+publisher:"Georgia Tech" +contributor:("Azizi, Bahareh")

Georgia Tech

1. Walker, Christopher L. Green fluorescent protein inspired chromophore as estrogen receptor agonist-synthesis, biological evaluations and cellular application.

Degree: PhD, Chemistry and Biochemistry, 2019, Georgia Tech

URL: http://hdl.handle.net/1853/61211

► Nuclear receptors are ligand activated transcription factors that are widely distributed throughout the mammalians. There are 48 known human nuclear receptors within the body located… (more)

▼ Nuclear receptors are ligand activated transcription factors that are widely distributed throughout the mammalians. There are 48 known human nuclear receptors within the body located in various systems. While some nuclear receptors can be located wholly within certain regions and tissues the clear majority are widely distributed, overlapping expression in the same locations. The role of nuclear receptors as transcription factors has caused them to be implicated in a vast number of diseases including metabolic, cardiovascular and neurological. The role of nuclear receptors in diseases and the potential to promote ligand activated transcription makes nuclear receptors of pharmaceutical significance. Currently it is estimated that 33% of nuclear receptors are targeted by the pharmaceutical industry resulting in ~20% of pharmaceutical development worldwide. The potential to control physiological responses via introduction of a ligand to nuclear receptors has continued the interest in development of new ligands to further the understanding of nuclear receptor behavior. The challenge nuclear receptors present is to develop ligands that are selective in targeting within families and among different classes of nuclear receptors. At the core, ligand activated nuclear receptor modulation is chiefly centered around the relationship between the ligand binding pocket of the receptor and the ligand. Composed primarily of non-polar amino acid residues the ligand binding pocket is the cavity by which small hydrophobic molecules bind. Demonstrating large variance across classes of nuclear receptor and little divergence within families the ligand binding pocket serves as the focal point for targeting selectivity. Successful binding and thus receptor response is contingent upon the ligand meeting criteria established by the ligand binding pocket such as satisfactory size/volume of the ligand and key ligand-receptor amino acid residue interaction. Research conducted by Katzenellenbogen was paramount in understanding the relationship between the estrogen receptors and its ligands. His established pharmacophore unraveled features for potential ligands that are exchangeable from those that are indispensable. The commercial success of estrogen receptor ligands has fueled the interest in not only understanding ligand-receptor binding interactions but its subcellular movement. The Green Fluorescent Protein completely revolutionized the way in which cellular probing is conducted. The chromophore internally synthesized by the protein through a series of folding of amino acid residues afforded the opportunity to monitor cellular movements with the aid of fluorescence. Commonly utilized in visualization as a fusion protein, the GFP chromophore provided the ideal tool for understanding protein cellular movement and interaction. Simply put due to the chromophore that resides at the center, GFP provides the perfect technique for cellular probing. Here in we report the use of GFP-chromophore inspired ligands for utility as estrogen receptor agonist.… Advisors/Committee Members: Williams, Loren (advisor), Liotta, Charles (committee member), Snell, Terry (committee member), Oyelere, Adegboyega (committee member), Azizi, Bahareh (committee member).

Subjects/Keywords: Estrogen receptor

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APA (6^th Edition):

Walker, C. L. (2019). Green fluorescent protein inspired chromophore as estrogen receptor agonist-synthesis, biological evaluations and cellular application. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/61211

Chicago Manual of Style (16^th Edition):

Walker, Christopher L. “Green fluorescent protein inspired chromophore as estrogen receptor agonist-synthesis, biological evaluations and cellular application.” 2019. Doctoral Dissertation, Georgia Tech. Accessed January 15, 2021. http://hdl.handle.net/1853/61211.

MLA Handbook (7^th Edition):

Walker, Christopher L. “Green fluorescent protein inspired chromophore as estrogen receptor agonist-synthesis, biological evaluations and cellular application.” 2019. Web. 15 Jan 2021.

Vancouver:

Walker CL. Green fluorescent protein inspired chromophore as estrogen receptor agonist-synthesis, biological evaluations and cellular application. [Internet] [Doctoral dissertation]. Georgia Tech; 2019. [cited 2021 Jan 15]. Available from: http://hdl.handle.net/1853/61211.

Council of Science Editors:

Walker CL. Green fluorescent protein inspired chromophore as estrogen receptor agonist-synthesis, biological evaluations and cellular application. [Doctoral Dissertation]. Georgia Tech; 2019. Available from: http://hdl.handle.net/1853/61211

2. Rood, Michael K. Enzyme-activated growth: development of a nuclear receptor based genetic selection system for engineering biocatalysts.

Degree: PhD, Chemistry and Biochemistry, 2014, Georgia Tech

URL: http://hdl.handle.net/1853/53072

► Beyond their physiological roles, nuclear receptors have been exploited for their ability to act as intracellular sensors of small molecules. Accordingly, yeast two- and three-hybrid… (more)

▼ Beyond their physiological roles, nuclear receptors have been exploited for their ability to act as intracellular sensors of small molecules. Accordingly, yeast two- and three-hybrid systems have been developed, exploiting them to control reporter gene expression. These systems may be used to identify nuclear receptor ligand interaction, or for protein engineering applications, particularly of the nuclear receptor ligand binding domain. In this work, the use of estrogen receptors as sensors for enzyme catalysis is explored, where expression of a reporter gene is induced in the presence of the product from an enzymatic reaction. This system, which we have called enzyme-activated growth, has applications for the engineering of biocatalysts. Biocatalytic routes are currently being explored in industrial applications since they often have financial and environmental benefits over traditional heterogeneous catalysis. Enzyme-activated growth is designed to serve as a system to select for engineered enzymes capable of catalyzing the desired reaction. For this work, a new yeast two-hybrid strain has been developed and characterized to allow for detection of both agonist and antagonist compounds. To increase the sensitivity of this assay, a variant of the estrogen receptor was created through random mutation, which responded to ligand concentrations an order of magnitude lower than the wild type receptor. The five mutations identified in the best variant were previously unknown in the literature and the roles of each of these are investigated, as is the mechanism by which they alter ligand sensitivity. As a proof-of-principle, the enzymatic production of genistein, an estrogenic metabolite from plants, using the enzyme isoflavone synthase, as well as the production of estrogen from testosterone, is explored. Synthesis of genistein from the starting material naringenin in vivo was detected in the yeast two-hybrid strain; however, attempts at pairing this with estrogen receptor activation and cell growth were met with limited success. Lastly, targeting the estrogen receptor with a series of novel anti-cancer therapeutics is explored. These compounds were designed to both bind and (in)activate the estrogen receptor while inhibiting histone deacetylase activity. The (anti-)estrogenic properties were analyzed as well as their potency as histone deacetylase inhibitors. These properties were compared to their anti-proliferative effects against various cancerous and healthy cell lines to determine their potential as selective anti-cancer therapeutics. Advisors/Committee Members: Hud, Nicholas V. (advisor), Azizi, Bahareh (committee member), Bommarius, Andreas S. (committee member), Marder, Seth R. (committee member), Ortlund, Eric A. (committee member), Williams, Loren D. (committee member).

Subjects/Keywords: Estrogen receptor; Protein engineering; Genetic selection; Biocatalysis; Breast cancer; Nuclear receptors

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APA (6^th Edition):

Rood, M. K. (2014). Enzyme-activated growth: development of a nuclear receptor based genetic selection system for engineering biocatalysts. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/53072

Chicago Manual of Style (16^th Edition):

Rood, Michael K. “Enzyme-activated growth: development of a nuclear receptor based genetic selection system for engineering biocatalysts.” 2014. Doctoral Dissertation, Georgia Tech. Accessed January 15, 2021. http://hdl.handle.net/1853/53072.

MLA Handbook (7^th Edition):

Rood, Michael K. “Enzyme-activated growth: development of a nuclear receptor based genetic selection system for engineering biocatalysts.” 2014. Web. 15 Jan 2021.

Vancouver:

Rood MK. Enzyme-activated growth: development of a nuclear receptor based genetic selection system for engineering biocatalysts. [Internet] [Doctoral dissertation]. Georgia Tech; 2014. [cited 2021 Jan 15]. Available from: http://hdl.handle.net/1853/53072.

Council of Science Editors:

Rood MK. Enzyme-activated growth: development of a nuclear receptor based genetic selection system for engineering biocatalysts. [Doctoral Dissertation]. Georgia Tech; 2014. Available from: http://hdl.handle.net/1853/53072

3. Duraj-Thatte, Anna. Fluorescent GFP chromophores as potential ligands for various nuclear receptors.

Degree: PhD, Chemistry and Biochemistry, 2012, Georgia Tech

URL: http://hdl.handle.net/1853/44764

► Nuclear receptors are ligand activated transcription factors, where upon binding with small molecule ligands, these proteins are involved in the regulation of gene expression. To… (more)

▼ Nuclear receptors are ligand activated transcription factors, where upon binding with small molecule ligands, these proteins are involved in the regulation of gene expression. To date there are approximately 48 human nuclear receptors known, involved in multiple biological and cellular processes, ranging from differentiation to maintenance of homeostasis. Due to their critical role in transcriptional regulation, these receptors are implicated in several diseases. Currently, 13% of prescribed drugs in the market are NR ligands for diseases such as cancer, diabetes and osteoporosis. In addition to drug discovery, the mechanism of function, mobility and trafficking of these receptors is poorly understood. Gaining insight into the relationship between the function and /or dysfunction of these receptors and their mobility will aid in a better understanding of the role of these receptors. The green fluorescent protein (GFP) has revolutionized molecular biology by providing the ability to monitor protein function and structure via fluorescence. The fluorescence contribution from this biological marker is the chromophore, formed from the polypeptide backbone of three amino acid residues, buried inside 11-stranded â-barrel protein. Synthesis of GFP derivatives of is based on the structure of the arylmethyleneimidazolidinone (AMI), creating a molecule that is only weakly fluorescent. Characterizing these AMI derivatives for other proteins can provide a powerful visualization tool for analysis of protein function and structure. This development could provide a very powerful method for protein analysis in vitro and in vivo. Development of such fluorescent ligands will prove beneficial for the nuclear receptors. In this work, libraries of AMIs derviatives were synthesized by manipulating various R groups around the core structure, and tested for their ability to serve as nuclear receptor ligands with the ability to fluoresce upon binding. The fluorogens are developed for steroidal and non-steroidal receptors, two general classes of nuclear receptors. Specific AMIs were designed and developed for steroid receptor estrogen receptor á (ERá). These ligands are showed to activate the receptor with an EC50 of value 3 ìM and the 10-fold activation with AMI 1 and AMI 2 in comparison to the 21-fold activation observed with natural ERá ligand, 17â-estradiol. These novel ligands were not able to display the fluorescence upon binding the receptor. However, fluorescence localized in nucleus was observed in case of another AMI derivative, AMI 10, which does not activate the receptor. Such ligands open new avenues for developing fluorescent probes for ERá that do not involve fluorescent conjugates attached to a known ERá ligand core. AMIs were also characterized for non-steroidal receptors,specifically the pregnane x receptor (PXR) and retinoic acid receptor á (RARá). To date, fluorogens which turn fluorescence upon binding and activate the receptor have not been developed for these receptors. With respect to… Advisors/Committee Members: Tolbert, Laren (Committee Chair), Azizi, Bahareh (Committee Co-Chair), Bommarius, Andreas (Committee Member), Gaucher, Eric (Committee Member), Hud, Nicholas (Committee Member), Williams, Loren (Committee Member).

Subjects/Keywords: GFPchromophore; Ligand; Fluorescent ligand; Nuclear receptor; Green fluorescent protein; Ligand binding (Biochemistry); Ligands (Biochemistry)

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Duraj-Thatte, A. (2012). Fluorescent GFP chromophores as potential ligands for various nuclear receptors. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/44764

Chicago Manual of Style (16^th Edition):

Duraj-Thatte, Anna. “Fluorescent GFP chromophores as potential ligands for various nuclear receptors.” 2012. Doctoral Dissertation, Georgia Tech. Accessed January 15, 2021. http://hdl.handle.net/1853/44764.

MLA Handbook (7^th Edition):

Duraj-Thatte, Anna. “Fluorescent GFP chromophores as potential ligands for various nuclear receptors.” 2012. Web. 15 Jan 2021.

Vancouver:

Duraj-Thatte A. Fluorescent GFP chromophores as potential ligands for various nuclear receptors. [Internet] [Doctoral dissertation]. Georgia Tech; 2012. [cited 2021 Jan 15]. Available from: http://hdl.handle.net/1853/44764.

Council of Science Editors:

Duraj-Thatte A. Fluorescent GFP chromophores as potential ligands for various nuclear receptors. [Doctoral Dissertation]. Georgia Tech; 2012. Available from: http://hdl.handle.net/1853/44764

4. Castillo, Hilda S. Mutational analysis and engineering of the human vitamin D receptor to bind and activate in response to a novel small molecule ligand.

Degree: PhD, Chemistry and Biochemistry, 2011, Georgia Tech

URL: http://hdl.handle.net/1853/39502

► Nuclear receptors (NRs) are ligand-activated transcription factors that regulate the expression of genes involved in all physiological activities. Disruption in NR function (e.g. mutations) can… (more)

▼ Nuclear receptors (NRs) are ligand-activated transcription factors that regulate the expression of genes involved in all physiological activities. Disruption in NR function (e.g. mutations) can lead to a variety of diseases; making these receptors important targets for drug discovery. The ability to bind a broad range of 'drug-like' molecules also make these receptors attractive candidates for protein engineering, such that they can be engineered to bind novel small molecule ligands, for several applications. One application is the creation of potential molecular switches, tools that can be used for controlling gene expression. Gaining knowledge of specific molecular interactions that occur between a receptor and its ligand is of interest, as they contribute towards the activation or repression of target genes. The focus of this work has been to investigate the structural and functional relationships between the human vitamin D receptor (hVDR) and its ligands. To date, mutational assessments of the hVDR have focused on alanine scanning and residues typically lining the ligand binding pocket (LBP)that are involved in direct interactions with the ligand. A comprehensive analysis of the tolerance of these residues in the binding and activation of the receptor by its ligands has not been performed. Furthermore, residues not in contact with the ligand or that do not line the LBP may also play an important role in determining the activation profiles observed for NRs, and therefore need to be explored further. In order to engineer and use the hVDR in chemical complementation, a genetic selection system in which the survival of yeast is linked to the activation of a NR by an agonist, the hVDR gene was isolated from cDNA. To gain insight into how chemical and physical changes within the ligand binding domain (LBD) affect receptor-ligand interactions, libraries of hVDR variants exploring the role and tolerance of hVDR residues were created. To develop a comprehensive mutational analysis while also engineering the hVDR to bind a novel small molecule ligand, a rational and a random mutagenic approach were used to create the libraries. A variant, hVDRC410Y, that displayed enhanced activity with lithocholic acid (LCA), a known hVDR ligand, and novel activation with cholecalciferol (chole), a precursor of the hVDR's natural ligand known not to activate the wild-type hVDR, was discovered. The presence of a tyrosine at the C410 position resulting in novel activation profiles with both LCA and chole, and the fact that this residue does not line the hVDR's LBP led to interest in determining whether a physical or chemical property of the residue was responsible for the observed activity. When residue C410 was further assessed for its tolerance to varying amino acids, the results indicated that bulkiness at this end of the pocket is important for activation with these ligands. Both LCA and chole have reduced molecular volumes compared to the natural ligand, 1alpha, 25(OH)2D3. As a result, increased bulkiness at the… Advisors/Committee Members: Azizi, Bahareh (Committee Chair), Doyle, Donald (Committee Chair), Bommarius, Andreas (Committee Co-Chair), Williams, Loren (Committee Co-Chair), Hud, Nicholas (Committee Member), May, Sheldon (Committee Member).

Subjects/Keywords: Mutagenesis; Protein engineering; Nuclear receptor; Vitamin D receptor; Lithocholic acid; Cholecalciferol; Ligands (Biochemistry); Vitamin D in the body; Nuclear receptors (Biochemistry)

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APA (6^th Edition):

Castillo, H. S. (2011). Mutational analysis and engineering of the human vitamin D receptor to bind and activate in response to a novel small molecule ligand. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/39502

Chicago Manual of Style (16^th Edition):

Castillo, Hilda S. “Mutational analysis and engineering of the human vitamin D receptor to bind and activate in response to a novel small molecule ligand.” 2011. Doctoral Dissertation, Georgia Tech. Accessed January 15, 2021. http://hdl.handle.net/1853/39502.

MLA Handbook (7^th Edition):

Castillo, Hilda S. “Mutational analysis and engineering of the human vitamin D receptor to bind and activate in response to a novel small molecule ligand.” 2011. Web. 15 Jan 2021.

Vancouver:

Castillo HS. Mutational analysis and engineering of the human vitamin D receptor to bind and activate in response to a novel small molecule ligand. [Internet] [Doctoral dissertation]. Georgia Tech; 2011. [cited 2021 Jan 15]. Available from: http://hdl.handle.net/1853/39502.

Council of Science Editors:

Castillo HS. Mutational analysis and engineering of the human vitamin D receptor to bind and activate in response to a novel small molecule ligand. [Doctoral Dissertation]. Georgia Tech; 2011. Available from: http://hdl.handle.net/1853/39502

5. Ousley, Amanda. Engineering the human vitamin D receptor to bind a novel small molecule: investigating the structure-function relationship between human vitamin d receptor and various ligands.

Degree: PhD, Chemistry and Biochemistry, 2011, Georgia Tech

URL: http://hdl.handle.net/1853/39580

► The human vitamin D receptor (hVDR) is a member of the nuclear receptor superfamily, involved in calcium and phosphate homeostasis; hence implicated in a number… (more)

Subjects/Keywords: Lithocholic acid; Cholecalciferol; Human vitamin D receptor; Nuclear receptors; Vitamin D in the body; Protein engineering; Ligand binding (Biochemistry); Receptor complexes (Biochemistry); Mutagenesis

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APA (6^th Edition):

Ousley, A. (2011). Engineering the human vitamin D receptor to bind a novel small molecule: investigating the structure-function relationship between human vitamin d receptor and various ligands. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/39580

Chicago Manual of Style (16^th Edition):

Ousley, Amanda. “Engineering the human vitamin D receptor to bind a novel small molecule: investigating the structure-function relationship between human vitamin d receptor and various ligands.” 2011. Doctoral Dissertation, Georgia Tech. Accessed January 15, 2021. http://hdl.handle.net/1853/39580.

MLA Handbook (7^th Edition):

Ousley, Amanda. “Engineering the human vitamin D receptor to bind a novel small molecule: investigating the structure-function relationship between human vitamin d receptor and various ligands.” 2011. Web. 15 Jan 2021.

Vancouver:

Ousley A. Engineering the human vitamin D receptor to bind a novel small molecule: investigating the structure-function relationship between human vitamin d receptor and various ligands. [Internet] [Doctoral dissertation]. Georgia Tech; 2011. [cited 2021 Jan 15]. Available from: http://hdl.handle.net/1853/39580.

Council of Science Editors:

Ousley A. Engineering the human vitamin D receptor to bind a novel small molecule: investigating the structure-function relationship between human vitamin d receptor and various ligands. [Doctoral Dissertation]. Georgia Tech; 2011. Available from: http://hdl.handle.net/1853/39580

6. Taylor, Jennifer. Engineering and improving a molecular switch system for gene therapy applications.

Degree: PhD, Chemistry and Biochemistry, 2011, Georgia Tech

URL: http://hdl.handle.net/1853/39501

► Molecular switch systems that activate gene expression by a small molecule are effective technologies that are widely used in applied biological research. Previously, two orthogonal… (more)

▼ Molecular switch systems that activate gene expression by a small molecule are effective technologies that are widely used in applied biological research. Previously, two orthogonal ligand receptor pairs (OLRP) were developed as potential molecular switch systems by modifying nuclear receptors, ligand-activated transcription factors, to bind and activate gene expression with the synthetic ligand LG335 and not with the natural ligand 9-cis retinoic acid (9cRA). The two OLRP previously discovered were RXR variant 130 (I268A, I310A, F313A, and L436F) (also known as GR130) and the RXR variant QCIMFI (Q275C, I310M, and F313I) and (also known as GRQCIMFI). The OLRP were further developed into molecular switches to provide controlled gene expression and potentially benefit gene therapy applications by replacing the DNA binding domain (DBD) with a Gal4 DBD, a yeast transcription factor. Both molecular switches are able to bind Gal4 RE in response to LG335 and activate expression of a luciferase or GFP reporter gene in either a two- or one-component system. When characterizing the GR130 variant in the two-component system, no activation was observed with the natural ligand 9cRA, and the variant displayed a 19±5-fold activation and a 50 nM EC50 value in the presence of LG335. When the GRQCIMFI variant was evaluated in the two-component system, activation was observed in the presence of LG335 with a 10 nM EC50 value and a 6±2-fold induction, and 9cRA induced activation only at the highest concentration. The GRQCIMFI variant was also characterized with the one-component system containing the reporter gene GFP in a transient transfection as well as through retroviral transduction, displaying green fluorescence in 30% of the cells in the presence of 10 µM LG335. Several attempts were made to improve the molecular switch system. The VP16 activation domain was fused to GRQCIMFI in an effort to increase the fold induction; however, the addition of the VP16 created a constitutively active protein. Another approach to improve the molecular switch incorporated error-prone PCR to discover a new variant, Q275C, I310M, F313I, L455M (QCIMFILM), which displayed a 10-fold increase in sensitivity towards LG335 with a 5 nM EC50 value. Examination of the L455 position in the crystal structure of RXR revealed this residue is located outside of the ligand binding pocket on helix 12 (H12), but is able to significantly enhance receptor function. In fact, the single variant, L455M, was able to enhance receptor activation, compensate for a nonfunctional variant, as well as influence coactivator association. The long-term goal of this research is to develop a gene regulation system that would be used in human gene therapy trials. In the process of creating this system a deeper assessment of the nuclear receptor structure and function is made, which can be used for the enhancement and development of transcriptional regulation mechanisms. Advisors/Committee Members: Doyle, Donald (Committee Chair), Williams, Loren (Committee Co-Chair), Azizi, Bahareh (Committee Member), Fahrni, Christoph (Committee Member), Hud, Nicholas (Committee Member), Le Doux, Joseph (Committee Member), Spencer, H. Trent (Committee Member).

Subjects/Keywords: Protein engineering; Gene therapy; Molecular switch systems; Gene regulation systems; RXR; Nuclear receptors; Gene therapy; Nuclear receptors (Biochemistry); Ligands (Biochemistry)

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Taylor, J. (2011). Engineering and improving a molecular switch system for gene therapy applications. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/39501

Chicago Manual of Style (16^th Edition):

Taylor, Jennifer. “Engineering and improving a molecular switch system for gene therapy applications.” 2011. Doctoral Dissertation, Georgia Tech. Accessed January 15, 2021. http://hdl.handle.net/1853/39501.

MLA Handbook (7^th Edition):

Taylor, Jennifer. “Engineering and improving a molecular switch system for gene therapy applications.” 2011. Web. 15 Jan 2021.

Vancouver:

Taylor J. Engineering and improving a molecular switch system for gene therapy applications. [Internet] [Doctoral dissertation]. Georgia Tech; 2011. [cited 2021 Jan 15]. Available from: http://hdl.handle.net/1853/39501.

Council of Science Editors:

Taylor J. Engineering and improving a molecular switch system for gene therapy applications. [Doctoral Dissertation]. Georgia Tech; 2011. Available from: http://hdl.handle.net/1853/39501

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