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1,142 results on '"Chang, Michelle"'

1. Investigating impacts of the mycothiazole chemotype as a chemical probe for the study of mitochondrial function and aging

Author

Dutta, Naibedya, Gerke, Joe A., Odron, Sofia F., Morris, Joseph D., Hruby, Adam, Kim, Juri, Torres, Toni Castro, Shemtov, Sarah J., Clarke, Jacqueline G., Chang, Michelle C., Shaghasi, Hooriya, Ray, Marissa N., Averbukh, Maxim, Hoang, Sally, Oorloff, Maria, Alcala, Athena, Vega, Matthew, Mehta, Hemal H., Thorwald, Max A., Crews, Phillip, Vermulst, Marc, Garcia, Gilberto, Johnson, Tyler A., and Higuchi-Sanabria, Ryo

Published
2024
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4. Geospatial analysis of Plasmodium falciparum serological indicators: school versus community sampling in a low-transmission malaria setting

Author

Jaramillo-Underwood, Alicia, Herman, Camelia, Jean, Samuel E., Nace, Doug, Elder, E. Scott, Robinson, Keri, Knipes, Alaine, Worrell, Caitlin M., Fox, LeAnne M., Desir, Luccene, Fayette, Carl, Javel, Alain, Monestime, Franck, Mace, Kimberly E., Udhayakumar, Venkatachalam, Won, Kimberly Y., Chang, Michelle A., Lemoine, Jean F., and Rogier, Eric

Published
2024
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6. A cellular platform for production of C4 monomers.

Author

Davis, Matthew, Yu, Vivian, Fu, Beverly, Wen, Miao, Koleski, Edward, Silverman, Joshua, Berdan, Charles, Nomura, Daniel, and Chang, Michelle

Abstract

Living organisms carry out a wide range of remarkable functions, including the synthesis of thousands of simple and complex chemical structures for cellular growth and maintenance. The manipulation of this reaction network has allowed for the genetic engineering of cells for targeted chemical synthesis, but it remains challenging to alter the program underlying their fundamental chemical behavior. By taking advantage of the unique ability of living systems to use evolution to find solutions to complex problems, we have achieved yields of up to ∼95% for three C4 commodity chemicals, n-butanol, 1,3-butanediol, and 4-hydroxy-2-butanone. Genomic sequencing of the evolved strains identified pcnB and rpoBC as two gene loci that are able to alter carbon flow by remodeling the transcriptional landscape of the cell, highlighting the potential of synthetic pathways as a tool to identify metabolic control points.

Published
2023

7. Biocatalytic control of site-selectivity and chain length-selectivity in radical amino acid halogenases

Author

Kissman, Elijah N, Neugebauer, Monica E, Sumida, Kiera H, Swenson, Cameron V, Sambold, Nicholas A, Marchand, Jorge A, Millar, Douglas C, and Chang, Michelle CY

Subjects
Inorganic Chemistry, Organic Chemistry, Chemical Sciences, Amino Acids, Lysine, Halogenation, Ornithine, biocatalysis, enzymology, bioinorganic chemistry, structural biology, C-H activation
Abstract

Biocatalytic C-H activation has the potential to merge enzymatic and synthetic strategies for bond formation. FeII/αKG-dependent halogenases are particularly distinguished for their ability both to control selective C-H activation as well as to direct group transfer of a bound anion along a reaction axis separate from oxygen rebound, enabling the development of new transformations. In this context, we elucidate the basis for the selectivity of enzymes that perform selective halogenation to yield 4-Cl-lysine (BesD), 5-Cl-lysine (HalB), and 4-Cl-ornithine (HalD), allowing us to probe how site-selectivity and chain length selectivity are achieved. We now report the crystal structure of the HalB and HalD, revealing the key role of the substrate-binding lid in positioning the substrate for C4 vs C5 chlorination and recognition of lysine vs ornithine. Targeted engineering of the substrate-binding lid further demonstrates that these selectivities can be altered or switched, showcasing the potential to develop halogenases for biocatalytic applications.

Published
2023

9. Engineering site-selective incorporation of fluorine into polyketides.

Author

Sirirungruang, Sasilada, Ad, Omer, Privalsky, Thomas, Ramesh, Swetha, Sax, Joel, Dong, Hongjun, Baidoo, Edward, Amer, Bashar, Khosla, Chaitan, and Chang, Michelle

Subjects
Acyltransferases, Biological Products, Escherichia coli, Fluorine, Polyketides
Abstract

Although natural products and synthetic small molecules both serve important medicinal functions, their structures and chemical properties are relatively distinct. To expand the molecular diversity available for drug discovery, one strategy is to blend the effective attributes of synthetic and natural molecules. A key feature found in synthetic compounds that is rare in nature is the use of fluorine to tune drug behavior. We now report a method to site-selectively incorporate fluorine into complex structures to produce regioselectively fluorinated full-length polyketides. We engineered a fluorine-selective trans-acyltransferase to produce site-selectively fluorinated erythromycin precursors in vitro. We further demonstrated that these analogs could be produced in vivo in Escherichia coli on engineering of the fluorinated extender unit pool. By using engineered microbes, elaborate fluorinated compounds can be produced by fermentation, offering the potential for expanding the identification and development of bioactive fluorinated small molecules.

Published
2022

11. Factors Associated With Coronary Angiography Performed Within 6 Months of Randomization to the Conservative Strategy in the ISCHEMIA Trial

Author

Pracoń, Radosław, Spertus, John A., Broderick, Samuel, Bangalore, Sripal, Rockhold, Frank W., Ruzyllo, Witold, Demchenko, Elena, Nageh, Thuraia, Grossman, Gabriel Blacher, Mavromatis, Kreton, Manjunath, Cholenahally N., Smanio, Paola E.P., Stone, Gregg W., Mancini, G.B. John, Boden, William E., Newman, Jonathan D., Reynolds, Harmony R., Hochman, Judith S., Maron, David J., Doan, John, Linefsky, Jason, Lee, Raven, Patel, Risha, Miller, Todd, Yang Cho, So, Milbrandt, Susan, Shelstad, Dawn, Banerjee, Subhash, Kamath, Preeti, Tejani, Ishita, Cobos, Stanley E., Quiles, Kirsten J., Dwyer, Raven R., Donnino, Robert M., Espinosa, Dalisa, Phillips, Lawrence M., Saric, Muhamed, Abdul-Nour, Khaled, Schley, Allison, Golden, Heather, Stone, Peter H., Osseni, Hermine, Wiyarand, Charlene, Douglass, Peter, Pomeroy, Hayley, Craft, Alexandra, Harvey, Bethany, Jang, James J., Anaya, Olivia, Yee, Gennie, Goold, Phoebe, Weitz, Steven, Giovannone, Steven, Pritchard, Lori, Arnold, Suzanne, Gans, Rosann, Henry O’Keefe, Jr, James, Kennedy, Paul, Shapiro, Michael D., Ganesan, Shobana, Schlichting, David, Naher, Aynun, El-Hajjar, Mohammad, Sidhu, Mandeep S., Fein, Steven A., Stewart, Wendy L., Torosoff, Mikhail T., Salmi, Kristin M., Lyubarova, Radmila, Mookherjee, Sulagna, Drzymalski, Krzysztof, McFalls, Edward O., Garcia, Santiago A., Bertog, Stefan C., Johnson, Debra K., Siddiqui, Rizwan A., Herrmann, Rebekah R., Ishani, Areef, Hansen, Ronnell A., Georges Khouri, Michel, Arges, Kristine, LeFevre, Melissa, Tomfohr, Jennifer, Goldberg, Jonathan L., Ann Byrne, Kimberly, Zappernick, Taissa, Goldweit, Richard, Canada, Sallie, Kakade, Meghana, Mieses, Patricia, Cobos, Stanley E., Dwyer, Raven R., Cohen, Ronny A., Espinosa, Dalisa, Mirrer, Brooks, Quiles, Kirsten J., Navarro, Victor, Rantinella, Magdalena, Rodriguez, Jessica, Mancilla, Olivia, Winchester, David E., Stinson, Susan, Kronenberg, Marvin, Weyand, Terry, Rogal, Philip, Crook, Sherron C., McFarren, Christopher, Heitner, John F., Ho, Jean, Khan, Saadat, Mohamed, Mahmoud, Dauber, Ira M., Soltau, Mary R., Rose, Delsa K., Wimmer, Rebecca J., Siegel, Kathy E., Derbyshire, Susan, Cannan, Charles, Dixon, Michelle, Leonard, Gerald, Sudarshan, Sriram, Heard, Ciarra, Gabriel, Viviana, Desire, Sukie, Mehta, Puja K., McDaniel, Michael, Rashid, Fauzia, Lerakis, Stamatios, Asier, Senait, Quyyumi, Arshed, Patel, Keyur, Wenger, Nanette K., Hedgepeth, Chester M., Gillis, Jennifer, Hurlburt, Heather, Manocchia, Megan, Rosen, Alan, Moore, Susan, Congdon, Elizabeth, Sahul, Zakir, Brandt, Gail, Marchelletta, Nora, Wippler, Kristina, Booth, David, Taul, Yvonne, Leung, Steve, Isaacs, Jennifer, Abdel-Latif, Ahmed, Bulkley, Viktoria, Reda, Hassan, Rodgers, Caroline, Ziada, Khaled, Setty, Sampoornima, Halverson, Kimberly E., Roraff, Christine, Thorsen, Jonean, Barua, Rajat S., Ojajuni, Amarachi, Olurinde, Oni, Surineni, Kamalakar, Hage, Fadi, Valaiyapathi, Badhma, Caldeira, Christiano, Davies, James E., Leesar, Massoud, Heo, Jaekyeong, Iskandrian, Amy, Al Solaiman, Firas, Singh, Satinder, Dajani, Khaled, Kartje, Carol M., El-Hajjar, Mohammad, Mesropian, Paul Der, Sacco, Joseph, Rawlins, Michele, McCandless, Brian, Thomson, Jennifer, Orgera, Marisa, Sidhu, Mandeep S., Colleen Rogge, Mary, Arif, Imran, Bunke, Julie, Kerr, Hanan, Unterbrink, Kendra, Fannon, Jacqueline, Burman, Cynthia, Trejo, Jorge F., Dubin, Marcia F., Fletcher, Gerald, Lane, Gary E., Neeson, Lynn M., Parikh, Pragnesh P., Pollak, Peter M., Shapiro, Brian P., Landolfo, Kevin, Gemignani, Anthony, Beaudry, Sarah, O’Rourke, Daniel, Meadows, Judith L., Tirado, Stephanie A., Halliday, Janet, Julian, Pamela, Call, Jason T., Lane, Stephanie M., Stanford, Jennifer L., Hannan, Joseph, Bojar, Robert, Arsenault, Patricia, Kumar, Deepti, Sigel, Pamela, Mukai, John, Martin, Edward T., Brooks, Miriam, Vorobiof, Gabriel, Douangvila, Ladda, Gevorgyan, Rubine, Moorman, Alec, Ranjbaran, Fatima, Smith, Bryn, Ohmart, Carly, Kinlay, Scott, Hamburger, Robert J., Rocco, Thomas P., Ly, Samantha, Bhatt, Deepak L., Quinn, Margot C., Croce, Kevin, Temiyasathit, Sara, Quin, Jacquelyn A, Do, Jacquelyn, Anumpa, Jati, Tobin, Desiree, Zenati, Marco, Faxon, David P, Rayos, Glenn, Langdon, Jennifer, Werner Bayer, Marcia, Seedhom, Ashraf, O’Malley, Amanda, Sullenberger, Lance, Orvis, Erin, Kumkumian, Gregory, Murphy, Mandy, Greenberg, Ann, Iraola, Margaret, Sedlis, Steven P., Maranan, Leandro C., Donnino, Robert M., Lorin, Jeffrey, Tamis-Holland, Jacqueline E., Malinay, Ammy, Kornberg, Robert, Leber, Robert, Saba, Souheil, Edillo, Candice P., Lee, Michael W., Small, Delano R., Nona, Wassim, Alexander, Patrick B., Rehman, Iram, Badami, Umesh, Ostrander, Ann, Wasmiller, Stephanie, Marzo, Kevin, Drewes, Wendy, Patel, Dipti, Robbins, Inga H., Levite, Howard A., White, Jackie M, Shetty, Sanjay, Hallam, Alison, Patel, Mayuri, Hamroff, Glenn S., Spooner, Benjamin J, Hollenweger, Linda M, Little, Raymond W., Little, Holly, Zimbelman, Brandi D., Little, Tiffany, Lui, Charles Y., Eskelson, Nona A, Smith, Brigham R., Vezina, Daniel P., Khor, Lillian L., Abraham, Josephine D., Bull, David A., McKellar, Stephen H., Booth, David, Taul, Yvonne, Kotter, John, Rodgers, Caroline, Abdel-Latif, Ahmed, Isaacs, Jennifer, Bulkley, Viktoria, Hu, Bob, Kaneshiro, Renee, Labovitz, Arthur J., Berlowitz, Michael, Kirby, Bonnie J., Rogal, Philip, Tran, Nhi N., McFarren, Christopher, Jahrsdorfer, Catherine, Matar, Fadi, Caldeira, Christiano, Rodriguez, Fatima, Yunis, Reem, Schnittger, Ingela, Patro, Jhina, Fearon, William F., Deedwania, Prakash, Vega, Antonia, Reddy, Kiran, Sweeny, Joseph, Bloise-Adames, Hugo, Jimenez, Santa, Saint Vrestil, Nicole, Bhandari, Reyna, Spizzieri, Christopher, Schade, Danielle, Yost, Roxanne, Hochberg, Claudia P, Beardsley, Paula, Fine, Denise, Salerno, William D., Tancredi, Jana, Arakelian, Patricia, Mathus, Susan, O’Neill, Deborah, Wyman, Ray, Burkhardt, Joy, Hosino, Suellen, Lubyanaya, Oksana A., Salas, Jose D., Zarka, Amer, Aguirre, Maria, Shah, Anil V., Dhawan, Manu, Parra, Diana, Tran, Tri, Haldis, Thomas, Weick, Catherine, Fowler-Lehman, Katie, Spitzer, Natalie, Riedberger, Casey, Weick, Catherine, Kohn, Jeffrey A., Cobos, Stanley E., Dwyer, Raven R., Espinosa, Dalisa, Quiles, Kirsten J., Girotra, Saket, Drum, Carrie, Miller-Cox, Kimberly, Ollinger, Amy, Almousalli, Omar, Capasso-Gulve, Elizabeth, Melanie Loehr, Alaine, Mosley, Marlowe, Krishnam, Mayil S., Heydari, Shirin, Milliken, Jeffrey C., Lundeen, Andrea M., Patel, Pranav M., Karanjah, Edgar, Seto, Arnold H., Marfori, Wanda C., Harley, Kevin T., Hernandez-Rangel, Eduardo, Gibson, Michael A., Singh, Pam, Allen, Byron J., Coram, Rita, Marie Webb, Anne, Fridell, Ellie, Wilson, Heidi, Thomas, Sabu, Kim, Angela, Schwartz, Ronald G, Wilmot, Patrick, Chen, Wei, El Shahawy, Mahfouz, Stevens, Ramona, Stafford, James, Black, Loriane, Abernethy, William B., Hull, Amber B., Lim, Olivia J., Tucker, Helen C., Putnam, Natasha C., Hall, Linda L., Cauthren, Tia, Tucker, Trish, Zurick, Andrew, Horton, Hollie, Orga, Jan, Meyer, Thomas M., White, Joyce R., Morford, Ronald G., Baumann, Cynthia, Rutkin, Bruce, Seeratan, Vidya, Bokhari, Sabahat, Jimenez, Magnolia, Sokol, Seth I., Schultz, Cidney, Meisner, Jay, Russo, Jeanne, Hamzeh, Ihab, Misra, Arunima, Huda, Zohra, Wall, Matthew, Boan, Araceli, Lenges De Rosen, Veronica, Alam, Mahboob, Turner, Michael C., Hinton, Christine R, Mulhearn, Thomas J., Good, Arnold P., Archer, Beth A., Dionne, Julia S., Allardyce, Cheryl A., Sikora, Lindsey N., Czerniak, Jennifer H., Mull, Jennifer A., Ferguson, Elizabeth, Laube, Frances, Shammas, Nicolas W., Shammas, Gail A, Christensen, Lori, Park, Holly, Chilton, Robert, Hecht, Joan, Nguyen, Patricia K., Vo, Davis, Hirsch, James, Jezior, Matthew, Bindeman, Jody, Salkind, Sara, Espinosa, Dalisa, Desimone, Lori-Ann, Gordon, Paul C., Felix-Stern, Lina, Crain, Thomas, Gomes, Jassira, Gordon, Catherine, Stenberg, Robert, Mann, Aimee, McCreary, Theresa, Pedalino, Ronald P., Cobos, Stanley E., Dwyer, Raven R., Espinosa, Dalisa, Quiles, Kirsten J., Wiesel, Joseph, Cobos, Stanley E., Dwyer, Raven R., Espinosa, Dalisa, Quiles, Kirsten J., Juang, George J., Gopaul, Candace, Hultberg, Karen, Huk, Tauqir, Hussain, Afshan, Al-Amoodi, Mohammed, Zambrano, Yesenia, Medina Rodriguez, Sarah, Milner, Trudie, Wohns, David, Mulder, Abbey, Van Oosterhout, Stacie, Lader, Ellis W., Meyer, Martha, Mumma, Michael, Clapp, Nancy L., Barrentine, Heather, Dharmarajan, Lekshmi, Jose, Jenne M., Cobos, Stanley E., Dwyer, Raven R., Espinosa, Dalisa, Quiles, Kirsten J., Manchery, Jenne, McGarvey Jr, Joseph F.X., McKinney, Vera, Schwarz, Linda, Downes, Thomas R., Kaczkowski, Scott M., Luckasen, Gary J., Jaskowiak, Adam J., Klitch, Joel, Cheong, Benjamin, Dees, Debra, Potluri, Srinivasa, Vasquez, Precilia, Mastouri, Ronald A., Breall, Jeffery A., Hannemann, Elise L., Revtyak, George E., Mae Foltz, Judy, Bazeley, Jonathan W., Li, Dayuan, DeRosa, Emily, Jorgenson, Beth, Riestenberg-Smith, Joyce, Giedd, Kenneth, Old, Wayne, Bariciano, Rebecca, Burt, Francis, Sokhon, Kozhaya, Waldron, Jessica, Mayon, Michelle, Gopal, Deepika, Valeti, Uma S., Ann Peichel, Gretchen, Kobashigawa, Jon, Starks, Brandy, Garcia, Lucilla, Thottam, Maria, Bhargava, Balram, Anand, Anjali, Chakanalil Govindan, Sajeev, Raj, Janitha, Gopalan Nair, Rajesh, Ravindran, Reshma, Rajalekshmi, VS, Nataraj, Nandita, Moorthy, Nagaraja, Nayak, Soundarya, Mylarappa, Mahevamma, Narayanappa, Suryaprakash, Pandit, Neeraj, Bajaj, Sheromani, Kumar Nath, Ranjit, Yadav, Vandana, Mishra, Girish, Dwivedi, S.K., Tewari, Roma, Narain, V.S., Mishra, Meenakshi, Chandra, Sharad, Patel, Shivali, Singh, Suman, Wander, Gurpreet S., Tandon, Rohit, Ralhan, Sarju, Kaur, Baljeet, Aslam, Naved, Gupta, Sonika, Goyal, Abhishek, Bhargava, Balram, Suvarna, Chandini, Karthikeyan, G., Ramakrishnan, S., Seth, Sandeep, Yadav, Rakesh, Singh, Sandeep, Roy, Ambuj, Parakh, Neeraj, Kumar Verma, Sunil, Narang, Rajiv, Mishra, Sundeep, Naik, Nitish, Sharma, Gautam, Kumar Choudhary, Shiv, Patel, Chetan, Gulati, Gurpreet, Sharma, Sanjeev, Bahl, V K, Mathew, Anoop, Mannekkattukudy Kurian, Binoy, Punnoose, Eapen, Avdhoot Gadkari, Milind, Rupesh Karwa, Sheetal, Gadage, Siddharth, Kolhe, Suvarna, Umesh Pillay, Tapan, Satheesh, Santhosh, Vindhya, R. J., Jain, Peeyush, Seth, Ashok, Singh Meharwal, Zile, Mathur, Atul, Verma, Atul, Kaul, Upendra, Bhatia, Mona, Sachdeva, Ankush, Indira Devi, Thounaojam, Jungla, Nungshi, Christopher, Johann, Manjula Rani, K., Menon, Rajeev, Sowjanya Reddy, M., Kumar, Nirmal, Preethi, K., Oomman, Abraham, sidh, Rinu R, Mao, Robert, Ramakrishnan, T., Solomon, Hilda, Francis, Rajesh, Naik, Sudhir, Vamshi, Priya P., Parveen Khan, Sajeeda, Christopher, Johann, Preethi, Kotiboinna, Kumar, Nirmal, Grant, Purvez, Hande, Shweta, Sonawane, Poonam, Kachru, Ranjan, Dubey, Abhishek, Rawat, Kavita, Kumar, Ajit, Ganapathi, Sanjay, K, Jayakumar, CP, Vineeth, Sivadasanpillai, Harikrishnan, Chacko, Manas, Sasidharan, Bijulal, Babu, Suresh, TR, Kapilamoorthy, Christopher, Johann, Reddy, Sowjanya, Polamuri, Praneeth, Rani, Manjula, Kaul, Upendra, Arambam, Priyadarshani, Singh, Bebek, Senior, Roxy, Fox, Keith AA, Young, Grace M., Carruthers, Kathryn, Senior, Roxy, Elghamaz, Ahmed, Gurunathan, Sothinathan, Karogiannis, Nikolaos, Young, Grace M., Shah, Benoy N, Kinsey, Christopher, Trimlett, Richard HJ, Kavalakkat, Raisa, Rubens, Michael B, Evans, Jo, Nicol, Edward D, Hassan, Ikraam, Mittal, Tarun K, Hampson, Reinette, Andreas Gamma, Reto, Williams, Sarah, Holland, Kim, Swan, Karen, de Belder, Mark A, Atkinson, Bev, Thambyrajah, Jeet, Kunhunny, Swapna, Davies, John R, Lindsay, Steven J., Atkinson, Craig, Kurian, John, Krannila, Carita, Jamil, Haqeel, Vinod, Manitha, Raheem, Osama, Hoye, Angela, Chaytor, Lisa, Cox, Leanne, Morrow, Julie, Rowe, Kay, Donnelly, Patrick, Kelly, Stephanie, Valecka, Bernardas, Regan, Susan, Turnbull, Dawn, Chauhan, Anoop, Fleming, Catherine, Ghosh, Arijit, Gratrix, Karen, Preston, Stephen, Barr, Craig, Cartwright, Anne, Alfakih, Khaled, Knighton, Abigail, Byrne, Jonathan, Martin, Katherine, Webb, Ian, Henriksen, Peter, Flint, Laura, Harrison, James, OKane, Peter, Lakeman, Nicki, Ljubez, Anja, de Silva, Ramesh, Conway, Dwayne S. G., Wright, Judith, Exley, Donna, Sirker, Alexander A, Andiapen, Mervyn, Richards, Amy J., Hoole, Stephen P, Wong, Lisa, Witherow, Fraser N., Munro, Melanie J., Johnston, Nicola, Harbinson, Mark, McEvoy, Michelle, Walsh, Simon, Brown, Caroline, Douglas, Hanna, Luckie, Matthew, Charles, Thabitha, Kolakaluri, Laurel, Phillips, Hannah, Sobolewska, Jolanta, Morby, Louise, Hallett, Karen, Corbett, Carolyn, Winstanley, Lynne, Jeetley, Paramjit, Smit, Angelique, Patel, Niket, Kotecha, Tushar, Travill, Christopher, Gent, Susan, Karimullah, Iqbal, Hussain, Nafisa, Al-Bustami, Mahmud, Braganza, Denise, Haines, Fiona, Taaffe, Joanne, Henderson, Robert, Burton, Jane, Pointon, Kate, Colton, Maria, Naik, Surendra, King, Rachel, Mathew, Thomas, Brown, Ammani, Docherty, Andrew, Berry, Colin, McCloy, Lisa, Collison, Damien, Robb, Kate, Roditi, Giles, Paterson, Craig, Crawford, Wenda, Kelly, Joanne, McGregor, Lorraine, Moriarty, Andrew J, Mackin, Anne, Glover, Jason D., Knight, Janet P, Pradhan, Jiwan, Mikhail, Ghada, Bose, Tuhina, Francis, Darrel P., Dzavik, Vladimir, Goodman, Shaun, Gosselin, Gilbert, Gosselin, Gilbert, Proietti, Anna, Brousseau, Myriam, Corfias, Magalie, Blaise, Patricia, Harvey, Luc, Diaz, Ariel, Rheault, Philippe, Barrero, Miguel, Gagné, Carl-Éric, Alarie, Patricia, Pépin-Dubois, Yanek, Arcand, Linda, Costa, Ricardo, Roy, Isabelle, Tung Sia, Ying, Montpetit, Estelle, Lemay, Catherine, Gisbert, Alejandro, Gervais, Pierre, Rheault, Alain, Drouin, Katia, Carl Phaneuf, Denis, Bergeron, Christine, Gosselin, Gilbert, Shelley, Christine, Masson, Christine, Garg, Pallav, Carr, Sandy, Bone, Catherine, Chow, Benjamin J.W., Moga, Ermina, Hessian, Renee C., Kourzenkova, Janetta, Beanlands, Rob S., Walter, Olga, Davies, Richard F., Bainey, Kevin R., Hogg, Norma, Welsh, Suzanne, Cheema, Asim N., Bagai, Akshay, Wald, Ron, Goodman, Shaun, Kushniriuk, Khrystyna, Joseph Graham, John, Hussain, Mohammed, Peterson, Mark, Bello, Olugbenga, Chow, Chi-Ming, Abramson, Beth, Nazir Cheema, Asim, Syed, Ishba, Hussain, Mohammed, Kushniriuk, Khrystyna, Cha, James, Otis, Judy, Otis, Rebecca, Howarth, Andrew G, Seib, Michelle M, Rivest, Sandra M, Sandonato, Rosa, Wong, Graham, Chow, Jackie, Starovoytov, Andrew, Uchida, Naomi, Meadows, Ngaire, Uxa, Amar, Asif, Nadia, Tavares, Suzana, Galiwango, Paul, Bozek, Bev, Kassam, Saleem, Shier, Maria, Mukherjee, Ashok, Larmand, Lori-Ann, Ricci, A. Joseph, Janmohamed, Amir, Hart, Brenda, Lam, Andy, Marucci, Jane, Tai, Sharon, Mehta, Shamir, Brons, Sonya, Beck, Chris, Wong, Glenda, Etherington, Krystal, Arumairajah, Thippeekaa, Udell, Jacob, Aprile, Maria, Karlsson, Sara, Webber, Susan, Généreux, Philippe, Mercure, Chantale, Hameed, Adnan, Aedy, Nancy, Daba, Ledjalem, Farquharson, Fran, Siddiqui, Anam, Carlos Carvalho, Antonio, Lopes, Renato D., Hueb, Whady, Emy Takiuti, Myrthes, Cury Rezende, Paulo, Eustáquio Ribeiro Silva, Expedito, Ciappina Hueb, Alexandre, Pizzol Caetano, Leonardo, Schaan de Quadros, Alexandre, Abdala Karam Kalil, Renato, Peixoto Deiro, Aline, Luiz da Costa Vieira, José, Manica Muller, Alice, Antonieta Pereira de Moraes, Maria, Píccaro de Oliveira, Pedro, Maria Ascoli, Bruna, Bridi, Leonardo, Zottis Poletti, Sílvia, Savaris, Simone, Vitola, João V, Cerci, Rodrigo J, Zier, Sandra S., Farias, Fabio R, Veiga Jr, Vilmar, Fernandes, Miguel M, Antonio Marin-Neto, José, Schmidt, André, de Oliveira Lima Filho, Moysés, Franca da Cunha, Diego, Mendes Oliveira, Ricardo, Reynaldo Abbud Chierice, João, Polanczyk, Carísi A., Rucatti, Guilherme G, Furtado, Mariana V., Igansi, Fernanda, Smidt, Luis F., Haeffner, Mauren P, Carlos Carvalho, Antonio, Almeida, Viviane, Pucci, Gustavo, Sanchez de Souza, Gabriela, Lyra, Flavio, Rabelo Alves Junior, Alvaro, Almeida, Mayana, dos Santos, Viviane, Dracoulakis, Marianna D. A., Oliveira, Natalia S, Lima, Rodolfo G. S. 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2024
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15. Determining seropositivity-A review of approaches to define population seroprevalence when using multiplex bead assays to assess burden of tropical diseases.

Author

Chan, YuYen, Fornace, Kimberly, Wu, Lindsey, Arnold, Benjamin F, Priest, Jeffrey W, Martin, Diana L, Chang, Michelle A, Cook, Jackie, Stresman, Gillian, and Drakeley, Chris

Subjects
Biological Sciences, Medical and Health Sciences, Tropical Medicine
Abstract

BackgroundSerological surveys with multiplex bead assays can be used to assess seroprevalence to multiple pathogens simultaneously. However, multiple methods have been used to generate cut-off values for seropositivity and these may lead to inconsistent interpretation of results. A literature review was conducted to describe the methods used to determine cut-off values for data generated by multiplex bead assays.Methodology/principal findingsA search was conducted in PubMed that included articles published from January 2010 to January 2020, and 308 relevant articles were identified that included the terms "serology", "cut-offs", and "multiplex bead assays". After application of exclusion of articles not relevant to neglected tropical diseases (NTD), vaccine preventable diseases (VPD), or malaria, 55 articles were examined based on their relevance to NTD or VPD. The most frequently applied approaches to determine seropositivity included the use of presumed unexposed populations, mixture models, receiver operating curves (ROC), and international standards. Other methods included the use of quantiles, pre-exposed endemic cohorts, and visual inflection points.Conclusions/significanceFor disease control programmes, seropositivity is a practical and easily interpretable health metric but determining appropriate cut-offs for positivity can be challenging. Considerations for optimal cut-off approaches should include factors such as methods recommended by previous research, transmission dynamics, and the immunological backgrounds of the population. In the absence of international standards for estimating seropositivity in a population, the use of consistent methods that align with individual disease epidemiological data will improve comparability between settings and enable the assessment of changes over time.

Published
2021

16. Association between the proportion of Plasmodium falciparum and Plasmodium vivax infections detected by passive surveillance and the magnitude of the asymptomatic reservoir in the community: a pooled analysis of paired health facility and community data

Author

Stresman, Gillian, Sepúlveda, Nuno, Fornace, Kimberly, Grignard, Lynn, Mwesigwa, Julia, Achan, Jane, Miller, John, Bridges, Daniel J, Eisele, Thomas P, Mosha, Jacklin, Lorenzo, Pauline Joy, Macalinao, Maria Lourdes, Espino, Fe Esperanza, Tadesse, Fitsum, Stevenson, Jennifer C, Quispe, Antonio M, Siqueira, André, Lacerda, Marcus, Yeung, Shunmay, Sovannaroth, Siv, Pothin, Emilie, Gallay, Joanna, Hamre, Karen E, Young, Alyssa, Lemoine, Jean Frantz, Chang, Michelle A, Phommasone, Koukeo, Mayxay, Mayfong, Landier, Jordi, Parker, Daniel M, Von Seidlein, Lorenz, Nosten, Francois, Delmas, Gilles, Dondorp, Arjen, Cameron, Ewan, Battle, Katherine, Bousema, Teun, Gething, Peter, D'Alessandro, Umberto, and Drakeley, Chris

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Sciences, Infectious Diseases, Malaria, Clinical Research, Rare Diseases, Vector-Borne Diseases, Aetiology, Detection, screening and diagnosis, 2.2 Factors relating to the physical environment, 4.4 Population screening, Infection, Good Health and Well Being, Adolescent, Adult, Africa, Aged, Aged, 80 and over, Americas, Asia, Asymptomatic Infections, Bayes Theorem, Child, Child, Preschool, Cluster Analysis, Cross-Sectional Studies, Disease Reservoirs, Female, Health Facilities, Humans, Infant, Longitudinal Studies, Malaria, Falciparum, Malaria, Vivax, Male, Middle Aged, Prevalence, Public Health Surveillance, Seasons, Young Adult, Public Health and Health Services, Microbiology, Clinical sciences, Medical microbiology, Epidemiology
Abstract

BackgroundPassively collected malaria case data are the foundation for public health decision making. However, because of population-level immunity, infections might not always be sufficiently symptomatic to prompt individuals to seek care. Understanding the proportion of all Plasmodium spp infections expected to be detected by the health system becomes particularly paramount in elimination settings. The aim of this study was to determine the association between the proportion of infections detected and transmission intensity for Plasmodium falciparum and Plasmodium vivax in several global endemic settings.MethodsThe proportion of infections detected in routine malaria data, P(Detect), was derived from paired household cross-sectional survey and routinely collected malaria data within health facilities. P(Detect) was estimated using a Bayesian model in 431 clusters spanning the Americas, Africa, and Asia. The association between P(Detect) and malaria prevalence was assessed using log-linear regression models. Changes in P(Detect) over time were evaluated using data from 13 timepoints over 2 years from The Gambia.FindingsThe median estimated P(Detect) across all clusters was 12·5% (IQR 5·3-25·0) for P falciparum and 10·1% (5·0-18·3) for P vivax and decreased as the estimated log-PCR community prevalence increased (adjusted odds ratio [OR] for P falciparum 0·63, 95% CI 0·57-0·69; adjusted OR for P vivax 0·52, 0·47-0·57). Factors associated with increasing P(Detect) included smaller catchment population size, high transmission season, improved care-seeking behaviour by infected individuals, and recent increases (within the previous year) in transmission intensity.InterpretationThe proportion of all infections detected within health systems increases once transmission intensity is sufficiently low. The likely explanation for P falciparum is that reduced exposure to infection leads to lower levels of protective immunity in the population, increasing the likelihood that infected individuals will become symptomatic and seek care. These factors might also be true for P vivax but a better understanding of the transmission biology is needed to attribute likely reasons for the observed trend. In low transmission and pre-elimination settings, enhancing access to care and improvements in care-seeking behaviour of infected individuals will lead to an increased proportion of infections detected in the community and might contribute to accelerating the interruption of transmission.FundingWellcome Trust.

Published
2020

19. Chemoenzymatic Platform for Synthesis of Chiral Organofluorines Based on Type II Aldolases

Author

Fang, Jason, Hait, Diptarka, Head‐Gordon, Martin, and Chang, Michelle CY

Subjects
Medicinal and Biomolecular Chemistry, Organic Chemistry, Chemical Sciences, Sustainable Cities and Communities, Biocatalysis, Fluorine, Fructose-Bisphosphate Aldolase, Hydrocarbons, Fluorinated, Pyruvates, Stereoisomerism, Substrate Specificity, aldol reaction, biocatalysis, fluorine, lyases, Chemical sciences
Abstract

Aldolases are C-C bond forming enzymes that have become prominent tools for sustainable synthesis of complex synthons. However, enzymatic methods of fluorine incorporation into such compounds are lacking due to the rarity of fluorine in nature. Recently, the use of fluoropyruvate as a non-native aldolase substrate has arisen as a solution. Here, we report that the type II HpcH aldolases efficiently catalyze fluoropyruvate addition to diverse aldehydes, with exclusive (3S)-selectivity at fluorine that is rationalized by DFT calculations on a mechanistic model. We also measure the kinetic parameters of aldol addition and demonstrate engineering of the hydroxyl group stereoselectivity. Our aldolase collection is then employed in the chemoenzymatic synthesis of novel fluoroacids and ester derivatives in high stereopurity (d.r. 80-98 %). The compounds made available by this method serve as precursors to fluorinated analogs of sugars, amino acids, and other valuable chiral building blocks.

Published
2019

20. Priority use cases for antibody-detecting assays of recent malaria exposure as tools to achieve and sustain malaria elimination

Author

Greenhouse, Bryan, Daily, Jennifer, Guinovart, Caterina, Goncalves, Bronner, Beeson, James, Bell, David, Chang, Michelle A, Cohen, Justin M, Ding, Xavier, Domingo, Gonzalo, Eisele, Thomas P, Lammie, Patrick J, Mayor, Alfredo, Merienne, Nicolas, Monteiro, Wuelto, Painter, John, Rodriguez, Isabel, White, Michael, Drakeley, Chris, and Mueller, Ivo

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Sciences, Rare Diseases, Malaria, Vector-Borne Diseases, Infectious Diseases, Biotechnology, HIV/AIDS, Detection, screening and diagnosis, 4.4 Population screening, Infection, Good Health and Well Being, Malaria Serology Convening, Elimination, Serology, Use Cases, Biomedical and clinical sciences, Health sciences
Abstract

Measurement of malaria specific antibody responses represents a practical and informative method for malaria control programs to assess recent exposure to infection. Technical advances in recombinant antigen production, serological screening platforms, and analytical methods have enabled the identification of several target antigens for laboratory based and point-of-contact tests. Questions remain as to how these serological assays can best be integrated into malaria surveillance activities to inform programmatic decision-making. This report synthesizes discussions from a convening at Institut Pasteur in Paris in June 2017 aimed at defining practical and informative use cases for serology applications and highlights five programmatic uses for serological assays including: documenting the absence of transmission; stratification of transmission; measuring the effect of interventions; informing a decentralized immediate response;  and testing and treating P. vivax hypnozoite carriers.

Published
2019

21. ISCHEMIA-EXTEND studies: Rationale and design

Author

Anthopolos, Rebecca, Maron, David J., Bangalore, Sripal, Reynolds, Harmony R., Xu, Yifan, O'Brien, Sean M., Troxel, Andrea B., Mavromichalis, Stavroula, Chang, Michelle, Contreras, Aira, and Hochman, Judith S.

Published
2022
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24. Influence of Metal Artifact Reduction Tool of Two Cone Beam CT on the Detection of Bone Graft Loss Around Titanium and Zirconium Implants—An Ex Vivo Diagnostic Accuracy Study.

Author

Chang, Michelle, Felizardo, Henrique Mateus Alves, Oliveira‐Santos, Christiano, and Gaêta‐Araujo, Hugo

Subjects
*CONE beam computed tomography, *BONE grafting, *DENTAL implants, *DIAGNOSTIC imaging, *STATISTICAL hypothesis testing
Abstract

ABSTRACT Objective Material and Methods Results Conclusion The objective of this study is to investigate the influence of metal artifact reduction (MAR) on two cone beam computed tomography (CBCT) units in the evaluation of bone graft loss adjacent to titanium (Ti) and zirconium (Zr) implants.Twelve Ti and twelve Zr implants were placed in the posterior region of dry human mandibles. Bone graft was applied to the level of the cover screw. Bone graft loss was simulated in half of the sample (6 Ti and 6 Zr) by removing the graft material up to the third implant thread on the buccal surface. CBCT images were acquired on two units, varying the application of MAR (OP300—off and on; Eagle 3D—standard, intermediate, and extreme). The images were assessed by five evaluators that scored the presence of graft loss according to a 5‐point scale. The diagnostic values were calculated and compared by non‐parametric tests with a significance level of 5%.Higher diagnostic values were achieved with MAR activated in the OP300 unit, for Ti and Zr (p < 0.05). On the Eagle 3D unit, MAR in extreme mode resulted in lower diagnostic values for both types of implants (p < 0.05). The diagnostic values of Ti implants were higher than Zr implants (p < 0.05).The application of MAR influences the diagnosis of bone graft loss adjacent to Ti and Zr dental implants. However, the extreme mode of MAR in the Eagle 3D unit can impair the diagnostic task in both types of implants and should be avoided. [ABSTRACT FROM AUTHOR]

Published
2024
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25. Squamous cell carcinoma of the nail in patients with Fitzpatrick phototypes IV–VI: a systematic review.

Author

Chang, Michelle J., Schwartz Kahn, Michelle, and Khachemoune, Amor

Subjects
*SQUAMOUS cell carcinoma, *MOHS surgery, *DELAYED diagnosis, *HUMAN skin color, *FINGERNAILS, *SKIN cancer
Abstract

Squamous cell carcinoma of the nail unit (nSCC) is a rare malignant tumor of the hand and nail. Although skin cancer rarely affects individuals with phototypes IV–VI, its occurrence in these groups is often associated with greater morbidity and mortality. This study aims to characterize the clinical symptoms, presentations, and treatments of nSCC in patients with darker skin types. A systematic review of PubMed and Embase was performed in May 2023 for all peer‐reviewed, English‐language nSCC studies involving individuals with Fitzpatrick types IV–VI. Most tumors were located on the fingernails (84%), with the right third finger being the most frequently affected (31%). The nail bed (67%) exhibited a higher prevalence than the lateral/proximal nail folds (33%). The duration of symptoms before diagnosis ranged from 1 month to 7 years. nSCC was most commonly treated with Mohs surgery (38%), followed by amputation (35%). Our study was limited to case reports because of a lack of large nSCC studies that provide information on race or images of each patient. These tumors are generally slow‐growing yet often misdiagnosed, leading to delays in presentation and diagnosis. Increased awareness about nSCC in phototype IV–VI individuals will reduce misdiagnoses, unnecessary treatment, and recurrences. [ABSTRACT FROM AUTHOR]

Published
2024
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27. Multistate Outbreak of SARS-CoV-2 Infections, Including Vaccine Breakthrough Infections, Associated with Large Public Gatherings, United States

Author

Gharpure, Radhika, Sami, Samira, Vostok, Johanna, Johnson, Hillary, Hall, Noemi, Foreman, Anne, Sabo, Rebecca T., Schubert, Petra L., Shephard, Hanna, Brown, Vance R., Brumfield, Ben, Ricaldi, Jessica N., Conley, Andrew B., Zielinski, Lindsay, Malec, Lenka, Newman, Alexandra P., Chang, Michelle, Finn, Lauren E., Stainken, Cameron, Mangla, Anil T., Eteme, Patrick, Wieck, Morgan, Green, Alison, Edmundson, Alexandra, Reichbind, Diana, Brown, Vernell, Jr., Quinones, Laura, Longenberger, Allison, Hess, Elke, Gumke, Megan, Manion, Alicia, Thomas, Hannah, Barrios, Carla A., Koczwara, Adrianna, Williams, Thelonious W., Pearlowitz, Marcia, Assoumou, Moussokoura, Pajares, Alessandra F. Senisse, Dishman, Hope, Schardin, Cody, Wang, Xiong, Stephens, Kendalyn, Moss, Nakema S., Singh, Gurpalik, Feaster, Christine, Webb, Lindsey Martin, Krueger, Anna, Dickerson, Kristen, Dewart, Courtney, Barbeau, Bree, Salmanson, Amelia, Madoff, Lawrence C., Villanueva, Julie M., Brown, Catherine M., and Laney, A. Scott

Subjects
Epidemics -- Statistics -- Risk factors -- Massachusetts, Meetings -- Health aspects, Disease transmission -- Risk factors -- Statistics, Health
Abstract

In recent months, the B.1.617.2 (Delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally and has become the predominant circulating variant within the United States (1). [...]

Published
2022
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29. Structural and Biochemical Studies of Substrate Selectivity in Ascaris suum Thiolases.

Author

Blaisse, Michael R, Fu, Beverly, and Chang, Michelle C Y

Subjects
Acetyl-CoA C-Acyltransferase: metabolism, physiology, Amino Acid Sequence, Animals, Ascaris suum: enzymology, physiology, Binding Sites, Catalytic Domain: physiology, Kinetics, Models, Molecular, Protein Conformation, Substrate Specificity: physiology
Abstract

Thiolases are a class of carbon-carbon bond forming enzymes with important applications in biotechnology and metabolic engineering as they provide a general method for the condensation of two acyl coenzyme A (CoA) substrates. As such, developing a greater understanding of their substrate selectivity would expand our ability to engineer the enzymatic or microbial production of a broad range of small-molecule targets. Here, we report the crystal structures and biochemical characterization of Acat2 and Acat5, two biosynthetic thiolases from Ascaris suum with varying selectivity toward branched compared to linear compounds. The structure of the Acat2-C91S mutant bound to propionyl-CoA shows that the terminal methyl group of the substrate, representing the α-branch point, is directed toward the conserved Phe 288 and Met 158 residues. In Acat5, the Phe ring is rotated to accommodate a hydroxyl-π interaction with an adjacent Thr side chain, decreasing space in the binding pocket and possibly accounting for its strong preference for linear substrates compared to Acat2. Comparison of the different Acat thiolase structures shows that Met 158 is flexible, adopting alternate conformations with the side chain rotated toward or away from a covering loop at the back of the active site. Mutagenesis of residues in the covering loop in Acat5 with the corresponding residues from Acat2 allows for highly increased accommodation of branched substrates, whereas the converse mutations do not significantly affect Acat2 substrate selectivity. Our results suggest an important contribution of second-shell residues to thiolase substrate selectivity and offer insights into engineering this enzyme class.

Published
2018

30. Entropy drives selective fluorine recognition in the fluoroacetyl–CoA thioesterase from Streptomyces cattleya

Author

Weeks, Amy M, Wang, Ningkun, Pelton, Jeffrey G, and Chang, Michelle CY

Subjects
Acetyl Coenzyme A, Bacterial Proteins, Catalytic Domain, Entropy, Fluorine, Nuclear Magnetic Resonance, Biomolecular, Phenylalanine, Protein Binding, Streptomyces, Substrate Specificity, enzyme selectivity, fluorine, organofluorine, molecular recognition, metabolism
Abstract

Fluorinated small molecules play an important role in the design of bioactive compounds for a broad range of applications. As such, there is strong interest in developing a deeper understanding of how fluorine affects the interaction of these ligands with their targets. Given the small number of fluorinated metabolites identified to date, insights into fluorine recognition have been provided almost entirely by synthetic systems. The fluoroacetyl-CoA thioesterase (FlK) from Streptomyces cattleya thus provides a unique opportunity to study an enzyme-ligand pair that has been evolutionarily optimized for a surprisingly high 106 selectivity for a single fluorine substituent. In these studies, we synthesize a series of analogs of fluoroacetyl-CoA and acetyl-CoA to generate nonhydrolyzable ester, amide, and ketone congeners of the thioester substrate to isolate the role of fluorine molecular recognition in FlK selectivity. Using a combination of thermodynamic, kinetic, and protein NMR experiments, we show that fluorine recognition is entropically driven by the interaction of the fluorine substituent with a key residue, Phe-36, on the lid structure that covers the active site, resulting in an ∼5- to 20-fold difference in binding (KD). Although the magnitude of discrimination is similar to that found in designed synthetic ligand-protein complexes where dipolar interactions control fluorine recognition, these studies show that hydrophobic and solvation effects serve as the major determinant of naturally evolved fluorine selectivity.

Published
2018

31. Fight Bite with Tendon Laceration

Author

Chang, Michelle, Wei, Grant, Bryczkowski, Christopher, Yan, Sha, and Shah, Chirag

Subjects
Water bath ultrasound, tendon laceration, extensor tendon injury, fight bite, hand injury, orthopedics
Abstract

ABSTRACT: History of present illness: A 57-year-old male presented 24 hours after punching another individual in the mouth and injuring his right hand. He complained of pain and decreased range of motion in his 4th digit. On exam, the patient had a 1 cm laceration to his right 4th metacarpophalangeal joint with soft tissue swelling and limited extension of the digit against resistance. Significant findings: The video shows a water bath ultrasound of the right 4th digit, demonstrating soft tissue swelling with a hypoechoic region along the tendon consistent with edema and tendon disruption (see video and annotated still image). Discussion: Hand extensor tendon injuries can be caused by laceration, trauma, or overuse.1 Extensor tendon injuries are classified into eight zones.2 This patient suffered a Zone V partial tendon injury, commonly termed a “fight bite.” Management of tendon injuries is dependent on: partial vs full, closed vs open, and injury location.3,4 Closed tendon injuries require a volar extension splint with hand surgery follow-up within one week. Open tendon injuries involving >50% tendon width can be repaired in the emergency department, though some will require delayed repair.4 Ruptures involving 50% of tendon width should be sutured.3 Injuries to Zones II-IV and Zone VI may be repaired in the emergency department.4 However, injuries to other zones, the thumb, open fractures, neurovascular compromise, grossly contaminated wounds, or immunocompromised patients should be referred to a hand surgeon.5 “Fight bite” injuries should be treated with antibiotics and hand surgery consult for possible operative intervention.6After a normal X-ray, a bedside water-bath ultrasound was performed, revealing a Zone V extensor tendon rupture. The patient received tetanus prophylaxis, IV antibiotics, was splinted and admitted to the hand surgery service for operative washout of the wound and delayed tendon repair. Topics: Water bath ultrasound, tendon laceration, extensor tendon injury, fight bite, hand injury, orthopedics.

Published
2018

37. Fluorothreonyl-tRNA deacylase prevents mistranslation in the organofluorine producer Streptomyces cattleya

Author

McMurry, Jonathan L and Chang, Michelle CY

Subjects
Biochemistry and Cell Biology, Biological Sciences, Genetics, Prevention, Biotechnology, Acylation, Amino Acids, Carboxylic Ester Hydrolases, Fluorine, Protein Biosynthesis, RNA, Transfer, Streptomyces, Threonine, tRNA editing, translation, secondary metabolism, organofluorine
Abstract

Fluorine is an element with unusual properties that has found significant utility in the design of synthetic small molecules, ranging from therapeutics to materials. In contrast, only a few fluorinated compounds made by living organisms have been found to date, most of which derive from the fluoroacetate/fluorothreonine biosynthetic pathway first discovered in Streptomyces cattleya While fluoroacetate has long been known to act as an inhibitor of the tricarboxylic acid cycle, the fate of the amino acid fluorothreonine is still not well understood. Here, we show that fluorothreonine can be misincorporated into protein in place of the proteinogenic amino acid threonine. We have identified two conserved proteins from the organofluorine biosynthetic locus, FthB and FthC, that are involved in managing fluorothreonine toxicity. Using a combination of biochemical, genetic, physiological, and proteomic studies, we show that FthB is a trans-acting transfer RNA (tRNA) editing protein, which hydrolyzes fluorothreonyl-tRNA 670-fold more efficiently than threonyl-RNA, and assign a role to FthC in fluorothreonine transport. While trans-acting tRNA editing proteins have been found to counteract the misacylation of tRNA with commonly occurring near-cognate amino acids, their role has yet to be described in the context of secondary metabolism. In this regard, the recruitment of tRNA editing proteins to biosynthetic clusters may have enabled the evolution of pathways to produce specialized amino acids, thereby increasing the diversity of natural product structure while also attenuating the risk of mistranslation that would ensue.

Published
2017

38. Elucidating the mechanism of fluorinated extender unit loading for improved production of fluorine-containing polyketides.

Author

Ad, Omer, Thuronyi, BW, and Chang, Michelle CY

Subjects
Polyketide Synthases, Acyltransferases, Biological Products, Protein Engineering, Halogenation, Polyketides, fluorine, natural products, polyketide synthase, synthetic biology, Generic health relevance
Abstract

Polyketides are a large family of bioactive natural products synthesized by polyketide synthase (PKS) enzyme complexes predominantly from acetate and propionate. Given the structural diversity of compounds produced using these two simple building blocks, there has been longstanding interest in engineering the incorporation of alternative extender units. We have been investigating the mechanism of fluorinated monomer insertion by three of the six different modules of the PKS involved in erythromycin biosynthesis (6-deoxyerythronolide B synthase, DEBS) to begin understanding the contribution of different steps, such as enzyme acylation, transacylation, C-C bond formation, and chain transfer, to the overall selectivity and efficiency of this process. In these studies, we observe that inactivation of a cis-acyltransferase (AT) domain to circumvent its native extender unit preference leads concurrently to a change of mechanism in which chain extension with fluorine-substituted extender units switches largely to an acyl carrier protein (ACP)-independent mode. This result suggests that the covalent linkage between the growing polyketide chain and the enzyme is lost in these cases, which would limit efficient chain elongation after insertion of a fluorinated monomer. However, use of a standalone trans-acting AT to complement modules with catalytically deficient AT domains leads to enzyme acylation with the fluoromalonyl-CoA extender unit. Formation of the canonical ACP-linked intermediate with fluoromalonyl-CoA allows insertion of fluorinated extender units at 43% of the yield of the wild-type system while also amplifying product yield in single chain-extension experiments and enabling multiple chain extensions to form multiply fluorinated products.

Published
2017

40. Biosynthesis of Strained Amino Acids by a PLP‐Dependent Enzyme through Cryptic Halogenation.

Author

Sosa, Max B., Leeman, Jacob T., Washington, Lorenzo J., Scheller, Henrik V., and Chang, Michelle C. Y.

Subjects
AMINO acids, BIOSYNTHESIS, HALOGENATION, SMALL molecules, FUNCTIONAL groups, RIBOSOMES, SPECIALTY chemicals
Abstract

Amino acids (AAs) are modular building blocks which nature uses to synthesize both macromolecules, such as proteins, and small molecule natural products, such as alkaloids and non‐ribosomal peptides. While the 20 main proteinogenic AAs display relatively limited side chain diversity, a wide range of non‐canonical amino acids (ncAAs) exist that are not used by the ribosome for protein synthesis, but contain a broad array of structural features and functional groups. In this communication, we report the discovery of the biosynthetic pathway for a new ncAA, pazamine, which contains a cyclopropane ring formed in two steps. In the first step, a chlorine is added onto the C4 position of lysine by a radical halogenase, PazA. The cyclopropane ring is then formed in the next step by a pyridoxal‐5′‐phosphate‐dependent enzyme, PazB, via an SN2‐like attack at C4 to eliminate chloride. Genetic studies of this pathway in the native host, Pseudomonas azotoformans, show that pazamine potentially inhibits ethylene biosynthesis in growing plants based on alterations in the root phenotype of Arabidopsis thaliana seedlings. We further show that PazB can be utilized to make an alternative cyclobutane‐containing AA. These discoveries may lead to advances in biocatalytic production of specialty chemicals and agricultural biotechnology. [ABSTRACT FROM AUTHOR]

Published
2024
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47. MamO Is a Repurposed Serine Protease that Promotes Magnetite Biomineralization through Direct Transition Metal Binding in Magnetotactic Bacteria.

Author

Hershey, David M, Ren, Xuefeng, Melnyk, Ryan A, Browne, Patrick J, Ozyamak, Ertan, Jones, Stephanie R, Chang, Michelle CY, Hurley, James H, and Komeili, Arash

Subjects
Magnetospirillum, Transition Elements, Bacterial Proteins, Evolution, Molecular, Catalytic Domain, Ferrosoferric Oxide, Serine Proteases, Proteolysis, Evolution, Molecular, Developmental Biology, Biological Sciences, Medical and Health Sciences, Agricultural and Veterinary Sciences
Abstract

Many living organisms transform inorganic atoms into highly ordered crystalline materials. An elegant example of such biomineralization processes is the production of nano-scale magnetic crystals in magnetotactic bacteria. Previous studies implicated the involvement of two putative serine proteases, MamE and MamO, during the early stages of magnetite formation in Magnetospirillum magneticum AMB-1. Here, using genetic analysis and X-ray crystallography, we show that MamO has a degenerate active site, rendering it incapable of protease activity. Instead, MamO promotes magnetosome formation through two genetically distinct, noncatalytic activities: activation of MamE-dependent proteolysis of biomineralization factors and direct binding to transition metal ions. By solving the structure of the protease domain bound to a metal ion, we identify a surface-exposed di-histidine motif in MamO that contributes to metal binding and show that it is required to initiate biomineralization in vivo. Finally, we find that pseudoproteases are widespread in magnetotactic bacteria and that they have evolved independently in three separate taxa. Our results highlight the versatility of protein scaffolds in accommodating new biochemical activities and provide unprecedented insight into the earliest stages of biomineralization.

Published
2016

48. Nationwide Monitoring for Plasmodium falciparum Drug-Resistance Alleles to Chloroquine, Sulfadoxine, and Pyrimethamine, Haiti, 2016-2017

Author

Rogier, Eric, Herman, Camelia, Huber, Curtis S., Hamre, Karen E.S., Pierre, Baby, Mace, Kimberly E., Presume, Jacquelin, Mondelus, Gina, Romilus, Ithamare, Elisme, Tamara, Eisele, Thomas P., Druetz, Thomas, Existe, Alexandre, Boncy, Jacques, Lemoine, Jean F., Udhayakumar, Venkatachalam, and Chang, Michelle A.

Subjects
United States. Centers for Disease Control and Prevention, Alleles, Antimalarials, Pyrimethamine, DNA sequencing, Gene mutation, Drug resistance, Plasmodium falciparum, Malaria, Codons, Health
Abstract

The island of Hispaniola remains the last location with endemic malaria in the Caribbean region, and ongoing elimination efforts aim to achieve zero cases from local transmission by the year [...]

Published
2020
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49. Hybrid bioinorganic approach to solar-to-chemical conversion

Author

Nichols, Eva M, Gallagher, Joseph J, Liu, Chong, Su, Yude, Resasco, Joaquin, Yu, Yi, Sun, Yujie, Yang, Peidong, Chang, Michelle CY, and Chang, Christopher J

Subjects
Affordable and Clean Energy, Carbon Dioxide, Catalysis, Electrolysis, Hydrogen, Light, Materials Testing, Methane, Methanosarcina barkeri, Photosynthesis, Silicon, Solar Energy, Sunlight, Temperature, Water, artificial photosynthesis, solar fuels, photocatalysis, carbon dioxide fixation, water splitting
Abstract

Natural photosynthesis harnesses solar energy to convert CO2 and water to value-added chemical products for sustaining life. We present a hybrid bioinorganic approach to solar-to-chemical conversion in which sustainable electrical and/or solar input drives production of hydrogen from water splitting using biocompatible inorganic catalysts. The hydrogen is then used by living cells as a source of reducing equivalents for conversion of CO2 to the value-added chemical product methane. Using platinum or an earth-abundant substitute, α-NiS, as biocompatible hydrogen evolution reaction (HER) electrocatalysts and Methanosarcina barkeri as a biocatalyst for CO2 fixation, we demonstrate robust and efficient electrochemical CO2 to CH4 conversion at up to 86% overall Faradaic efficiency for ≥ 7 d. Introduction of indium phosphide photocathodes and titanium dioxide photoanodes affords a fully solar-driven system for methane generation from water and CO2, establishing that compatible inorganic and biological components can synergistically couple light-harvesting and catalytic functions for solar-to-chemical conversion.

Published
2015

50. Impacts of sea level rise and climate change on coastal plant species in the central California coast

Author

Garner, Kendra L, Chang, Michelle Y, Fulda, Matthew T, Berlin, Jonathan A, Freed, Rachel E, Soo-Hoo, Melissa M, Revell, Dave L, Ikegami, Makihiko, Flint, Lorraine E, Flint, Alan L, and Kendall, Bruce E

Subjects
Sea level rise, Plants, Coastal, Inundation, Flooding, Erosion, Habitat
Abstract

Local increases in sea level caused by global climate change pose a significant threat to the persistence of many coastal plant species through exacerbating inundation, flooding, and erosion. In addition to sea level rise (SLR), climate changes in the form of air temperature and precipitation regimes will also alter habitats of coastal plant species. Although numerous studies have analyzed the effect of climate change on future habitats through species distribution models (SDMs), none have incorporated the threat of exposure to SLR. We developed a model that quantified the effect of both SLR and climate change on habitat for 88 rare coastal plant species in San Luis Obispo, Santa Barbara, and Ventura Counties, California, USA (an area of 23,948 km2). Our SLR model projects that by the year 2100, 60 of the 88 species will be threatened by SLR. We found that the probability of being threatened by SLR strongly correlates with a species’ area, elevation, and distance from the coast, and that 10 species could lose their entire current habitat in the study region. We modeled the habitat suitability of these 10 species under future climate using a species distribution model (SDM). Our SDM projects that 4 of the 10 species will lose all suitable current habitats in the region as a result of climate change. While SLR accounts for up to 9.2 km2 loss in habitat, climate change accounts for habitat suitability changes ranging from a loss of 1,439 km2 for one species to a gain of 9,795 km2 for another species. For three species, SLR is projected to reduce future suitable area by as much as 28% of total area. This suggests that while SLR poses a higher risk, climate changes in precipitation and air temperature represents a lesser known but potentially larger risk and a small cumulative effect from both.

Published
2015

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