23 results on '"Hixon, Jeff"'
Search Results
2. Interaction between host G3BP and viral nucleocapsid protein regulates SARS-CoV-2 replication
- Author
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Yang, Zemin, primary, Johnson, Bryan A., additional, Meliopoulos, Victoria A., additional, Ju, Xiaohui, additional, Zhang, Peipei, additional, Hughes, Michael P., additional, Wu, Jinjun, additional, Koreski, Kaitlin P., additional, Chang, Ti-Cheng, additional, Wu, Gang, additional, Hixon, Jeff, additional, Duffner, Jay, additional, Wong, Kathy, additional, Lemieux, Rene, additional, Lokugamage, Kumari G., additional, Alvardo, Rojelio E., additional, Crocquet-Valdes, Patricia A., additional, Walker, David H., additional, Plante, Kenneth S., additional, Plante, Jessica A., additional, Weaver, Scott C., additional, Kim, Hong Joo, additional, Meyers, Rachel, additional, Schultz-Cherry, Stacey, additional, Ding, Qiang, additional, Menachery, Vineet D., additional, and Taylor, J. Paul, additional
- Published
- 2023
- Full Text
- View/download PDF
3. Identification of small molecule inhibitors of G3BP-driven stress granule formation
- Author
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Freibaum, Brian D., primary, Messing, James, additional, Nakamura, Haruko, additional, Yurtsever, Ugur, additional, Wu, Jinjun, additional, Kim, Hong Joo, additional, Hixon, Jeff, additional, Lemieux, Rene, additional, Duffner, Jay, additional, Huynh, Walter, additional, Wong, Kathy, additional, White, Michael, additional, Lee, Christia, additional, Meyers, Rachel, additional, Parker, Roy, additional, and Taylor, J. Paul, additional
- Published
- 2023
- Full Text
- View/download PDF
4. AG-348 enhances pyruvate kinase activity in red blood cells from patients with pyruvate kinase deficiency
- Author
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Kung, Charles, Hixon, Jeff, Kosinski, Penelope A., Cianchetta, Giovanni, Histen, Gavin, Chen, Yue, Hill, Collin, Gross, Stefan, Si, Yaguang, Johnson, Kendall, DeLaBarre, Byron, Luo, Zhiyong, Gu, Zhiwei, Yao, Gui, Tang, Huachun, Fang, Cheng, Xu, Yingxia, Lv, Xiaobing, Biller, Scott, Su, Shin-San Michael, Yang, Hua, Popovici-Muller, Janeta, Salituro, Francesco, Silverman, Lee, and Dang, Lenny
- Published
- 2017
- Full Text
- View/download PDF
5. Abstract ND01: KSQ-4279: A first-in-class USP1 inhibitor for the treatment of cancers with homologous recombination deficiencies
- Author
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Cadzow, Louise, primary, Tobin, Erica, additional, Sullivan, Pamela, additional, Shenker, Sol, additional, Nayak, Sumeet, additional, Ali, Janid, additional, Gannon, Hugh, additional, Dodson, Anne, additional, Grasberger, Paula, additional, Carlson, Alyssa, additional, McGuire, Michael, additional, Brenneman, Jehrod, additional, Liu, Hanlan, additional, Olaharski, Andrew, additional, Sinkevicius, Kerstin, additional, Hixon, Jeff, additional, Krall, Elsa, additional, Schlabach, Mike, additional, Goulet, Matt, additional, Wilt, Jeremy, additional, Harris, Patricia, additional, Stegmeier, Frank, additional, and Wylie, Andrew, additional
- Published
- 2022
- Full Text
- View/download PDF
6. 2020 Calendar Year Digital Book eLending Statistics.
- Author
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Hixon, Jeff. Schafer, Andy. Kansas Government Information (KGI) Online Library., Kansas State Library. Division of Statewide Services., Hixon, Jeff. Schafer, Andy. Kansas Government Information (KGI) Online Library., and Kansas State Library. Division of Statewide Services.
- Abstract
See tabs below for each platform's specific collection, circulation, and usage statistics. Questions about these statistics? Please email audiobooks@ks.gov Please note that not all services have the same statistics possible. Example: E-STAX only tracks materials usage. BookFlix tracks materials usage and number of sessions. What platforms can I get just local stats for? RBdigital (formly OneClick) has circulation by zip code, and quarterly we run patrons by zip as well. See Librarians->Digital Book eLending->Stats for those spreadsheets. BookFlix - local stats available with local setup (available for all libraries). Form on Librarians->Digital Book eLending->Linking eBooks - coming later, we'll be able to extract stats based on the Kansas Library eCard. Progress: Freading - COMPLETE - See Librarians->Digital Book eLending->Stats for spreadsheet. Cloud Library - COMPLETE - See Librarians->Digital Book eLending->Stats for spreadsheet. Enki - testing complete, shelved for now while they work on the SimplyE project.
- Published
- 2021
7. 2018 Calendar Year Digital Book eLending Statistics.
- Author
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Hixon, Jeff. Schafer, Andy. Kansas Government Information (KGI) Online Library., Kansas State Library. Division of Statewide Services., Hixon, Jeff. Schafer, Andy. Kansas Government Information (KGI) Online Library., and Kansas State Library. Division of Statewide Services.
- Abstract
For "1. Stats-DigitalBooks" click on "OPEN WITH" at top of screen and select "GOOGLE SHEETS" to view full document. BE SURE TO CLICK ON TABS AT THE BOTTOM OF THIS GOOGLE DOCUMENT FOR OTHER PAGES WITHIN THE DOCUMENT. "See tabs below for each platform's specific collection, circulation, and usage statistics." "Questions about these statistics? Please email audiobooks@ks.gov" "Please note that not all services have the same statistics possible. Example: E-STAX only tracks materials usage. BookFlix tracks materials usage and number of sessions." "What platforms can I get just local stats for? RBdigital (formly OneClick) has circulation by zip code, and quarterly we run patrons by zip as well. See Librarians->Digital Book eLending->Stats for those spreadsheets. BookFlix - local stats available with local setup (available for all libraries). Form on Librarians->Digital Book eLending->Linking eBooks - coming later, we'll be able to extract stats based on the Kansas Library eCard. Progress: Freading - COMPLETE - See Librarians->Digital Book eLending->Stats for spreadsheet. Cloud Library - COMPLETE - See Librarians->Digital Book eLending->Stats for spreadsheet. Enki - testing complete, shelved for now while they work on the SimplyE project. Total Boox - when they rolled out the code it deleted all previous patron checkouts (this was undone). We have asked them to shelve the project for now and revisit after future updates."
- Published
- 2019
8. 2017 Calendar Year Digital Book eLending Statistics.
- Author
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Hixon, Jeff. Flax, Lianne. Kansas Government Information (KGI) Online Library., Kansas State Library. Division of Statewide Services., Hixon, Jeff. Flax, Lianne. Kansas Government Information (KGI) Online Library., and Kansas State Library. Division of Statewide Services.
- Abstract
For "1. Stats-DigitalBooks" click on "OPEN WITH" at top of screen and select "GOOGLE SHEETS" to view full document. BE SURE TO CLICK ON TABS AT THE BOTTOM OF THIS GOOGLE DOCUMENT FOR OTHER PAGES WITHIN THE DOCUMENT. "See tabs below for each platform's specific collection, circulation, and usage statistics." "Questions about these statistics? Please email audiobooks@ks.gov" "Please note that not all services have the same statistics possible. Example: E-STAX only tracks materials usage. BookFlix tracks materials usage and number of sessions." "What platforms can I get just local stats for? RBdigital (formly OneClick) has circulation by zip code, and quarterly we run patrons by zip as well. See Librarians->Digital Book eLending->Stats for those spreadsheets. BookFlix - local stats available with local setup (available for all libraries). Form on Librarians->Digital Book eLending->Linking eBooks - coming later, we'll be able to extract stats based on the Kansas Library eCard. Progress: Freading - COMPLETE - See Librarians->Digital Book eLending->Stats for spreadsheet. Enki - testing complete, shelved for now while they work on the SimplyE project. Cloud Library - restarting project (April 2017) Total Boox - when they rolled out the code it deleted all previous patron checkouts (this was undone). We have asked them to shelve the project for now and revisit after future updates."
- Published
- 2018
9. 2016 Calendar Year Digital Book eLending Statistics.
- Author
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Hixon, Jeff. Flax, Lianne. Kansas Government Information (KGI) Online Library., Kansas State Library. Division of Statewide Services., Hixon, Jeff. Flax, Lianne. Kansas Government Information (KGI) Online Library., and Kansas State Library. Division of Statewide Services.
- Abstract
For "1. Stats-DigitalBooks" click on "OPEN WITH" at top of screen and select "GOOGLE SHEETS" to view full document. BE SURE TO CLICK ON TABS AT THE BOTTOM OF THIS GOOGLE DOCUMENT FOR OTHER PAGES WITHIN THE DOCUMENT. 1. Stats-DigitalBooks-2016 (State Library of Kansas Digital Book Statistics - MULTIPLE TABS: About; OneClickdigital; Cloud Library; Freading; Enki Library; Freading; Total Boox; BookFlix; Tumblebooks; E-STAX). "See tabs below for each platform's specific collection, circulation, and usage statistics." "Please note that not all services have the same statistics possible. Example: TumbleBooks only tracks materials usage. BookFlix tracks materials usage and number of sessions." "What platforms can I get just local stats for? OneClickdigital has circulation by zip code, and quarterly we run patrons by zip as well. See Librarians->Digital Book eLending->Stats for those spreadsheets. BookFlix - local stats available with local setup (available for all libraries). Form on Librarians->Digital Book eLending->Linking eBooks - coming later, we'll be able to extract stats based on the Kansas Library eCard. Progress: Freading - COMPLETE Enki - testing complete, shelved for now while they work on the SimplyE project. Cloud Library - testing Total Boox - when they rolled out the code it deleted all previous patron checkouts (this was undone). We have asked them to shelve the project for now and revisit after future updates."
- Published
- 2017
10. 2015 Calendar Year Digital Book eLending Statistics.
- Author
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Hixon, Jeff. Flax, Lianne. Kansas Government Information (KGI) Online Library., Kansas State Library. Division of Statewide Services., Hixon, Jeff. Flax, Lianne. Kansas Government Information (KGI) Online Library., and Kansas State Library. Division of Statewide Services.
- Abstract
For "1. Stats-DigitalBooks" and "3. OneClickDigital-CircByZip" Click on "OPEN WITH" at top of screen and select "GOOGLE SHEETS" to view full documents. BE SURE TO CLICK ON TABS AT THE BOTTOM OF THESE GOOGLE SHEETS FOR OTHER PAGES WITHIN THE DOCUMENT. "See tabs below for each platform's specific collection, circulation, and usage statistics." "Questions about these statistics? Please email audiobooks@ks.gov" "Please note that not all services have the same statistics possible. Example: E-STAX only tracks materials usage. BookFlix tracks materials usage and number of sessions." "What platforms can I get just local stats for? OneClick has circulation by zip code, and quarterly we run patrons by zip as well. See Librarians->Digital Book eLending->Stats for those spreadsheets. BookFlix - local stats available with local setup (available for all libraries). Form on Librarians->Digital Book eLending->Linking" edited and arranged by Jeff Hixon, Kansas State Library Division of Statewide Services.
- Published
- 2016
11. 2014 Calendar Year Digital Book eLending Statistics.
- Author
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Hixon, Jeff. Flax, Lianne. Kansas Government Information (KGI) Online Library., Kansas State Library. Division of Statewide Services., Hixon, Jeff. Flax, Lianne. Kansas Government Information (KGI) Online Library., and Kansas State Library. Division of Statewide Services.
- Abstract
"See tabs below for each platform's specific collection, circulation, and usage statistics." For "1. Stats-DigitalBooks" and "3. OneClickDigital-CircByZip" Click on "OPEN WITH" at top of screen and select "GOOGLE SHEETS" to view full documents. BE SURE TO CLICK ON TABS AT THE BOTTOM OF THESE GOOGLE SHEETS FOR OTHER PAGES WITHIN THE DOCUMENT. edited and arranged by Jeff Hixon, Kansas State Library Division of Statewide Services. "See tabs below for each platform's specific collection, circulation, and usage statistics." "Questions about these statistics? Please email audiobooks@ks.gov" "Please note that not all services have the same statistics possible. Example: E-STAX only tracks materials usage. BookFlix tracks materials usage and number of sessions." "What platforms can I get just local stats for? OneClick has circulation by zip code, and quarterly we run patrons by zip as well. See Librarians->Digital Book eLending->Stats for those spreadsheets. BookFlix - local stats available with local setup (available for all libraries). Form on Librarians->Digital Book eLending->Linking"
- Published
- 2015
12. 2013 Calendar Year Digital Book eLending Statistics.
- Author
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Hixon, Jeff. Flax, Lianne. Kansas Government Information (KGI) Online Library., Kansas State Library. Division of Statewide Services., Hixon, Jeff. Flax, Lianne. Kansas Government Information (KGI) Online Library., and Kansas State Library. Division of Statewide Services.
- Abstract
For "1. Stats-DigitalBooks" and "3. OneClickDigital-CircByZip" Click on "OPEN WITH" at top of screen and select "GOOGLE SHEETS" to view full documents. BE SURE TO CLICK ON TABS AT THE BOTTOM OF THESE GOOGLE SHEETS FOR OTHER PAGES WITHIN THE DOCUMENT. edited and arranged by Jeff Hixon, Kansas State Library Division of Statewide Services.
- Published
- 2014
13. AG-348 Activation of Pyruvate Kinase in Vivo Enhances Red Cell Glycolysis in Mice
- Author
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Kung, Charles, primary, Hill, Collin, additional, Chen, Yue, additional, Jha, Abhishek, additional, Kosinski, Penelope, additional, Clasquin, Michelle, additional, Si, Yaguang, additional, Kim, Hyeryun, additional, Hixon, Jeff, additional, Dang, Lenny, additional, Agresta, Sam, additional, Silverman, Lee, additional, and Yang, Hua, additional
- Published
- 2014
- Full Text
- View/download PDF
14. AG-348 enhances pyruvate kinase activity in red blood cells from patients with pyruvate kinase deficiency.
- Author
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Charles Kung, Hixon, Jeff, Kosinski, Penelope A., Cianchetta, Giovanni, Histen, Gavin, Yue Chen, Hill, Collin, Gross, Stefan, Yaguang Si, Johnson, Kendall, DeLaBarre, Byron, Zhiyong Luo, Zhiwei Gu, Gui Yao, Huachun Tang, Cheng Fang, Yingxia Xu, Xiaobing Lv, Biller, Scott, and Michael Su, Shin-San
- Subjects
- *
HEMOLYTIC anemia , *PYRUVATE kinase , *ERYTHROCYTES , *GLYCOLYSIS , *CLINICAL trials - Abstract
Pyruvate kinase (PK) deficiency is a rare genetic disease that causes chronic hemolytic anemia. There are currently no targeted therapies for PKdeficiency. Here,we describe the identification and characterization of AG-348, an allosteric activator ofPKthat is currently in clinical trials for the treatment of PK deficiency. We demonstrate that AG-348 can increase the activity of wild-type and mutant PK enzymes in biochemical assays and in patient red blood cells treated ex vivo. These data illustrate the potential for AG-348 to restore the glycolytic pathway activity in patients withPKdeficiencyand ultimately lead to clinical benefit. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
15. Effects of thermal aging on Stress Corrosion Cracking and mechanical properties of stainless steel weld metals
- Author
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Ronald G. Ballinger., Massachusetts Institute of Technology. Dept. of Nuclear Science and Engineering., Hixon, Jeff, Ronald G. Ballinger., Massachusetts Institute of Technology. Dept. of Nuclear Science and Engineering., and Hixon, Jeff
- Abstract
Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Nuclear Science and Engineering, 2006., Includes bibliographical references (p. 589)., Stress Corrosion Cracking (SCC) in and around primary loop piping welds in Boiling Water Reactors has been observed worldwide as plants continue to operate at temperatures and pressures near 2880C (5500F) and 6.9 MPa (1000 PSI). An experimental program was designed to explore the effect of thermal aging on the SCC crack growth rate in weld materials for type 316 and 304 stainless steels. An autoclave facility was designed and constructed for the measurement of SCC crack growth rates under BWR conditions and testing was underway at the time of this writing. The effects of composition and thermal aging on mechanical properties (i.e. tensile, micro-hardness, nano-hardness, Jic, and Charpy-impact toughness) was in process and initial results show an increase in yield strength and a decrease in fracture toughness after aging for 1000 hours at 430 and 400 *C. Thermal aging results in no discernable changes to the 6-ferrite morphology when viewed optically at 500 X agnifications and in the scanning electron microscope., by Jeff Hixon., S.M.
- Published
- 2008
16. Small Molecule Activation Of Pyruvate Kinase Normalizes Metabolic Activity In Red Cells From Patients With Pyruvate Kinase Deficiency-Associated Hemolytic Anemia
- Author
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Kung, Charles, primary, Hixon, Jeff, additional, Kosinski, Penelope, additional, Histen, Gavin, additional, Hill, Collin, additional, Si, Yaguang, additional, Kernytsky, Andrew, additional, Chen, Yue, additional, DeLaBarre, Byron, additional, Clasquin, Michelle, additional, Ho, Helen, additional, Cossor, Furha I., additional, Neufeld, Ellis J., additional, Salituro, Frank, additional, Popovici-Muller, Janeta, additional, Agresta, Samuel, additional, Silverman, Lee, additional, and Dang, Lenny, additional
- Published
- 2013
- Full Text
- View/download PDF
17. Small Molecule Activation of PKM2 in Cancer Cells Induces Serine Auxotrophy
- Author
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Kung, Charles, primary, Hixon, Jeff, additional, Choe, Sung, additional, Marks, Kevin, additional, Gross, Stefan, additional, Murphy, Erin, additional, DeLaBarre, Byron, additional, Cianchetta, Giovanni, additional, Sethumadhavan, Shalini, additional, Wang, Xiling, additional, Yan, Shunqi, additional, Gao, Yi, additional, Fang, Cheng, additional, Wei, Wentao, additional, Jiang, Fan, additional, Wang, Shaohui, additional, Qian, Kevin, additional, Saunders, Jeff, additional, Driggers, Ed, additional, Woo, Hin Koon, additional, Kunii, Kaiko, additional, Murray, Stuart, additional, Yang, Hua, additional, Yen, Katharine, additional, Liu, Wei, additional, Cantley, Lewis C., additional, Vander Heiden, Matthew G., additional, Su, Shinsan M., additional, Jin, Shengfang, additional, Salituro, Francesco G., additional, and Dang, Lenny, additional
- Published
- 2012
- Full Text
- View/download PDF
18. Abstract 1002: Induced dependency on amino acid metabolism in proliferating cancer cells upon PKM2 activation
- Author
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Kung, Charles, primary, Jin, Shengfang, additional, Hixon, Jeff, additional, Gross, Stefan, additional, Gao, Yi, additional, Cheng, Fang, additional, Wang, Xiling, additional, Wang, Shaohui, additional, Salituro, Francesco, additional, Saunders, Jeff, additional, Driggers, Ed, additional, Marks, Kevin, additional, Woo, Hin Koon, additional, Murray, Stuart, additional, Choe, Sung, additional, Yang, Hua, additional, Yen, Katherine, additional, Su, Michael, additional, and Dang, Lenny, additional
- Published
- 2012
- Full Text
- View/download PDF
19. Myths, mistakes, and making it in voiceover
- Author
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Hixon, Jeff
- Subjects
Arts and entertainment industries ,Business - Abstract
It's true every facet of the entertainment business has its share of myths--from Lana Turner's discovery at Schwab's Drugstore to recent sightings of Elvis. And the voiceover industry is no [...]
- Published
- 2011
20. Identification of small molecule inhibitors of G3BP-driven stress granule formation.
- Author
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Freibaum, Brian D., Messing, James, Haruko Nakamura, Yurtsever, Ugur, Jinjun Wu, Hong Joo Kim, Hixon, Jeff, Lemieux, Rene Marc, Duffner, Jay, Huynh, Walter, Wong, Kathy, White, Michael, Lee, Christina, Meyers, Rachel E., Parker, Roy, and Taylor, J. Paul
- Subjects
- *
SMALL molecules , *RNA-binding proteins , *GRANULE cells , *DISEASE progression , *NEURODEGENERATION - Abstract
Stress granule formation is triggered by the release of mRNAs from polysomes and is promoted by the action of the RNA-binding proteins G3BP1/2. Stress granules have been implicated in several disease states, including cancer and neurodegeneration. Consequently, compounds that limit stress granule formation or promote their dissolution have potential as both experimental tools and novel therapeutics. Herein, we describe two small molecules, G3BP inhibitor a and b (G3Ia and G3Ib), designed to bind to a specific pocket in G3BP1/2 that is targeted by viral inhibitors of G3BP1/2 function. In addition to disrupting the co-condensation of RNA, G3BP1, and caprin 1 in vitro, these compounds inhibit stress granule formation in cells treated prior to or concurrent with stress and dissolve pre-existing stress granules. These effects are consistent across multiple cell types and a variety of initiating stressors. Thus, these compounds represent powerful tools to probe the biology of stress granules and hold promise for therapeutic interventions designed to modulate stress granule formation. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
21. The USP1 Inhibitor KSQ-4279 Overcomes PARP Inhibitor Resistance in Homologous Recombination-Deficient Tumors.
- Author
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Cadzow L, Brenneman J, Tobin E, Sullivan P, Nayak S, Ali JA, Shenker S, Griffith J, McGuire M, Grasberger P, Mishina Y, Murray M, Dodson AE, Gannon H, Krall E, Hixon J, Chipumuro E, Sinkevicius K, Gokhale PC, Ganapathy S, Matulonis UA, Liu JF, Olaharski A, Sangurdekar D, Liu H, Wilt J, Schlabach M, Stegmeier F, and Wylie AA
- Subjects
- Humans, Animals, Mice, Female, BRCA2 Protein genetics, BRCA2 Protein deficiency, Cell Line, Tumor, Homologous Recombination, Neoplasms drug therapy, Neoplasms genetics, Neoplasms pathology, Mutation, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, Poly(ADP-ribose) Polymerase Inhibitors therapeutic use, Drug Resistance, Neoplasm genetics, Xenograft Model Antitumor Assays, Ubiquitin-Specific Proteases genetics, Ubiquitin-Specific Proteases antagonists & inhibitors, Ubiquitin-Specific Proteases metabolism, BRCA1 Protein deficiency, BRCA1 Protein genetics
- Abstract
Defects in DNA repair pathways play a pivotal role in tumor evolution and resistance to therapy. At the same time, they create vulnerabilities that render tumors dependent on the remaining DNA repair processes. This phenomenon is exemplified by the clinical activity of PARP inhibitors in tumors with homologous recombination (HR) repair defects, such as tumors with inactivating mutations in BRCA1 or BRCA2. However, the development of resistance to PARP inhibitors in BRCA-mutant tumors represents a high unmet clinical need. In this study, we identified deubiquitinase ubiquitin-specific peptidase-1 (USP1) as a critical dependency in tumors with BRCA mutations or other forms of HR deficiency and developed KSQ-4279, the first potent and selective USP1 inhibitor to enter clinical testing. The combination of KSQ-4279 with a PARP inhibitor was well tolerated and induced durable tumor regression across several patient-derived PARP-resistant models. These findings indicate that USP1 inhibitors represent a promising therapeutic strategy for overcoming PARP inhibitor resistance in patients with BRCA-mutant/HR-deficient tumors and support continued testing in clinical trials. Significance: KSQ-4279 is a potent and selective inhibitor of USP1 that induces regression of PARP inhibitor-resistant tumors when dosed in combination with PARP inhibitors, addressing an unmet clinical need for BRCA-mutant tumors., (©2024 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2024
- Full Text
- View/download PDF
22. Interaction between host G3BP and viral nucleocapsid protein regulates SARS-CoV-2 replication.
- Author
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Yang Z, Johnson BA, Meliopoulos VA, Ju X, Zhang P, Hughes MP, Wu J, Koreski KP, Chang TC, Wu G, Hixon J, Duffner J, Wong K, Lemieux R, Lokugamage KG, Alvardo RE, Crocquet-Valdes PA, Walker DH, Plante KS, Plante JA, Weaver SC, Kim HJ, Meyers R, Schultz-Cherry S, Ding Q, Menachery VD, and Taylor JP
- Abstract
G3BP1/2 are paralogous proteins that promote stress granule formation in response to cellular stresses, including viral infection. G3BP1/2 are prominent interactors of the nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the functional consequences of the G3BP1-N interaction in the context of viral infection remain unclear. Here we used structural and biochemical analyses to define the residues required for G3BP1-N interaction, followed by structure-guided mutagenesis of G3BP1 and N to selectively and reciprocally disrupt their interaction. We found that mutation of F17 within the N protein led to selective loss of interaction with G3BP1 and consequent failure of the N protein to disrupt stress granule assembly. Introduction of SARS-CoV-2 bearing an F17A mutation resulted in a significant decrease in viral replication and pathogenesis in vivo, indicating that the G3BP1-N interaction promotes infection by suppressing the ability of G3BP1 to form stress granules., Competing Interests: Conflict of interest: JPT is a consultant for Nido Biosciences.
- Published
- 2023
- Full Text
- View/download PDF
23. Identification of small molecule inhibitors of G3BP-driven stress granule formation.
- Author
-
Freibaum BD, Messing J, Nakamura H, Yurtsever U, Wu J, Kim HJ, Hixon J, Lemieux R, Duffner J, Huynh W, Wong K, White M, Lee C, Meyers R, Parker R, and Taylor JP
- Abstract
Stress granule formation is triggered by the release of mRNAs from polysomes and is promoted by the action of the paralogs G3BP1 and G3BP2. G3BP1/2 proteins bind mRNAs and thereby promote the condensation of mRNPs into stress granules. Stress granules have been implicated in several disease states, including cancer and neurodegeneration. Consequently, compounds that limit stress granule formation or promote their dissolution have potential as both experimental tools and novel therapeutics. Herein, we describe two small molecules, referred to as G3BP inhibitor a and b (G3Ia and G3Ib), designed to bind to a specific pocket in G3BP1/2 that is known to be targeted by viral inhibitors of G3BP1/2 function. In addition to disrupting co-condensation of RNA, G3BP1, and caprin 1 in vitro , these compounds inhibit stress granule formation in cells treated prior to or concurrent with stress, and dissolve pre-existing stress granules when added to cells after stress granule formation. These effects are consistent across multiple cell types and a variety of initiating stressors. Thus, these compounds represent ideal tools to probe the biology of stress granules and hold promise for therapeutic interventions designed to modulate stress granule formation., Competing Interests: Conflict of interest: JPT is a consultant for Nido Biosciences.
- Published
- 2023
- Full Text
- View/download PDF
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