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Zeitschriftenartikel zum Thema "Genetic modifier factors"
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Ginsburg, David. „Genetic Modifiers of Thrombosis in Mice.“ Blood 114, Nr. 22 (20.11.2009): SCI—44—SCI—44. http://dx.doi.org/10.1182/blood.v114.22.sci-44.sci-44.
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Abstract Abstract SCI-44 The genetic factors responsible for the highly variable clinical course of inherited bleeding disorders including von Willebrand disease and hemophilia are largely unknown. Similar factors are also likely to contribute to the variability of common thrombotic disorders, including factor V Leiden. Studies by our lab over the past 10 years have used the power of mouse genetics to identify genes contributing to this variability (referred to as ‘modifier‘ genes). By performing genetic crosses between inbred strains of mice with elevated plasma levels of von Willebrand Factor (VWF) and other strains with low levels, we have mapped a total of 6 genetic factors contributing to the control of murine plasma VWF levels. Similar studies in ADAMTS13-deficient mice are in progress aimed at characterizing genes modifying susceptibility thrombotic thrombocytopenic purpura. We have also conducted large scale mutagenesis studies in the mouse in an effort to identify larger numbers of genes contributing to thrombosis risk in the setting of Factor V Leiden, and most recently are extending this approach to similar genetic screens in zebrafish. Finally, recent advances in human genetics are expanding the potential opportunities for directly identifying bleeding and thrombosis modifier genes in humans. Disclosures No relevant conflicts of interest to declare.
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Mésinèle, Julie, Manon Ruffin, Loïc Guillot und Harriet Corvol. „Modifier Factors of Cystic Fibrosis Phenotypes: A Focus on Modifier Genes“. International Journal of Molecular Sciences 23, Nr. 22 (17.11.2022): 14205. http://dx.doi.org/10.3390/ijms232214205.
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Although cystic fibrosis (CF) is recognized as a monogenic disease, due to variants within the CFTR (Cystic Fibrosis Transmembrane Regulator) gene, an extreme clinical heterogeneity is described among people with CF (pwCF). Apart from the exocrine pancreatic status, most studies agree that there is little association between CFTR variants and disease phenotypes. Environmental factors have been shown to contribute to this heterogeneity, accounting for almost 50% of the variability of the lung function of pwCF. Nevertheless, pwCF with similar CFTR variants and sharing the same environment (such as in siblings) may have highly variable clinical manifestations not explained by CFTR variants, and only partly explained by environmental factors. It is recognized that genetic variants located outside the CFTR locus, named “modifier genes”, influence the clinical expression of the disease. This short review discusses the latest studies that have described modifier factors associated with the various CF phenotypes as well as the response to the recent CFTR modulator therapies.
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Butnariu, Lăcrămioara Ionela, Elena Țarcă, Elena Cojocaru, Cristina Rusu, Ștefana Maria Moisă, Maria-Magdalena Leon Constantin, Eusebiu Vlad Gorduza und Laura Mihaela Trandafir. „Genetic Modifying Factors of Cystic Fibrosis Phenotype: A Challenge for Modern Medicine“. Journal of Clinical Medicine 10, Nr. 24 (13.12.2021): 5821. http://dx.doi.org/10.3390/jcm10245821.
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Cystic fibrosis (CF) is a monogenic autosomal recessive disease caused by cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations. CF is characterized by a high phenotypic variability present even in patients with the same genotype. This is due to the intervention of modifier genes that interact with both the CFTR gene and environmental factors. The purpose of this review is to highlight the role of non-CFTR genetic factors (modifier genes) that contribute to phenotypic variability in CF. We analyzed literature data starting with candidate gene studies and continuing with extensive studies, such as genome-wide association studies (GWAS) and whole exome sequencing (WES). The results of both types of studies revealed that the number of modifier genes in CF patients is impressive. Their identification offers a new perspective on the pathophysiological mechanisms of the disease, paving the way for the understanding of other genetic disorders. In conclusion, in the future, genetic analysis, such as GWAS and WES, should be performed routinely. A challenge for future research is to integrate their results in the process of developing new classes of drugs, with a goal to improve the prognosis, increase life expectancy, and enhance quality of life among CF patients.
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Davidson, Courtney E., Qian Li, Gary A. Churchill, Lucy R. Osborne und Heather E. McDermid. „Modifier locus for exencephaly in Cecr2 mutant mice is syntenic to the 10q25.3 region associated with neural tube defects in humans“. Physiological Genomics 31, Nr. 2 (Oktober 2007): 244–51. http://dx.doi.org/10.1152/physiolgenomics.00062.2007.
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Neural tube defects (NTDs), the second most common birth defect in humans, are multifactorial with complex genetic and environmental causes, although the genetic factors are almost completely unknown. In mice, >100 single gene mutations cause NTDs; however, the penetrance in many of these single gene mutant lines is highly dependent on the genetic background. We previously reported that a homozygous Cecr2 mutation on a BALB/c background causes exencephaly at a frequency of 74% compared with 0% on an FVB/N background. We now report that a major genetic modifier on chromosome 19, mapped using whole genome linkage analysis, increases the relative risk of exencephaly by 3.74 times in homozygous BALB embryos vs. BALB/FVB heterozygotes. Scanning electron microscopy revealed that the modifier does not affect the location of neural tube closure site 2, a known murine susceptibility factor for exencephaly. Crossing the Sp ( Splotch) mutation in the Pax3 gene onto the FVB/N background for two generations indicated that this resistant strain also decreases the penetrance of spina bifida. The chromosome 19 modifier region corresponds to a linkage region on human chromosome 10q25.3 mapped in a whole genome scan of human NTD families. Since the FVB/N genetic background affects susceptibility to both exencephaly and spina bifida, the human homolog of the chromosome 19 modifier locus may be a better candidate for human NTD susceptibility factors than genes that when mutated actually cause NTDs in mice.
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Shcherbakova, N. V., A. B. Zhironkina, V. Yu Voinova, R. A. Ildarova und M. A. Shkolnikova. „Phenotypic variability and modifier variants in children with hereditary heart diseases“. Rossiyskiy Vestnik Perinatologii i Pediatrii (Russian Bulletin of Perinatology and Pediatrics) 66, Nr. 3 (01.07.2021): 12–19. http://dx.doi.org/10.21508/1027-4065-2021-66-3-12-19.
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Despite the recent achievements in searching for the causes of monogenic human diseases, there is still a massive gap in understanding the molecular causes of phenotypic variability. At the moment, it is evident that the pathogenic genetic variant often acts together with the other genetic and non-genetic factors that can reduce or, on the contrary, aggravate the severity of the disease. Thus, to completely understand the disease, we shall consider the entire set of mechanisms leading to the resulting phenotype. This paper reviews the current state of the art in identifying genetic and non-genetic phenotype modifiers for rare monogenic cardiovascular diseases.
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Hyun, Cheol Hwan, Chae Young Yoon, He-Jin Lee und Seung-Jae Lee. „LRRK2 as a Potential Genetic Modifier of Synucleinopathies: Interlacing the Two Major Genetic Factors of Parkinson’s Disease“. Experimental Neurobiology 22, Nr. 4 (30.12.2013): 249–57. http://dx.doi.org/10.5607/en.2013.22.4.249.
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Alcaraz, Wendy A., Edward Chen, Phoebe Valdes, Eunnie Kim, Yuan Hung Lo, Jennifer Vo und Bruce A. Hamilton. „Modifier genes and non-genetic factors reshape anatomical deficits in Zfp423-deficient mice“. Human Molecular Genetics 20, Nr. 19 (05.07.2011): 3822–30. http://dx.doi.org/10.1093/hmg/ddr300.
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Pelucchi, Sara, Giulia Ravasi, Cristina Arosio, Mario Mauri, Rocco Piazza, Raffaella Mariani und Alberto Piperno. „HIF1A: A Putative Modifier of Hemochromatosis“. International Journal of Molecular Sciences 22, Nr. 3 (27.01.2021): 1245. http://dx.doi.org/10.3390/ijms22031245.
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HFE-related hereditary hemochromatosis (HH) is characterized by marked phenotypic heterogeneity. Homozygosity for p.C282Y is a low penetrance genotype suggesting that the HFE-HH is a multifactorial disease resulting from a complex interaction involving a major gene defect, genetic background and environmental factors. We performed a targeted NGS-based gene panel to identify new candidate modifiers by using an extreme phenotype sampling study based on serum ferritin and iron removed/age ratio. We found an increased prevalence of the HIF1A p.Phe582Ser and p.Ala588Thr variants in patients with a severe iron and clinical phenotype. Accordingly, Huh-7 cells transfected with both variants showed significantly lower HAMP promoter activity by luciferase assay. The qRT-PCR assays showed a downregulation of hepcidin and an upregulation of the HIF1A target genes (VEGF, HMOX, FUR, TMPRSS6) in cells transfected with the HIF1A-P582S vector. We identified mutations in other genes (e.g., Serpina1) that might have some relevance in single cases in aggravating or mitigating disease manifestation. In conclusion, the present study identified HIF1A as a possible modifier of the HFE-HH phenotype cooperating with the genetic defect in downregulating hepcidin synthesis. In addition, this study highlights that an NGS-based approach could broaden our knowledge and help in characterizing the genetic complexity of HFE-HH patients with a severe phenotype expression.
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Durán, Anyelo, David A. Priestman, Macarena Las Las Heras, Boris Rebolledo-Jaramillo, Valeria Olguín, Juan F. Calderón, Silvana Zanlungo, Jaime Gutiérrez, Frances M. Platt und Andrés D. Klein. „A Mouse Systems Genetics Approach Reveals Common and Uncommon Genetic Modifiers of Hepatic Lysosomal Enzyme Activities and Glycosphingolipids“. International Journal of Molecular Sciences 24, Nr. 5 (03.03.2023): 4915. http://dx.doi.org/10.3390/ijms24054915.
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Identification of genetic modulators of lysosomal enzyme activities and glycosphingolipids (GSLs) may facilitate the development of therapeutics for diseases in which they participate, including Lysosomal Storage Disorders (LSDs). To this end, we used a systems genetics approach: we measured 11 hepatic lysosomal enzymes and many of their natural substrates (GSLs), followed by modifier gene mapping by GWAS and transcriptomics associations in a panel of inbred strains. Unexpectedly, most GSLs showed no association between their levels and the enzyme activity that catabolizes them. Genomic mapping identified 30 shared predicted modifier genes between the enzymes and GSLs, which are clustered in three pathways and are associated with other diseases. Surprisingly, they are regulated by ten common transcription factors, and their majority by miRNA-340p. In conclusion, we have identified novel regulators of GSL metabolism, which may serve as therapeutic targets for LSDs and may suggest the involvement of GSL metabolism in other pathologies.
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Tebbi, Cameron K. „Sickle Cell Disease, a Review“. Hemato 3, Nr. 2 (30.05.2022): 341–66. http://dx.doi.org/10.3390/hemato3020024.
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Sickle cell disease and its variants constitute the most common inherited blood disorders affecting millions of individuals worldwide. Significant information regarding the nature of the genetic mutations and modifier genes that result in increased or decreased severity of the disease are available. In recent years, detailed data regarding molecular genetics, pathophysiology, mechanisms for the development of symptoms and side effects of sickle cell disease have been published. The relationship of physiological changes, cellular interactions, coexisting coagulation disorders, effects of association with other genetic disorders and a number of intervening factors have been explored. New techniques for pre-conception, prenatal, in utero, and neonatal screening are available. Means for prediction of the severity of the disease, clinical course of the disorder, and prevention of some of its major complications have been developed. The effects of psychosocial and environmental factors have been explored. Various therapeutic strategies including bone marrow and stem cell transplantation are currently employed in the treatment of patients with sickle cell disease. Recent progress in understanding the molecular pathways controlling mammalian erythropoiesis and globin switching, as well as advances in genome engineering, particularly the gene-editing techniques, have opened a venue for genetic-based treatment of the disease. Currently, sickle cell disease is often associated with a high rate of complications and mortality. The development of new pharmacological agents, methods for gene therapy, and alterations and modification of the coexisting genetic factors and modifiers for treatment of the disease are encouraging.
Dissertationen zum Thema "Genetic modifier factors"
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Shen, Yuelei. „MHC Class I Antigen Presentation is Regulated by the SUMO-Conjugating Enzyme UBC9: a Dissertation“. eScholarship@UMMS, 2003. https://escholarship.umassmed.edu/gsbs_diss/111.
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CD8 T cells recognize complexes of MHC class I and peptide on the surface of target cells. MHC class I antigen presentation is a long pathway, in which proteins are degraded by proteasomes to generating oligopeptides, which may be further trimmed by aminopeptidases in the cytosol. Peptides are transported into the ER, where they may be further trimmed by ER lumenal aminopeptidases and bind to newly-synthesized MHC class I complexes. Proteins degraded by the proteasome are generally tagged with ubiquitin by a combination of ubiquitin-conjugating enzymes and ubiquitin ligases. UBC9 is one ubiquitin conjugating enzyme, which does not conjugate ubiquitin, but instead conjugates small ubiquitin-like molecules (SUMO) to target protein. UBC9 has been found to regulate the functions of many proteins in vivo, most importantly by modifying nuclear transportation and function. Curing [During] my thesis work, I studied the function of UBC9 in MHC class I antigen presentation.
UBC9 over-expression in COS cells co-expressing ovalbumin markedly increased presentation SIINFEKL (the immunodominant epitope from ovalbumin in the context of H-2Kb), and UBC9 overexpression increased cell surface H-2Kbin general, suggesting that Ubc9 increased MHC class I antigen presentation by increasing peptide supply.
UBC9 did not increase synthesis or degradation of ovalbumin. In transient transfection experiments, Ubc9 increased presentation of SIINFEKL precursors that did, and that did not, depend on proteasomes for processing, as well as SIINFEKL precursors targeted to the ER, bypassing cytosolic processing altogether. However, a C-terminal extended precursor of SIINFEKL, which requires only proteasomal processing before presentation, was the most markedly affected by UBC9 overexpression. This suggested that UBC9 was affecting the pattern of cleavages made by proteasomes in ways that enhance the generation of the C-terminus of SIINFEKL. Because presentation of SIINFEKL itself (which requires no further proteolytic processing) was also enhanced, UBC9 must also affect steps in the class I pathway that occur after the generation of the mature epitopes. UBC9 did not affect the rate of peptide degradation in cytosolic extracts or in intact cells.
These findings suggested that UBC9 might have multiple effects on the MHC class I antigen presentation pathway. Immunofluorescent microscopy demonstrated that UBC9 increased the expression of the beta subunits of immunoproteasomes (LMP2, LMP7, and MECL1) as well as of TAP1 and tapasin. In contrast, UBC9 expression did not increase levels of calnexin, calreticulin, ERp57, or Protein disulfide isomerase (PDI). Similarly, levels of leucine aminopeptidase were not increased in UBC9-transfected cells. Therefore, UBC9 overexpression increases the levels of some but not all components of the class I pathway.
UBC9 overexpression increased protein levels of MECL1, LMP2 or LMP7 that were under the control of viral promoters, and levels of MECL1 mRNA were similar in control vector and UBC9 transfected cells. Therefore, UBC9 did not increase the level of expression of these subunits through increased transcription. Pulse-chase experiments showed that UBC9 overexpression reduced the degradation of MECL1. Therefore, UBC9 increases the levels of at least some of these components of the MHC class I antigen presentation pathway by increasing their stability.
To know the biological significance of UBC9 in MHC class I antigen presentation, I used small interfering RNA (siRNA) to knock down UBC9. Though UBC9 can be successfully knocked down by siRNA, the UBC9-negative cells became very sick, and were not suitable for the study of MHC class I antigen presentation.
There are three forms of SUMO molecules in mammalian cells: SUMO-1, SUMO-2 and SUMO-3. My study suggested that SUMO-2 may be involved in UBC9's regulation of MHC class I antigen presentation, since mutant SUMO-2 blocked UBC9's ability to increase H-2Kb-SIINFEKL levels on the cell surface after the cells were loaded with ovalbumin.
To further study the function of UBC9, I mutated the active amino acid Cys 93 of UBC9 to Ser (UBC9OH). Unexpectedly, this mutant form (UBC9OH) has very similar effects as wild-type UBC9, increasing Kb-SIINFEKL levels at the cells surface. This suggested that UBC9 protein regulates MHC class I antigen presentation pathway proteins by direct or indirect protein interaction, rather than (or as well as) by SUMO conjugation. Taking account of SUMO-2 results, I propose that wild-type UBC9 (either transfected or endogenous) conjugates SUMO-2 to its substrates, and then UBC9 (wild-type or mutant) interacts with its sumoylated targets, thus affecting protein functions.
I also studied heat shock protein Hsp27, which is known to be a substrate for UBC9 in vivo. Hsp27 is expressed in a variety of tissues in the absence of stress, and may regulate actin dynamics.
Hsp27 overexpression decreased generation of H-2Kb-SIINFEKL complexes from SIINFEKL precursors that did, and did not, require proteasomes for processing, or that were targeted to the ER. Hsp27 over-expression did not affect protein synthesis, and globally decreased cell surface H2-Kb and H2-Dblevels, but did not affect HLA-A0302 level. Hsp27 overexpression inhibits the presentation of ER-localized SIINFEKL. Taken together, my data suggested that HSP27 may inhibit MHC class I antigen presentation by affecting MHC class I molecules itself rather than peptide supply.
After Hsp27 was eliminated with siRNA, the effects were very similar to those seen with Hsp27 overexpression. Levels of H-2Kb-SIINFEKL decreased, and overall cell surface H-2Kb and H-2Db levels decreased. It is possible that when Hsp27 is over-expressed, it acts as a dominant negative form, conferring a similar phenotype to Hsp27 knockdown. These observations suggest that Hsp27 plays an important role in MHC class I antigen presentation.
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Vossen, Carolina Y. „Genetic risk factors for venous thrombosis : key players or minor risk modifiers ? /“. [S.l. : s.n], 2005. http://catalogue.bnf.fr/ark:/12148/cb402235083.
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Pennison, Michael James. „Constitutively Decreased Transforming Growth Factor Beta Receptor 1 (TGFBR1) Signaling Modifies Colorectal Cancer Predisposition“. Thesis, Northwestern University, 2015. http://pqdtopen.proquest.com/#viewpdf?dispub=3741319.
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Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the third leading cause of cancer death in the United States. Twin cohort studies indicate that inherited susceptibility accounts for approximately 35% of all CRC cases, but only 5-6% of CRC cases can be attributed to known functional mutations. We were the first to identify a germline mutation in Transforming Growth Factor Beta Receptor 1 (TGFBR1) that is also somatically acquired in tumors, a 9 bp in frame deletion within exon 1 (rs11466445), which results in a receptor with decreased TGF-β signaling properties. The observed association between this hypomorphic variant and cancer risk led us to hypothesize that constitutively decreased TGF-β signaling may contribute to the development of CRC.
In this dissertation, we developed a novel mouse model of Tgfbr1 haploinsufficiency (Tgfbr1+/−) and found that Tgfbr1+/− mice were twice as likely as Tgfbr1+/+ mice to develop CRC. We subsequently identified two human haplotypes associated with constitutively decreased TGFBR1 expression and CRC risk and found that decreased TGFBR1 expression is strongly associated with three SNPs: rs7034462, rs11466445 and rs11568785. Further examination of TGFBR1 haplotype tagging SNPs suggests that the TGFBR1 rs7034462-TT is a novel moderate penetrance risk genotype, which has high penetrance among African Americans, the ethnic group with the highest risk for CRC. Our results provide strong support for the novel notion that rs7034462-TT is a potentially clinically relevant CRC susceptibility genotype that may identify individuals at high risk of dying from CRC.
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Parodi, Livia. „Identification of genetic modifiers in Hereditary Spastic Paraplegias due to SPAST/SPG4 mutations Spastic paraplegia due to SPAST mutations is modified by the underlying mutation and sex Hereditary spastic paraplegia: More than an upper motor neuron disease“. Thesis, Sorbonne université, 2019. http://www.theses.fr/2019SORUS317.
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Les Paraplégies Spastiques Héréditaires (PSHs) sont un groupe de maladies neurodégénératives rares qui surviennent suite à la dégénérescence progressive des voies corticospinales, entraînant une spasticité des membres inférieurs, signe distinctif de la pathologie. Elles se caractérisent par une extrême hétérogénéité qui concerne à la fois les facteurs génétiques et cliniques, ainsi que d’autres aspects de la maladie, tels que l’âge d’apparition et la sévérité des signes. Cette variabilité est typiquement observée chez les patients porteurs de mutations pathogènes dans SPAST, le gène le plus fréquemment muté dans les PSHs. Après avoir réuni une cohorte de 842 patients mutés dans SPAST, nous avons utilisé une combinaison de différentes approches de Séquençage de Nouvelle Génération (NGS) afin de mieux comprendre les causes de l’hétérogénéité observée chez les patients, afin d’identifier des facteurs génétiques responsables de variations de l’âge au début de la maladie. Les données résultantes du génotypage de l’ensemble du génome ont ainsi été utilisées pour effectuer des analyses d’association et de liaison qui, combinées aux données de séquençage de l’ARN, ont permis d’identifier différents variantes/gènes candidats, potentiellement impliqués comme facteurs modificateurs de l’âge de début des SPAST-PSHsHereditary Spastic Paraplegias (HSPs) are a group of rare, inherited, neurodegenerative disorders that arise following the progressive degeneration of the corticospinal tracts, leading to lower limbs spasticity, the disorder hallmark. HSPs are characterized by an extreme heterogeneity that encompasses both genetic and clinical features, extending to additional disorder’s features, such as age of onset and severity. This phenotypic variability is typically observed among HSP patients carrying pathogenic mutations in SPAST, the most frequently mutated HSP causative gene. After assembling a cohort of 842 SPAST-HSP patients, a combination of different Next Generation Sequencing approaches was used to dig deeper into the causes of the observed heterogeneity, especially focusing on the identification of age of onset genetic modifiers. Sequencing data resulting from Whole Genome Genotyping were used to perform both association and linkage analysis that, combined with RNA sequencing expression data, allowed to identify different candidate variants/genes, potentially acting as SPAST-HSP age of onset modifiers
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Louis, Jeanne. „Syndrοme de Li-Fraumeni : apprοches fοnctiοnnelles visant à appréhender la variabilité génοtypique et phénοtypique“. Electronic Thesis or Diss., Normandie, 2025. http://www.theses.fr/2025NORMR002.
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Le syndrome de Li-Fraumeni (LFS) prédispose les porteurs de variations pathogènes de TP53 à un large spectre de tumeurs dès l’enfance. La variabilité phénotypique du LFS complique la prise en charge des patients et peut s’expliquer en partie par le type de variations de TP53, mais également par l'influence de facteurs modificateurs génétiques. Afin d’évaluer ces facteurs modificateurs, il est nécessaire de mettre au point des tests fonctionnels adaptés.L’activité des isoformes de p53 suggère qu’elles pourraient agir comme facteurs modificateurs du LFS. C’est pourquoi nous avons mis au point des techniques pour l’analyse des transcrits alternatifs, présentées dans la première partie de ces travaux de thèse. Si nos résultats ont montré que ces techniques n’étaient pas adaptées pour répondre à cette hypothèse, elles nous ont néanmoins permis d’identifier un nouveau transcrit physiologique, non décrit dans la littérature, augmenté chez une patiente porteuse d’une variation située sur le site accepteur d’épissage du dernier exon de TP53. Ce transcrit démontre l’existence d’un épissage alternatif du dernier exon de TP53 avec un exon terminal alternatif situé à plus de 2 kb en aval.Afin d’aider à la classification des variations de TP53, notre laboratoire évalue l’activité transcriptionnelle de p53 dans le contexte génétique du patient. Ce test ne permet donc pas de s’affranchir de l’influence potentielle des facteurs modificateurs génétiques individuels. C’est pourquoi, dans la deuxième partie de ces travaux de thèse, nous avons mis au point un modèle cellulaire de cellules souches pluripotentes induites humaines permettant d’étudier les variations de TP53 insérées par CRISPR-Cas9 dans un fond génétique commun. Ces travaux soulignent l’importance de l’expression de TP53, notamment pour l’étude des variations dont la pénétrance est moindre par rapport aux variations « hot-spot ». Par ailleurs, nous montrons que les variations en phase exercent un impact différentiel sur l’activité fonctionnelle de p53, selon le domaine protéique dans lequel elles se situent. L’avantage de notre modèle réside également sur son hétérozygotie pour PEX4 sur lequel nous avons pu insérer une seconde variation, ici le polymorphisme p.(Pro47Ser) inséré en trans d’une variation pathogène. Nos résultats soulignent l’importance du contexte génétique dans l’analyse des variations de TP53. L’ensemble de ces travaux de thèse mettent en lumière la nécessité d’étudier l’activité transcriptionnelle de p53 dans un contexte physiologique, sans surexpression, dans le but de mieux comprendre ce syndrome et d’optimiser la prise en charge des patients LFSLi-Fraumeni Syndrome (LFS) predisposes carriers of pathogenic TP53 variants to a wide spectrum of cancers throughout life. The phenotypic variability of LFS complicates patient management and can be partly attributed to the type of TP53 variant, as well as the influence of genetic modifier factors. To evaluate these modifier factors, it is essential to develop suitable functional tests.The activity of p53 isoforms suggests that they may act as modifier factors in LFS. Consequently, we developed assays for analyzing alternative transcripts, as presented in the first part of this work. While our results demonstrated that these assays were not well-suited to addressing this specific hypothesis, they nevertheless led us to the discovery of a novel physiological transcript not previously described in the literature. This transcript was found to be increased in a patient carrying a variant located at the splice acceptor site of TP53’s last exon, revealing an alternative splicing event involving TP53’s final exon and an alternative terminal exon located more than 2 kb downstream.To facilitate the classification of TP53 variants, our laboratory evaluates p53’s transcriptional activity in the patient’s specific genetic context. However, this approach does not allow us to fully disentangle the potential influence of individual genetic modifier factors. Therefore, in the second part of this work, we developed a human-induced pluripotent stem cell model to study TP53 variants introduced by CRISPR-Cas9 within a standardized genetic background. Our findings highlight the importance of physiological TP53 expression, particularly for studying variants with lower penetrance compared to "hot-spot" variants. Additionally, we show that in-frame variants exert differential impacts on p53’s functional activity, depending on the protein domain in which they are located. The advantage of our model also lies in its heterozygosity for PEX4, into which we were able to insert a second variant, in this case, the p.(Pro47Ser) polymorphism, inserted in trans with a pathogenic variant. Our results highlight the importance of the genetic context in the analysis of TP53 variants. This thesis work emphasizes the necessity of studying p53 transcriptional activity in a physiological context, without overexpression, with the aim of improving our understanding of this syndrome and optimizing the management of LFS patients
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Olson, Theodore. „Transcriptional Regulation of Neurogenic Atrophy-Induced Gene Expression by Muscle Ring Finger-1 and Myogenic Regulatory Factors“. UNF Digital Commons, 2014. http://digitalcommons.unf.edu/etd/495.
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Skeletal muscle wasting is a consequence of numerous physiological conditions, including denervation, corticosteroid treatment, immobilization, and aging. The E3 ubiquitin ligases, MuRF1 and MAFbx, are induced under nearly all atrophy conditions and are believed to play a key role in protein degradation in atrophying muscle. However, the preliminary data described in this study provides new evidence that MuRF1 may also act as a transcriptional modulator of atrophy-induced gene activity, including the regulation of MAFbx and MuRF1 expression. To characterize the transcriptional regulation of MuRF1 and MAFbx, reporter gene constructs containing fragments of the proximal promoter regions of these genes were developed, transfected into C2C12 cells with or without a MuRF1 expression plasmid and monitored for differences in reporter gene activity. The MuRF1 and MAFbx reporters each showed repressed activity in cells ectopically expressing MuRF1 compared to cells that did not overexpress MuRF1. Furthermore, ectopic expression of the myogenic regulatory factors (MRFs), MyoD1 and myogenin, caused significant activation of the MuRF1 and MAFbx reporter constructs. However, co-overexpression of MuRF1 with MyoD1 or myogenin resulted in reversal of MRF induction of reporter gene activity, and synergistic repression of a constructed E-box reporter system. To further characterize the role of the MuRF1 gene product in repression of MuRF1 expression, a MuRF1 RING domain mutant and a MuRF1 c-terminal mutant were created. The mutant constructs were then co-transfected along with MRF expression plasmids and the MuRF1 reporter construct into C2C12 cells and reporter gene activity was assessed. The MuRF1 RING mutant failed to reverse MRF activation of the reporter gene, while the c-terminal mutant successfully reversed activation of the reporter gene. These findings suggest that ubiquitin ligase activity is required for MuRF1 transcriptional regulatory effects. These data offer exciting evidence of a potential new function for MuRF1 as a transcriptional modulator of atrophy-induced changes in gene expression.
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Arnaud, Pauline. „Identification de nouveaux gènes et de facteurs de gravité dans les formes familiales d'anévrisme de l'aorte ascendante“. Thesis, Sorbonne Paris Cité, 2019. http://www.theses.fr/2019USPCC098.
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Les patients atteints de syndrome de Marfan (MFS) présentent une atteinte de plusieurs systèmes, dont les systèmes cardiovasculaire, ophtalmologique et squelettique. La variabilité clinique est importante, entre individus de familles différentes, et au sein d’une même famille. L’atteinte cardiovasculaire, avec un anévrisme de l’aorte ascendante (TAA), voire une dissection aortique, conditionne le pronostic vital des patients. Le MFS ainsi que les formes familiales de TAA se transmettent selon un mode autosomique dominant. Au moins 29 gènes ont été associés à l’apparition d’un TAA. Certains codent pour des protéines de la matrice extracellulaire comme la fibrilline-1. Sur le plan physiopathologique, la voie de signalisation TGF-β a également un rôle clé. Pour certaines familles, le défaut moléculaire impliqué n’a pas été identifié, mettant en évidence une part d’hérédité manquante. Par ailleurs, l’architecture génétique qui sous-tend la variabilité phénotypique est encore inconnue.Le premier objectif a été d’identifier de nouveaux gènes impliqués dans les formes familiales de TAA. Une stratégie de WES a été mise en place pour plusieurs familles et a permis l’identification d’un nouveau gène causal, le gène LOX. La contribution des différents gènes à des formes non syndromiques d’anévrisme de l’aorte ascendante a ensuite été évaluée.Le second objectif a été d’identifier des mécanismes et des facteurs génétiques associés à la gravité du MFS. Une étude ciblée sur le locus FBN1 a permis d’identifier des formes cliniques modérées liées à la présence de deux allèles hypomorphes. Il a également été constaté que certains patients étaient porteurs de deux variants situés dans deux gènes déjà connus pour être impliqués dans ces pathologies, illustrant un mécanisme de gravité lié à une double hétérozygotie. Par le croisement de plusieurs stratégies pangénomiques, il a été possible d’identifier 3 loci modificateurs majeurs ainsi que 6 loci modificateurs potentiels de l’atteinte cardiologique. Certains de ces loci étaient situés à proximité de gènes codant pour des protéines de la voie BMP, qui est proche de la voie TGF-β. Des différences significatives de l’expression des gènes SMAD1, SMAD6 et MEF2C ont été mises en évidence à partir de différentes lignées de CML d’aortes de patients présentant un MFS. Ceci illustre la mise en place de mécanismes de régulation de la voie BMP différents en fonction de la nature du variant pathogène initial. Enfin, par un croisement de données expérimentales humaines et murines, nous avons montré que des voies communes de signalisation associées à la contractilité musculaire étaient dérégulées dans le MFS, identifiant une cible thérapeutique potentielle, le baclofènePatients who present a Marfan syndrome (MFS) have different clinical features, affecting several systems, including the cardiovascular, the ocular and the skeletal systems. The phenotypic variability is high, between individuals from different families, and within families. Cardiovascular features, that is to say Thoracic Aortic Aneurysm (TAA), and aortic dissection, are life-threatening. MFS and familial forms of TAA are transmitted as autosomal dominant diseases. At least 29 genes have already been associated with TAA. Some of them encode extracellular matrix proteins, such as the fibrillin-1. TGF-βsignaling also has a key role in the physiopathology of these diseases. For some families, the causal molecular defect had not been identified, highlighting a part of missing heritability. Furthermore, the genetic architecture underlying the phenotypic variability is still unknown. The first objective was to identify new disease causing genes in familial forms of TAA. A WES strategy was applied to several families, leading to the identification of a new disease causing gene, the LOXgene. The contribution of the different genes to non syndromic forms of TAA was then evaluated.The second objective was to identify mechanisms and genetic factors that explain MFS severity. A study was focused on the FBN1 locus and lead to the identification of moderate forms associated to two hypomorphic alleles. We also noticed that some patients have two variants in two known disease causing genes, underlying a mechanism of severity linked to a double heterozygosity.Through the crossmapping of different genomic strategies, it was possible to identify 3 major modifiers loci and 6 putative modifiers loci. Some of them were located near genes encoding proteins involved in the BMP pathway, which is close to the TGF-β pathway. Significant differences in the expression of SMAD1, SMAD6 and MEF2C genes were observed in different aortic smooth muscle celllines from MFS patients. This highlight new regulation processes in the BMP pathway depending onthe type of the initial pathogenic variant. Finally, comparing human and murine experimental data, we found that common signaling pathways associated with muscle cell contractility are down regulated in MFS, identifying a new potential therapeutic target, the baclofen
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Fruchon, Séverine. „Modulation de la surcharge en fer dans un modèle murin d'hémochromatose : mise en évidence de facteurs génétiques et études d'expression génique“. Toulouse 3, 2004. http://www.theses.fr/2004TOU30274.
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L'hémochromatose génétique de type 1 est caractérisée par une surcharge en fer dans les organes parenchymateux. Elle est provoquée par une mutation ponctuelle (C282Y) du gène HFE, très fréquente dans les populations originaires du nord ouest de l'Europe. Des études épidémiologiques récentes mettent en évidence une pénétrance incomplète et une variabilité de l'expressivité de la maladie. Ceci peut s'expliquer par l'action de facteurs non génétiques (âge, alimentation, dons de sang réguliers. . . ) et génétiques. Pour étudier l'action de ces derniers dans l'intensité de la surcharge hépatique, nous avons utilisé un modèle murin d'hémochromatose : les souris Hfe-/-. L'étude comparative de 4 souches de souris consanguines (C57BL/6, CBA, DBA/2 et 129/Sv) a montré des différences de régulation du métabolisme du fer selon les souches. L'analyse de souris Hfe-/- sous deux fonds génétiques distincts (C57BL/6 et DBA/2) a révélé que l'intensité de la surcharge en fer varie en fonction de la souche et fait intervenir d'autres gènes qui modulent l'action de HFE. Nous avons démontré que les souris Hfe-/- des deux fonds génétiques varient, non seulement par l'intensité de la surcharge mais aussi par les régulations transcriptionnelles mises en jeu dans le duodénum. Par une approche de criblage du génome, nous avons identifié quatre régions chromosomiques avec un lod score significatif d'une liaison génétique. Enfin, le niveau hépatique d'expression des ARNm de diverses molécules dont l'hepcidine a été dosé chez des souris Hfe-/- de deux souches (C57BL/6 et DBA/2). Bien que nous n'ayons pas mis en évidence de différence significative de l'expression de l'ARNm de l'hepcidine 1 entre les souris Hfe+/+ et Hfe-/-, nos résultats révèlent que l'expression des ARNm de l'hepcidine 1 et 2 varie selon la souche de sourisType 1 genetic hemochromatosis is characterised by an iron overload in parenchyme organs. A mutation (C282Y) in the HFE gene is the cause of the disease which is very frequent in the populations of North West Europe origins. Recent epidemiological studies revealed an incomplete penetrance and a variable expression of the disease. Involvement of non genetic factors (age, nutrition, regular blood donations. . . ) and of genetic factors can explain this picture. To characterise the role of the genetic factors in hepatic iron loading, we have used the Hfe-/- mouse as a murine model of hereditary hemochromatosis. The comparative study of 4 consanguineous mouse strains (DBA/2, C57BL/6, CBA and 129/Sv) showed differences in the regulation of iron metabolism between strains. Hfe-/- mice with two different genetic backgrounds (C57BL/6 and DBA/2) showed differences on iron overload levels which are controlled by other genes modulating HFE gene. We showed that in these two Hfe-/- strains, the iron overload levels and the transcriptional regulations in duodenum are different. Screening the whole genome, four chromosomic regions with a significant LOD score of genetic linkage were identified. The mRNA expression was quantified for hepcidin and other molecules among the two strains of Hfe-/- mice. Though there was no significant differences in hepcidin 1 mRNA levels between the Hfe-/- and Hfe+/+ mice, our results showed that there was higher mRNA expression for hepcidin 1 than for hepcidin 2 in C57BL/6 mice and the opposite was observed in DBA/2 mice
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Winbo, Annika. „Long QT syndrome in Sweden : founder effects and associated cardiac phenotypes“. Doctoral thesis, Umeå universitet, Pediatrik, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-57724.
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Background: We aimed to increase the knowledge regarding the familial arrhythmogenic disorder Long QT Syndrome (LQTS) and its recessive variant Jervell and Lange-Nielsen Syndrome (JLNS) in Sweden, including prevalences and clinical phenotypes. A specific focus was directed towards two KCNQ1 mutations –p.Y111C and p.R518X- commonly identified in Swedish LQTS index cases. Methods: Cases and families with LQTS (p.Y111C or p.R518X) and JLNS were recruited via regional clinical practices, national referrals to the Clinical Genetics laboratory, Umeå University Hospital, and a national inventory. Molecular genetics methods were used for case ascertainment. Clinical data was obtained via medical records, a questionnaire, and/or an interview. Electrocardiograms were manually assessed. In p.R518X heterozygotes intra-familial phenotypic variability (QTc and cardiac events) was assessed by analysis of sequence variants (modifier genes). The origins of the mutations p.Y111C and p.R518X were investigated using genealogical and haplotype analysis (microsatellite markers). In families sharing a common haplotype mutation age and associated prevalence was analyzed using ESTIAGE and DMLE computer software. Results: We identified p.Y111C (170 mutation-carriers) and p.R518X (101 mutation-carriers) as two major causes of LQTS/JLNS in Sweden. LQTS phenotype was revealed to be relatively benign in p.Y111C and p.R518X (annual incidence of life-threatening cardiac events, before therapy 0.05% and 0.04%, respectively). Gender-specific effects of genetic modifiers on phenotypic expression were seen. A founder origin, approximately 600-700 years ago in two northern river valleys was established for p.Y111C and p.R518X, and a high prevalence of LQTS founder descendants suggested. A minimum JLNS prevalence of 1:200 000 in preadolescent Swedish children was revealed. JLNS phenotype was mainly severe, with a cumulative incidence of life-threatening cardiac events of 53% (annual incidence rate before therapy 5%) and four sudden deaths. Possible founder effects regarding four KCNQ1 mutations; p.Y111C (8%), p.R518X (50%), c.572_576del (17%) and p.Q530X (8%) together explained 83% of the JLNS mutation-spectrum in Sweden, consisting of 8 KCNQ1 mutations. Conclusion: The high prevalence of p.Y111C- and p.R518X-related LQTS as well as JLNS revealed in Sweden could be explained by the combination of mild clinical phenotypes in heterozygotes and strong founder effects present during the population development of northern Sweden. Increased knowledge regarding the occurrence of LQTS and JLNS as well as mutation- and/or genotype-specific data constitute prerequisites for possible improvement of patient management.
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„Transgenic expression of human granulocyte colony-stimulating factor in rice“. 2005. http://library.cuhk.edu.hk/record=b5892380.
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by Ng Wing Man.Thesis (M.Phil.)--Chinese University of Hong Kong, 2005.
Includes bibliographical references (leaves 156-174).
Abstracts in English and Chinese.
Acknowledgements --- p.iii
Abstract --- p.v
摘要 --- p.vii
Table of Contents --- p.ix
List of Figures --- p.xiii
List of Tables --- p.xvi
List of Graphs --- p.xvii
List of Abbreviations --- p.xviii
Chapter Chapter 1 --- General Introduction --- p.1
Chapter Chapter 2 --- Literature Review --- p.3
Chapter 2.1 --- Human granulocyte colony-stimulating factor (hG-CSF) --- p.3
Chapter 2.1.1 --- Historical background --- p.3
Chapter 2.1.2 --- Physiological Roles --- p.5
Chapter 2.1.3 --- Molecular properties --- p.8
Chapter 2.1.4 --- Biochemical properties --- p.9
Chapter 2.1.5 --- Comparison to G-CSF of other species --- p.11
Chapter 2.1.6 --- Biological Activities --- p.12
Chapter 2.1.7 --- Clinical Applications --- p.14
Chapter 2.1.7.1 --- Clinical use in myelosuppressive chemotherapy and neutropenic fever --- p.14
Chapter 2.1.7.2 --- Clinical use in bone marrow transplantation (BMT) and peripheral blood progenitor cell (PBPC) transplantation --- p.14
Chapter 2.1.7.3 --- Clinical use in HIV infection --- p.16
Chapter 2.1.7.4 --- Clinical use in diabetes mellitus --- p.17
Chapter 2.1.7.5 --- Clinical use in severe chronic neutropenia --- p.18
Chapter 2.1.7.6 --- Future prospects --- p.18
Chapter 2.1.7.7 --- Dosages and adverse effects --- p.19
Chapter 2.1.8 --- Economic value --- p.20
Chapter 2.2 --- Plant as bioractor --- p.20
Chapter 2.2.1 --- Medical molecular farming --- p.20
Chapter 2.2.2 --- Commercial biopharmaceutical proteins --- p.25
Chapter 2.2.3 --- Transgenic plants producing hematopoietic growth factors --- p.25
Chapter 2.2.3.1 --- Granulocyte-macrophage colony-stimulating factor (GM-CSF) --- p.26
Chapter 2.2.3.2 --- Interleukin-2 (IL-2) --- p.28
Chapter 2.3 --- Rice as expression system --- p.29
Chapter 2.3.1 --- Characteristics --- p.29
Chapter 2.3.2 --- Advantages of using rice as bioreactor --- p.30
Chapter 2.3.3 --- Previous studies --- p.31
Chapter 2.3.4 --- Transformation method --- p.33
Chapter 2.3.5 --- Super-binary vector --- p.34
Chapter 2.4 --- Strategies for enhancing protein expression level --- p.36
Chapter 2.4.1 --- Vacuolar targeting --- p.36
Chapter 2.4.1.1 --- Protein targeting signals --- p.38
Chapter 2.4.1.2 --- Binding protein of 80kDa (BP-80) --- p.39
Chapter 2.4.1.3 --- a-Tonoplast intrinsic protein (α-TIP) --- p.39
Chapter 2.4.1.4 --- Receptor homology region-transmembrane domain-Ring H2 motif (RMR) --- p.40
Chapter 2.4.2 --- Fusion with glutelin in rice --- p.41
Chapter 2.5 --- Hypotheses and aims of this study --- p.43
Chapter Chapter 3 --- Materials and Methods --- p.45
Chapter 3.1 --- Introduction --- p.45
Chapter 3.2 --- Chemicals --- p.45
Chapter 3.3 --- Bacterial strains --- p.46
Chapter 3.4 --- Chimeric genes construction --- p.46
Chapter 3.4.1 --- Protein targeting constructs --- p.51
Chapter 3.4.2 --- Enterokinase site constructs --- p.60
Chapter 3.4.3 --- Glutein signal peptide constructs --- p.65
Chapter 3.4.4 --- Glutelin fusion constructs --- p.70
Chapter 3.4.5 --- Sequence fidelity of chimeric genes --- p.77
Chapter 3.4.6 --- Cloning of chimeric genes into rice super-binary vector --- p.77
Chapter 3.5 --- Rice transformation --- p.79
Chapter 3.5.1 --- Plant materials --- p.79
Chapter 3.5.2 --- Agrobacterium transformation --- p.79
Chapter 3.5.3 --- A grobacterium-mediated transformation of rice --- p.79
Chapter 3.6 --- Transgenic expression --- p.81
Chapter 3.6.1 --- Extraction of leaf genomic DNA --- p.81
Chapter 3.6.2 --- Synthesis of DIG-labeled double-stranded DNA probe --- p.82
Chapter 3.6.3 --- Southern blot analysis --- p.83
Chapter 3.6.4 --- Extraction of total RNA from immature rice seeds --- p.84
Chapter 3.6.5 --- Northern blot analysis --- p.85
Chapter 3.6.6 --- Protein extraction --- p.86
Chapter 3.6.7 --- Tricine SDS-PAGE --- p.86
Chapter 3.6.8 --- Western blot analysis --- p.87
Chapter 3.6.9 --- Enterokinase digestion of EK fusion proteins --- p.88
Chapter 3.7 --- Confocal immunoflorescence studies of rhG-CSF in rice grain --- p.89
Chapter 3.7.1 --- Preparation of sample sections --- p.89
Chapter 3.7.2 --- Double-labeling of fluorescence probes --- p.89
Chapter 3.7.3 --- Image collection --- p.90
Chapter 3.8 --- Functional analysis of rhG-CSF --- p.91
Chapter 3.8.1 --- Culture of NFS-60 cells --- p.91
Chapter 3.8.2 --- MTT cell proliferation assay --- p.92
Chapter 3.9 --- Bacterial expression of anti-hG-CSF --- p.93
Chapter 3.9.1 --- pET expression in E. coli --- p.93
Chapter 3.9.2 --- Purification of His-hG-CSF --- p.97
Chapter 3.9.3 --- Immunization of rabbits --- p.97
Chapter Chapter 4 --- Results --- p.99
Chapter 4.1 --- Construction of chimeric genes for rice transformation --- p.99
Chapter 4.2 --- "Rice transformation, selection and regeneration" --- p.103
Chapter 4.3 --- Southern blot analysis --- p.105
Chapter 4.4 --- Northern blot analysis --- p.109
Chapter 4.5 --- Western blot analysis --- p.114
Chapter 4.6 --- Enterokinase digestion of EK fusion proteins --- p.125
Chapter 4.7 --- Confocal immunofluorescence studies of rhG-CSF in transgenic rice grain --- p.128
Chapter 4.8 --- Functional analysis of rhG-CSF --- p.132
Chapter 4.9 --- Bacterial expression of anti-hG-CSF --- p.135
Chapter 4.9.1 --- Expression and purification of recombinant His-hG-CSF in E. coli --- p.135
Chapter 4.9.2 --- Titer and specificity of the anti-serum --- p.137
Chapter Chapter 5 --- Discussion --- p.139
Chapter 5.1 --- Introduction --- p.139
Chapter 5.2 --- Fusion of hG-CSF with protein sorting determinants --- p.141
Chapter 5.3 --- Fusion of hG-CSF with rice glutelin --- p.145
Chapter 5.4 --- Glutelin signal peptide --- p.146
Chapter 5.5 --- O-glycosylation --- p.148
Chapter 5.6 --- Enterokinase digestion --- p.148
Chapter 5.7 --- Expression level of rhG-CSF --- p.149
Chapter 5.8 --- Functional analysis of rhG-CSF --- p.151
Chapter 5.9 --- Future perspectives --- p.151
Chapter Chapter 6 --- Conclusion --- p.155
References --- p.156
Bücher zum Thema "Genetic modifier factors"
1
Leo n, Rosa, Ph. D., Galva n. Aurora und Ferna ndez Emilio, Hrsg. Transgenic microalgae as green cell factories. New York, N.Y: Springer Science+Business Media/Landes Bioscience, 2007.
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2
Eithan, Galun, Hrsg. The manufacture of medical and health products by transgenic plants. London: Imperial College Press, 2001.
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3
Plant transcription factors: Methods and protocols. New York: Humana, 2011.
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4
Transgenic Microalgae As Green Cell Factories. Springer London, Limited, 2008.
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5
Transgenic Microalgae as Green Cell Factories. Springer, 2014.
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6
LeVine III, Harry. Genetic Engineering. 2. Aufl. ABC-CLIO, 2006. http://dx.doi.org/10.5040/9798400656170.
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From Dolly the sheep to Frankenfood, life-saving medicines, and beyond, this insightful work describes the technology and controversy behind genetic engineering. From the publication of Aldous Huxley'sBrave New Worldin 1932 to the cloning of Dolly the sheep in 1996, the public has long been fascinated by the idea that humans may one day be able to mold or even create life. In less than 30 years, genetic engineering has itself mutated from science fiction to science fact. Supporters claim such innovations as genetically modified crops and gene therapy are poised to bring unparalleled benefits by eliminating hunger and hereditary disease, whereas critics warn the dream could easily become a nightmare. Packed with key facts and analysis,Genetic Engineering: A Reference Handbook, Second Editionprovides an expert guide to the very latest discoveries in genetic engineering and genetic modification and the technology's complex ethical, scientific, and economic implications.
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Yang, Jin, Pei Han, Wei Li und Ching-Pin Chang. Epigenetics and post-transcriptional regulation of cardiovascular development. Herausgegeben von José Maria Pérez-Pomares, Robert G. Kelly, Maurice van den Hoff, José Luis de la Pompa, David Sedmera, Cristina Basso und Deborah Henderson. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198757269.003.0032.
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Cardiac organogenesis requires the control of gene expression at distinct developmental windows in order to organize morphogenetic steps in the correct sequence for heart development. This is facilitated by concerted regulation at three levels: chromatin, transcription, and post-transcriptional modifications. Epigenetic regulation at the chromatin level changes the chromatin scaffold of DNA to regulate accessibility of the DNA sequence to transcription factors for genetic activation or repression. At the genome, long non-coding RNAs work with epigenetic factors to alter the chromatin scaffold or form DNA-RNA complexes at specific genomic loci to control the transcription of genetic information. After RNA transcription, the expression of genetic information can be further modified by microRNAs. Each layer of gene regulation requires the participation of many factors, with their combinatorial interactions providing variations of genetic expression at distinct pathophysiological phases of the heart. The major functions of chromatin remodellers and non-coding RNAs are discussed.
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Biopharmaceuticals in plants: Toward the next century of medicine. Boca Raton: Taylor & Francis, 2010.
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9
Kwabi-Addo, Bernard, und Tia Laura Lindstrom. Cancer Causes and Controversies. ABC-CLIO, LLC, 2011. http://dx.doi.org/10.5040/9798400623189.
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This book offers clear, accessible information on the causes of cancer and the multiple ways people can reduce their risk for this insidious disease. Like no other work, this much-needed volume gathers the latest research and understanding about the causes of cancer and methods of preventing the disease—and makes it all clear and accessible to the general reader. Cancer Causes and Controversies: Understanding Risk Reduction and Prevention describes common risk factors associated with particular types of cancer, including genetic predisposition, radiation and chemical carcinogens, diet, hormonal factors, infection, and smoking. The book then looks at the scientific evidence supporting the positive role of healthy nutrition, exercise, and diet in lowering cancer risk, as well as the dangers posed by a dysfunctional immune system compromised by chronic infection, unhealthy lifestyles, stress, and poor psychological health. Finally, the book provides an unbiased assessment of a number of controversies surrounding cancer causes and prevention, including screening and genetic testing, vitamin supplementation, genetically modified foods, chemical food additives, and cellular phones and deodorants as potential cancer-causing agents.
Buchteile zum Thema "Genetic modifier factors"
1
Spittau, Björn, Eleni Roussa, Klaus Unsicker und Kerstin Krieglstein. „Transforming Growth Factor-Beta Superfamily: Animal Models for Development and Disease“. In Genetically Modified Organisms and Genetic Engineering in Research and Therapy, 39–49. Basel: S. KARGER AG, 2012. http://dx.doi.org/10.1159/000339188.
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2
Glatt, Stephen J., Stephen V. Faraone und Ming T. Tsuang. „How Does the Environment Influence Schizophrenia?“ In Schizophrenia. Oxford University Press, 2019. http://dx.doi.org/10.1093/oso/9780198813774.003.0012.
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Although there is very strong evidence for a genetic piece to schizophrenia, the lack of full concordance between identical twins shows that the environment also plays a role. We define an ‘environmental risk factor’ as any event that is not due to genes, specifically the individual differences in the DNA sequence.These events may be biological (e.g., head injuries, viral infections), psychological (e.g., disrupted family relationships), or social (e.g., poverty).Over the past few decades, scientists have found evidence for environmental risk factors in at least some cases of schizophrenia. Before reviewing this research, we must make an important distinction: some environmental factors may cause or contribute to schizophrenia while others modify or change the illness in someone who is already sick. In this book we use the term ‘cause’ to refer to any factor that can produce the illness or increase the chance of illness in someone who has not yet been affected by schizophrenia. This cause does not have to be either necessary or sufficient. This means that other causes may exist that also produce the illness, and that any given cause may need to interact with other causes for the disorder to occur. We use the term ‘modifier’ to refer to anything that changes the symptoms of the illness in someone who is already affected. As we discuss in a later chapter, knowing modifiers can help with the treatment of the disorder. However, they should not be confused with causes.Scientists who study schizophrenia and other psychiatric disorders have long ago abandoned the ‘nature–nurture’ controversy. In the past, many philosophers and scientists had taken one of two extreme positions. Some believed that psychiatric illness was only caused by innate or genetic factors; others felt that mental illness was the sole product of adverse environmental events. Today, we know that the question ‘genes or environment?’ is too simplistic. As Dr Paul Meehl realized several decades ago, the better question is much more complex: ‘What group of environmental risk factors work together with which genes to produce schizophrenia?’Before discussing specific environmental risk factors that may cause schizophrenia we should clarify why we believe that the study of such factors is essential.
3
Rozen, Rima. „Genetic Risk Factors for Neural Tube Defects: Variants in Folate Metabolism“. In Neural Tube Defects, 176–84. Oxford University PressNew York, NY, 2005. http://dx.doi.org/10.1093/oso/9780195166033.003.0015.
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Abstract Neural tube defects (NTDs) are multifactorial disorders that are influenced by genetic and nongenetic factors. Inadequate dietary folate has been recognized for some time as an important nongenetic contributor to the risk for NTD. In contrast, the identification of genetic factors that alter NTD risk is a relatively newer area of investigation. One sequence change, at bp 677 in the gene encoding a folate-metabolizing enzyme, methylenetetrahydrofolate reductase (MTHFR), has emerged as the first genetic risk factor for NTD. However, the expectation for complex traits is that combinations of genetic polymorphisms and environmental modifiers will influence the disease risk; a polymorphism is a mutation (base change or sequence variant) with a prevalence >1%. Consequently, other variants in MTHFR and sequence changes in other genes involved in folate metabolism are being explored as possible genetic risk factors for NTD, but additional data are required for these candidates before their role can be confirmed. This chapter will present an overview of folate metabolism, discuss the findings on MTHFR as a risk factor for NTD, and summarize the information on some of the other candidate genes in folate metabolism that have been investigated as potential risk factors.
4
Shore, Angela C. „Pathogenesis of microvascular disease“. In Oxford Textbook of Endocrinology and Diabetes, 1920–24. Oxford University Press, 2011. http://dx.doi.org/10.1093/med/9780199235292.003.1506.
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Disturbed microvascular function precedes clinically apparent microvascular complications. Complications are not confined to the eye and the kidney; they occur in many tissues, e.g. the heart and brain. Microvascular complications are the result of the combined effects of hyperglycaemia and haemodynamic factors on cells, modulated by genetic predisposition (Fig. 13.5.1.1). The intracellular pathway involved varies with the stage (i.e. whether in the initiation or progressive phase) and organ (kidney, eye), and may be modified by treatment. This chapter describes the generic factors involved in the pathogenesis of microvascular complications. Further details are available in recent reviews (1–10).
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Taylor, Kathleen. „4. Risk factors“. In Dementia: A Very Short Introduction, 74–104. Oxford University Press, 2020. http://dx.doi.org/10.1093/actrade/9780198825784.003.0004.
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Would everyone get dementia if we lived long enough? ‘Risk factors’ focuses on the genetic, environmental, and physiological factors that makes dementia more or less likely to affect us. The media often distorts scientific findings with false correlations. We must be aware of these ourselves, particularly in relation to cause and effect; a factor that we may see as a cause of dementia might be a symptom. Risk factors include age, overall poor physical and mental health, blood sugar, blood and brain function, inflammation, and not using the brain. Many of these can be modified, even the effects of ageing, but there is no single cause or one-size-fits-all solution.
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Panja, Amrita, Brahmarshi Das, Tuphan Kanti Dolai und Sujata Maiti Choudhury. „The Key Genetic Determinants Behind the Phenotypic Heterogeneity of HbE/β-thalassemia Patients and the Probable Management Strategy“. In Thalassemia Syndromes - New Insights and Transfusion Modalities [Working Title]. IntechOpen, 2023. http://dx.doi.org/10.5772/intechopen.109999.
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HbE/β-thalassemia is the most common severe form of thalassemia which is very prominent in South East Asian countries. It is responsible for nearly one-half of all the severe types of β-thalassemia all over the world. It is also known to represent a wide range of phenotypic diversity which varies from asymptomatic to transfusion-dependent severe phenotype. The most important predictive factor is mutations within the beta-globin gene (HBB). Apart from the primary genetic modifiers, there are certain other determinants regulating the phenotypic heterogeneity including, co-inheritance of alpha thalassemia mutations and other secondary modifiers including Xmn1 polymorphism, HBS1L-MYB, GATA-1, BCL11A polymorphism, and presence of HPFH mutations. Although the degree of severity is also determined by other tertiary genetic modifiers like increase in serum erythropoietin due to anemia, previous infection with malaria, environmental factors, splenectomy, etc. This review aimed to reveal the potential genetic predictors of HbE/β-thalassemia patients and the probable management strategy. This also enhances the generation of “personalized medicine” for better patient care. The instability of clinical phenotype and remarkable variation indicate careful monitoring of treatment for each patient and the therapeutic approaches should be monitored over time.
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Velankar, Radhika, Gauri Nerkar, Mukta Nagpurkar und Kiran Jagtap. „Genetically Modified Crops: A Pivotal Endeavor in Biotechnology“. In Genetically Modified Organisms [Working Title]. IntechOpen, 2024. http://dx.doi.org/10.5772/intechopen.1005578.
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Transgenic technology has significantly contributed to the genetic improvement of crop plants by improving important agronomic traits like insect/pest resistance, disease resistance, herbicide tolerance, abiotic stress tolerance, and quality improvement. Conventional breeding programs are time consuming and laborious involving screening thousands of progenies for the development of a new hybrid variety. Genetic engineering is a precise tool to develop a new variety in a short duration. Genetically Modified Crops have been used for expression of recombinant proteins of high therapeutic value, monoclonal antibodies, nutraceuticals, edible vaccines, and improved saccharification efficiency of biofuel crops for bioethanol production. The agricultural productivity is limited by global climate changes and unfavorable abiotic and biotic factors posing challenges for crop scientists to meet the rising demand for global food supply. Developing climate-resilient crops will bring more land under agriculture and more vegetation for carbon sequestration thereby annulling global warming. This chapter provides an insight into the principles, advantages, and limitations of the methods used in genetic transformation and the advancements in genome editing, agronomic traits improved in Genetically Modified Crops, potential applications of transgenic technology in biopharming and bioethanol production, biosafety and regulation of transgenic crops, and the challenges in the development of Genetically Modified Crops.
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„Genetic Principles“. In DNA Fingerprinting, herausgegeben von Lorne t. Kirby. Oxford University Press, 1993. http://dx.doi.org/10.1093/oso/9780716770015.003.0005.
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Genetics is the study of heredity. Each individual’s makeup, or phenotype, is determined by nature and modified by environmental factors. DNA identity analysis is based strictly on heredity, and only in the rare case where a human had a bone marrow transplant would the white blood cell genotype differ from that inherited. Difficulties can arise with specimens because of DNA degradation or contamination by extraneous materials, and mixed cell populations could be present in tumorous tissue. The analyst must always be cognizant of these complicating factors. The concept of the gene was advanced by the Moravian monk Gregor Mendel in 1865 based on observations he made after crossing different varieties of garden peas; these experiments are considered the beginning of the discipline of genetics. (The term gene was actually coined by the Danish plant scientist W. Johannsen in the early 1900s.) Mendel formulated two laws. The law of segregation or separation states that two members of each gene pair (alleles) in a diploid organism separate to different gametes during sex cell formation. The law of independent assortment states that members of different pairs of alleles, if located on separate chromosomes or far apart on the same homologous chromosome pair, assort independently into gametes. These laws are basic to the understanding of biological family relationships and play a critical role in such contemporary issues as paternity testing and immigration disputes. The basic unit of life is the cell. Cells are microfactories in which raw materials (amino acids, simple carbohydrates, lipids, and trace elements) are received, new substances (proteins, complex lipids, carbohydrates, and nucleic acids) are produced, and wastes are removed. The thousands of different enzymes required for the myriad ongoing chemical reactions are key to the efficient functioning of cells. Each cell has the ability to self-replicate using the deoxyribonucleic acid (DNA) code as the blueprint, raw materials as building blocks, and enzymes as catalysts. It has been estimated that the average human being is composed of approximately 100 trillion cells—a considerable amount of DNA.
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Thomas, Alison. „Further Mendelian Principles“. In Thrive in Genetics. Oxford University Press, 2013. http://dx.doi.org/10.1093/hesc/9780199694624.003.0003.
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This chapter investigates modified Mendelian inheritance patterns, which indicate various genetic interactions and influencing factors. Genes and their alleles are always inherited according to Mendelian principles, but the phenotypic expression of a trait does not always follow simple Mendelian patterns. Different phenotypic ratios occur among F2 progeny in Mendelian breeding experiments when alleles are incomplete or co-dominant, epistatic interactions occur between genes, and an allele is located on a sex chromosome or organelle chromosome. There may be more than two alleles possible at a given locus. The chapter then looks at multiple alleles, lethal alleles, sex-linked traits, extrachromosomal inheritance, epistasis, and pedigree analysis.
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Chen, Qiang. „Plants as Factories for the Production of Protein Biologics“. In Plants, Genes & Agriculture. Oxford University Press, 2017. http://dx.doi.org/10.1093/hesc/9781605356846.003.0022.
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This chapter examines plants as factories for the production of protein biologics. Plants have been used as a source of natural pharmaceuticals for a long time, and still provide a quarter of all prescription pharmaceuticals. They are not used as a source of protein pharmaceuticals, but can be modified to produce protein-based biologics. Genes for biologics can be delivered into plant cells either directly by particle bombardment with a gene gun or indirectly through infection with modified plant viruses or Agrobacterium-mediated transformation of the nuclear genome. The chapter then looks at agroinfiltration, new vectors for gene delivery, and how a plant-manufactured biologic has been approved to treat a genetic disease in humans.
Konferenzberichte zum Thema "Genetic modifier factors"
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Steffens Henrique, Alisson, Ricardo Martins Brasil Soares, Rudimar Luis Scaranto Dazzi und Rodrigo Lyra. „Genetic Algorithm in Survival Shooter Games NPCs“. In Computer on the Beach. Itajaí: Universidade do Vale do Itajaí, 2020. http://dx.doi.org/10.14210/cotb.v11n1.p413-418.
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Games must engage players by keeping them in the game flow. Tobetter define the game difficulty according to the player, GeneticAlgorithms can be used. One of the interesting characteristics ofGenetic Algorithm is that it is a non-deterministic algorithm. For theplayer’s vision, it means that enemies are unpredictable. By notknowing which NPCs he will face, the gameplay turns moreinteresting. Another amusing factor for gaming is its adaptability,causing NPCs to slowly struggle to find a way to beat the player. Thesetwo characteristics make Genetic Algorithms good tools to makegames more entertaining. This paper aims to demonstrate thisadaptation capability in the Survival Shooter, developed by Unityenterprise and modified by the author for the algorithmimplementation. As result, it shows that players could stay in the gameflow while playing against genetically modified enemies.
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Einolander, Jarno, und Hannu Vanharanta. „Degree of Commitment Among Students at a Technological University – Testing a New Research Instrument“. In Applied Human Factors and Ergonomics Conference. AHFE International, 2020. http://dx.doi.org/10.54941/ahfe100379.
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Just as commitment in organizations is very important for long-term success, commitment to one’s educational institute is important, too. Higher education provides the foundation for the social, economic and political growth of a country. Therefore, improving student retention by successfully delivering quality education, leading to student graduation and integration in the workforce, is crucial. It has been argued that students stay in their higher education institutes for similar reasons to those that make employees committed and engaged in organizations.In our previous studies we have created a literature-based generic model of organizational commitment and engagement that could be used in conjunction with an Internet-based application to evaluate their various components and primary correlate constructs. In this study we took this evaluation model to the context of a higher educational institute to try to evaluate students’ commitment to their university.As a result, we identified several development needs in order to evaluate students’ commitment with our application. Because the statements in our original instrument were aimed for use in the organizational domain, some of them were not suited to studies on commitment in an educational institute. Looking at the results of our study, we decided that the overall construct of our model and the wording of applicable statements should be modified in order to create an appropriate instrument for use in an academic institution. This was done based on Bean’s Student Attrition Model. However, collective analysis of the test results clearly identified that even with the preliminary model it is possible to find where students see the needs for greatest development and how they view their current state of engagement.
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Nagy, D. A., Lawrence J. Shadle, Rob Hovsapian, Manish Mohanpurkar und D. Tucker. „A New Method for Valuing Nontraditional Stakeholder Parameters in Novel Power Systems Analysis“. In ASME Power Applied R&D 2023. American Society of Mechanical Engineers, 2023. http://dx.doi.org/10.1115/power2023-108956.
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Abstract Unregulated electricity markets have shifted to a five minute time period. Generation asset (GA) valuation calculations do not take these changes and several emerging factors into account when valuing electricity GAs. A dynamic Levelized Cost of Electricity (d-LCOE) was developed to accommodate the dynamics of the electrical power markets. In addition, traditional multi-objective optimization methods have been modified to include nontraditional stakeholder parameters in valuing a project, both from a parametric sensitivity and constraint point of view. Factors are integrated into a traditional LCOE to include inputs from stakeholders such that the application of the model can be geographically accommodated and technology agnostic [12]. By aggregating factors into costs and revenues, a generic valuation framework is posed to compare different technologies in situations where nontraditional inputs can be considered by decisionmakers for financing novel power generation.
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Santhanam, Sridhar. „A Method to Extract Interface Stress Intensity Factors Using Interlayers“. In ASME 2005 International Mechanical Engineering Congress and Exposition. ASMEDC, 2005. http://dx.doi.org/10.1115/imece2005-79651.
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A method is presented here to extract stress intensity factors for interface cracks in plane bimaterial fracture problems. The method relies on considering a companion problem wherein a very thin elastic interlayer is artificially inserted between the two material regions of the original bimaterial problem. The crack in the companion problem is located in the middle of the interlayer with its tip located within the homogeneous interlayer material. When the thickness of the interlayer is small compared with the other length scales of the problem, a universal relation can be established between the actual interface stress intensity factors at the crack tip for the original problem and the mode I and II stress intensity factors associated with the companion problem. The universal relation is determined by formulating and solving a boundary value problem. This universal relation now allows the determination of the stress intensity factors for a generic plane interface crack problem as follows. For a given interface crack problem, the companion problem is formulated and solved using the finite element method. Mode I and II stress intensity factors are obtained using the modified virtual crack closure method. The universal relation is next used to obtain the corresponding interface stress intensity factors for the original interface crack problem. An example problem involving a finite interface crack between two semi-infinite blocks is considered for which analytical solutions exist. It is shown that the method described above provides very acceptable results.
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Bárcena Pasamontes, Lucía, Fernando Gómez Torres, Daniel Zwick, Sebastian Schafhirt und Michael Muskulus. „Support Structure Optimization for Offshore Wind Turbines With a Genetic Algorithm“. In ASME 2014 33rd International Conference on Ocean, Offshore and Arctic Engineering. American Society of Mechanical Engineers, 2014. http://dx.doi.org/10.1115/omae2014-24252.
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This study considers the use of a genetic algorithm for the structural design optimization of support structures for offshore wind turbines. Member diameters, thicknesses and locations of nodes are jointly optimized. Analysis of each design is performed with a complete wind turbine simulation, for a load case in the time domain. Structural assessment is in terms of fatigue damage, evaluated for each joint using the hot-spot stress approach. This defines performance constraints. Designs are optimized with respect to their weight. The approach has been tested with the modified 4-legged UpWind jacket from the OC4 project. The weight is quickly reduced, convergence slows after about 100 iterations, and few changes occur after 250 iterations. Interestingly, the fatigue constraint is not active for any member, and it is the validity of stress concentration factors that determines the best design, which utilizes less than 90 percent of the available fatigue lifetime. These results of the preliminary study using the genetic algorithm demonstrate that automatic optimization of wind turbine support structures is feasible under consideration of the simplified load approach. Even for complex, multi-member structures such as the considered jacket a weight reduction was achieved.
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Kaminski, Meghan, Andrew D'Hooge und Zackery Borton. „Design Parameter Impact of Wind-Averaged Drag Optimization“. In WCX SAE World Congress Experience. 400 Commonwealth Drive, Warrendale, PA, United States: SAE International, 2025. https://doi.org/10.4271/2025-01-8772.
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<div class="section abstract"><div class="htmlview paragraph">With the increasing prevalence of electric vehicles (EVs), decreasing vehicle drag is of upmost importance, as range is a primary consideration for customers and has a direct bearing on the cost of the vehicle. While the relationship between drag and range is well understood, there exists a discrepancy between the label range and the real-world range experienced by customers. One of the factors influencing the difference is the ambient wind condition that modifies the resultant air speed and yaw angle, which is typically minimized during SAE coast-down testing. The following study implements a singular wind-averaged drag (WAD) coefficient which is derived from a 3-point yaw curve to show the impact of yaw as compared to the zero-yaw condition. This leads to an interesting dilemma for the vehicle aerodynamicist: whether to optimize the vehicle's exterior shape for low wind (zero yaw) conditions or for real-world conditions where the ambient wind generally produces a few degrees of yaw. This paper uses a generic truck and SUV model (GTU) modified to contain a flat floor to simulate an electric vehicle and evaluated in CFD simulation to demonstrate the difference in common aerodynamic features when optimizing for zero-yaw drag vs wind-averaged drag.</div></div>
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Gideon, Olugbenga, Thomas Ulrich, Roger Lew, Benjamin Barton und Zethnouneay Dubois. „Early-Stage Usability Testing of Thermal Power Dispatch Simulator Using Novice Operators“. In 15th International Conference on Applied Human Factors and Ergonomics (AHFE 2024). AHFE International, 2024. http://dx.doi.org/10.54941/ahfe1005026.
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Flexible Plant Operations and Generation (FPOG) allow nuclear power plants (NPPs) to exploit alternative, non-electric revenue streams while ensuring their sustained role as dependable and environmentally friendly sources of baseload electrical power. The surplus thermal energy produced by NPPs during periods of low electricity demand can be directed to industrial processes through a thermal power dispatch (TPD) system such as high temperature steam electrolysis (HTSE) hydrogen production. Previous work at the Idaho National Laboratory (INL) involved developing and implementing a TPD system. An early-stage test using students as operator surrogates (n=12) was conducted using a modified GSE Generic Pressurized Water Reactor (GPWR) simulator on a desktop computer display. The study is the first to evaluate the usability of the dual-train TPD design and operating procedures toward identifying HSI issues common to students and expert users. Participants completed a startup and shutdown scenario with the control system in a manual and auto-ramp mode for a 2x2 factor design. The qualitative data analysis identified issues within three themes: information display, perceptual organization, and procedural confusion. The most notable issues were the use of small font sizes, the non-salient nature of essential dynamic features, and the ineffective groupings of interface elements. Using student participants to identify usability issues at this early stage of the dual-train TPD development is a proactive and cost-effective approach that will enable a full-scope study using expert operators.
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Larsen, Glann R., Mark Metzger, Yitzak Blue und Kim Henson. „PHARMACOKINETICS OF GENETICALLY MODIFIED T-PA IN RAT“. In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644614.
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To better understand the non-saturable mechanism responsible for the rapid systemic clearance of t-pa, previously demonstrated in all animal species tested so far, we have synthesized a genetically altered form of t-pa and analyzed the pharmacokinetic profile and organ distribution of this mutant. The mutant t-pa has been deleted in the fibronectin finger and epidermal growth factor domain, plus genetically modified to prevent N-linked glycosylation from occurring. Mammalian cells secreting either wild-type or mutant t-pa were radiolabeled with 35S-metnionine. The metabolically labeled t-pa was purified to homogeneity from conditioned medium and injected into the tail vein of rats. Multiple plasma samples were taken, post infusion, and analyzed for levels of acid-precipitable radioactivity. All rats were sacrificed fifteen minutes post infusion to determine the distribution of radioactivity in the liver, kidney or lung. The clearance profile of wild-type t-pa (n=8) was biphasi.e. with an initial alpha-phase half-life of 0.8 minutes (r=0.99) for approximately 80% of the protein and a beta-phase half-life of 12.2 minutes (r=0.97). Essentially all of the radioactivity recovered at fifteen minutes post-infusion was found in the liver. The mutant was analyzed (n=3) in identicle fashion and found to have only a single clearance phase with a 15.4 minute half-life (r=-97). Radioactivity determinations performed on organs showed proportionally less protein to be resident in the liver with a substantial increase in radioactivity observed in the kidneys. In conclusion, we have synthesized a genetic variant of t-pa which has a significantly increased half-life in the rat.
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Budiyanto, Agung, Erif Maha Nugraha Setyawan, Dwi Sunu Datrianto, Dony Nurcahya und Budi Pramono. „Application of Artificial Insemination (AI) Tool Based on Oestrus Automatic Detection to Improve Goat Pregnancy in Yogyakarta“. In 3rd International Conference on Community Engagement and Education for Sustainable Development. AIJR Publisher, 2023. http://dx.doi.org/10.21467/proceedings.151.3.
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This study aims to determine the level of pregnancy in goats and sheep in Indonesia, especially in the Yogyakarta area, by comparing the use of conventional AI devices with AI devices equipped with endoscopes. Many factors, including livestock, breeders, officers, spermatozoa, and environmental factors, strongly influence reproductive performance. The process of pregnancy in goats and sheep begins with the process of estrus, mating, pregnancy, birth, and postpartum estrus as the beginning of a continuous cycle. The problem found that the pregnancy rate in goats and sheep is relatively low. The low genetic quality of goats and sheep causes population growth in Yogyakarta to run slowly. This research was conducted by direct observation of the animal’s condition, then observation using an AI smart endoscope. AI Smart endoscopy was used to observe estrus time and followed up with AI in goats that had shown AI time. Observation of pregnancy was carried out two months after AI. The results showed that AI using smart endoscopy AI Gun on 20 goats resulted in 55% pregnancy. This is higher than conventional AI, which is 35%. The success of AI using the estrus synchronization method is 65%. The benefit of this research is the achievement of increasing pregnancy and improving the genetic quality of goats and sheep by using an AI device equipped with an endoscope. The target of veterinarians and field paramedics is more accustomed to using modified AI devices to make it easier to detect estrus. This program is expected to increase both the number of fetuses from an average of only 1-2 to 2-3 births and the success rate of AI increases.
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Korkmaz, Jessica, und Raymond Ghajar. „The Modified hybrid Multi-Objective Genetic Algorithm and Loss Sensitivity Factor for Optimal Siting and Sizing of PV-Based Distributed Generation in Distribution Networks“. In 2023 IEEE 4th International Multidisciplinary Conference on Engineering Technology (IMCET). IEEE, 2023. http://dx.doi.org/10.1109/imcet59736.2023.10368224.
Der volle Inhalt der QuelleBerichte der Organisationen zum Thema "Genetic modifier factors"
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Crawford, Keith W. Genetic Susceptibility Factors in Aggressive Breast Cancer in African-American Women and the Effects of Carcinogens and Modifiers. Fort Belvoir, VA: Defense Technical Information Center, Mai 1998. http://dx.doi.org/10.21236/ada353792.
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Fluhr, Robert, und Volker Brendel. Harnessing the genetic diversity engendered by alternative gene splicing. United States Department of Agriculture, Dezember 2005. http://dx.doi.org/10.32747/2005.7696517.bard.
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Our original objectives were to assess the unexplored dimension of alternative splicing as a source of genetic variation. In particular, we sought to initially establish an alternative splicing database for Arabidopsis, the only plant for which a near-complete genome has been assembled. Our goal was to then use the database, in part, to advance plant gene prediction programs that are currently a limiting factor in annotating genomic sequence data and thus will facilitate the exploitation of the ever increasing quantity of raw genomic data accumulating for plants. Additionally, the database was to be used to generate probes for establishing high-throughput alternative transcriptome analysis in the form of a splicing-specific oligonucleotide microarray. We achieved the first goal and established a database and web site termed Alternative Splicing In Plants (ASIP, http://www.plantgdb.org/ASIP/). We also thoroughly reviewed the extent of alternative splicing in plants (Arabidopsis and rice) and proposed mechanisms for transcript processing. We noted that the repertoire of plant alternative splicing differs from that encountered in animals. For example, intron retention turned out to be the major type. This surprising development was proven by direct RNA isolation techniques. We further analyzed EST databases available from many plants and developed a process to assess their alternative splicing rate. Our results show that the lager genome-sized plant species have enhanced rates of alternative splicing. We did advance gene prediction accuracy in plants by incorporating scoring for non-canonical introns. Our data and programs are now being used in the continuing annotation of plant genomes of agronomic importance, including corn, soybean, and tomato. Based on the gene annotation data developed in the early part of the project, it turned out that specific probes for different exons could not be scaled up to a large array because no uniform hybridization conditions could be found. Therefore, we modified our original objective to design and produce an oligonucleotide microarray for probing alternative splicing and realized that it may be reasonable to investigate the extent of alternative splicing using novel commercial whole genome arrays. This possibility was directly examined by establishing algorithms for the analysis of such arrays. The predictive value of the algorithms was then shown by isolation and verification of alternative splicing predictions from the published whole genome array databases. The BARD-funded work provides a significant advance in understanding the extent and possible roles of alternative splicing in plants as well as a foundation for advances in computational gene prediction.
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Handa, Avtar K., Yuval Eshdat, Avichai Perl, Bruce A. Watkins, Doron Holland und David Levy. Enhancing Quality Attributes of Potato and Tomato by Modifying and Controlling their Oxidative Stress Outcome. United States Department of Agriculture, Mai 2004. http://dx.doi.org/10.32747/2004.7586532.bard.
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General The final goal and overall objective of the current research has been to modify lipid hydroperoxidation in order to create desirable phenotypes in two important crops, potato and tomato, which normally are exposed to abiotic stress associated with such oxidation. The specific original objectives were: (i) the roles of lipoxygenase (LOX) and phospholipids hydroperoxide glutathione peroxidase (PHGPx) in regulating endogenous levels of lipid peroxidation in plant tissues; (ii) the effect of modified lipid peroxidation on fruit ripening, tuber quality, crop productivity and abiotic stress tolerance; (iii) the effect of simultaneous reduction of LOX and increase of PHGPx activities on fruit ripening and tuber quality; and (iv) the role of lipid peroxidation on expression of specific genes. We proposed to accomplish the research goal by genetic engineering of the metabolic activities of LOX and PHGPx using regulatable and tissue specific promoters, and study of the relationships between these two consecutive enzymes in the metabolism and catabolism of phospholipids hydroperoxides. USA Significant progress was made in accomplishing all objectives of proposed research. Due to inability to regenerate tomato plants after transforming with 35S-PHGPx chimeric gene construct, the role of low catalase induced oxidative stress instead of PHGPx was evaluated on agronomical performance of tomato plant and fruit quality attributes. Effects of polyamine, that protects DNA from oxidative stress, were also evaluated. The transgenic plants under expressing lipoxygenase (LOX-sup) were crossed with catalase antisense (CAT-anti) plants or polyamine over producing plants (SAM-over) and the lines homozygous for the two transgenes were selected. Agronomical performance of these line showed that low catalase induced oxidative stress negatively affected growth and development of tomato plants and resulted in a massive change in fruit gene expression. These effects of low catalase activity induced oxidative stress, including the massive shift in gene expression, were greatly overcome by the low lipoxygenase activity. Collectively results show that oxidative stress plays significant role in plant growth including the fruit growth. These results also for the first time indicated that a crosstalk between oxidative stress and lipoxygenase regulated processes determine the outcome during plant growth and development. Israel Regarding PHGPx, most of the study has concentrated on the first and the last specific objectives, since it became evident that plant transformation with this gene is not obvious. Following inability to achieve efficient transformation of potato and tomato using a variety of promoters, model plant systems (tobacco and potato cell cultures, tobacco calli and plantlets, and Arabidopsis) were used to establish the factors and to study the obstacles which prohibited the regeneration of plants carrying the genetic machinery for overproduction of PHGPx. Our results clearly demonstrate that while genetic transformation and over-expression of PHGPx occurs in pre-developmental tissue stage (cell culture, calli clusters) or in completed plant (Arabidopsis), it is likely that over-expression of this enzyme before tissue differentiation is leading to a halt of the regeneration process. To support this assumption, experiments, in which genetic engineering of a point-mutated PHGPx gene enable transformation and over-expression in plants of PhSPY modified in its catalytic site and thus inactive enzymatically, were successfully carried out. These combined results strongly suggest, that if in fact, like in animals and as we established in vitro, the plant PHGPx exhibits PH peroxidase activity, these peroxides are vital for the organisms developmental process.
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Delmer, Deborah, Nicholas Carpita und Abraham Marcus. Induced Plant Cell Wall Modifications: Use of Plant Cells with Altered Walls to Study Wall Structure, Growth and Potential for Genetic Modification. United States Department of Agriculture, Mai 1995. http://dx.doi.org/10.32747/1995.7613021.bard.
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Our previous work indicated that suspension-cultured plant cells show remarkable flexibility in altering cell wall structure in response either to growth on saline medium or in the presence of the cellulose synthesis inhibitor 2,-6-dichlorobenzonitrile (DCB). We have continued to analyze the structure of these modified cell walls to understand how the changes modify wall strength, porosity, and ability to expand. The major load-bearing network in the walls of DCB-adapted dicot cells that lack a substantial cellulose-xyloglucan network is comprised of Ca2+-bridged pectates; these cells also have an unusual and abundant soluble pectic fraction. By contrast, DCB-adapted barley, a graminaceous monocot achieves extra wall strength by enhanced cross-linking of its non-cellulosic polysaccharide network via phenolic residues. Our results have also shed new light on normal wall stucture: 1) the cellulose-xyloglucan network may be independent of other wall networks in dicot primary walls and accounts for about 70% of the total wall strength; 2) the pectic network in dicot walls is the primary determinant of wall porosity; 3) both wall strength and porosity in graminaceous monocot primary walls is greatly influenced by the degree of phenolic cross-linking between non-cellulosic polysaccharides; and 4) the fact that the monocot cells do not secrete excess glucuronoarabinoxylan and mixed-linked glucan in response to growth on DCB, suggests that these two non-cellulosic polymers do not normally interact with cellulose in a manner similar to xyloglucan. We also attempted to understand the factors which limit cell expansion during growth of cells in saline medium. Analyses of hydrolytic enzyme activities suggest that xyloglucan metabolism is not repressed during growth on NaCl. Unlike non-adapted cells, salt-adapted cells were found to lack pectin methyl esterase, but it is not clear how this difference could relate to alterations in wall expansibility. Salt-adaped cell walls contain reduced hyp and secrete two unique PRPP-related proteins suggesting that high NaCl inhibits the cross-linking of these proteins into the walls, a finding that might relate to their altered expansibility.
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Wideman, Jr., Robert F., Nicholas B. Anthony, Avigdor Cahaner, Alan Shlosberg, Michel Bellaiche und William B. Roush. Integrated Approach to Evaluating Inherited Predictors of Resistance to Pulmonary Hypertension Syndrome (Ascites) in Fast Growing Broiler Chickens. United States Department of Agriculture, Dezember 2000. http://dx.doi.org/10.32747/2000.7575287.bard.
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Background PHS (pulmonary hypertension syndrome, ascites syndrome) is a serious cause of loss in the broiler industry, and is a prime example of an undesirable side effect of successful genetic development that may be deleteriously manifested by factors in the environment of growing broilers. Basically, continuous and pinpointed selection for rapid growth in broilers has led to higher oxygen demand and consequently to more frequent manifestation of an inherent potential cardiopulmonary incapability to sufficiently oxygenate the arterial blood. The multifaceted causes and modifiers of PHS make research into finding solutions to the syndrome a complex and multi threaded challenge. This research used several directions to better understand the development of PHS and to probe possible means of achieving a goal of monitoring and increasing resistance to the syndrome. Research Objectives (1) To evaluate the growth dynamics of individuals within breeding stocks and their correlation with individual susceptibility or resistance to PHS; (2) To compile data on diagnostic indices found in this work to be predictive for PHS, during exposure to experimental protocols known to trigger PHS; (3) To conduct detailed physiological evaluations of cardiopulmonary function in broilers; (4) To compile data on growth dynamics and other diagnostic indices in existing lines selected for susceptibility or resistance to PHS; (5) To integrate growth dynamics and other diagnostic data within appropriate statistical procedures to provide geneticists with predictive indices that characterize resistance or susceptibility to PHS. Revisions In the first year, the US team acquired the costly Peckode weigh platform / individual bird I.D. system that was to provide the continuous (several times each day), automated weighing of birds, for a comprehensive monitoring of growth dynamics. However, data generated were found to be inaccurate and irreproducible, so making its use implausible. Henceforth, weighing was manual, this highly labor intensive work precluding some of the original objectives of using such a strategy of growth dynamics in selection procedures involving thousands of birds. Major conclusions, solutions, achievements 1. Healthy broilers were found to have greater oscillations in growth velocity and acceleration than PHS susceptible birds. This proved the scientific validity of our original hypothesis that such differences occur. 2. Growth rate in the first week is higher in PHS-susceptible than in PHS-resistant chicks. Artificial neural network accurately distinguished differences between the two groups based on growth patterns in this period. 3. In the US, the unilateral pulmonary occlusion technique was used in collaboration with a major broiler breeding company to create a commercial broiler line that is highly resistant to PHS induced by fast growth and low ambient temperatures. 4. In Israel, lines were obtained by genetic selection on PHS mortality after cold exposure in a dam-line population comprising of 85 sire families. The wide range of PHS incidence per family (0-50%), high heritability (about 0.6), and the results in cold challenged progeny, suggested a highly effective and relatively easy means for selection for PHS resistance 5. The best minimally-invasive diagnostic indices for prediction of PHS resistance were found to be oximetry, hematocrit values, heart rate and electrocardiographic (ECG) lead II waves. Some differences in results were found between the US and Israeli teams, probably reflecting genetic differences in the broiler strains used in the two countries. For instance the US team found the S wave amplitude to predict PHS susceptibility well, whereas the Israeli team found the P wave amplitude to be a better valid predictor. 6. Comprehensive physiological studies further increased knowledge on the development of PHS cardiopulmonary characteristics of pre-ascitic birds, pulmonary arterial wedge pressures, hypotension/kidney response, pulmonary hemodynamic responses to vasoactive mediators were all examined in depth. Implications, scientific and agricultural Substantial progress has been made in understanding the genetic and environmental factors involved in PHS, and their interaction. The two teams each successfully developed different selection programs, by surgical means and by divergent selection under cold challenge. Monitoring of the progress and success of the programs was done be using the in-depth estimations that this research engendered on the reliability and value of non-invasive predictive parameters. These findings helped corroborate the validity of practical means to improve PHT resistance by research-based programs of selection.
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Chamovitz, Daniel, und Albrecht Von Arnim. Translational regulation and light signal transduction in plants: the link between eIF3 and the COP9 signalosome. United States Department of Agriculture, November 2006. http://dx.doi.org/10.32747/2006.7696515.bard.
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The COP9 signalosome (CSN) is an eight-subunit protein complex that is highly conserved among eukaryotes. Genetic analysis of the signalosome in the plant model species Arabidopsis thaliana has shown that the signalosome is a repressor of light dependent seedling development as mutant Arabidopsis seedlings that lack this complex develop in complete darkness as if exposed to light. These mutant plants die following the seedling stage, even when exposed to light, indicating that the COP9 signalosome also has a central role in the regulation of normal photomorphogenic development. The biochemical mode of action of the signalosome and its position in eukaryotic cell signaling pathways is a matter of controversy and ongoing investigation, and recent results place the CSN at the juncture of kinase signaling pathways and ubiquitin-mediated protein degradation. We have shown that one of the many CSN functions may relate to the regulation of translation through the interaction of the CSN with its related complex, eukaryotic initiation factor (eIF3). While we have established a physical connection between eIF3 subunits and CSN subunits, the physiological and developmental significance of this interaction is still unknown. In an effort to understand the biochemical activity of the signalosome, and its role in regulating translation, we originally proposed to dissect the contribution of "h" subunit of eIF3 (eIF3h) along the following specific aims: (i) Isolation and phenotypic characterization of an Arabidopsis loss-of-function allele for eIF3h from insertional mutagenesis libraries; (ii) Creation of designed gain and loss of function alleles for eIF3h on the basis of its nucleocytoplasmic distribution and its yeast-two-hybrid interactions with other eIF3 and signalosome partner proteins; (iii) Determining the contribution of eIF3h and its interaction with the signalosome by expressing specific mutants of eIF3h in the eIF3h- loss-of function background. During the course of the research, these goals were modified to include examining the genetic interaction between csn and eif3h mutations. More importantly, we extended our effort toward the genetic analysis of mutations in the eIF3e subunit, which also interacts with the CSN. Through the course of this research program we have made several critical scientific discoveries, all concerned with the apparent diametrically opposed roles of eIF3h and eIF3e. We showed that: 1) While eIF3e is essential for growth and development, eIF3h is not essential for growth or basal translation; 2) While eIF3e has a negative role in translational regulation, eIF3h is positively required for efficient translation of transcripts with complex 5' UTR sequences; 3) Over-accumulation of eIF3e and loss-of-function of eIF3h both lead to cop phenotypes in dark-grown seedlings. These results were published in one publication (Kim et al., Plant Cell 2004) and in a second manuscript currently in revision for Embo J. Are results have led to a paradigm shift in translation research – eIF3 is now viewed in all systems as a dynamic entity that contains regulatory subuits that affect translational efficiency. In the long-term agronomic outlook, the proposed research has implications that may be far reaching. Many important plant processes, including developmental and physiological responses to light, abiotic stress, photosynthate, and hormones operate in part by modulating protein translation [23, 24, 40, 75]. Translational regulation is slowly coming of age as a mechanism for regulating foreign gene expression in plants, beginning with translational enhancers [84, 85] and more recently, coordinating the expression of multiple transgenes using internal ribosome entry sites. Our contribution to understanding the molecular mode of action of a protein complex as fundamental as eIF3 is likely to lead to advances that will be applicable in the foreseeable future.
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Olszewski, Neil, und David Weiss. Role of Serine/Threonine O-GlcNAc Modifications in Signaling Networks. United States Department of Agriculture, September 2010. http://dx.doi.org/10.32747/2010.7696544.bard.
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Significant evidence suggests that serine/threonine-O-linked N-acetyl glucosamine0-(GlcNAc) modifications play a central role in the regulation of plant signaling networks. Forexample, mutations in SPINDLY,) SPY (an O-GlcNAc transferase,) OGT (promote gibberellin GA) (signal transduction and inhibit cytokinin responses. In addition, mutating both Arabidopsis OGTsSEC (and SPY) causes embryo lethality. The long-term goal of this research is to elucidate the mechanism by which Arabidopsis OGTs regulate signaling networks. This project investigated the mechanisms of O-GlcNAc regulation of cytokinin and gibberellin signaling, identified additional processes regulated by this modification and investigated the regulation of SEC activity. Although SPY is a nucleocytoplasmic protein, its site of action and targets were unknown. Severalstudies suggested that SPY acted in the nucleus where it modified nuclear components such as the DELLA proteins. Using chimeric GFP-SPY fused to a nuclear-export signal or to a nuclear-import signal, we showed that cytosolic, but not nuclear SPY, regulated cytokinin and GA signaling. We also obtained evidence suggesting that GA and SPY affect cytokinin signaling via a DELLA-independent pathway. Although SEC and SPY were believed to have overlapping functions, the role of SEC in cytokinin and GA signaling was unclear. The role of SEC in cytokinin and GA responses was investigated by partially suppressing SPY expression in secplants using a synthetic Spymicro RNA miR(SPY). The possible contribution of SEC to the regulation of GA and cytokinin signaling wastest by determining the resistance of the miR spy secplants to the GA biosynthesis inhibitor paclobutrazol and to cytokinin. We found that the transgenic plants were resistant to paclobutrazol and to cytokinin, butonlyata level similar to spy. Moreover, expressing SEC under the 35S promoter in spy mutant did not complement the spy mutation. Therefore, we believe that SEC does not act with SPY to regulate GA or cytokinin responses. The cellular targets of Spy are largely unknown. We identified the transcription factor TCP15 in a two-hybrid screen for SPY-interacting proteins and showed that both TCP15 and its closely homolog TCP14 were O-GlcNAc modified by bacterially-produced SEC. The significance of the interaction between SPY and these TCPs was examined by over-expressing the minwild-type and spy-4plants. Overexpression of TCP14 or TCP15 in wild-type background produced phenotypes typical of plants with increased cytokinin and reduced GA signaling. TCP14 overexpression phenotypes were strongly suppressed in the spy background, suggesting that TCP14 and TCP15 affect cytokinin and GA signaling and that SPY activates them. In agreement with this hypothesis, we created a tcp14tcp15 double mutant and found that it has defects similar to spyplants. In animals, O-GlcNAc modification is proposed to regulate the activity of the nuclear pore. Therefore, after discovering that SEC modified a nucleoporinNUP) (that also interacts with SPY, we performed genetic experiments exploring the relationship between NUPs and SPY nupspy double mutants exhibited phenotypes consistent with SPY and NUPs functioning in common processes and nupseeds were resistant to GA biosynthesis inhibitors. All eukaryotic OGTs have a TPR domain. Deletion studies with bacterially-expressed SEC demonstrated SEC'sTPR domain inhibits SEC enzymatic activity. Since the TPR domain interacts with other proteins, we propose that regulatory proteins regulate OGT activity by binding and modulating the inhibitory activity of the TPR domain.
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Applebaum, Shalom W., Lawrence I. Gilbert und Daniel Segal. Biochemical and Molecular Analysis of Juvenile Hormone Synthesis and its Regulation in the Mediterranean Fruit Fly (Ceratitis capitata). United States Department of Agriculture, 1995. http://dx.doi.org/10.32747/1995.7570564.bard.
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Original Objectives and revisions: (1) "To determine the biosynthetic pathway of JHB3 in the adult C. capitata CA in order to establish parameters for the future choice and synthesis of suitable inhibitors". Modified: to determine the pattern of FR-7 biosynthesis during normal reproductive maturation, and identify enzymes potentially involved in its synthesis. (2) "To correlate allatal epoxidase activity to the biosynthesis of JHB3 at different stages of reproductive maturation/vitellogenesis and evaluate the hypothesis that a specific JH-epoxidase may be rate limiting". Modified: to study the effects of epoxidase inhibitors on the pattern of allatal JH biosynthesis in vitro and on female reproduction in vive. (3) "To probe and clone the gene homologous to ap from C. capitata, determine its exon-intron organization, sequence it and demonstrate its spatial and temporal expression in larvae, pupae and adults." The "Medfly" (Ceratitis capitata) is a serious polyphagous fruit pest, widely distributed in subtropical regions. Damage is caused by oviposition and subsequent development of larvae. JH's are dominant gonadotropic factors in insects. In the higher Diptera, to which the Medfly belongs, JHB3 is a major homolog. It comprises 95% of the total JH produced in vitro in D. melanogaster, with JH-III found as a minor component. The biosynthesis of both JH-III and JHB3 is dependent on epoxidation of double bonds in the JH molecule. The specificity of such epoxidases is unknown. The male accessory gland D. melanogaster produces a Sex Peptide, transferred to the female during copulation. SP reduces female receptivity while activating specific JH biosynthesis in vitro and inducing oviposition in vive. It also reduces pheromone production and activates CA of the moth Helicoverpa armigera. In a previous study, mutants of the apterous (ap) gene of D. melanogaster were analyzed. This gene induces previteilogenic arrest which can be rescued by external application of JH. Considerable progress has been made in recombinant DNA technology of the Medfly. When fully operative, it might be possible to effectively transfer D. melanogaster endocrine gene-lesions into the Medfly as a strategy for their genetic control. A marked heterogeneity in the pattern of JH homologs produced by Medfly CA was observed. Contrary to the anticipated biosynthesis of JHB;, significant amounts of an unknown JH-like compound, of unknown structure and provisionally termed FR-7, were produced, in addition to significant amounts of JH-III and JHB3. Inhibitors of monooxygenases, devised for their effects on ecdysteroid biosynthesis, affect Medfly JH biosynthesis but do not reduce egg deposition. FR-7 was isolated from incubation media of Medfly CA and examined by various MS procedures, but its structure is not yet resolved. MS analysis is being done in collaboration with Professor R.R.W. Rickards of the Australian National University in Canberra, Australia. A homologue of the ap gene of D. melanogaster exists in the Medfly. LIM domains and the homeo-domain, important for the function of the D. melanogaster ap gene, are conserved here too. Attempts to clone the complete gene were unsuccessful. Due to the complexity of JH homologs, presence of related FR-7 in the biosynthetic products of Medfly CA and lack of reduction in eggs deposited in the presence of monooxygenase inhibitors, inhibition of epoxidases is not a feasible alternative to control Medfly reproduction, and raises questions which cannot be resolved within the current dogma of hormonal control of reproduction in Diptera. The Medfly ap gene has similar domains to the D. melanogaster ap gene. Although mutant ap genes are involved in JH deficiency, ap is a questionable candidate for an endocrine lesion, especially since the D. melanogoster gene functions is a transcription factor.
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Barash, Itamar, und Robert E. Rhoads. Translational Mechanisms that Govern Milk Protein Levels and Composition. United States Department of Agriculture, November 2004. http://dx.doi.org/10.32747/2004.7586474.bard.
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Original objectives: The long term objective of the project is to achieve higher content of protein in the milk of ruminants by modulating the translational machinery in the mammary gland. The first specific aim of the BARD proposal was to characterize responsiveness of various experimental systems to combination of lactogenic hormones and amino acids with particular emphasis on discrimination between the control of total protein synthesis and milk protein synthesis. Based on the results, we planned to proceed by characterizing the stage of protein synthesis in which the stimulation by lactogenic hormones and amino acid occur and finally we proposed to identify which components of the translation machinery are modified. Background to the topic: Milk protein is the most valuable component in milk, both for direct human consumption and for manufacturing cheese and other protein-based products. Attempts to augment protein content by the traditional methods of genetic selection and improved nutritional regimes have failed. The proposal was based on recent results suggesting that the limiting factor for augmenting protein synthesis in the bovine mammary gland is the efficiency of converting amino acids to milk proteins. Major conclusions, solutions, achievements: Insulin and prolactin synergistically stimulate â-casein mRNA translation by cytoplasmatic polyadenylation. The interaction between insulin and prolactin was demonstrated two decades ago as crucial for milk-protein synthesis, but the molecular mechanisms involved were not elucidated. We found in differentiated CID 9 mouse mammary epithelial cells line that insulin and prolactin synergistically increases the rate of milk protein mRNA translation. We focused on â-casein, the major milk protein, and found that the increase in â-casein mRNA translation was reflected in a shift to larger polysomes, indicating an effect on translational initiation. Inhibitors of the PI3K, mTOR, and MAPK pathways blocked insulin-stimulated total protein and â-casein synthesis but not the synergistic stimulation. Conversely, cordycepin, a polyadenylation inhibitor, abolished synergistic stimulation of protein synthesis without affecting insulin-stimulated translation. The poly(A) tract of â-casein mRNA progressively increased over 30 min of treatment with insulin plus prolactin. The 3’-untranslated region of â-casein mRNA was found to contain a cytoplasmic polyadenylation element (CPE), and in reporter constructs, this was sufficient for the translational enhancement and mRNA-specific polyadenylation. Furthermore, insulin and prolactin stimulated phosphorylation of cytoplasmic polyadenylation element binding protein (CPEB) but did not increase cytoplasmic polyadenylation.
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Glazer, Itamar, Alice Churchill, Galina Gindin und Michael Samish. Genomic and Organismal Studies to Elucidate the Mechanisms of Infectivity of Entomopathogenic Fungi to Ticks. United States Department of Agriculture, Januar 2013. http://dx.doi.org/10.32747/2013.7593382.bard.
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The overall goal of this research was to elucidate the factors affecting early development of Metarhizium spp. (previously named M. anisopliae) on ticks or tick cuticle extracts and the molecular basis of these early infection processes. The original objectives were: 1. Characterize the pre-penetration events (adhesion, germination and appressorium formation) of spores of M. anisopliae strains with high or low virulence during tick infection. 2. Create GFP-expressing strains of M. anisopliae tick pathogens having high and low virulence to compare their progress of infection by microscopy. 3. Use microarray analyses, primarily with existing M. anisopliae EST sequences in GenBank, to identify and characterize fungal genes whose expression is regulated in response to host cuticle extracts. Objective 3 was later modified (as approved by BARD) to use RNAseq to characterize the early stages of fungal gene expression during infection of intact host cuticles. This new method provides a massively larger and more informative dataset and allows us to take advantage of a) recently published genomes of Metarhizium robertsii and M. acridum for RNAseq data analysis, and b) newly developed and highly efficient cDNA sequencing technologies that are relatively low cost and, therefore, allow deep sequencing of multiple transcriptome samples. We examined pre-penetration and penetration events that differentiate high and low virulence strains of Metarhizium spp., focusing on spore adhesion, germination, appressorium formation, and penetration of tick integuments. Initiation of fungal infection was compared on susceptible and resistant tick species at different tick developmental stages. In vitro studies comparing the effects of protein and fatty acid profiles from tick cuticle extracts demonstrated that resistant tick cuticles contain higher concentrations of specific lipids that inhibit fungal development than do susceptible tick cuticles, suggesting one mechanism of Ixodidae resistance to fungal entomopathogens (Objective 1). We used molecular markers to determine that the three M. anisopliae strains from Israel that we studied actually were three distinct species. M. brunneum is highly virulent against the tick Rhipicephalus annulatus, M. pingshaense and M. robertsii are intermediate in virulence, and M. majus is of low virulence. We transformed all four Metarhizium species to express GFP and used them in pathogenicity assays against diverse tick species. Key findings were that a) resistant ticks inhibit Metarhizium infection prior to hemocoel invasion by reducing fungal viability on the cuticle surface (Objective 2), as was supported by the in vitro studies of Objective 1, and b) Metarhizium kills susceptible ticks after cuticle penetration but prior to hemocoel colonization. Transcriptome studies of the most virulent species, M. brunneum, are in progress and include analyses of ungerminated conidia and conidia germination and development on a low nutrient medium or on susceptible R. annulatus exoskeleton (Objective 3). We anticipate these studies will contribute to identifying fungal genetic factors that increase virulence and speed of kill and may help reveal tick chemistries that could be included in biocontrol formulations to increase efficacy. Methodologies developed to screen tick cuticle extracts for ability to support conidia germination and development may help in the selection of wild fungi with increased virulence against resistant ticks. The overall knowledge gained should contribute not only to the improvement of tick control but also to the control of other blood-sucking arthropods and related plant pests. Use of bio-based agents for controlling arthropods will contribute to a healthier, more sustainable environment and serve a growing number of organic food farmers.