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6. Rapid discovery and evolution of nanosensors containing fluorogenic amino acids

Author

Kuru, Erkin, Rittichier, Jonathan, de Puig, Helena, Flores, Allison, Rout, Subhrajit, Han, Isaac, Reese, Abigail E., Bartlett, Thomas M., De Moliner, Fabio, Bernier, Sylvie G., Galpin, Jason D., Marchand, Jorge, Bedell, William, Robinson-McCarthy, Lindsey, Ahern, Christopher A., Bernhardt, Thomas G., Rudner, David Z., Collins, James J., Vendrell, Marc, and Church, George M.

Published
2024
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8. Perspective on Schistosomiasis Drug Discovery: Highlights from a Schistosomiasis Drug Discovery Workshop at Wellcome Collection, London, September 2022

Author

Caldwell, Nicola, Afshar, Rana, Baragaña, Beatriz, Bustinduy, Amaya L, Caffrey, Conor R, Collins, James J, Fusco, Daniela, Garba, Amadou, Gardner, Mark, Gomes, Mireille, Hoffmann, Karl F, Hsieh, Michael, Lo, Nathan C, McNamara, Case W, Nono, Justin Komguep, Padalino, Gilda, Read, Kevin D, Roestenberg, Meta, Spangenberg, Thomas, Specht, Sabine, and Gilbert, Ian H

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Orphan Drug, Vector-Borne Diseases, Infectious Diseases, Rare Diseases, Digestive Diseases, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Infection, Good Health and Well Being, Animals, London, Schistosomiasis, Praziquantel, Anthelmintics, Schistosoma, schistosomiasis, neglected tropical disease, infectious disease, drug discovery, therapeutic s, anthelmintic s, target product profile, anthelmintics, therapeutics, Medical microbiology
Abstract

In September 2022, the Drug Discovery Unit at the University of Dundee, UK, organised an international meeting at the Wellcome Collection in London to explore the current clinical situation and challenges associated with treating schistosomiasis. The aim of this meeting was to discuss the need for new treatments in view of the clinical situation and to ascertain what the key requirements would be for any potential new anti-schistosomals. This information will be essential to inform ongoing drug discovery efforts for schistosomiasis. We also discussed the potential drug discovery pathway and associated criteria for progressing compounds to the clinic. To date, praziquantel (PZQ) is the only drug available to treat all species causing schistosomiasis, but it is often unable to completely clear parasites from an infected patient, partially due to its inactivity against juvenile worms. PZQ-mediated mass drug administration campaigns conducted in endemic areas (e.g., sub-Saharan Africa, where schistosomiasis is primarily prevalent) have contributed to reducing the burden of disease but will not eliminate the disease as a public health problem. The potential for Schistosoma to develop resistance towards PZQ, as the sole treatment available, could become a concern. Consequently, new anthelmintic medications are urgently needed, and this Perspective aims to capture some of the learnings from our discussions on the key criteria for new treatments.

Published
2023

9. Discovery of a structural class of antibiotics with explainable deep learning

Author

Wong, Felix, Zheng, Erica J., Valeri, Jacqueline A., Donghia, Nina M., Anahtar, Melis N., Omori, Satotaka, Li, Alicia, Cubillos-Ruiz, Andres, Krishnan, Aarti, Jin, Wengong, Manson, Abigail L., Friedrichs, Jens, Helbig, Ralf, Hajian, Behnoush, Fiejtek, Dawid K., Wagner, Florence F., Soutter, Holly H., Earl, Ashlee M., Stokes, Jonathan M., Renner, Lars D., and Collins, James J.

Published
2024
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15. Intron mutations and early transcription termination in Duchenne and Becker muscular dystrophy.

Author

Waldrop, Megan A, Moore, Steven A, Mathews, Katherine D, Darbro, Benjamin W, Medne, Livja, Finkel, Richard, Connolly, Anne M, Crawford, Thomas O, Drachman, Daniel, Wein, Nicolas, Habib, Ali A, Krzesniak-Swinarska, Monika A, Zaidman, Craig M, Collins, James J, Jokela, Manu, Udd, Bjarne, Day, John W, Ortiz-Guerrero, Gloria, Statland, Jeff, Butterfield, Russell J, Dunn, Diane M, Weiss, Robert B, and Flanigan, Kevin M

Subjects
Humans, Muscular Dystrophy, Duchenne, Dystrophin, RNA Splice Sites, Mutation, Introns, Becker muscular dystrophy, Duchenne muscular dystrophy, deep intronic, pseudoexon, telescripting, transcription termination, Muscular Dystrophy, Biotechnology, Human Genome, Genetics, Intellectual and Developmental Disabilities (IDD), Duchenne/ Becker Muscular Dystrophy, Brain Disorders, Rare Diseases, Pediatric, Musculoskeletal, Clinical Sciences, Genetics & Heredity
Abstract

DMD pathogenic variants for Duchenne and Becker muscular dystrophy are detectable with high sensitivity by standard clinical exome analyses of genomic DNA. However, up to 7% of DMD mutations are deep intronic and analysis of muscle-derived RNA is an important diagnostic step for patients who have negative genomic testing but abnormal dystrophin expression in muscle. In this study, muscle biopsies were evaluated from 19 patients with clinical features of a dystrophinopathy, but negative clinical DMD mutation analysis. Reverse transcription-polymerase chain reaction or high-throughput RNA sequencing methods identified 19 mutations with one of three pathogenic pseudoexon types: deep intronic point mutations, deletions or insertions, and translocations. In association with point mutations creating intronic splice acceptor sites, we observed the first examples of DMD pseudo 3'-terminal exon mutations causing high efficiency transcription termination within introns. This connection between splicing and premature transcription termination is reminiscent of U1 snRNP-mediating telescripting in sustaining RNA polymerase II elongation across large genes, such as DMD. We propose a novel classification of three distinct types of mutations identifiable by muscle RNA analysis, each of which differ in potential treatment approaches. Recognition and appropriate characterization may lead to therapies directed toward full-length dystrophin expression for some patients.

Published
2022

21. ImmGen at 15

Author

Aguilar, Stephanie Vargas, Aguilar, Oscar, Allan, Rhys, Amir, El Ad David, Angeli, Veronique, Artyomov, Maxim N, Asinovski, Natasha, Astarita, Jilian, Austen, K Frank, Bajpai, Geetika, Barrett, Nora, Baysoy, Alev, Benoist, Christophe, Bellemare-Pelletier, Angelique, Berg, Brad, Best, Adam, Bezman, Natalie, Blair, David, Blander, Julie M, Bogunovic, Milena, Brennan, Patrick, Brenner, Michael, Brown, Brian, Buechler, Matthew, Buenrostro, Jason, Casanova, Maria Acebes, Choi, Kyunghee, Chow, Andrew, Chudnovskiy, Aleksey, Cipoletta, Daniela, Cohen, Nadia, Collins, James J, Colonna, Marco, Cook, Alison, Costello, James, Cremasco, Viviana, Crowl, Ty, Crozat, Karine, Cruse, Richard, D'Angelo, June, Dalod, Marc, Davis, Scott, Demiralp, Cagatay, Deng, Tianda, Desai, Jigar V, Desland, Fiona, Dhainaut, Maxime, Ding, Jiarui, Doedens, Andrew, Dominguez, Claudia, Doran, Graeme, Dress, Regine, Dustin, Michael, Dwyer, Daniel, Dzhagalov, Ivan, Elpek, Kutlu, Ergun, Ayla, Ericson, Jeff, Esomonu, Eunice, Fairfax, Keke, Fletcher, Anne, Frascoli, Michela, Fuchs, Anja, Gainullina, Anastasiia, Gal-Oz, Shani, Gallagher, Michael, Gautier, Emmanuel, Gazit, Roi, Gibbings, Sophie, Giraud, Matthieu, Ginhoux, Florent, Goldrath, Ananda, Gotthardt, Dagmar, Gray, Daniel, Greter, Melanie, Grieshaber-Bouyer, Ricardo, Guilliams, Martin, Haidermota, Sara, Hardy, Randy, Hashimoto, Daigo, Helft, Julie, Hendricks, Deborah, Heng, Tracy, Hill, Jonathan, Hyatt, Gordon, Idoyaga, Juliana, Jakubzick, Claudia, Jarjoura, Jessica, Jepson, Daniel, Jia, Baosen, Jianu, Radu, Johanson, Tim, Jordan, Stefan, Jojic, Vladimir, Kamimura, Yosuke, Kana, Veronica, Kang, Joonsoo, Kapoor, Varun, and Kenigsberg, Ephriam

Subjects
Animals, Gene Expression Regulation, Gene Regulatory Networks, Genomics, History, 21st Century, Immune System, Immunologic Techniques, Mice, Immunological Genome Project, Immunology
Published
2020

22. Lateral flow test engineering and lessons learned from COVID-19

Author

Budd, Jobie, Miller, Benjamin S., Weckman, Nicole E., Cherkaoui, Dounia, Huang, Da, Decruz, Alyssa Thomas, Fongwen, Noah, Han, Gyeo-Re, Broto, Marta, Estcourt, Claudia S., Gibbs, Jo, Pillay, Deenan, Sonnenberg, Pam, Meurant, Robyn, Thomas, Michael R., Keegan, Neil, Stevens, Molly M., Nastouli, Eleni, Topol, Eric J., Johnson, Anne M., Shahmanesh, Maryam, Ozcan, Aydogan, Collins, James J., Fernandez Suarez, Marta, Rodriguez, Bill, Peeling, Rosanna W., and McKendry, Rachel A.

Published
2023
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29. The sound of silence: Transgene silencing in mammalian cell engineering

Author

Cabrera, Alan, Edelstein, Hailey I., Glykofrydis, Fokion, Love, Kasey S., Palacios, Sebastian, Tycko, Josh, Zhang, Meng, Lensch, Sarah, Shields, Cara E., Livingston, Mark, Weiss, Ron, Zhao, Huimin, Haynes, Karmella A., Morsut, Leonardo, Chen, Yvonne Y., Khalil, Ahmad S., Wong, Wilson W., Collins, James J., Rosser, Susan J., Polizzi, Karen, Elowitz, Michael B., Fussenegger, Martin, Hilton, Isaac B., Leonard, Joshua N., Bintu, Lacramioara, Galloway, Kate E., and Deans, Tara L.

Published
2022
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37. RNA-responsive elements for eukaryotic translational control

Author

Zhao, Evan M., Mao, Angelo S., de Puig, Helena, Zhang, Kehan, Tippens, Nathaniel D., Tan, Xiao, Ran, F. Ann, Han, Isaac, Nguyen, Peter Q., Chory, Emma J., Hua, Tiffany Y., Ramesh, Pradeep, Thompson, David B., Oh, Crystal Yuri, Zigon, Eric S., English, Max A., and Collins, James J.

Published
2022
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38. Field validation of the performance of paper-based tests for the detection of the Zika and chikungunya viruses in serum samples

Author

Karlikow, Margot, da Silva, Severino Jefferson Ribeiro, Guo, Yuxiu, Cicek, Seray, Krokovsky, Larissa, Homme, Paige, Xiong, Yilin, Xu, Talia, Calderón-Peláez, Maria-Angelica, Camacho-Ortega, Sigrid, Ma, Duo, de Magalhães, Jurandy Júnior Ferraz, Souza, Bárbara Nayane Rosário Fernandes, de Albuquerque Cabral, Diego Guerra, Jaenes, Katariina, Sutyrina, Polina, Ferrante, Tom, Benitez, Andrea Denisse, Nipaz, Victoria, Ponce, Patricio, Rackus, Darius G., Collins, James J., Paiva, Marcelo, Castellanos, Jaime E., Cevallos, Varsovia, Green, Alexander A., Ayres, Constância, Pena, Lindomar, and Pardee, Keith

Published
2022
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39. An enhanced CRISPR repressor for targeted mammalian gene regulation

Author

Yeo, Nan Cher, Chavez, Alejandro, Lance-Byrne, Alissa, Chan, Yingleong, Menn, David, Milanova, Denitsa, Kuo, Chih-Chung, Guo, Xiaoge, Sharma, Sumana, Tung, Angela, Cecchi, Ryan J, Tuttle, Marcelle, Pradhan, Swechchha, Lim, Elaine T, Davidsohn, Noah, Ebrahimkhani, Mo R, Collins, James J, Lewis, Nathan E, Kiani, Samira, and Church, George M

Subjects
Biochemistry and Cell Biology, Biological Sciences, Biotechnology, Genetics, Human Genome, CRISPR-Associated Protein 9, CRISPR-Cas Systems, Gene Expression Regulation, Gene Silencing, Genes, Synthetic, HEK293 Cells, Humans, Methyl-CpG-Binding Protein 2, RNA, Guide, Kinetoplastida, Recombinant Fusion Proteins, Repressor Proteins, Technology, Medical and Health Sciences, Developmental Biology, Biological sciences
Abstract

The RNA-guided endonuclease Cas9 can be converted into a programmable transcriptional repressor, but inefficiencies in target-gene silencing have limited its utility. Here we describe an improved Cas9 repressor based on the C-terminal fusion of a rationally designed bipartite repressor domain, KRAB-MeCP2, to nuclease-dead Cas9. We demonstrate the system's superiority in silencing coding and noncoding genes, simultaneously repressing a series of target genes, improving the results of single and dual guide RNA library screens, and enabling new architectures of synthetic genetic circuits.

Published
2018

49. Antibiotic-Induced Changes to the Host Metabolic Environment Inhibit Drug Efficacy and Alter Immune Function

Author

Yang, Jason H, Bhargava, Prerna, McCloskey, Douglas, Mao, Ning, Palsson, Bernhard O, and Collins, James J

Subjects
Vaccine Related, Prevention, Infectious Diseases, Antimicrobial Resistance, Emerging Infectious Diseases, 2.1 Biological and endogenous factors, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Aetiology, Inflammatory and immune system, Infection, Animals, Anti-Bacterial Agents, Disease Models, Animal, Escherichia coli Infections, Immunologic Factors, Metabolome, Metabolomics, Mice, Inbred C57BL, Microbial Viability, Mitochondria, Peritonitis, Phagocytosis, LC-MS/MS, antibiotic, germ-free, immunomodulation, metabolic environment, metabolomics, phagocytosis, respiration, systems biology, Microbiology, Medical Microbiology, Immunology
Abstract

Bactericidal antibiotics alter microbial metabolism as part of their lethality and can damage mitochondria in mammalian cells. In addition, antibiotic susceptibility is sensitive to extracellular metabolites, but it remains unknown whether metabolites present at an infection site can affect either treatment efficacy or immune function. Here, we quantify local metabolic changes in the host microenvironment following antibiotic treatment for a peritoneal Escherichia coli infection. Antibiotic treatment elicits microbiome-independent changes in local metabolites, but not those distal to the infection site, by acting directly on host cells. The metabolites induced during treatment, such as AMP, reduce antibiotic efficacy and enhance phagocytic killing. Moreover, antibiotic treatment impairs immune function by inhibiting respiratory activity in immune cells. Collectively, these results highlight the immunomodulatory potential of antibiotics and reveal the local metabolic microenvironment to be an important determinant of infection resolution.

Published
2017

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