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1. A PRMT5-ZNF326 axis mediates innate immune activation upon replication stress

Author

Hoang, Phuong Mai, Torre, Denis, Jaynes, Patrick, Ho, Jessica, Mohammed, Kevin, Alvstad, Erik, Lam, Wan Yee, Khanchandani, Vartika, Lee, Jie Min, Toh, Chin Min Clarissa, Lee, Rui Xue, Anbuselvan, Akshaya, Lee, Sukchan, Sebra, Robert P, Martin J Walsh, Marazzi, Ivan, Kappei, Dennis, Guccione, Ernesto, and Jeyasekharan, Anand D

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Genetics, Cancer, 1.1 Normal biological development and functioning, Aetiology, 2.1 Biological and endogenous factors, Underpinning research, Protein-Arginine N-Methyltransferases, Humans, Immunity, Innate, DNA Replication, Signal Transduction, Arginine, Stress, Physiological, DNA-Binding Proteins, DNA Damage, Transcription Factors
Abstract

DNA replication stress (RS) is a widespread phenomenon in carcinogenesis, causing genomic instability and extensive chromatin alterations. DNA damage leads to activation of innate immune signaling, but little is known about transcriptional regulators mediating such signaling upon RS. Using a chemical screen, we identified protein arginine methyltransferase 5 (PRMT5) as a key mediator of RS-dependent induction of interferon-stimulated genes (ISGs). This response is also associated with reactivation of endogenous retroviruses (ERVs). Using quantitative mass spectrometry, we identify proteins with PRMT5-dependent symmetric dimethylarginine (SDMA) modification induced upon RS. Among these, we show that PRMT5 targets and modulates the activity of ZNF326, a zinc finger protein essential for ISG response. Our data demonstrate a role for PRMT5-mediated SDMA in the context of RS-induced transcriptional induction, affecting physiological homeostasis and cancer therapy.

Published
2024

2. Nuclear RNA catabolism controls endogenous retroviruses, gene expression asymmetry, and dedifferentiation.

Author

Torre, Denis, Fstkchyan, Yesai, Ho, Jessica, Cheon, Youngseo, Patel, Roosheel, Degrace, Emma, Mzoughi, Slim, Schwarz, Megan, Mohammed, Kevin, Seo, Ji-Seon, Romero-Bueno, Raquel, Demircioglu, Deniz, Hasson, Dan, Tang, Weijing, Mahajani, Sameehan, Campisi, Laura, Zheng, Simin, Song, Won-Suk, Wang, Ying-Chih, Shah, Hardik, Francoeur, Nancy, Soto, Juan, Salfati, Zelda, Weirauch, Matthew, Warburton, Peter, Beaumont, Kristin, Smith, Melissa, Mulder, Lubbertus, Jang, Cholsoon, Lee, Daeyoup, De Rubeis, Silvia, Cobos, Inma, Tam, Oliver, Hammell, Molly, Seldin, Marcus, Sebra, Robert, Rosenberg, Brad, Benner, Chris, Guccione, Ernesto, Basu, Uttiya, Sebastiano, Vittorio, Shi, Yongsheng, Kessenbrock, Kai, Villalta, Sergio, Marazzi, Ivan, and Byun, Minji

Subjects
2CLC, Integrator, MERVL, RNA catabolism, elongation, endogenous retrovirus, non-coding RNA, stem cell, totipotent-like cells, transcription-associated RNA degradation, Endogenous Retroviruses, RNA, Nuclear, Epigenesis, Genetic, Heterochromatin, Gene Expression
Abstract

Endogenous retroviruses (ERVs) are remnants of ancient parasitic infections and comprise sizable portions of most genomes. Although epigenetic mechanisms silence most ERVs by generating a repressive environment that prevents their expression (heterochromatin), little is known about mechanisms silencing ERVs residing in open regions of the genome (euchromatin). This is particularly important during embryonic development, where induction and repression of distinct classes of ERVs occur in short temporal windows. Here, we demonstrate that transcription-associated RNA degradation by the nuclear RNA exosome and Integrator is a regulatory mechanism that controls the productive transcription of most genes and many ERVs involved in preimplantation development. Disrupting nuclear RNA catabolism promotes dedifferentiation to a totipotent-like state characterized by defects in RNAPII elongation and decreased expression of long genes (gene-length asymmetry). Our results indicate that RNA catabolism is a core regulatory module of gene networks that safeguards RNAPII activity, ERV expression, cell identity, and developmental potency.

Published
2023

3. Multiscale mapping of transcriptomic signatures for cardiotoxic drugs

Author

Hansen, Jens, Xiong, Yuguang, Siddiq, Mustafa M., Dhanan, Priyanka, Hu, Bin, Shewale, Bhavana, Yadaw, Arjun S., Jayaraman, Gomathi, Tolentino, Rosa E., Chen, Yibang, Martinez, Pedro, Beaumont, Kristin G., Sebra, Robert, Vidovic, Dusica, Schürer, Stephan C., Goldfarb, Joseph, Gallo, James M., Birtwistle, Marc R., Sobie, Eric A., Azeloglu, Evren U., Berger, Seth I., Chan, Angel, Schaniel, Christoph, Dubois, Nicole C., and Iyengar, Ravi

Published
2024
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5. Using EGFR amplification to stratify recurrent glioblastoma treated with immune checkpoint inhibitors.

Author

Friedman, Joshua, Jun, Tomi, Rashidipour, Omid, Huang, Kuan-Lin, Ellis, Ethan, Kadaba, Priyanka, Belani, Puneet, Nael, Kambiz, Tsankova, Nadejda, Sebra, Robert, and Hormigo, Adília

Subjects
EGFR amplification, Next-generation sequencing, Nivolumab, Pembrolizumab, Recurrent glioblastoma, Adult, Humans, Glioblastoma, Immune Checkpoint Inhibitors, Retrospective Studies, Antineoplastic Agents, Immunological, Prospective Studies, Neoplasm Recurrence, Local, ErbB Receptors
Abstract

PURPOSE: While immune checkpoint inhibitors (ICI) have had success with various malignancies, their efficacy in brain cancer is still unclear. Retrospective and prospective studies using PD-1 inhibitors for recurrent glioblastoma (GBM) have not established survival benefit. This study evaluated if ICI may be effective for select patients with recurrent GBM. METHODS: This was a single-center retrospective study of adult patients diagnosed with first recurrence GBM and received pembrolizumab or nivolumab with or without concurrent bevacizumab. Archival tissue was used for immunohistochemistry (IHC) and targeted DNA next-generation sequencing (NGS) analysis. RESULTS: Median overall survival (mOS) from initial diagnosis was 24.5 months (range 10-42). mOS from onset of ICI was 10 months (range 1-31) with 75% surviving > 6 months and 46% > 12 months. Additional IHC analysis on tumors from eight patients demonstrated a trend of longer survival after ICI for those with elevated PD-L1 expression. NGS of samples from 15 patients identified EGFR amplification at initial diagnosis and at any time point to be associated with worse survival after ICI (HR 12.2, 95% CI 1.37-108, p = 0.025 and HR 3.92, 95% CI 1.03-14.9, p = 0.045, respectively). This significance was corroborated with previously tested EGFR amplification via in situ hybridization. CONCLUSION: ICI did not extend overall survival for recurrent GBM. However, molecular sequencing identified EGFR amplification as associated with worse survival. Prospective studies can validate if EGFR amplification is a biomarker of ICI resistance and determine if its use can stratify responders from non-responders.

Published
2023

6. Isoform-resolved transcriptome of the human preimplantation embryo

Author

Torre, Denis, Francoeur, Nancy J, Kalma, Yael, Gross Carmel, Ilana, Melo, Betsaida S, Deikus, Gintaras, Allette, Kimaada, Flohr, Ron, Fridrikh, Maya, Vlachos, Konstantinos, Madrid, Kent, Shah, Hardik, Wang, Ying-Chih, Sridhar, Shwetha H, Smith, Melissa L, Eliyahu, Efrat, Azem, Foad, Amir, Hadar, Mayshar, Yoav, Marazzi, Ivan, Guccione, Ernesto, Schadt, Eric, Ben-Yosef, Dalit, and Sebra, Robert

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Reproductive Medicine, Pediatric, Biotechnology, Human Genome, Underpinning research, 1.1 Normal biological development and functioning, Generic health relevance, Animals, Humans, Transcriptome, Embryonic Development, Zygote, Gene Expression Profiling, Protein Isoforms, Sequence Analysis, RNA, Alternative Splicing, Blastocyst
Abstract

Human preimplantation development involves extensive remodeling of RNA expression and splicing. However, its transcriptome has been compiled using short-read sequencing data, which fails to capture most full-length mRNAs. Here, we generate an isoform-resolved transcriptome of early human development by performing long- and short-read RNA sequencing on 73 embryos spanning the zygote to blastocyst stages. We identify 110,212 unannotated isoforms transcribed from known genes, including highly conserved protein-coding loci and key developmental regulators. We further identify 17,964 isoforms from 5,239 unannotated genes, which are largely non-coding, primate-specific, and highly associated with transposable elements. These isoforms are widely supported by the integration of published multi-omics datasets, including single-cell 8CLC and blastoid studies. Alternative splicing and gene co-expression network analyses further reveal that embryonic genome activation is associated with splicing disruption and transient upregulation of gene modules. Together, these findings show that the human embryo transcriptome is far more complex than currently known, and will act as a valuable resource to empower future studies exploring development.

Published
2023

7. Gemcitabine and cisplatin plus nivolumab as organ-sparing treatment for muscle-invasive bladder cancer: a phase 2 trial

Author

Galsky, Matthew D., Daneshmand, Siamak, Izadmehr, Sudeh, Gonzalez-Kozlova, Edgar, Chan, Kevin G., Lewis, Sara, Achkar, Bassam El, Dorff, Tanya B., Cetnar, Jeremy Paul, Neil, Brock O., D’Souza, Anishka, Mamtani, Ronac, Kyriakopoulos, Christos, Jun, Tomi, Gogerly-Moragoda, Mahalya, Brody, Rachel, Xie, Hui, Nie, Kai, Kelly, Geoffrey, Horowitz, Amir, Kinoshita, Yayoi, Ellis, Ethan, Nose, Yohei, Ioannou, Giorgio, Cabal, Rafael, Del Valle, Diane M., Haines, G. Kenneth, Wang, Li, Mouw, Kent W., Samstein, Robert M., Mehrazin, Reza, Bhardwaj, Nina, Yu, Menggang, Zhao, Qianqian, Kim-Schulze, Seunghee, Sebra, Robert, Zhu, Jun, Gnjatic, Sacha, Sfakianos, John, and Pal, Sumanta K.

Published
2023
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8. Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative.

Author

Butler-Laporte, Guillaume, Povysil, Gundula, Kosmicki, Jack, Cirulli, Elizabeth, Drivas, Theodore, Furini, Simone, Saad, Chadi, Schmidt, Axel, Olszewski, Pawel, Korotko, Urszula, Quinodoz, Mathieu, Çelik, Elifnaz, Kundu, Kousik, Walter, Klaudia, Jung, Junghyun, Stockwell, Amy, Sloofman, Laura, Jordan, Daniel, Thompson, Ryan, Del Valle, Diane, Simons, Nicole, Cheng, Esther, Sebra, Robert, Schadt, Eric, Kim-Schulze, Seunghee, Gnjatic, Sacha, Merad, Miriam, Buxbaum, Joseph, Beckmann, Noam, Charney, Alexander, Przychodzen, Bartlomiej, Chang, Timothy, Pottinger, Tess, Shang, Ning, Brand, Fabian, Fava, Francesca, Mari, Francesca, Chwialkowska, Karolina, Niemira, Magdalena, Pula, Szymon, Baillie, J, Stuckey, Alex, Salas, Antonio, Bello, Xabier, Pardo-Seco, Jacobo, Gómez-Carballa, Alberto, Rivero-Calle, Irene, Martinón-Torres, Federico, Ganna, Andrea, Karczewski, Konrad, Veerapen, Kumar, Bourgey, Mathieu, Bourque, Guillaume, Eveleigh, Robert, Forgetta, Vincenzo, Morrison, David, Langlais, David, Lathrop, Mark, Mooser, Vincent, Nakanishi, Tomoko, Frithiof, Robert, Hultström, Michael, Lipcsey, Miklos, Marincevic-Zuniga, Yanara, Nordlund, Jessica, Schiabor Barrett, Kelly, Lee, William, Bolze, Alexandre, White, Simon, Riffle, Stephen, Tanudjaja, Francisco, Sandoval, Efren, Neveux, Iva, Dabe, Shaun, Casadei, Nicolas, Motameny, Susanne, Alaamery, Manal, Massadeh, Salam, Aljawini, Nora, Almutairi, Mansour, Arabi, Yaseen, Alqahtani, Saleh, Al Harthi, Fawz, Almutairi, Amal, Alqubaishi, Fatima, Alotaibi, Sarah, Binowayn, Albandari, Alsolm, Ebtehal, El Bardisy, Hadeel, Fawzy, Mohammad, Cai, Fang, Soranzo, Nicole, Butterworth, Adam, Geschwind, Daniel, Arteaga, Stephanie, Stephens, Alexis, Butte, Manish, Boutros, Paul, Yamaguchi, Takafumi, and Tao, Shu

Subjects
Humans, Exome, Genome-Wide Association Study, COVID-19, Genetic Predisposition to Disease, Toll-Like Receptor 7, SARS-CoV-2
Abstract

Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.

Published
2022

9. Author Correction: Gemcitabine and cisplatin plus nivolumab as organ-sparing treatment for muscle-invasive bladder cancer: a phase 2 trial

Author

Galsky, Matthew D., Daneshmand, Siamak, Izadmehr, Sudeh, Gonzalez-Kozlova, Edgar, Chan, Kevin G., Lewis, Sara, Achkar, Bassam El, Dorff, Tanya B., Cetnar, Jeremy Paul, Neil, Brock O., D’Souza, Anishka, Mamtani, Ronac, Kyriakopoulos, Christos, Jun, Tomi, Gogerly-Moragoda, Mahalya, Brody, Rachel, Xie, Hui, Nie, Kai, Kelly, Geoffrey, Horowitz, Amir, Kinoshita, Yayoi, Ellis, Ethan, Nose, Yohei, Ioannou, Giorgio, Cabal, Rafael, Del Valle, Diane M., Haines, G. Kenneth, Wang, Li, Mouw, Kent W., Samstein, Robert M., Mehrazin, Reza, Bhardwaj, Nina, Yu, Menggang, Zhao, Qianqian, Kim-Schulze, Seunghee, Sebra, Robert, Zhu, Jun, Gnjatic, Sacha, Sfakianos, John, and Pal, Sumanta K.

Published
2024
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10. MacroH2A restricts inflammatory gene expression in melanoma cancer-associated fibroblasts by coordinating chromatin looping

Author

Filipescu, Dan, Carcamo, Saul, Agarwal, Aman, Tung, Navpreet, Humblin, Étienne, Goldberg, Matthew S., Vyas, Nikki S., Beaumont, Kristin G., Demircioglu, Deniz, Sridhar, Subhasree, Ghiraldini, Flavia G., Capparelli, Claudia, Aplin, Andrew E., Salmon, Hélène, Sebra, Robert, Kamphorst, Alice O., Merad, Miriam, Hasson, Dan, and Bernstein, Emily

Published
2023
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11. Mapping disease regulatory circuits at cell-type resolution from single-cell multiomics data

Author

Chen, Xi, Wang, Yuan, Cappuccio, Antonio, Cheng, Wan-Sze, Zamojski, Frederique Ruf, Nair, Venugopalan D., Miller, Clare M., Rubenstein, Aliza B., Nudelman, German, Tadych, Alicja, Theesfeld, Chandra L., Vornholt, Alexandria, George, Mary-Catherine, Ruffin, Felicia, Dagher, Michael, Chawla, Daniel G., Soares-Schanoski, Alessandra, Spurbeck, Rachel R., Ndhlovu, Lishomwa C., Sebra, Robert, Kleinstein, Steven H., Letizia, Andrew G., Ramos, Irene, Fowler, Jr, Vance G., Woods, Christopher W., Zaslavsky, Elena, Troyanskaya, Olga G., and Sealfon, Stuart C.

Published
2023
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14. Mutations in cancer-relevant genes are ubiquitous in histologically normal endometrial tissue

Author

Pandya, Deep, Tomita, Shannon, Rhenals, Maria Padron, Swierczek, Sabina, Reid, Katherine, Camacho-Vanegas, Olga, Camacho, Catalina, Engelman, Kelsey, Polukort, Stephanie, RoseFigura, Jordan, Chuang, Linus, Andikyan, Vaagn, Cohen, Samantha, Fiedler, Paul, Sieber, Steven, Shih, Ie-Ming, Billaud, Jean-Noël, Sebra, Robert, Reva, Boris, Dottino, Peter, and Martignetti, John A.

Published
2024
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17. Pan-cancer proteogenomics characterization of tumor immunity

Author

Abelin, Jennifer, Aguet, François, Akiyama, Yo, An, Eunkyung, Anand, Shankara, Anurag, Meenakshi, Babur, Özgün, Bavarva, Jasmin, Birger, Chet, Birrer, Michael J., Cao, Song, Carr, Steven A., Chan, Daniel W., Chinnaiyan, Arul M., Cho, Hanbyul, Clauser, Karl, Colaprico, Antonio, Zhou, Daniel Cui, da Veiga Leprevost, Felipe, Day, Corbin, Dhanasekaran, Saravana M., Ding, Li, Domagalski, Marcin J., Dou, Yongchao, Druker, Brian J., Edwards, Nathan, Ellis, Matthew J., Foltz, Steven M., Francis, Alicia, Geffen, Yifat, Getz, Gad, Heiman, David I., Hong, Runyu, Hu, Yingwei, Huang, Chen, Jaehnig, Eric J., Jewell, Scott D., Ji, Jiayi, Jiang, Wen, Katsnelson, Lizabeth, Ketchum, Karen A., Kolodziejczak, Iga, Krug, Karsten, Kumar-Sinha, Chandan, Lei, Jonathan T., Liang, Wen-Wei, Liao, Yuxing, Lindgren, Caleb M., Liu, Tao, Liu, Wenke, McDermott, Jason, McKerrow, Wilson, Mesri, Mehdi, Mumphrey, Michael Brodie, Newton, Chelsea J., Oldroyd, Robert, Payne, Samuel H., Pugliese, Pietro, Rodland, Karin D., Rodrigues, Fernanda Martins, Ruggles, Kelly V., Savage, Sara R., Schadt, Eric E., Schnaubelt, Michael, Schraink, Tobias, Schürer, Stephan, Shi, Zhiao, Smith, Richard D., Song, Feng, Song, Yizhe, Stathias, Vasileios, Storrs, Erik P., Tan, Jimin, Terekhanova, Nadezhda V., Thangudu, Ratna R., Thiagarajan, Mathangi, Wang, Liang-Bo, Wen, Bo, Wu, Yige, Wyczalkowski, Matthew A., Yao, Lijun, Li, Qing Kay, Zhang, Hui, Zhang, Qing, Zhang, Xu, Zhang, Zhen, Petralia, Francesca, Ma, Weiping, Yaron, Tomer M., Caruso, Francesca Pia, Tignor, Nicole, Wang, Joshua M., Charytonowicz, Daniel, Johnson, Jared L., Huntsman, Emily M., Marino, Giacomo B., Calinawan, Anna, Evangelista, John Erol, Selvan, Myvizhi Esai, Chowdhury, Shrabanti, Rykunov, Dmitry, Krek, Azra, Song, Xiaoyu, Turhan, Berk, Christianson, Karen E., Lewis, David A., Deng, Eden Z., Clarke, Daniel J.B., Whiteaker, Jeffrey R., Kennedy, Jacob J., Zhao, Lei, Segura, Rossana Lazcano, Batra, Harsh, Raso, Maria Gabriela, Parra, Edwin Roger, Soundararajan, Rama, Tang, Ximing, Li, Yize, Yi, Xinpei, Satpathy, Shankha, Wang, Ying, Wiznerowicz, Maciej, González-Robles, Tania J., Iavarone, Antonio, Gosline, Sara J.C., Reva, Boris, Robles, Ana I., Nesvizhskii, Alexey I., Mani, D.R., Gillette, Michael A., Klein, Robert J., Cieslik, Marcin, Zhang, Bing, Paulovich, Amanda G., Sebra, Robert, Gümüş, Zeynep H., Hostetter, Galen, Fenyö, David, Omenn, Gilbert S., Cantley, Lewis C., Ma'ayan, Avi, Lazar, Alexander J., Ceccarelli, Michele, and Wang, Pei

Published
2024
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19. Molecular states during acute COVID-19 reveal distinct etiologies of long-term sequelae

Author

Thompson, Ryan C., Simons, Nicole W., Wilkins, Lillian, Cheng, Esther, Del Valle, Diane Marie, Hoffman, Gabriel E., Cervia, Carlo, Fennessy, Brian, Mouskas, Konstantinos, Francoeur, Nancy J., Johnson, Jessica S., Lepow, Lauren, Le Berichel, Jessica, Chang, Christie, Beckmann, Aviva G., Wang, Ying-chih, Nie, Kai, Zaki, Nicholas, Tuballes, Kevin, Barcessat, Vanessa, Cedillo, Mario A., Yuan, Dan, Huckins, Laura, Roussos, Panos, Marron, Thomas U., Glicksberg, Benjamin S., Nadkarni, Girish, Heath, James R., Gonzalez-Kozlova, Edgar, Boyman, Onur, Kim-Schulze, Seunghee, Sebra, Robert, Merad, Miriam, Gnjatic, Sacha, Schadt, Eric E., Charney, Alexander W., and Beckmann, Noam D.

Published
2023
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21. TOP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation

Author

Ho, Jessica Sook Yuin, Mok, Bobo Wing-Yee, Campisi, Laura, Jordan, Tristan, Yildiz, Soner, Parameswaran, Sreeja, Wayman, Joseph A, Gaudreault, Natasha N, Meekins, David A, Indran, Sabarish V, Morozov, Igor, Trujillo, Jessie D, Fstkchyan, Yesai S, Rathnasinghe, Raveen, Zhu, Zeyu, Zheng, Simin, Zhao, Nan, White, Kris, Ray-Jones, Helen, Malysheva, Valeriya, Thiecke, Michiel J, Lau, Siu-Ying, Liu, Honglian, Zhang, Anna Junxia, Lee, Andrew Chak-Yiu, Liu, Wen-Chun, Jangra, Sonia, Escalera, Alba, Aydillo, Teresa, Melo, Betsaida Salom, Guccione, Ernesto, Sebra, Robert, Shum, Elaine, Bakker, Jan, Kaufman, David A, Moreira, Andre L, Carossino, Mariano, Balasuriya, Udeni BR, Byun, Minji, Albrecht, Randy A, Schotsaert, Michael, Garcia-Sastre, Adolfo, Chanda, Sumit K, Miraldi, Emily R, Jeyasekharan, Anand D, TenOever, Benjamin R, Spivakov, Mikhail, Weirauch, Matthew T, Heinz, Sven, Chen, Honglin, Benner, Christopher, Richt, Juergen A, and Marazzi, Ivan

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Biodefense, Infectious Diseases, Vaccine Related, Pneumonia, Emerging Infectious Diseases, Lung, Pneumonia & Influenza, Prevention, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Inflammatory and immune system, Good Health and Well Being, Animals, COVID-19, Chlorocebus aethiops, DNA Topoisomerases, Type I, Humans, Inflammation, Mesocricetus, Mice, Mice, Transgenic, SARS-CoV-2, THP-1 Cells, Topoisomerase I Inhibitors, Topotecan, Vero Cells, COVID-19 Drug Treatment, chromatin, cytokine storm, epigenetics, inducible genes, inflammation, topoisomerase, topotecan, transcription, Biological Sciences, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Here, using multidimensional epigenetic, transcriptional, in vitro, and in vivo analyses, we report that topoisomerase 1 (TOP1) inhibition suppresses lethal inflammation induced by SARS-CoV-2. Therapeutic treatment with two doses of topotecan (TPT), an FDA-approved TOP1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as 4 days post-infection reduces morbidity and rescues mortality in a transgenic mouse model. These results support the potential of TOP1 inhibition as an effective host-directed therapy against severe SARS-CoV-2 infection. TPT and its derivatives are inexpensive clinical-grade inhibitors available in most countries. Clinical trials are needed to evaluate the efficacy of repurposing TOP1 inhibitors for severe coronavirus disease 2019 (COVID-19) in humans.

Published
2021

22. Rapid, scalable assessment of SARS-CoV-2 cellular immunity by whole-blood PCR

Author

Schwarz, Megan, Torre, Denis, Lozano-Ojalvo, Daniel, Tan, Anthony T., Tabaglio, Tommaso, Mzoughi, Slim, Sanchez-Tarjuelo, Rodrigo, Le Bert, Nina, Lim, Joey Ming Er, Hatem, Sandra, Tuballes, Kevin, Camara, Carmen, Lopez-Granados, Eduardo, Paz-Artal, Estela, Correa-Rocha, Rafael, Ortiz, Alberto, Lopez-Hoyos, Marcos, Portoles, Jose, Cervera, Isabel, Gonzalez-Perez, Maria, Bodega-Mayor, Irene, Conde, Patricia, Oteo-Iglesias, Jesús, Borobia, Alberto M., Carcas, Antonio J., Frías, Jesús, Belda-Iniesta, Cristóbal, Ho, Jessica S. Y., Nunez, Kemuel, Hekmaty, Saboor, Mohammed, Kevin, Marsiglia, William M., Carreño, Juan Manuel, Dar, Arvin C., Berin, Cecilia, Nicoletti, Giuseppe, Della Noce, Isabella, Colombo, Lorenzo, Lapucci, Cristina, Santoro, Graziano, Ferrari, Maurizio, Nie, Kai, Patel, Manishkumar, Barcessat, Vanessa, Gnjatic, Sacha, Harris, Jocelyn, Sebra, Robert, Merad, Miriam, Krammer, Florian, Kim-schulze, Seunghee, Marazzi, Ivan, Bertoletti, Antonio, Ochando, Jordi, and Guccione, Ernesto

Published
2022
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23. Tumoral and immune heterogeneity in an anti-PD-1 responsive glioblastoma: a case study

Author

Restrepo, Paula, Yong, Raymund, Laface, Ilaria, Tsankova, Nadejda, Nael, Kambiz, Akturk, Guray, Sebra, Robert, Gnjatic, Sacha, Hormigo, Adilia, and Losic, Bojan

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Brain Disorders, Human Genome, Genetics, Brain Cancer, Cancer, Neurosciences, Clinical Research, Rare Diseases, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Aged, Alleles, Antineoplastic Agents, Immunological, Biological Variation, Population, Biomarkers, Tumor, Biopsy, Brain Neoplasms, Clonal Evolution, DNA Copy Number Variations, DNA Mutational Analysis, Female, Gene Expression Regulation, Neoplastic, Gene Frequency, Genetic Heterogeneity, Glioblastoma, Humans, Molecular Targeted Therapy, Mutation, Programmed Cell Death 1 Receptor, Treatment Outcome, Tumor Microenvironment, glioblastoma, glioblastoma multiforme, Pharmacology and pharmaceutical sciences
Abstract

Clinical benefit of immune checkpoint blockade in glioblastoma (GBM) is rare, and we hypothesize that tumor clonal evolution and the immune microenvironment are key determinants of response. Here, we present a detailed molecular characterization of the intratumoral and immune heterogeneity in an IDH wild-type, MGMT-negative GBM patient who plausibly benefited from anti-PD-1 therapy with an unusually long 25-mo overall survival time. We leveraged multiplex immunohistochemistry, RNA-seq, and whole-exome data from the primary tumor and three resected regions of recurrent disease to survey regional tumor-immune interactions, genomic instability, mutation burden, and expression profiles. We found significant regional heterogeneity in the neoantigenic and immune landscape, with a differential T-cell signature among recurrent sectors, a uniform loss of focal amplifications in EGFR, and a novel subclonal EGFR mutation. Comparisons with recently reported correlates of checkpoint blockade in GBM and with TCGA-GBM revealed appreciable intratumoral heterogeneity that may have contributed to a differential PD-1 blockade response.

Published
2020

24. A master regulator of opioid reward in the ventral prefrontal cortex

Author

Smith, Alexander C. W., primary, Ghoshal, Soham, additional, Centanni, Samuel W., additional, Heyer, Mary P., additional, Corona, Alberto, additional, Wills, Lauren, additional, Andraka, Emma, additional, Lei, Ye, additional, O’Connor, Richard M., additional, Caligiuri, Stephanie P. B., additional, Khan, Sohail, additional, Beaumont, Kristin, additional, Sebra, Robert P., additional, Kieffer, Brigitte L., additional, Winder, Danny G., additional, Ishikawa, Masago, additional, and Kenny, Paul J., additional

Published
2024
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25. Urine scRNAseq reveals new insights into the bladder tumor immune microenvironment

Author

Tran, Michelle A., primary, Youssef, Dina, additional, Shroff, Sanjana, additional, Chowhan, Disha, additional, Beaumont, Kristin G., additional, Sebra, Robert, additional, Mehrazin, Reza, additional, Wiklund, Peter, additional, Lin, Jenny J., additional, Horowitz, Amir, additional, Farkas, Adam M., additional, Galsky, Matthew D., additional, Sfakianos, John P., additional, and Bhardwaj, Nina, additional

Published
2024
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26. Transient stabilization of human cardiovascular progenitor cells from hPSCs in vitro reflects stage-specific heart development in vivo

Author

Emiliano, Bolesani, primary, Dorothee, Bornhorst, additional, Iyer, Lavanya M, additional, Dorota, Zawada, additional, Nina, Friese, additional, Michael, Morgan, additional, Lucas, Lange, additional, David, Gonzalez, additional, Nadine, Schrode, additional, Andreas, Leffler, additional, Wunder, Julian, additional, Annika, Franke, additional, Lika, Drakhlis, additional, Sebra, Robert, additional, Axel, Schambach, additional, Alexander, Goedel, additional, Nicole, Dubois, additional, Gergana, Dobreva, additional, Alessandra, Moretti, additional, Zelarayán, Laura C, additional, Salim, Abdelilah-Seyfried, additional, and Robert, Zweigerdt, additional

Published
2024
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27. Transcriptomic sex differences in postmortem brain samples from patients with psychiatric disorders

Author

Xia, Yan, primary, Xia, Cuihua, additional, Jiang, Yi, additional, Chen, Yu, additional, Zhou, Jiaqi, additional, Dai, Rujia, additional, Han, Cong, additional, Mao, Zhongzheng, additional, Consortium, PsychENCODE, additional, Liu, Chunyu, additional, Chen, Chao, additional, Akbarian, Schahram, additional, Abyzov, Alexej, additional, Ahituv, Nadav, additional, Arasappan, Dhivya, additional, Almagro Armenteros, Jose Juan, additional, Beliveau, Brian J., additional, Bendl, Jaroslav, additional, Berretta, Sabina, additional, Bharadwaj, Rahul A., additional, Bhattacharya, Arjun, additional, Bicks, Lucy, additional, Brennand, Kristen, additional, Capauto, Davide, additional, Champagne, Frances A., additional, Chatterjee, Tanima, additional, Chatzinakos, Chris, additional, Chen, Yuhang, additional, Chen, H. Isaac, additional, Cheng, Yuyan, additional, Cheng, Lijun, additional, Chess, Andrew, additional, Chien, Jo-fan, additional, Chu, Zhiyuan, additional, Clarke, Declan, additional, Clement, Ashley, additional, Collado-Torres, Leonardo, additional, Cooper, Gregory M., additional, Crawford, Gregory E., additional, Daskalakis, Nikolaos P., additional, Davila-Velderrain, Jose, additional, Deep-Soboslay, Amy, additional, Deng, Chengyu, additional, DiPietro, Christopher P., additional, Dracheva, Stella, additional, Drusinsky, Shiron, additional, Duan, Ziheng, additional, Duong, Duc, additional, Dursun, Cagatay, additional, Eagles, Nicholas J., additional, Edelstein, Jonathan, additional, Emani, Prashant S., additional, Fullard, John F., additional, Galani, Kiki, additional, Galeev, Timur, additional, Gandal, Michael J., additional, Gaynor, Sophia, additional, Gerstein, Mark, additional, Geschwind, Daniel H., additional, Girdhar, Kiran, additional, Goes, Fernando S., additional, Greenleaf, William, additional, Grundman, Jennifer, additional, Guo, Hanmin, additional, Guo, Qiuyu, additional, Gupta, Chirag, additional, Hadas, Yoav, additional, Hallmayer, Joachim, additional, Han, Xikun, additional, Haroutunian, Vahram, additional, Hawken, Natalie, additional, He, Chuan, additional, Henry, Ella, additional, Hicks, Stephanie C., additional, Ho, Marcus, additional, Ho, Li-Lun, additional, Hoffman, Gabriel E., additional, Huang, Yiling, additional, Huuki-Myers, Louise A., additional, Hwang, Ahyeon, additional, Hyde, Thomas M., additional, Iatrou, Artemis, additional, Inoue, Fumitaka, additional, Jajoo, Aarti, additional, Jensen, Matthew, additional, Jiang, Lihua, additional, Jin, Peng, additional, Jin, Ting, additional, Jops, Connor, additional, Jourdon, Alexandre, additional, Kawaguchi, Riki, additional, Kellis, Manolis, additional, Khullar, Saniya, additional, Kleinman, Joel E., additional, Kleopoulos, Steven P., additional, Kozlenkov, Alex, additional, Kriegstein, Arnold, additional, Kundaje, Anshul, additional, Kundu, Soumya, additional, Lee, Cheyu, additional, Lee, Donghoon, additional, Li, Junhao, additional, Li, Mingfeng, additional, Lin, Xiao, additional, Liu, Shuang, additional, Liu, Jason, additional, Liu, Jianyin, additional, Lou, Shaoke, additional, Loupe, Jacob M., additional, Lu, Dan, additional, Ma, Shaojie, additional, Ma, Liang, additional, Margolis, Michael, additional, Mariani, Jessica, additional, Martinowich, Keri, additional, Maynard, Kristen R., additional, Mazariegos, Samantha, additional, Meng, Ran, additional, Myers, Richard M., additional, Micallef, Courtney, additional, Mikhailova, Tatiana, additional, Ming, Guo-li, additional, Mohammadi, Shahin, additional, Monte, Emma, additional, Montgomery, Kelsey S., additional, Moore, Jill E., additional, Moran, Jennifer R., additional, Mukamel, Eran A., additional, Nairn, Angus C., additional, Nemeroff, Charles B., additional, Ni, Pengyu, additional, Norton, Scott, additional, Nowakowski, Tomasz, additional, Omberg, Larsson, additional, Page, Stephanie C., additional, Park, Saejeong, additional, Patowary, Ashok, additional, Pattni, Reenal, additional, Pertea, Geo, additional, Peters, Mette A., additional, Phalke, Nishigandha, additional, Pinto, Dalila, additional, Pjanic, Milos, additional, Pochareddy, Sirisha, additional, Pollard, Katherine S., additional, Pollen, Alex, additional, Pratt, Henry, additional, Przytycki, Pawel F., additional, Purmann, Carolin, additional, Qin, Zhaohui S., additional, Qu, Ping-Ping, additional, Quintero, Diana, additional, Raj, Towfique, additional, Rajagopalan, Ananya S., additional, Reach, Sarah, additional, Reimonn, Thomas, additional, Ressler, Kerry J., additional, Ross, Deanna, additional, Roussos, Panos, additional, Rozowsky, Joel, additional, Ruth, Misir, additional, Ruzicka, W. Brad, additional, Sanders, Stephan J., additional, Schneider, Juliane M., additional, Scuderi, Soraya, additional, Sebra, Robert, additional, Sestan, Nenad, additional, Seyfried, Nicholas, additional, Shao, Zhiping, additional, Shedd, Nicole, additional, Shieh, Annie W., additional, Shin, Joo Heon, additional, Skarica, Mario, additional, Snijders, Clara, additional, Song, Hongjun, additional, State, Matthew W., additional, Stein, Jason, additional, Steyert, Marilyn, additional, Subburaju, Sivan, additional, Sudhof, Thomas, additional, Snyder, Michael, additional, Tao, Ran, additional, Therrien, Karen, additional, Tsai, Li-Huei, additional, Urban, Alexander E., additional, Vaccarino, Flora M., additional, van Bake, Harm, additional, Vo, Daniel, additional, Voloudakis, Georgios, additional, Wamsley, Brie, additional, Wang, Tao, additional, Wang, Sidney H., additional, Wang, Daifeng, additional, Wang, Yifan, additional, Warrell, Jonathan, additional, Wei, Yu, additional, Weimer, Annika K., additional, Weinberger, Daniel R., additional, Wen, Cindy, additional, Weng, Zhiping, additional, Whalen, Sean, additional, White, Kevin P., additional, Willsey, A. Jeremy, additional, Won, Hyejung, additional, Wong, Wing, additional, Wu, Hao, additional, Wu, Feinan, additional, Wuchty, Stefan, additional, Wylie, Dennis, additional, Xu, Siwei, additional, Yap, Chloe X., additional, Zeng, Biao, additional, Zhang, Pan, additional, Zhang, Chunling, additional, Zhang, Bin, additional, Zhang, Jing, additional, Zhang, Yanqiong, additional, Zhou, Xiao, additional, Ziffra, Ryan, additional, Zeier, Zane R., additional, and Zintel, Trisha M., additional

Published
2024
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28. Author Correction: Mapping disease regulatory circuits at cell-type resolution from single-cell multiomics data

Author

Chen, Xi, Wang, Yuan, Cappuccio, Antonio, Cheng, Wan-Sze, Zamojski, Frederique Ruf, Nair, Venugopalan D., Miller, Clare M., Rubenstein, Aliza B., Nudelman, German, Tadych, Alicja, Theesfeld, Chandra L., Vornholt, Alexandria, George, Mary-Catherine, Ruffin, Felicia, Dagher, Michael, Chawla, Daniel G., Soares-Schanoski, Alessandra, Spurbeck, Rachel R., Ndhlovu, Lishomwa C., Sebra, Robert, Kleinstein, Steven H., Letizia, Andrew G., Ramos, Irene, Fowler, Jr, Vance G., Woods, Christopher W., Zaslavsky, Elena, Troyanskaya, Olga G., and Sealfon, Stuart C.

Published
2023
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29. Klebsiella pneumoniae induces host metabolic stress that promotes tolerance to pulmonary infection

Author

Wong Fok Lung, Tania, Charytonowicz, Daniel, Beaumont, Kristin G., Shah, Shivang S., Sridhar, Shwetha H., Gorrie, Claire L., Mu, Andre, Hofstaedter, Casey E., Varisco, David, McConville, Thomas H., Drikic, Marija, Fowler, Brandon, Urso, Andreacarola, Shi, Wei, Fucich, Dario, Annavajhala, Medini K., Khan, Ibrahim N., Oussenko, Irina, Francoeur, Nancy, Smith, Melissa L., Stockwell, Brent R., Lewis, Ian A., Hachani, Abderrahman, Upadhyay Baskota, Swikrity, Uhlemann, Anne-Catrin, Ahn, Danielle, Ernst, Robert K., Howden, Benjamin P., Sebra, Robert, and Prince, Alice

Published
2022
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30. Deep oncopanel sequencing reveals within block position-dependent quality degradation in FFPE processed samples

Author

Zhang, Yifan, Blomquist, Thomas M., Kusko, Rebecca, Stetson, Daniel, Zhang, Zhihong, Yin, Lihui, Sebra, Robert, Gong, Binsheng, Lococo, Jennifer S., Mittal, Vinay K., Novoradovskaya, Natalia, Yeo, Ji-Youn, Dominiak, Nicole, Hipp, Jennifer, Raymond, Amelia, Qiu, Fujun, Arib, Hanane, Smith, Melissa L., Brock, Jay E., Farkas, Daniel H., Craig, Daniel J., Crawford, Erin L., Li, Dan, Morrison, Tom, Tom, Nikola, Xiao, Wenzhong, Yang, Mary, Mason, Christopher E., Richmond, Todd A., Jones, Wendell, Johann, Jr, Donald J., Shi, Leming, Tong, Weida, Willey, James C., and Xu, Joshua

Published
2022
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35. High‐Resolution Profiling of Human Vocal Fold Cellular Landscapes With Single‐Nuclei RNA Sequencing.

Author

Laitman, Benjamin M., Charytonowicz, Daniel, Zhu, Ashley J., Lynch, Katie, Varelas, Eleni A., Burton, Madeline, Andreou, Christina, Kore, Pragati, Kirke, Diana N., Chen, Ya‐Wen, Beaumont, Kristin G., Sebra, Robert, Genden, Eric M., and Courey, Mark S.

Abstract

Introduction: The function of the vocal folds (VFs) is determined by the phenotype, abundance, and distribution of differentiated cells within specific microenvironments. Identifying this histologic framework is crucial in understanding laryngeal disease. A paucity of studies investigating VF cellular heterogeneity has been undertaken. Here, we examined the cellular landscape of human VFs by utilizing single‐nuclei RNA‐sequencing. Methods: Normal true VF tissue was excised from five patients undergoing pitch elevation surgery. Tissue was snap frozen in liquid nitrogen and subjected to cellular digestion and nuclear extraction. Nuclei were processed for single‐nucleus sequencing using the 10X Genomics Chromium platform. Sequencing reads were assembled using cellranger and analyzed with the scanpy package in python. Results: RNA sequencing revealed 18 global cell clusters. While many were of epithelial origin, expected cell types, such as fibroblasts, immune cells, muscle cells, and endothelial cells were present. Subcluster analysis defined unique epithelial, immune, and fibroblast subpopulations. Conclusion: This study evaluated the cellular heterogeneity of normal human VFs by utilizing single‐nuclei RNA‐sequencing. With further confirmation through additional spatial sequencing and microscopic imaging, a novel cellular map of the VFs may provide insight into new cellular targets for VF disease. Level of Evidence: NA Laryngoscope, 134:3193–3200, 2024 [ABSTRACT FROM AUTHOR]

Published
2024
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37. Influenza virus infection causes global RNAPII termination defects

Author

Zhao, Nan, Sebastiano, Vittorio, Moshkina, Natasha, Mena, Nacho, Hultquist, Judd, Jimenez-Morales, David, Ma, Yixuan, Rialdi, Alex, Albrecht, Randy, Fenouil, Romain, Sánchez-Aparicio, Maria Teresa, Ayllon, Juan, Ravisankar, Sweta, Haddad, Bahareh, Ho, Jessica Sook Yuin, Low, Diana, Jin, Jian, Yurchenko, Vyacheslav, Prinjha, Rab K, Tarakhovsky, Alexander, Squatrito, Massimo, Pinto, Dalila, Allette, Kimaada, Byun, Minji, Smith, Melissa Laird, Sebra, Robert, Guccione, Ernesto, Tumpey, Terrence, Krogan, Nevan, Greenbaum, Benjamin, van Bakel, Harm, García-Sastre, Adolfo, and Marazzi, Ivan

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Microbiology, Clinical Sciences, Medical Microbiology, Infectious Diseases, Emerging Infectious Diseases, Biodefense, Influenza, Pneumonia & Influenza, Prevention, Genetics, Vaccine Related, 2.1 Biological and endogenous factors, 2.2 Factors relating to the physical environment, Aetiology, Infection, Humans, Influenza A virus, Influenza, Human, RNA Polymerase II, Terminator Regions, Genetic, Virulence, Chemical Sciences, Medical and Health Sciences, Biophysics, Developmental Biology, Biological sciences, Biomedical and clinical sciences, Chemical sciences
Abstract

Viral infection perturbs host cells and can be used to uncover regulatory mechanisms controlling cellular responses and susceptibility to infections. Using cell biological, biochemical, and genetic tools, we reveal that influenza A virus (IAV) infection induces global transcriptional defects at the 3' ends of active host genes and RNA polymerase II (RNAPII) run-through into extragenic regions. Deregulated RNAPII leads to expression of aberrant RNAs (3' extensions and host-gene fusions) that ultimately cause global transcriptional downregulation of physiological transcripts, an effect influencing antiviral response and virulence. This phenomenon occurs with multiple strains of IAV, is dependent on influenza NS1 protein, and can be modulated by SUMOylation of an intrinsically disordered region (IDR) of NS1 expressed by the 1918 pandemic IAV strain. Our data identify a strategy used by IAV to suppress host gene expression and indicate that polymorphisms in IDRs of viral proteins can affect the outcome of an infection.

Published
2018

38. Resistance to Ceftazidime-Avibactam Is Due to Transposition of KPC in a Porin-Deficient Strain of Klebsiella pneumoniae with Increased Efflux Activity

Author

Nelson, Kirk, Hemarajata, Peera, Sun, Dongxu, Rubio-Aparicio, Debora, Tsivkovski, Ruslan, Yang, Shangxin, Sebra, Robert, Kasarskis, Andrew, Nguyen, Hoan, Hanson, Blake M, Leopold, Shana, Weinstock, George, Lomovskaya, Olga, and Humphries, Romney M

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Microbiology, Clinical Sciences, Medical Microbiology, Lung, Infectious Diseases, Pneumonia, Pneumonia & Influenza, Antimicrobial Resistance, Aetiology, 2.1 Biological and endogenous factors, Azabicyclo Compounds, Bacterial Proteins, Carrier Proteins, Ceftazidime, DNA Transposable Elements, Drug Combinations, Drug Resistance, Multiple, Bacterial, Humans, Klebsiella pneumoniae, Microbial Sensitivity Tests, Plasmids, Porins, Trans-Activators, beta-Lactamases, ceftazidime-avibactam, KPC, Klebsiella pneurnoniae, porin mutation, resistance, Pharmacology and Pharmaceutical Sciences, Medical microbiology, Pharmacology and pharmaceutical sciences
Abstract

Ceftazidime-avibactam is an antibiotic with activity against serine beta-lactamases, including Klebsiella pneumoniae carbapenemase (KPC). Recently, reports have emerged of KPC-producing isolates resistant to this antibiotic, including a report of a wild-type KPC-3 producing sequence type 258 Klebsiella pneumoniae that was resistant to ceftazidime-avibactam. We describe a detailed analysis of this isolate, in the context of two other closely related KPC-3 producing isolates, recovered from the same patient. Both isolates encoded a nonfunctional OmpK35, whereas we demonstrate that a novel T333N mutation in OmpK36, present in the ceftazidime-avibactam resistant isolate, reduced the activity of this porin and impacted ceftazidime-avibactam susceptibility. In addition, we demonstrate that the increased expression of blaKPC-3 and blaSHV-12 observed in the ceftazidime-avibactam-resistant isolate was due to transposition of the Tn4401 transposon harboring blaKPC-3 into a second plasmid, pIncX3, which also harbored blaSHV-12, ultimately resulting in a higher copy number of blaKPC-3 in the resistant isolate. pIncX3 plasmid from the ceftazidime-avibactam resistant isolate, conjugated into a OmpK35/36-deficient K. pneumoniae background that harbored a mutation to the ramR regulator of the acrAB efflux operon recreated the ceftazidime-avibactam-resistant MIC of 32 μg/ml, confirming that this constellation of mutations is responsible for the resistance phenotype.

Published
2017

39. Single cell view of tumor microenvironment gradients in pleural mesothelioma

Author

Giotti, Bruno, primary, Dolasia, Komal, additional, Zhao, William, additional, Cai, Peiwen, additional, Sweeney, Robert, additional, Merritt, Elliot, additional, Kiner, Evgeny, additional, Kim, Grace, additional, Bhagwat, Atharva, additional, Hegde, Samarth, additional, Fitzgerald, Bailey, additional, Shroff, Sanjana, additional, Dawson, Travis, additional, Garcia-barros, Monica, additional, Abdul-ghafar, Jamshid, additional, Chen, Rachel, additional, Gnjatic, Sacha, additional, Soto, Alan, additional, Brody, Rachel, additional, Kim-Schulze, Seunghee, additional, Chen, Zhihong, additional, Beaumont, Kristin G., additional, Merad, Miriam, additional, Flores, Raja, additional, Sebra, Robert, additional, Horowitz, Amir, additional, Marron, Thomas U, additional, Tocheva, Anna, additional, Wolf, Andrea, additional, and Tsankov, Alexander M., additional

Published
2024
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40. Pan-cancer proteogenomics characterization of tumor immunity

Author

Petralia, Francesca, primary, Ma, Weiping, additional, Yaron, Tomer M., additional, Caruso, Francesca Pia, additional, Tignor, Nicole, additional, Wang, Joshua M., additional, Charytonowicz, Daniel, additional, Johnson, Jared L., additional, Huntsman, Emily M., additional, Marino, Giacomo B., additional, Calinawan, Anna, additional, Evangelista, John Erol, additional, Selvan, Myvizhi Esai, additional, Chowdhury, Shrabanti, additional, Rykunov, Dmitry, additional, Krek, Azra, additional, Song, Xiaoyu, additional, Turhan, Berk, additional, Christianson, Karen E., additional, Lewis, David A., additional, Deng, Eden Z., additional, Clarke, Daniel J.B., additional, Whiteaker, Jeffrey R., additional, Kennedy, Jacob J., additional, Zhao, Lei, additional, Segura, Rossana Lazcano, additional, Batra, Harsh, additional, Raso, Maria Gabriela, additional, Parra, Edwin Roger, additional, Soundararajan, Rama, additional, Tang, Ximing, additional, Li, Yize, additional, Yi, Xinpei, additional, Satpathy, Shankha, additional, Wang, Ying, additional, Wiznerowicz, Maciej, additional, González-Robles, Tania J., additional, Iavarone, Antonio, additional, Gosline, Sara J.C., additional, Reva, Boris, additional, Robles, Ana I., additional, Nesvizhskii, Alexey I., additional, Mani, D.R., additional, Gillette, Michael A., additional, Klein, Robert J., additional, Cieslik, Marcin, additional, Zhang, Bing, additional, Paulovich, Amanda G., additional, Sebra, Robert, additional, Gümüş, Zeynep H., additional, Hostetter, Galen, additional, Fenyö, David, additional, Omenn, Gilbert S., additional, Cantley, Lewis C., additional, Ma'ayan, Avi, additional, Lazar, Alexander J., additional, Ceccarelli, Michele, additional, Wang, Pei, additional, Abelin, Jennifer, additional, Aguet, François, additional, Akiyama, Yo, additional, An, Eunkyung, additional, Anand, Shankara, additional, Anurag, Meenakshi, additional, Babur, Özgün, additional, Bavarva, Jasmin, additional, Birger, Chet, additional, Birrer, Michael J., additional, Cao, Song, additional, Carr, Steven A., additional, Chan, Daniel W., additional, Chinnaiyan, Arul M., additional, Cho, Hanbyul, additional, Clauser, Karl, additional, Colaprico, Antonio, additional, Zhou, Daniel Cui, additional, da Veiga Leprevost, Felipe, additional, Day, Corbin, additional, Dhanasekaran, Saravana M., additional, Ding, Li, additional, Domagalski, Marcin J., additional, Dou, Yongchao, additional, Druker, Brian J., additional, Edwards, Nathan, additional, Ellis, Matthew J., additional, Foltz, Steven M., additional, Francis, Alicia, additional, Geffen, Yifat, additional, Getz, Gad, additional, Heiman, David I., additional, Hong, Runyu, additional, Hu, Yingwei, additional, Huang, Chen, additional, Jaehnig, Eric J., additional, Jewell, Scott D., additional, Ji, Jiayi, additional, Jiang, Wen, additional, Katsnelson, Lizabeth, additional, Ketchum, Karen A., additional, Kolodziejczak, Iga, additional, Krug, Karsten, additional, Kumar-Sinha, Chandan, additional, Lei, Jonathan T., additional, Liang, Wen-Wei, additional, Liao, Yuxing, additional, Lindgren, Caleb M., additional, Liu, Tao, additional, Liu, Wenke, additional, McDermott, Jason, additional, McKerrow, Wilson, additional, Mesri, Mehdi, additional, Mumphrey, Michael Brodie, additional, Newton, Chelsea J., additional, Oldroyd, Robert, additional, Payne, Samuel H., additional, Pugliese, Pietro, additional, Rodland, Karin D., additional, Rodrigues, Fernanda Martins, additional, Ruggles, Kelly V., additional, Savage, Sara R., additional, Schadt, Eric E., additional, Schnaubelt, Michael, additional, Schraink, Tobias, additional, Schürer, Stephan, additional, Shi, Zhiao, additional, Smith, Richard D., additional, Song, Feng, additional, Song, Yizhe, additional, Stathias, Vasileios, additional, Storrs, Erik P., additional, Tan, Jimin, additional, Terekhanova, Nadezhda V., additional, Thangudu, Ratna R., additional, Thiagarajan, Mathangi, additional, Wang, Liang-Bo, additional, Wen, Bo, additional, Wu, Yige, additional, Wyczalkowski, Matthew A., additional, Yao, Lijun, additional, Li, Qing Kay, additional, Zhang, Hui, additional, Zhang, Qing, additional, Zhang, Xu, additional, and Zhang, Zhen, additional

Published
2024
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41. Molecular profiling of human substantia nigra identifies diverse neuron types associated with vulnerability in Parkinson’s disease

Author

Wang, Qian, primary, Wang, Minghui, additional, Choi, Insup, additional, Sarrafha, Lily, additional, Liang, Marianna, additional, Ho, Lap, additional, Farrell, Kurt, additional, Beaumont, Kristin G., additional, Sebra, Robert, additional, De Sanctis, Claudia, additional, Crary, John F., additional, Ahfeldt, Tim, additional, Blanchard, Joel, additional, Neavin, Drew, additional, Powell, Joseph, additional, Davis, David A., additional, Sun, Xiaoyan, additional, Zhang, Bin, additional, and Yue, Zhenyu, additional

Published
2024
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42. Pathophysiology of SARS-CoV-2: the Mount Sinai COVID-19 autopsy experience

Author

Bryce, Clare, Grimes, Zachary, Pujadas, Elisabet, Ahuja, Sadhna, Beasley, Mary Beth, Albrecht, Randy, Hernandez, Tahyna, Stock, Aryeh, Zhao, Zhen, AlRasheed, Mohamed Rizwan, Chen, Joyce, Li, Li, Wang, Diane, Corben, Adriana, Haines, G. Kenneth, III, Westra, William H., Umphlett, Melissa, Gordon, Ronald E., Reidy, Jason, Petersen, Bruce, Salem, Fadi, Fiel, Maria Isabel, El Jamal, Siraj M., Tsankova, Nadejda M., Houldsworth, Jane, Mussa, Zarmeen, Veremis, Brandon, Sordillo, Emilia, Gitman, Melissa R., Nowak, Michael, Brody, Rachel, Harpaz, Noam, Merad, Miriam, Gnjatic, Sacha, Liu, Wen-Chun, Schotsaert, Michael, Miorin, Lisa, Aydillo Gomez, Teresa A., Ramos-Lopez, Irene, Garcia-Sastre, Adolfo, Donnelly, Ryan, Seigler, Patricia, Keys, Calvin, Cameron, Jennifer, Moultrie, Isaiah, Washington, Kae-Lynn, Treatman, Jacquelyn, Sebra, Robert, Jhang, Jeffrey, Firpo, Adolfo, Lednicky, John, Paniz-Mondolfi, Alberto, Cordon-Cardo, Carlos, and Fowkes, Mary E.

Published
2021
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43. Dietary fructose improves intestinal cell survival and nutrient absorption

Author

Taylor, Samuel R., Ramsamooj, Shakti, Liang, Roger J., Katti, Alyna, Pozovskiy, Rita, Vasan, Neil, Hwang, Seo-Kyoung, Nahiyaan, Navid, Francoeur, Nancy J., Schatoff, Emma M., Johnson, Jared L., Shah, Manish A., Dannenberg, Andrew J., Sebra, Robert P., Dow, Lukas E., Cantley, Lewis C., Rhee, Kyu Y., and Goncalves, Marcus D.

Published
2021
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45. A Drosophila platform identifies a novel, personalized therapy for a patient with adenoid cystic carcinoma

Author

Bangi, Erdem, Smibert, Peter, Uzilov, Andrew V., Teague, Alexander G., Gopinath, Sindhura, Antipin, Yevgeniy, Chen, Rong, Hecht, Chana, Gruszczynski, Nelson, Yon, Wesley J., Malyshev, Denis, Laspina, Denise, Selkridge, Isaiah, Wang, Huan, Gomez, Jorge, Mascarenhas, John, Moe, Aye S., Lau, Chun Yee, Taik, Patricia, Pandya, Chetanya, Sung, Max, Kim, Sara, Yum, Kendra, Sebra, Robert, Donovan, Michael, Misiukiewicz, Krzysztof, Ang, Celina, Schadt, Eric E., Posner, Marshall R., and Cagan, Ross L.

Published
2021
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46. Evolution and Transmission of Carbapenem-Resistant Klebsiella pneumoniae Expressing the blaOXA-232 Gene During an Institutional Outbreak Associated With Endoscopic Retrograde Cholangiopancreatography.

Author

Yang, Shangxin, Hemarajata, Peera, Hindler, Janet, Li, Fan, Adisetiyo, Helty, Aldrovandi, Grace, Sebra, Robert, Kasarskis, Andrew, MacCannell, Duncan, Didelot, Xavier, Russell, Dana, Rubin, Zachary, and Humphries, Romney

Subjects
Lung, Vaccine Related, Genetics, Pneumonia, Biotechnology, Emerging Infectious Diseases, Pneumonia & Influenza, Prevention, Biodefense, Carbapenems, Cholangiopancreatography, Endoscopic Retrograde, Cross Infection, Disease Outbreaks, Enzyme Activation, Genetic Variation, Genome, Bacterial, Humans, Klebsiella Infections, Klebsiella pneumoniae, Phylogeny, Plasmids, Whole Genome Sequencing, beta-Lactamases, CRE outbreak, whole-genome sequencing, ERCP, OXA-232, carbapenem-resistant Klebsiella pneumoniae, carbapenem-resistant Klebsiella pneumoniae., Biological Sciences, Medical and Health Sciences, Microbiology
Abstract

BackgroundWhole-genome sequencing (WGS) is an emerging and powerful technique by which to perform epidemiological studies in outbreak situations.MethodsWGS was used to identify and evaluate an outbreak of OXA-232-expressing carbapenem-resistant Klebsiella pneumoniae (CRKP) transmitted to 16 patients over the course of 40 weeks via endoscopic retrograde cholangiopancreatography procedures at a single institution. WGS was performed on 32 OXA-232 CRKP isolates (1-7 per patient) and single-nucleotide variants (SNVs) were analyzed, with reference to the index patient's isolate.ResultsInterhost genetic diversity of isolates was between 0 and 15 SNVs during the outbreak; molecular clock calculations estimated 12.31 substitutions per genome per year (95% credibility interval, 7.81-17.05). Both intra- and interpatient diversification at the plasmid and transposon level was observed, significantly impacting the antibiogram of outbreak isolates. The majority of isolates evaluated (n = 27) harbored a blaCTX-M-15 gene, but some (n = 5) lacked the transposon carrying this gene, which resulted in susceptibility to aztreonam and third- and fourth-generation cephalosporins. Similarly, an isolate from a colonized patient lacked the transposon carrying rmtF and aac(6')lb genes, resulting in susceptibility to aminoglycosides.ConclusionsThis study broadens the understanding of how bacteria diversify at the genomic level over the course of a defined outbreak and provides reference for future outbreak investigations.

Published
2017

50. Sexually dimorphic role of diet and stress on behavior, energy metabolism, and the ventromedial hypothalamus

Author

Shetty, Sanutha, primary, Duesman, Samuel J., additional, Patel, Sanil, additional, Huyhn, Pacific, additional, Shroff, Sanjana, additional, Das, Anika, additional, Chowhan, Disha, additional, Sebra, Robert, additional, Beaumont, Kristin, additional, McAlpine, Cameron S., additional, Rajbhandari, Prashant, additional, and Rajbhandari, Abha K., additional

Published
2023
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