroid cancer". W Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-2544.
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Seynaeve, C., P. Vencken, M. Hooning, M. Menke-Pluymers, A. Heemskerk-Gerritsen, Doorn L. Van, M. Collee i in. "P4-11-04: Risk of Primary (PBC) and Contralateral Breast Cancer (CBC) after Ovarian Cancer (OC) in BRCA1 and BRCA2 Mutation Carriers; Implications for Surveillance and Risk Reducing Mastectomy." W Abstracts: Thirty-Fourth Annual CTRC‐AACR San Antonio Breast Cancer Symposium‐‐ Dec 6‐10, 2011; San Antonio, TX. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/0008-5472.sabcs11-p4-11-04.
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Lu, Shun, Jian Fang, Lejie Cao, Xingya Li, Qisen Guo, Jianying Zhou, Ying Cheng i in. "Abstract CT031: Preliminary efficacy and safety results of savolitinib treating patients with pulmonary sarcomatoid carcinoma (PSC) and other types of non-small cell lung cancer (NSCLC) harboringMETexon 14 skipping mutations". W Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-ct031.
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Lu, Shun, Jian Fang, Lejie Cao, Xingya Li, Qisen Guo, Jianying Zhou, Ying Cheng i in. "Abstract CT031: Preliminary efficacy and safety results of savolitinib treating patients with pulmonary sarcomatoid carcinoma (PSC) and other types of non-small cell lung cancer (NSCLC) harboringMETexon 14 skipping mutations". W Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.am2019-ct031.
Pełny tekst źródłaRaporty organizacyjne na temat "PTC mutation"
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Sessa, Guido, i Gregory Martin. role of FLS3 and BSK830 in pattern-triggered immunity in tomato. United States Department of Agriculture, styczeń 2016. http://dx.doi.org/10.32747/2016.7604270.bard.
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Pattern-recognition receptors (PRRs) located on the plant cell surface initiate immune responses by perceiving conserved pathogen molecules known as pathogen-associated molecular patterns (PAMPs). PRRs typically function in multiprotein complexes that include transmembrane and cytoplasmickinases and contribute to the initiation and signaling of pattern-triggered immunity (PTI). An important challenge is to identify molecular components of PRR complexes and downstream signaling pathways, and to understand the molecular mechanisms that mediate their function. In research activities supported by BARD-4931, we studied the role of the FLAGELLIN SENSING 3 (FLS3) PRR in the response of tomato leaves to flagellin-derivedPAMPs and PTI. In addition, we investigated molecular properties of the tomato brassinosteroid signaling kinase 830 (BSK830) that physically interacts with FLS3 and is a candidate for acting in the FLS3 signaling pathway. Our investigation refers to the proposal original objectives that were to: 1) Investigate the role of FLS3 and its interacting proteins in PTI; 2) Investigate the role of BSK830 in PTI; 3) Examine molecular and phosphorylation dynamics of the FLS3-BSK830 interaction; 4) Examine the possible interaction of FLS3 and BSK830 with Pstand Xcveffectors. We used CRISPR/Cas9 techniques to develop plants carrying single or combined mutations in the FLS3 gene and in the paralogsFLS2.1 and FLS2.2 genes, which encode the receptor FLAGELLIN SENSING2 (FLS2), and analyzed their function in PTI. Domain swapping analysis of the FLS2 and FLS3 receptors revealed domains of the proteins responsible for PAMP detection and for the different ROS response initiated by flgII-28/FLS3 as compared to flg22/FLS2. In addition, in vitro kinase assays and point mutations analysis identified FLS2 and FLS3 domains required for kinase activity and ATP binding. In research activities on tomato BSK830, we found that it interacts with PRRs and with the co-receptor SERK3A and PAMP treatment affects part of these interactions. CRISPR/Cas9 bsk830 mutant plants displayed enhanced pathogen susceptibility and reduced ROS production upon PAMP treatment. In addition, BSK830 interacted with 8 Xanthomonastype III secreted effectors. Follow up analysis revealed that among these effectors XopAE is part of an operon, is translocated into plant cells, and displays E3 ubiquitinligase activity. Our investigation was also extended to other Arabidopsis and tomato BSK family members. Arabidopsis BSK5 localized to the plant cell periphery, interacted with receptor-like kinases, and it was phosphorylatedin vitro by the PEPR1 and EFRPRRs. bsk5 mutant plants displayed enhanced susceptibility to pathogens and were impaired in several, but not all, PAMP-induced responses. Conversely, BSK5 overexpression conferred enhanced disease resistance and caused stronger PTI responses. Genetic complementation suggested that proper localization, kinase activity, and phosphorylation by PRRs are critical for BSK5 function. BSK7 and BSK8 specifically interacted with the FLS2 PRR, their respective mutant plants were more susceptible to B. cinereaand displayed reduced flg22-induced responses. The tomato BSK Mai1 was found to interact with the M3KMAPKKK, which is involved in activation of cell death associated with effector-triggered immunity. Silencing of Mai1 in N. benthamianaplants compromised cell death induced by a specific class of immune receptors. In addition, co-expression of Mai1 and M3Kin leaves enhanced MAPKphosphorylation and cell death, suggesting that Mai1 acts as a molecular link between pathogen recognition and MAPK signaling. Finally, We identified the PP2C phosphatase Pic1 that acts as a negative regulator of PTI by interacting with and dephosphorylating the receptor-like cytoplasmickinase Pti1, which is a positive regulator of plant immunity. The results of this investigation shed new light on the molecular characteristics and interactions of components of the immune system of crop plants providing new knowledge and tools for development of novel strategies for disease control.
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Ohad, Itzhak, i Himadri Pakrasi. Role of Cytochrome B559 in Photoinhibition. United States Department of Agriculture, grudzień 1995. http://dx.doi.org/10.32747/1995.7613031.bard.
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The aim of this research project was to obtain information on the role of the cytochrome b559 in the function of Photosystem-II (PSII) with special emphasis on the light induced photo inactivation of PSII and turnover of the photochemical reaction center II protein subunit RCII-D1. The major goals of this project were: 1) Isolation and sequencing of the Chlamydomonas chloroplast psbE and psbF genes encoding the cytochrome b559 a and b subunits respectively; 2) Generation of site directed mutants and testing the effect of such mutation on the function of PSII under various light conditions; 3) To obtain further information on the mechanism of the light induced degradation and replacement of the PSII core proteins. This information shall serve as a basis for the understanding of the role of the cytochrome b559 in the process of photoinhibition and recovery of photosynthetic activity as well as during low light induced turnover of the D1 protein. Unlike in other organisms in which the psbE and psbF genes encoding the a and b subunits of cytochrome b559, are part of an operon which also includes the psbL and psbJ genes, in Chlamydomonas these genes are transcribed from different regions of the chloroplast chromosome. The charge distribution of the derived amino-acid sequences of psbE and psbF gene products differs from that of the corresponding genes in other organisms as far as the rule of "positive charge in" is concerned relative to the process of the polypeptide insertion in the thylakoid membrane. However, the sum of the charges of both subunits corresponds to the above rule possibly indicating co-insertion of both subunits in the process of cytochrome b559 assembly. A plasmid designed for the introduction of site-specific mutations into the psbF gene of C. reinhardtii. was constructed. The vector consists of a DNA fragment from the chromosome of C. reinhardtii which spans the region of the psbF gene, upstream of which the spectinomycin-resistance-conferring aadA cassette was inserted. This vector was successfully used to transform wild type C. reinhardtii cells. The spectinomycin resistant strain thus obtained can grow autotrophically and does not show significant changes as compared to the wild-type strain in PSII activity. The following mutations have been introduced in the psbF gene: H23M; H23Y; W19L and W19. The replacement of H23 involved in the heme binding to M and Y was meant to permit heme binding but eventually alter some or all of the electron transport properties of the mutated cytochrome. Tryptophane W19, a strictly conserved residue, is proximal to the heme and may interact with the tetrapyrole ring. Therefore its replacement may effect the heme properties. A change to tyrosine may have a lesser affect on the potential or electron transfer rate while a replacement of W19 by leucine is meant to introduce a more prominent disturbance in these parameters. Two of the mutants, FW19L and FH23M have segregated already and are homoplasmic. The rest are still grown under selection conditions until complete segregation will be obtained. All mutants contain assembled and functional PSII exhibiting an increased sensitivity of PSII to the light. Work is still in progress for the detailed characterization of the mutants PSII properties. A tobacco mutant, S6, obtained by Maliga and coworkers harboring the F26S mutation in the b subunit was made available to us and was characterized. Measurements of PSII charge separation and recombination, polypeptide content and electron flow indicates that this mutation indeed results in light sensitivity. Presently further work is in progress in the detailed characterization of the properties of all the above mutants. Information was obtained demonstrating that photoinactivation of PSII in vivo initiates a series of progressive changes in the properties of RCII which result in an irreversible modification of the RCII-D1 protein leading to its degradation and replacement. The cleavage process of the modified RCII-D1 protein is regulated by the occupancy of the QB site of RCII by plastoquinone. Newly synthesized D1 protein is not accumulated in a stable form unless integrated in reassembled RCII. Thus the degradation of the irreversibly modified RCII-D1 protein is essential for the recovery process. The light induced degradation of the RCII-D1 protein is rapid in mutants lacking the pD1 processing protease such as in the LF-1 mutant of the unicellular alga Scenedesmus obliquus. In this case the Mn binding site of PSII is abolished, the water oxidation process is inhibited and harmful cation radicals are formed following light induced electron flow in PSII. In such mutants photo-inactivation of PSII is rapid, it is not protected by ligands binding at the QB site and the degradation of the inactivated RCII-D1 occurs rapidly also in the dark. Furthermore the degraded D1 protein can be replaced in the dark in absence of light driven redox controlled reactions. The replacement of the RCII-D1 protein involves the de novo synthesis of the precursor protein, pD1, and its processing at the C-terminus end by an unknown processing protease. In the frame of this work, a gene previously isolated and sequenced by Dr. Pakrasi's group has been identified as encoding the RCII-pD1 C-terminus processing protease in the cyanobacterium Synechocystis sp. PCC 6803. The deduced sequence of the ctpA protein shows significant similarity to the bovine, human and insect interphotoreceptor retinoid-binding proteins. Results obtained using C. reinhardtii cells exposes to low light or series of single turnover light flashes have been also obtained indicating that the process of RCII-D1 protein turnover under non-photoinactivating conditions (low light) may be related to charge recombination in RCII due to back electron flow from the semiquinone QB- to the oxidised S2,3 states of the Mn cluster involved in the water oxidation process.
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Grumet, Rebecca, i Benjamin Raccah. Identification of Potyviral Domains Controlling Systemic Infection, Host Range and Aphid Transmission. United States Department of Agriculture, lipiec 2000. http://dx.doi.org/10.32747/2000.7695842.bard.
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Potyviruses form one of the largest and most economically important groups of plant viruses. Individual potyviruses and their isolates vary in symptom expression, host range, and ability to overcome host resistance genes. Understanding factors influencing these biological characteristics is of agricultural importance for epidemiology and deployment of resistance strategies. Cucurbit crops are subject to severe losses by several potyviruses including the highly aggressive and variable zucchini yellow mosaic virus (ZYMV). In this project we sought to investigate protein domains in ZYMV that influence systemic infection and host range. Particular emphasis was on coat protein (CP), because of known functions in both cell to cell and long distance movement, and helper component-protease (HC-Pro), which has been implicated to play a role in symptom development and long distance movement. These two genes are also essential for aphid mediated transmission, and domains that influence disease development may also influence transmissibility. The objectives of the approved BARD project were to test roles of specific domains in the CP and HC-Pro by making sequence alterations or switches between different isolates and viruses, and testing for infectivity, host range, and aphid transmissibility. These objectives were largely achieved as described below. Finally, we also initiated new research to identify host factors interacting with potyviral proteins and demonstrated interaction between the ZYMV RNA dependent RNA polymerase and host poly-(A)-binding protein (Wang et al., in press). The focus of the CP studies (MSU) was to investigate the role of the highly variable amino terminus (NT) in host range determination and systemic infection. Hybrid ZYMV infectious clones were produced by substituting the CP-NT of ZYMV with either the CP-NT from watermelon mosaic virus (overlapping, but broader host range) or tobacco etch virus (TEV) (non- overlapping host range) (Grumet et al., 2000; Ullah ct al., in prep). Although both hybrid viruses initially established systemic infection, indicating that even the non-cucurbit adapted TEV CP-NT could facilitate long distance transport in cucurbits, after approximately 4-6, the plants inoculated with the TEV-CPNT hybrid exhibited a distinct recovery of reduced symptoms, virus titer, and virus specific protection against secondary infection. These results suggest that the plant recognizes the presence of the TEV CP-NT, which has not been adapted to infection of cucurbits, and initiates defense responses. The CP-NT also appears to play a role in naturally occurring resistance conferred by the zym locus in the cucumber line 'Dina-1'. Patterns of virus accumulation indicated that expression of resistance is developmentally controlled and is due to a block in virus movement. Switches between the core and NT domains of ZYMV-NAA (does not cause veinal chlorosis on 'Dina-1'), and ZYMV-Ct (causes veinal chlorosis), indicated that the resistance response likely involves interaction with the CP-NT (Ullah and Grumet, submitted). At the Volcani Center the main thrust was to identify domains in the HC-Pro that affect symptom expression or aphid transmissibility. From the data reported in the first and second year report and in the attached publications (Peng et al. 1998; Kadouri et al. 1998; Raccah et al. 2000: it was shown that: 1. The mutation from PTK to PAK resulted in milder symptoms of the virus on squash, 2. Two mutations, PAK and ATK, resulted in total loss of helper activity, 3. It was established for the first time that the PTK domain is involved in binding of the HC-Pro to the potyvirus particle, and 4. Some of these experiments required greater amount of HC-Pro, therefore a simpler and more efficient purification method was developed based on Ni2+ resin.
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McClure, Michael A., Yitzhak Spiegel, David M. Bird, R. Salomon i R. H. C. Curtis. Functional Analysis of Root-Knot Nematode Surface Coat Proteins to Develop Rational Targets for Plantibodies. United States Department of Agriculture, październik 2001. http://dx.doi.org/10.32747/2001.7575284.bard.
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The goal of this research was to provide a better understanding of the interface between root-knot nematodes, Meloidogyne spp., and their host in order to develop rational targets for plantibodies and other novel methods of nematode control directed against the nematode surface coat (SC). Specific objectives were: 1. To produce additional monoclonal SC antibodies for use in Objectives 2, 3, and 4 and as candidates for development of plantibodies. 2. To determine the production and distribution of SC proteins during the infection process. 3. To use biochemical and immunological methods to perturbate the root-knot nematode SC in order to identify SC components that will serve as targets for rationally designed plantibodies. 4. To develop SC-mutant nematodes as additional tools for defining the role of the SC during infection. The external cuticular layer of nematodes is the epicuticle. In many nematodes, it is covered by a fuzzy material termed "surface coat" (SC). Since the SC is the outermost layer, it may playa role in the interaction between the nematode and its surroundings during all life stages in soil and during pathogenesis. The SC is composed mainly of proteins, carbohydrates (which can be part of glycoproteins), and lipids. SC proteins and glycoproteins have been labeled and extracted from preparasitic second-stage juveniles and adult females of Meloidogyne and specific antibodies have been raised against surface antigens. Antibodies can be used to gain more information about surface function and to isolate genes encoding for surface antigens. Characterization of surface antigens and their roles in different life-stages may be an important step towards the development of alternative control. Nevertheless, the role of the plant- parasitic nematode's surface in plant-nematode interaction is still not understood. Carbohydrates or carbohydrate-recognition domains (CROs) on the nematode surface may interact with CROs or carbohydrate molecules, on root surfaces or exudates, or be active after the nematode has penetrated into the root. Surface antigens undoubtedly play an important role in interactions with microorganisms that adhere to the nematodes. Polyclonal (PC) and monoclonal (MC) antibodies raised against Meloidogyne javanica, M. incognita and other plant-parasitic nematodes, were used to characterize the surface coat and secreted-excreted products of M. javanica and M. incognita. Some of the MC and PC antibodies raised against M. incognita showed cross-reactivity with the surface coat of M. javanica. Further characterization, in planta, of the epitopes recognized by the antibodies, showed that they were present in the parasitic juvenile stages and that the surface coat is shed during root penetration by the nematode and its migration between root cells. At the molecular level, we have followed two lines of experimentation. The first has been to identify genes encoding surface coat (SC) molecules, and we have isolated and characterized a small family of mucin genes from M. incognita. Our second approach has been to study host genes that respond to the nematode, and in particular, to the SC. Our previous work has identified a large suite of genes expressed in Lycopersicon esculentum giant cells, including the partial cDNA clone DB#131, which encodes a serine/threonine protein kinase. Isolation and predicted translation of the mature cDNA revealed a frame shift mutation in the translated region of nematode sensitive plants. By using primers homologous to conserved region of DB#131 we have identified the orthologues from three (nematode-resistant) Lycopersicon peruvianum strains and found that these plants lacked the mutation.
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Avni, Adi, i Gitta L. Coaker. Proteomic investigation of a tomato receptor like protein recognizing fungal pathogens. United States Department of Agriculture, styczeń 2015. http://dx.doi.org/10.32747/2015.7600030.bard.
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Maximizing food production with minimal negative effects on the environment remains a long-term challenge for sustainable food production. Microbial pathogens cause devastating diseases, minimizing crop losses by controlling plant diseases can contribute significantly to this goal. All plants possess an innate immune system that is activated after recognition of microbial-derived molecules. The fungal protein Eix induces defense responses in tomato and tobacco. Plants recognize Eix through a leucine-rich-repeat receptor- like-protein (LRR-RLP) termed LeEix. Despite the knowledge obtained from studies on tomato, relatively little is known about signaling initiated by RLP-type immune receptors. The focus of this grant proposal is to generate a foundational understanding of how the tomato xylanase receptor LeEix2 signals to confer defense responses. LeEix2 recognition results in pattern triggered immunity (PTI). The grant has two main aims: (1) Isolate the LeEix2 protein complex in an active and resting state; (2) Examine the biological function of the identified proteins in relation to LeEix2 signaling upon perception of the xylanase elicitor Eix. We used two separate approaches to isolate receptor interacting proteins. Transgenic tomato plants expressing LeEix2 fused to the GFP tag were used to identify complex components at a resting and activated state. LeEix2 complexes were purified by mass spectrometry and associated proteins identified by mass spectrometry. We identified novel proteins that interact with LeEix receptor by proteomics analysis. We identified two dynamin related proteins (DRPs), a coiled coil – nucleotide binding site leucine rich repeat (SlNRC4a) protein. In the second approach we used the split ubiquitin yeast two hybrid (Y2H) screen system to identified receptor-like protein kinase At5g24010-like (SlRLK-like) (Solyc01g094920.2.1) as an interactor of LeEIX2. We examined the role of SlNRC4a in plant immunity. Co-immunoprecipitation demonstrates that SlNRC4a is able to associate with different PRRs. Physiological assays with specific elicitors revealed that SlNRC4a generally alters PRR-mediated responses. SlNRC4a overexpression enhances defense responses while silencing SlNRC4 reduces plant immunity. We propose that SlNRC4a acts as a non-canonical positive regulator of immunity mediated by diverse PRRs. Thus, SlNRC4a could link both intracellular and extracellular immune perception. SlDRP2A localizes at the plasma membrane. Overexpression of SlDRP2A increases the sub-population of LeEIX2 inVHAa1 endosomes, and enhances LeEIX2- and FLS2-mediated defense. The effect of SlDRP2A on induction of plant immunity highlights the importance of endomembrane components and endocytosis in signal propagation during plant immune . The interaction of LeEIX2 with SlRLK-like was verified using co- immunoprecipitation and a bimolecular fluorescence complementation assay. The defence responses induced by EIX were markedly reduced when SlRLK-like was over-expressed, and mutation of slrlk-likeusing CRISPR/Cas9 increased EIX- induced ethylene production and SlACSgene expression in tomato. Co-expression of SlRLK-like with different RLPs and RLKs led to their degradation, apparently through an endoplasmic reticulum-associated degradation process. We provided new knowledge and expertise relevant to expression of specific be exploited to enhance immunity in crops enabling the development of novel environmentally friendly disease control strategies.
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Ohad, Nir, i Robert Fischer. Regulation of Fertilization-Independent Endosperm Development by Polycomb Proteins. United States Department of Agriculture, styczeń 2004. http://dx.doi.org/10.32747/2004.7695869.bard.
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Arabidopsis mutants that we have isolated, encode for fertilization-independent endosperm (fie), fertilization-independent seed2 (fis2) and medea (mea) genes, act in the female gametophyte and allow endosperm to develop without fertilization when mutated. We cloned the FIE and MEA genes and showed that they encode WD and SET domain polycomb (Pc G) proteins, respectively. Homologous proteins of FIE and MEA in other organisms are known to regulate gene transcription by modulating chromatin structure. Based on our results, we proposed a model whereby both FIE and MEA interact to suppress transcription of regulatory genes. These genes are transcribed only at proper developmental stages, as in the central cell of the female gametophyte after fertilization, thus activating endosperm development. To test our model, the following questions were addressed: What is the Composition and Function of the Polycomb Complex? Molecular, biochemical, genetic and genomic approaches were offered to identify members of the complex, analyze their interactions, and understand their function. What is the Temporal and Spatial Pattern of Polycomb Proteins Accumulation? The use of transgenic plants expressing tagged FIE and MEA polypeptides as well as specific antibodies were proposed to localize the endogenous polycomb complex. How is Polycomb Protein Activity Controlled? To understand the molecular mechanism controlling the accumulation of FIE protein, transgenic plants as well as molecular approaches were proposed to determine whether FIE is regulated at the translational or posttranslational levels. The objectives of our research program have been accomplished and the results obtained exceeded our expectation. Our results reveal that fie and mea mutations cause parent-of-origin effects on seed development by distinct mechanisms (Publication 1). Moreover our data show that FIE has additional functions besides controlling the development of the female gametophyte. Using transgenic lines in which FIE was not expressed or the protein level was reduced during different developmental stages enabled us for the first time to explore FIE function during sporophyte development (Publication 2 and 3). Our results are consistent with the hypothesis that FIE, a single copy gene in the Arabidopsis genome, represses multiple developmental pathways (i.e., endosperm, embryogenesis, shot formation and flowering). Furthermore, we identified FIE target genes, including key transcription factors known to promote flowering (AG and LFY) as well as shoot and leaf formation (KNAT1) (Publication 2 and 3), thus demonstrating that in plants, as in mammals and insects, PcG proteins control expression of homeobox genes. Using the Yeast two hybrid system and pull-down assays we demonstrated that FIE protein interact with MEA via the N-terminal region (Publication 1). Moreover, CURLY LEAF protein, an additional member of the SET domain family interacts with FIE as well. The overlapping expression patterns of FIE, with ether MEA or CLF and their common mutant phenotypes, demonstrate the versatility of FIE function. FIE association with different SET domain polycomb proteins, results in differential regulation of gene expression throughout the plant life cycle (Publication 3). In vitro interaction assays we have recently performed demonstrated that FIE interacts with the cell cycle regulatory component Retinobalsoma protein (pRb) (Publication 4). These results illuminate the potential mechanism by which FIE may restrain embryo sac central cell division, at least partly, through interaction with, and suppression of pRb-regulated genes. The results of this program generated new information about the initiation of reproductive development and expanded our understanding of how PcG proteins regulate developmental programs along the plant life cycle. The tools and information obtained in this program will lead to novel strategies which will allow to mange crop plants and to increase crop production.