11 results on '"Li, Yingcong"'
Search Results
2. Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs
- Author
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Eschweiler, Simon, Ramírez-Suástegui, Ciro, Li, Yingcong, King, Emma, Chudley, Lindsey, Thomas, Jaya, Wood, Oliver, von Witzleben, Adrian, Jeffrey, Danielle, McCann, Katy, Simon, Hayley, Mondal, Monalisa, Wang, Alice, Dicker, Martina, Lopez-Guadamillas, Elena, Chou, Ting-Fang, Dobbs, Nicola A., Essame, Louisa, Acton, Gary, Kelly, Fiona, Halbert, Gavin, Sacco, Joseph J., Schache, Andrew Graeme, Shaw, Richard, McCaul, James Anthony, Paterson, Claire, Davies, Joseph H., Brennan, Peter A., Singh, Rabindra P., Loadman, Paul M., Wilson, William, Hackshaw, Allan, Seumois, Gregory, Okkenhaug, Klaus, Thomas, Gareth J., Jones, Terry M., Ay, Ferhat, Friberg, Greg, Kronenberg, Mitchell, Vanhaesebroeck, Bart, Vijayanand, Pandurangan, and Ottensmeier, Christian H.
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- 2022
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3. Multi-layered study of T cells in inflammatory bowel disease pathogenesis
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Li, Yingcong
- Subjects
Immunology ,Genetics ,Inflammatory bowel disease ,Metabolism ,T cells - Abstract
Inflammatory bowel disease (IBD) is a complicated disease characterized by an inflammation of the gastrointestinal (GI) tract, but the mechanism remains unknown. Among all the immune cells, T cells showed strong association with IBD pathogenesis. In this thesis, we studied how T cells contribute to IBD through genetics and pathogenic transcriptomic programs. Genome wide association studies (GWAS) identify a site near the metabolism gene laccase domain containing 1 (LACC1) as a risk for Crohn’s disease (CD). We previously found in populations that the Crohn’s disease risk allele correlates with decreased LACC1 expression in T lymphocytes. Despite this, the mechanism by which T cell gene expression is affected, and a link to T cell function and inflammatory disease, remained unknown. Here we identified sites in the promoter region in a haploblock that influenced LACC1 gene expression. Direct association of disease-risk variants with lower LACC1 mRNA was confirmed by comparing transcript quantity of the alleles in LACC1 heterozygous human CD4+ T cells. Using gene editing, we validated the role of this LACC1 region in gene expression in T cells. Human CD4+ T cells with LACC1 gene knockdown showed altered metabolism and reduced regulatory T cell differentiation. Overall, our study connects a disease GWAS hit by linking promoter region alterations specifically to changes in T cell metabolism and function. In the other part of the thesis, to identify the pathogenic T cell subsets, we compared T cells from the inflamed and non-involved tissues of active UC patients, with T cells from healthy donors and remission patients whose UC symptoms were temporarily suppressed by medications. Single-cell RNA seq analysis indicated that CD4 and CD8 T cells from inflamed tissues both showed increased IL17A-expressing cells (TH17/TC17), and TCF7-expressing stem-like T cells, which all showed more activation and pro-inflammatory features. RNA velocity and TCR analyses implied that the pathogenic TH17/TC17 cells subsets were derived from TCF7-expressing stem-like T cells, thus we hypothesized that stemness program is critical for the disease development. To validate the idea, we adaptively transferred Bcl6-deficient T cells, whose stemness program was impaired, into Rag1-/- mice to induce colitis. Compared to WT T cells, Bcl6-deficient T cells induced much less severe colitis with lower expansion and lower pathogenic TH17/TC17 populations, which showed high TFH gene signatures. In summary, our study unveiled the novel stem-like T cells in colitis, which could lead to new therapies to the disease.
- Published
- 2023
4. Inhibition of JNK ameliorates depressive-like behaviors and reduces the activation of pro-inflammatory cytokines and the phosphorylation of glucocorticoid receptors at serine 246 induced by neuroinflammation
- Author
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Zhang, Juntao, Lin, Wenjuan, Tang, Mingming, Zhao, Yawei, Zhang, Ke, Wang, Xiaqing, and Li, Yingcong
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- 2020
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5. Transcriptomes and metabolism define mouse and human MAIT cell populations.
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Chandra, Shilpi, Ascui, Gabriel, Riffelmacher, Thomas, Chawla, Ashu, Ramírez-Suástegui, Ciro, Castelan, Viankail C., Seumois, Gregory, Simon, Hayley, Murray, Mallory P., Seo, Goo-Young, Premlal, Ashmitaa L. R., Schmiedel, Benjamin, Verstichel, Greet, Li, Yingcong, Lin, Chia-Hao, Greenbaum, Jason, Lamberti, John, Murthy, Raghav, Nigro, John, and Cheroutre, Hilde
- Subjects
CELL populations ,TRANSCRIPTOMES ,PET shops ,IMMUNOLOGIC memory ,MICROBIAL metabolites - Abstract
Mucosal-associated invariant T (MAIT) cells are a subset of T lymphocytes that respond to microbial metabolites. We defined MAIT cell populations in different organs and characterized the developmental pathway of mouse and human MAIT cells in the thymus using single-cell RNA sequencing and phenotypic and metabolic analyses. We showed that the predominant mouse subset, which produced IL-17 (MAIT17), and the subset that produced IFN-γ (MAIT1) had not only greatly different transcriptomes but also different metabolic states. MAIT17 cells in different organs exhibited increased lipid uptake, lipid storage, and mitochondrial potential compared with MAIT1 cells. All these properties were similar in the thymus and likely acquired there. Human MAIT cells in lung and blood were more homogeneous but still differed between tissues. Human MAIT cells had increased fatty acid uptake and lipid storage in blood and lung, similar to human CD8 T resident memory cells, but unlike mouse MAIT17 cells, they lacked increased mitochondrial potential. Although mouse and human MAIT cell transcriptomes showed similarities for immature cells in the thymus, they diverged more strikingly in the periphery. Analysis of pet store mice demonstrated decreased lung MAIT17 cells in these so-called "dirty" mice, indicative of an environmental influence on MAIT cell subsets and function. Editor's summary: Mucosal-associated invariant T (MAIT) cells are a subset of T cells that sense microbial metabolites. Chandra et al. analyzed MAIT cells in mice and humans to better understand how the local environment influences MAIT cell development and function. They used single-cell RNA sequencing and phenotypic and metabolic analyses and observed that MAIT cell transcriptional and metabolic programs originated in the thymus but was also influenced by local tissue environment. IL-17–producing MAIT cells (MAIT17) were dominant in murine lung, and IFN-γ–producing MAIT1 cells were more frequent in the liver. "Dirty" pet store mice had fewer lung MAIT17 cells compared with lab strains, indicating influence of external environment. Human MAIT cells showed less heterogeneity than murine counterparts, and their properties differed more strikingly in the periphery. These findings confirm that the environment influences MAIT cell development and function. —Christiana Fogg [ABSTRACT FROM AUTHOR]
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- 2023
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6. Dissecting Chain-of-Thought: A Study on Compositional In-Context Learning of MLPs
- Author
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Li, Yingcong, Sreenivasan, Kartik, Giannou, Angeliki, Papailiopoulos, Dimitris, and Oymak, Samet
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FOS: Computer and information sciences ,Computer Science - Machine Learning ,Artificial Intelligence (cs.AI) ,Computer Science - Computation and Language ,Computer Science - Artificial Intelligence ,Computation and Language (cs.CL) ,Machine Learning (cs.LG) - Abstract
Chain-of-thought (CoT) is a method that enables language models to handle complex reasoning tasks by decomposing them into simpler steps. Despite its success, the underlying mechanics of CoT are not yet fully understood. In an attempt to shed light on this, our study investigates the impact of CoT on the ability of transformers to in-context learn a simple to study, yet general family of compositional functions: multi-layer perceptrons (MLPs). In this setting, we reveal that the success of CoT can be attributed to breaking down in-context learning of a compositional function into two distinct phases: focusing on data related to each step of the composition and in-context learning the single-step composition function. Through both experimental and theoretical evidence, we demonstrate how CoT significantly reduces the sample complexity of in-context learning (ICL) and facilitates the learning of complex functions that non-CoT methods struggle with. Furthermore, we illustrate how transformers can transition from vanilla in-context learning to mastering a compositional function with CoT by simply incorporating an additional layer that performs the necessary filtering for CoT via the attention mechanism. In addition to these test-time benefits, we highlight how CoT accelerates pretraining by learning shortcuts to represent complex functions and how filtering plays an important role in pretraining. These findings collectively provide insights into the mechanics of CoT, inviting further investigation of its role in complex reasoning tasks.
- Published
- 2023
7. Stochastic Contextual Bandits with Long Horizon Rewards
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Qin, Yuzhen, Li, Yingcong, Pasqualetti, Fabio, Fazel, Maryam, and Oymak, Samet
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FOS: Computer and information sciences ,Computer Science - Machine Learning ,Artificial Intelligence (cs.AI) ,Computer Science - Artificial Intelligence ,Statistics - Machine Learning ,Machine Learning (stat.ML) ,Machine Learning (cs.LG) - Abstract
The growing interest in complex decision-making and language modeling problems highlights the importance of sample-efficient learning over very long horizons. This work takes a step in this direction by investigating contextual linear bandits where the current reward depends on at most $s$ prior actions and contexts (not necessarily consecutive), up to a time horizon of $h$. In order to avoid polynomial dependence on $h$, we propose new algorithms that leverage sparsity to discover the dependence pattern and arm parameters jointly. We consider both the data-poor ($T, Comment: 47 pages, to appear at AAAI 2023
- Published
- 2023
8. JAML immunotherapy targets recently activated tumor-infiltrating CD8+ T cells.
- Author
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Eschweiler, Simon, Wang, Alice, Ramírez-Suástegui, Ciro, von Witzleben, Adrian, Li, Yingcong, Chee, Serena J., Simon, Hayley, Mondal, Monalisa, Ellis, Matthew, Thomas, Gareth J., Chandra, Vivek, Ottensmeier, Christian H., and Vijayanand, Pandurangan
- Abstract
Junctional adhesion molecule-like protein (JAML) serves as a co-stimulatory molecule in γδ T cells. While it has recently been described as a cancer immunotherapy target in mice, its potential to cause toxicity, specific mode of action with regard to its cellular targets, and whether it can be targeted in humans remain unknown. Here, we show that JAML is induced by T cell receptor engagement, reveal that this induction is linked to cis -regulatory interactions between the CD3D and JAML gene loci. When compared with other immunotherapy targets plagued by low target specificity and end-organ toxicity, we find JAML to be mostly restricted to and highly expressed by tissue-resident memory CD8
+ T cells in multiple cancer types. By delineating the key cellular targets and functional consequences of agonistic anti-JAML therapy in a murine melanoma model, we show its specific mode of action and the reason for its synergistic effects with anti-PD-1. [Display omitted] • JAML is a co-stimulatory molecule in human and murine αβ T cells • JAML is induced by TCR stimulation and enriched in tumor-infiltrating T RM cells • JAML expression in T RM cells is associated with better survival outcomes in HNSCC • Agonistic anti-JAML controls tumor growth and synergizes with anti-PD-1 therapy Eschweiler et al. identify JAML as a promising immunotherapy target with low on-target/off-cell and on-target/off-tumor effects. When compared with other immunotherapy targets plagued by low target specificity and end-organ toxicity, they find JAML to be mostly restricted to and highly expressed by (tissue-resident) CD8+ T cells in multiple cancer types. [ABSTRACT FROM AUTHOR]- Published
- 2023
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9. DNA damage and S phase arrest induced by Ochratoxin A in human embryonic kidney cells (HEK 293).
- Author
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Yang, Qian, He, Xiaoyun, Li, Xiaohong, Xu, Wentao, Luo, Yunbo, Yang, Xuan, Wang, Yan, Li, Yingcong, and Huang, Kunlun
- Subjects
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DNA damage , *OCHRATOXINS , *NEPHROTOXICOLOGY , *HEPATOTOXICOLOGY , *IMMUNOTOXICOLOGY , *CELL cycle , *REACTIVE oxygen species - Abstract
Ochratoxin A (OTA) is a ubiquitous mycotoxin with potential nephrotoxic, hepatotoxic and immunotoxic effects. The mechanisms underlying the nephrotoxicity of OTA remain obscure. To investigate DNA damage and the changes of the cell cycle distribution induced by OTA, human embryonic kidney cells (HEK 293 cells) were incubated with various concentrations of OTA for 24 h in vitro . The results indicated that OTA treatment led to the production of reactive oxygen species (ROS) and to a decrease of the mitochondrial membrane potential (Δ Ψ m ). OTA-induced DNA damage in HEK 293 cells was evidenced by DNA comet tails formation and increased expression of γ-H2AX. In addition, OTA could induce cell cycle arrest at the S phase in HEK 293 cells. The expression of key cell cycle regulatory factors that were critical to the S phase, including cyclin A2, cyclin E1, and CDK2, were further detected. The expression of cyclin A2, cyclin E1, and CDK2 were significantly decreased by OTA treatment at both the mRNA and protein levels. The apoptosis of HEK 293 cells after OTA treatment was observed using Hoechst 33342 staining. The results confirmed that OTA did induce apoptosis in HEK 293 cells. In conclusion, our results provided new insights into the molecular mechanisms by which OTA might promote nephrotoxicity. [ABSTRACT FROM AUTHOR]
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- 2014
- Full Text
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10. JAML immunotherapy targets recently activated tumor-infiltrating CD8 + T cells.
- Author
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Eschweiler S, Wang A, Ramírez-Suástegui C, von Witzleben A, Li Y, Chee SJ, Simon H, Mondal M, Ellis M, Thomas GJ, Chandra V, Ottensmeier CH, and Vijayanand P
- Subjects
- Humans, Animals, Mice, Junctional Adhesion Molecules, CD8-Positive T-Lymphocytes metabolism, Immunotherapy, Lymphocytes, Tumor-Infiltrating metabolism, Cell Adhesion Molecules metabolism, Neoplasms
- Abstract
Junctional adhesion molecule-like protein (JAML) serves as a co-stimulatory molecule in γδ T cells. While it has recently been described as a cancer immunotherapy target in mice, its potential to cause toxicity, specific mode of action with regard to its cellular targets, and whether it can be targeted in humans remain unknown. Here, we show that JAML is induced by T cell receptor engagement, reveal that this induction is linked to cis-regulatory interactions between the CD3D and JAML gene loci. When compared with other immunotherapy targets plagued by low target specificity and end-organ toxicity, we find JAML to be mostly restricted to and highly expressed by tissue-resident memory CD8
+ T cells in multiple cancer types. By delineating the key cellular targets and functional consequences of agonistic anti-JAML therapy in a murine melanoma model, we show its specific mode of action and the reason for its synergistic effects with anti-PD-1., Competing Interests: Declaration of interests The La Jolla Institute of Immunology has filed a patent “Methods for modulating an immune response to cancer or tumor cells” related to this work, and S.E., P.V., and C.H.O. are co-inventors on this patent., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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11. CD4 + -mediated colitis in mice is independent of the GPR183 and GPR18 pathways.
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Dicker M, Li Y, Giles DA, Verstichel G, Castelan VC, Ascui-Gac G, Chou TF, Perez-Jeldres T, Cheroutre H, and Kronenberg M
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- Mice, Humans, Animals, Dextran Sulfate adverse effects, Mice, Inbred C57BL, Disease Models, Animal, Receptors, G-Protein-Coupled genetics, Receptors, G-Protein-Coupled metabolism, CD4-Positive T-Lymphocytes metabolism, Genome-Wide Association Study, Colitis chemically induced, Colitis genetics
- Abstract
Colitis is characterized by an exacerbated intestinal immune response, but the genetic and other mechanisms regulating immune activation remain incompletely understood. In order to identify new pathways leading to colitis, we sought to identify genes with increased expression in the colons of patients that also are near loci identified by genome wide association studies (GWAS) associated with IBD risk. One such SNP, rs9557195 was of particular interest because it is within an intron of G-protein-coupled receptor (GPR) 183 , known to be important for lymphocyte migration. Furthermore, this SNP is in close proximity to the gene encoding another G-protein coupled receptor, GPR18 . Analyzing publicly available datasets, we found transcripts of GPR183 and GPR18 to be increased in colon biopsies from ulcerative colitis and Crohn's disease patients, and GPR183 was even more increased in patients resistant to TNF treatment. Expression of both genes also was increased in mouse models of colitis. Therefore, our aim was to understand if increased expression of these GPRs in the intestine is related to disease severity in colitis models. Here we investigated the role of these receptors in the T cell transfer model and the dextran sulfate sodium model. In the T cell transfer model, GPR183 expression on donor T cells, as well as on other cell types in the Rag
-/- recipients, was not essential for severe colitis induction. Furthermore, deficiency in Rag-/- mice for the enzyme that synthesizes a cholesterol metabolite that is a major ligand for GPR183 also did not affect disease. Similarly, lack of GPR18 expression in T cells or other cell types did not affect colitis pathogenesis in the T cell transfer or in the dextran sulfate sodium model. Therefore, despite increased expression of transcripts for these genes in the intestine during inflammation in humans and mice, they are not required for disease severity in mouse models of colitis induced by chemical injury or T cell cytokines, perhaps due to redundancy in mechanisms important for homing and survival of lymphocytes to the inflamed intestine., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dicker, Li, Giles, Verstichel, Castelan, Ascui-Gac, Chou, Perez-Jeldres, Cheroutre and Kronenberg.)- Published
- 2022
- Full Text
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