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4. Context-aware single-cell multiomics approach identifies cell-type-specific lung cancer susceptibility genes

Author

Long, Erping, Yin, Jinhu, Shin, Ju Hye, Li, Yuyan, Li, Bolun, Kane, Alexander, Patel, Harsh, Sun, Xinti, Wang, Cong, Luong, Thong, Xia, Jun, Han, Younghun, Byun, Jinyoung, Zhang, Tongwu, Zhao, Wei, Landi, Maria Teresa, Rothman, Nathaniel, Lan, Qing, Chang, Yoon Soo, Yu, Fulong, Amos, Christopher I., Shi, Jianxin, Lee, Jin Gu, Kim, Eun Young, and Choi, Jiyeon

Published
2024
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5. Author Correction: Context-aware single-cell multiomics approach identifies cell-type-specific lung cancer susceptibility genes

Author

Long, Erping, Yin, Jinhu, Shin, Ju Hye, Li, Yuyan, Li, Bolun, Kane, Alexander, Patel, Harsh, Sun, Xinti, Wang, Cong, Luong, Thong, Xia, Jun, Han, Younghun, Byun, Jinyoung, Zhang, Tongwu, Zhao, Wei, Landi, Maria Teresa, Rothman, Nathaniel, Lan, Qing, Chang, Yoon Soo, Yu, Fulong, Amos, Christopher I., Shi, Jianxin, Lee, Jin Gu, Kim, Eun Young, and Choi, Jiyeon

Published
2024
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17. No Association of IFNL4 Genotype With Opportunistic Infections and Cancers Among Men With Human Immunodeficiency Virus 1 Infection

Author

Fang, Michelle Z, Jackson, Sarah S, Pfeiffer, Ruth M, Kim, Eun-Young, Chen, Sabrina, Hussain, Shehnaz K, Jacobson, Lisa P, Martinson, Jeremy, Prokunina-Olsson, Ludmila, Thio, Chloe L, Duggal, Priya, Wolinsky, Steven, and O’Brien, Thomas R

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Immunology, Cancer, HIV/AIDS, Rare Diseases, Infectious Diseases, Sexually Transmitted Infections, Genetics, Emerging Infectious Diseases, 2.1 Biological and endogenous factors, 2.2 Factors relating to the physical environment, Infection, Good Health and Well Being, Male, Humans, HIV-1, Cohort Studies, Sarcoma, Kaposi, Genotype, HIV Infections, Opportunistic Infections, Herpes Simplex, Cytomegalovirus Infections, Interleukins, Polymorphism, Single Nucleotide, cytomegalovirus, genetics, herpes simplex virus, interferon lambda, Kaposi sarcoma, interferon λ, Biological Sciences, Medical and Health Sciences, Microbiology, Clinical sciences
Abstract

BackgroundIFNL4 genetic variants that are strongly associated with clearance of hepatitis C virus have been linked to risk of certain opportunistic infections (OIs) and cancers, including Kaposi sarcoma, cytomegalovirus infection, and herpes simplex virus infection. As the interferon (IFN) λ family plays a role in response to viral, bacterial, and fungal infections, IFNL4 genotype might affect risk for a wide range of OIs/cancers.MethodsWe examined associations between genotype for the functional IFNL4 rs368234815 polymorphism and incidence of 16 OIs/cancers among 2310 men with human immunodeficiency virus (2038 white; 272 black) enrolled in the Multicenter AIDS Cohort Study during 1984-1990. Our primary analyses used Cox proportional hazards models adjusted for self-reported racial ancestry to estimate hazard ratios with 95% confidence intervals, comparing participants with the genotypes that generate IFN-λ4 and those with the genotype that abrogates IFN-λ4. We censored follow-up at the introduction of highly effective antiretroviral therapies.ResultsWe found no statistically significant association between IFNL4 genotype and the incidence of Kaposi sarcoma (hazard ratio, 0.92 [95% confidence interval, .76-1.11]), cytomegalovirus infection (0.94 [.71-1.24]), herpes simplex virus infection (1.37 [.68-2.93]), or any other OI/cancer. We observed consistent results using additive genetic models and after controlling for CD4 cell count through time-dependent adjustment or restriction to participants with a low CD4 cell count.ConclusionsThe absence of associations between IFNL4 genotype and these OIs/cancers provides evidence that this gene does not affect the risk of disease from opportunistic pathogens.

Published
2023

20. Proteomic and genetic analyses of influenza A viruses identify pan-viral host targets

Author

Haas, Kelsey M, McGregor, Michael J, Bouhaddou, Mehdi, Polacco, Benjamin J, Kim, Eun-Young, Nguyen, Thong T, Newton, Billy W, Urbanowski, Matthew, Kim, Heejin, Williams, Michael AP, Rezelj, Veronica V, Hardy, Alexandra, Fossati, Andrea, Stevenson, Erica J, Sukerman, Ellie, Kim, Tiffany, Penugonda, Sudhir, Moreno, Elena, Braberg, Hannes, Zhou, Yuan, Metreveli, Giorgi, Harjai, Bhavya, Tummino, Tia A, Melnyk, James E, Soucheray, Margaret, Batra, Jyoti, Pache, Lars, Martin-Sancho, Laura, Carlson-Stevermer, Jared, Jureka, Alexander S, Basler, Christopher F, Shokat, Kevan M, Shoichet, Brian K, Shriver, Leah P, Johnson, Jeffrey R, Shaw, Megan L, Chanda, Sumit K, Roden, Dan M, Carter, Tonia C, Kottyan, Leah C, Chisholm, Rex L, Pacheco, Jennifer A, Smith, Maureen E, Schrodi, Steven J, Albrecht, Randy A, Vignuzzi, Marco, Zuliani-Alvarez, Lorena, Swaney, Danielle L, Eckhardt, Manon, Wolinsky, Steven M, White, Kris M, Hultquist, Judd F, Kaake, Robyn M, García-Sastre, Adolfo, and Krogan, Nevan J

Subjects
Microbiology, Medical Microbiology, Biomedical and Clinical Sciences, Biological Sciences, Influenza, Biotechnology, Genetics, Lung, Biodefense, Pneumonia & Influenza, Emerging Infectious Diseases, Infectious Diseases, 2.1 Biological and endogenous factors, 2.2 Factors relating to the physical environment, Infection, Humans, Influenza A virus, Influenza, Human, Influenza A Virus, H5N1 Subtype, Influenza A Virus, H3N2 Subtype, Proteomics, Virus Replication, COVID-19, SARS-CoV-2, Antiviral Agents, Host-Pathogen Interactions
Abstract

Influenza A Virus (IAV) is a recurring respiratory virus with limited availability of antiviral therapies. Understanding host proteins essential for IAV infection can identify targets for alternative host-directed therapies (HDTs). Using affinity purification-mass spectrometry and global phosphoproteomic and protein abundance analyses using three IAV strains (pH1N1, H3N2, H5N1) in three human cell types (A549, NHBE, THP-1), we map 332 IAV-human protein-protein interactions and identify 13 IAV-modulated kinases. Whole exome sequencing of patients who experienced severe influenza reveals several genes, including scaffold protein AHNAK, with predicted loss-of-function variants that are also identified in our proteomic analyses. Of our identified host factors, 54 significantly alter IAV infection upon siRNA knockdown, and two factors, AHNAK and coatomer subunit COPB1, are also essential for productive infection by SARS-CoV-2. Finally, 16 compounds targeting our identified host factors suppress IAV replication, with two targeting CDK2 and FLT3 showing pan-antiviral activity across influenza and coronavirus families. This study provides a comprehensive network model of IAV infection in human cells, identifying functional host targets for pan-viral HDT.

Published
2023

21. Long-term outcomes of enzyme replacement therapy from a large cohort of Korean patients with mucopolysaccharidosis IVA (Morquio A syndrome)

Author

Sung, Juyoung, Kim, Insung, Im, Minji, Ahn, Yoon Ji, Kim, Sang-Mi, Jang, Ja-Hyun, Park, Hyung-Doo, Jeon, Tae Yeon, Ko, Kyung Rae, Park, Se-Jun, Lee, Jun Hwa, Kim, Eun Young, Cheon, Chong Kun, Kang, Eungu, Moon, Jung-Eun, Sohn, Young Bae, Lin, Hsiang-Yu, Chuang, Chih-Kuang, Lin, Shuan-Pei, and Cho, Sung Yoon

Published
2025
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25. Africa-specific human genetic variation near CHD1L associates with HIV-1 load

Author

McLaren, Paul J., Porreca, Immacolata, Iaconis, Gennaro, Mok, Hoi Ping, Mukhopadhyay, Subhankar, Karakoc, Emre, Cristinelli, Sara, Pomilla, Cristina, Bartha, István, Thorball, Christian W., Tough, Riley H., Angelino, Paolo, Kiar, Cher S., Carstensen, Tommy, Fatumo, Segun, Porter, Tarryn, Jarvis, Isobel, Skarnes, William C., Bassett, Andrew, DeGorter, Marianne K., Sathya Moorthy, Mohana Prasad, Tuff, Jeffrey F., Kim, Eun-Young, Walter, Miriam, Simons, Lacy M., Bashirova, Arman, Buchbinder, Susan, Carrington, Mary, Cossarizza, Andrea, De Luca, Andrea, Goedert, James J., Goldstein, David B., Haas, David W., Herbeck, Joshua T., Johnson, Eric O., Kaleebu, Pontiano, Kilembe, William, Kirk, Gregory D., Kootstra, Neeltje A., Kral, Alex H., Lambotte, Olivier, Luo, Ma, Mallal, Simon, Martinez-Picado, Javier, Meyer, Laurence, Miro, José M., Moodley, Pravi, Motala, Ayesha A., Mullins, James I., Nam, Kireem, Obel, Niels, Pirie, Fraser, Plummer, Francis A., Poli, Guido, Price, Matthew A., Rauch, Andri, Theodorou, Ioannis, Trkola, Alexandra, Walker, Bruce D., Winkler, Cheryl A., Zagury, Jean-François, Montgomery, Stephen B., Ciuffi, Angela, Hultquist, Judd F., Wolinsky, Steven M., Dougan, Gordon, Lever, Andrew M. L., Gurdasani, Deepti, Groom, Harriet, Sandhu, Manjinder S., and Fellay, Jacques

Published
2023
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32. Transcriptome-wide changes in gene expression, splicing, and lncRNAs in response to a live attenuated dengue virus vaccine

Author

Kim, Eun-Young, Che, Yan, Dean, Hansi J, Lorenzo-Redondo, Ramon, Stewart, Michael, Keller, Caroline K, Whorf, Daniel, Mills, Dawson, Dulin, Nikita N, Kim, Tiffany, Votoupal, Megan, Walter, Miriam, Fernandez-Sesma, Ana, Kim, Heejin, and Wolinsky, Steven M

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biodefense, Immunization, Biotechnology, Infectious Diseases, Genetics, Rare Diseases, Prevention, Vaccine Related, Vector-Borne Diseases, Emerging Infectious Diseases, Infection, Good Health and Well Being, Antibodies, Neutralizing, Antibodies, Viral, Dengue, Dengue Vaccines, Dengue Virus, Humans, Immunogenicity, Vaccine, RNA, Long Noncoding, Transcriptome, Vaccines, Attenuated, Viral Vaccines, gene correlation networks, live attenuated dengue virus vaccine, long noncoding RNA, modular transcriptional repertoire, splicing, transcriptome, Biochemistry and Cell Biology, Medical Physiology, Biological sciences
Abstract

The tetravalent dengue vaccine candidate, TAK-003, induces a functional antibody response, but the titers of antibodies against the four serotypes of the dengue virus (DENV) can vary. Here, through a transcriptomic analysis on whole blood collected from recipients of a two-dose schedule of TAK-003, we examine gene expression, splicing, and transcript isoform-level changes for both protein-coding and noncoding genes to broaden our understanding of the immune response. Our analysis reveals a dynamic pattern of vaccine-associated regulation of long noncoding RNAs (lncRNAs), differential splicing of interferon-stimulated gene exons, and gene expression changes related to multiple signaling pathways that detect viral infection. Co-expression networks isolate immune cell-type-related and interferon-response modules that represent specific biological processes that correlate with more robust antibody responses. These data provide insights into the early determinants of the variable immune response to the vaccine, highlighting the significance of splicing and isoform-level gene regulatory mechanisms in defining vaccine immunogenicity.

Published
2022

33. HIV-infection and cocaine use regulate semen extracellular vesicles proteome and miRNAome in a manner that mediates strategic monocyte haptotaxis governed by miR-128 network

Author

Kaddour, Hussein, Kopcho, Steven, Lyu, Yuan, Shouman, Nadia, Paromov, Victor, Pratap, Siddharth, Dash, Chandravanu, Kim, Eun-Young, Martinson, Jeremy, McKay, Heather, Epeldegui, Marta, Margolick, Joseph B, Stapleton, Jack T, and Okeoma, Chioma M

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Neurosciences, Drug Abuse (NIDA only), Substance Misuse, Biotechnology, HIV/AIDS, Prevention, Infectious Diseases, Aetiology, 2.1 Biological and endogenous factors, Infection, Adolescent, Adult, Aged, Aged, 80 and over, Base Sequence, Chemotaxis, Cocaine, Comorbidity, Extracellular Vesicles, Gene Regulatory Networks, HIV Infections, Humans, MicroRNAs, Middle Aged, Monocytes, Proteome, Semen, Young Adult, Extracellular vesicles, Haptotaxis, Proteomics, Small RNA-Seq, miR-128-3p, HIV-1, Systems biology, Physiology, Clinical Sciences, Biochemistry & Molecular Biology, Biochemistry and cell biology, Medical biochemistry and metabolomics, Oncology and carcinogenesis
Abstract

BackgroundExtracellular vesicles (EVs) are regulators of cell-cell interactions and mediators of horizontal transfer of bioactive molecules between cells. EV-mediated cell-cell interactions play roles in physiological and pathophysiological processes, which maybe modulated by exposure to pathogens and cocaine use. However, the effect of pathogens and cocaine use on EV composition and function are not fully understood.ResultsHere, we used systems biology and multi-omics analysis to show that HIV infection (HIV +) and cocaine (COC) use (COC +) promote the release of semen-derived EVs (SEV) with dysregulated extracellular proteome (exProtein), miRNAome (exmiR), and exmiR networks. Integrating SEV proteome and miRNAome revealed a significant decrease in the enrichment of disease-associated, brain-enriched, and HIV-associated miR-128-3p (miR-128) in HIV + COC + SEV with a concomitant increase in miR-128 targets-PEAK1 and RND3/RhoE. Using two-dimensional-substrate single cell haptotaxis, we observed that in the presence of HIV + COC + SEV, contact guidance provided by the extracellular matrix (ECM, collagen type 1) network facilitated far-ranging haptotactic cues that guided monocytes over longer distances. Functionalizing SEV with a miR-128 mimic revealed that the strategic changes in monocyte haptotaxis are in large part the result of SEV-associated miR-128.ConclusionsWe propose that compositionally and functionally distinct HIV + COC + and HIV-COC- SEVs and their exmiR networks may provide cells relevant but divergent haptotactic guidance in the absence of chemotactic cues, under both physiological and pathophysiological conditions.

Published
2022

45. Short Communication: Plasma Lymphocyte Activation Gene 3 and Subclinical Coronary Artery Disease in the Multicenter AIDS Cohort Study.

Author

Sarkar, Sudipa, Haberlen, Sabina, Post, Wendy S, Kelesidis, Theodoros, Wiley, Dorothy, Kingsley, Lawrence, Kim, Eun-Young, Palella, Frank J, Witt, Mallory D, Budoff, Matthew J, Rodriguez, Annabelle, and Brown, Todd T

Subjects
Biomedical and Clinical Sciences, Immunology, Atherosclerosis, Aging, Heart Disease - Coronary Heart Disease, Heart Disease, Sexually Transmitted Infections, Prevention, Cardiovascular, Clinical Research, HIV/AIDS, Infectious Diseases, Good Health and Well Being, Acquired Immunodeficiency Syndrome, Antigens, CD, Cohort Studies, Coronary Artery Disease, HIV Infections, Humans, Lymphocyte Activation, Male, Lymphocyte Activation Gene 3 Protein, LAG3, cardiovascular disease, HIV, Clinical Sciences, Virology, Clinical sciences
Abstract

Chronic inflammation, including among people with HIV (PWH), elevates immune cell expression of lymphocyte activation gene 3 (LAG3); however, low plasma LAG3 predicts cardiovascular disease (CVD) events in the general population. The associations among LAG3 plasma levels, subclinical atherosclerosis, inflammation, and HIV infection have not been well described. We measured plasma LAG3 in 704 men with and without HIV from the multicenter AIDS cohort study, who underwent coronary computed tomography angiography. HIV serostatus was not independently associated with LAG3 after adjustment for sociodemographic and CVD risk factors. Current smoking status and African American race were associated with lower LAG3, and age and sTNFαRI concentration were associated with greater LAG3. LAG3 was not associated with coronary artery stenosis. Thus, no difference was found in plasma LAG3 concentration by HIV serostatus, and no association between LAG3 and subclinical coronary atherosclerosis in men with and without HIV was observed.

Published
2021

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