IU Indianapolis ScholarWorks :: Browsing by Author "Yang, Kai"

Browsing by Author "Yang, Kai"

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Advanced Functions Embedded in the Second Version of Database, Global Evaluation of SARS-CoV-2/hCoV-19 Sequences 2
(Frontiers Media, 2022-04-11) Li, Kailing; Wang, Audrey K.Y.; Liu, Sheng; Fang, Shuyi; Lu, Alex Z.; Shen, Jikui; Yang, Lei; Hu, Chang-Deng; Yang, Kai; Wan, Jun; BioHealth Informatics, School of Informatics and Computing
The Global Evaluation of SARS-CoV-2/hCoV-19 Sequences 2 (GESS v2 https://shiny.ph.iu.edu/GESS_v2/) is an updated version of GESS, which has offered a handy query platform to analyze single-nucleotide variants (SNVs) on millions of high coverages and high-quality severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) complete genomes provided by the Global Initiative on Sharing Avian Influenza Data (GISAID). Including the tools in the first version, the GESS v2 is embedded with new functions, which allow users to search SNVs, given the viral nucleotide or amino acid sequence. The GESS v2 helps users to identify SNVs or SARS-CoV-2 lineages enriched in countries of user's interest and show the migration path of a selected lineage on a world map during specific time periods chosen by the users. In addition, the GESS v2 can recognize the dynamic variations of newly emerging SNVs in each month to help users monitor SNVs, which will potentially become dominant soon. More importantly, multiple sets of analyzed results about SNVs can be downloaded directly from the GESS v2 by which users can conduct their own independent research. With these significant updates, the GESS v2 will continue to serve as a public open platform for researchers to explore SARS-CoV-2 evolutionary patterns from the perspectives of the prevalence and impact of SNVs.
Autophagy modulates CD4+ T-cell lineage recommitment upon pathogen infection
(Springer Nature, 2020-07) Yang, Kai; Chi, Hongbo; Pediatrics, School of Medicine
BATF Regulates T Regulatory Cell Functional Specification and Fitness of Triglyceride Metabolism in Restraining Allergic Responses
(American Association of Immunologists, 2021) Xu, Chengxian; Fu, Yongyao; Liu, Sheng; Trittipo, Jack; Lu, Xiaoyu; Qi, Rong; Du, Hong; Yan, Cong; Zhang, Chi; Wan, Jun; Kaplan, Mark H.; Yang, Kai; Pediatrics, School of Medicine
Preserving appropriate function and metabolism in regulatory T (Treg) cells is crucial for controlling immune tolerance and inflammatory responses. Yet how Treg cells coordinate cellular metabolic programs to support their functional specification remains elusive. In this study, we report that BATF couples the TH2-suppressive function and triglyceride (TG) metabolism in Treg cells for controlling allergic airway inflammation and IgE responses. Mice with Treg-specific ablation of BATF developed an inflammatory disorder characterized by TH2-type dominant responses and were predisposed to house dust mite-induced airway inflammation. Loss of BATF enabled Treg cells to acquire TH2 cell-like characteristics. Moreover, BATF-deficient Treg cells displayed elevated levels of cellular TGs, and repressing or elevating TGs, respectively, restored or exacerbated their defects. Mechanistically, TCR/CD28 costimulation enhanced expression and function of BATF, which sustained IRF4 activity to preserve Treg cell functionality. Thus, our studies reveal that BATF links Treg cell functional specification and fitness of cellular TGs to control allergic responses, and suggest that therapeutic targeting of TG metabolism could be used for the treatment of allergic disease.
BATF sustains homeostasis and functionality of bone marrow Treg cells to preserve homeostatic regulation of hematopoiesis and development of B cells
(Frontiers Media, 2023-02-22) Tikka, Chiranjeevi; Beasley, Lindsay; Xu, Chengxian; Yang, Jing; Cooper, Scott; Lechner, Joseph; Gutch, Sarah; Kaplan, Mark H.; Capitano, Maegan; Yang, Kai; Pediatrics, School of Medicine
Bone marrow Treg cells (BM Tregs) orchestrate stem cell niches crucial for hematopoiesis. Yet little is known about the molecular mechanisms governing BM Treg homeostasis and function. Here we report that the transcription factor BATF maintains homeostasis and functionality of BM Tregs to facilitate homeostatic regulation of hematopoiesis and B cell development. Treg-specific ablation of BATF profoundly compromised proportions of BM Tregs associated with reduced expression of Treg effector molecules, including CD44, ICOS, KLRG1, and TIGIT. Moreover, BATF deficiency in Tregs led to increased numbers of hematopoietic stem cells (HSCs), multipotent progenitors (MPPs), and granulocyte-macrophage progenitors (GMPs), while reducing the functionality of myeloid progenitors and the generation of common lymphoid progenitors. Furthermore, Tregs lacking BATF failed to support the development of B cells in the BM. Mechanistically, BATF mediated IL-7 signaling to promote expression of effector molecules on BM Tregs and their homeostasis. Our studies reveal a previously unappreciated role for BATF in sustaining BM Treg homeostasis and function to ensure hematopoiesis.
Combinatorial analyses reveal cellular composition changes have different impacts on transcriptomic changes of cell type specific genes in Alzheimer’s Disease
(Springer Nature, 2021-01-11) Johnson, Travis S.; Xiang, Shunian; Dong, Tianhan; Huang, Zhi; Cheng, Michael; Wang, Tianfu; Yang, Kai; Ni, Dong; Huang, Kun; Zhang, Jie; Biostatistics, School of Public Health
Alzheimer’s disease (AD) brains are characterized by progressive neuron loss and gliosis. Previous studies of gene expression using bulk tissue samples often fail to consider changes in cell-type composition when comparing AD versus control, which can lead to differences in expression levels that are not due to transcriptional regulation. We mined five large transcriptomic AD datasets for conserved gene co-expression module, then analyzed differential expression and differential co-expression within the modules between AD samples and controls. We performed cell-type deconvolution analysis to determine whether the observed differential expression was due to changes in cell-type proportions in the samples or to transcriptional regulation. Our findings were validated using four additional datasets. We discovered that the increased expression of microglia modules in the AD samples can be explained by increased microglia proportions in the AD samples. In contrast, decreased expression and perturbed co-expression within neuron modules in the AD samples was likely due in part to altered regulation of neuronal pathways. Several transcription factors that are differentially expressed in AD might account for such altered gene regulation. Similarly, changes in gene expression and co-expression within astrocyte modules could be attributed to combined effects of astrogliosis and astrocyte gene activation. Gene expression in the astrocyte modules was also strongly correlated with clinicopathological biomarkers. Through this work, we demonstrated that combinatorial analysis can delineate the origins of transcriptomic changes in bulk tissue data and shed light on key genes and pathways involved in AD.
Corrigendum: Regulatory T cells targeting a pathogenic MHC class II: insulin peptide epitope postpone spontaneous autoimmune diabetes
(Frontiers Media, 2024-03-07) Obarorakpor, Nyerhovwo; Patel, Deep; Boyarov, Reni; Amarsaikhan, Nansalmaa; Cepeda, Joseph Ray; Eastes, Doreen; Robertson, Sylvia; Johnson, Travis; Yang, Kai; Tang, Qizhi; Zhang, Li; Biostatistics and Health Data Science, School of Medicine
In the published article, there was an error in the Funding statement. Grant “JDRF 2-SRA-2018-648-S-B” grant was missing in the statement. The correct Funding statement appears below. Funding This study was supported by grants from NIH R03AI139811-01A1, DoD W81XWH2210087, JDRF 2-SRA-2018-648-S-B, and a Pilot and Feasibility Award from the CDMD NIH/NIDDK Grant Number P30 DK097512 (to LZ). The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.
Development of Cancer-Genomics-Guided Precision Immunotherapy for Triple-Negative Breast Cancer
(2023-05) Sun, Yifan; Lu, Xiongbin; Kaplan, Mark H.; Hopewell, Emily L.; Zhang, Chi; Yang, Kai
Triple-negative breast cancer (TNBC), which accounts for 15-20% of all breast cancers, is highly aggressive and metastatic with the poorest overall rates. While surgery, radiation, and chemotherapy remain the main treatment options, TNBC represents an unmet medical need for better treatment strategies. Tremendous efforts have been made to develop effective therapies over the past years. However, TNBC treatment options are still very limited due to the lack of good drug targets and the low response rate of current therapies. In this study, we developed two different strategies to treat TNBC based on its cancer genomic features: 1) heterozygous loss of chromosome 17p (17p loss) and 2) high mutation load. 17p loss is one of the most frequent genomic events in breast cancer including TNBC, rendering cancer cells vulnerable to the inhibition of POLR2A via α-amanitin (POLR2A-specific inhibitor). Here, we developed a new drug T-Ama (α-amanitin-conjugated trastuzumab) targeting HER2-low TNBC with 17p loss by combining the effects of α-amanitin and trastuzumab (HER2+ breast cancer therapy). Our results showed that T-Ama exhibited superior efficacy in treating HER2-low TNBC with 17p loss in vitro and in vivo, and surprisingly induced immunogenic cell death (ICD) which further enhanced T cell infiltration and cytotoxicity levels and delivered greater efficacy in combination with immune checkpoint blockade therapy. Collectively, the therapeutic window created by 17p loss and HER2 expression will make HER2-low TNBC clinically feasible targets of T-Ama. As another genetic feature of TNBC, the higher genomic instability and mutational burden results in more neoantigens presented on MHC-I, along with the higher level of tumor-infiltrating T cells, making TNBC a perfect model for immunotherapy compared to the other breast cancer subtypes. Here, we designed a deconvolution-algorithm-derived library screening to find new therapeutic targets and identified PIK3C2α as a key player that determines MHC-I turnover and reduces the MHC-I-restricted antigen presentation on tumor cells. In preclinical models, inhibition of PIK3C2α profoundly suppressed breast tumor growth, increased tumor-infiltrating CD8+ T cells, and showed high potential enhancing the efficacy of anti-PD-1 therapy, suggesting that PIK3C2α is a potential therapeutic target for TNBC immunotherapy.
Distinct Cell Survival and Metabolic Programming Determines Germinal Center Tfh Survival of HIV-1 Infection
(2023-07) Syed, Fahim; Yu, Qigui; Dent, Alexander; Yang, Kai; Wan, Jun
HIV-1 is the causative agent of AIDS in people living with HIV-1 (PLHIV). HIV-1 predominantly targets and kills immune cells that are needed for defense against infections and illnesses. Although therapy can control the spread of HIV-1 in PLHIV and decrease the amount of virus present in the body, some subsets of infected immune cells are able to survive HIV-1 and escape treatment. Any pause in therapy leads to a return to high levels of viral loads due to these surviving infected cells. These subsets of infected immune cells escaping treatment represent a major obstacle to the eradication of HIV-1. One such subset of immune cells, the Germinal Center T follicular helper (GC Tfh) cells, can both survive infection and expand in PLHIV. Using human tonsil tissues, the major site of GC Tfh cells, our lab was able to find two critical factors that influence the GC Tfh cells’ ability to survive and thrive while infected by HIV-1. First, we found that GC Tfh cells have a distinct metabolic profile compared to other types of CD4 T cells found in human tonsils. This was characterized by a preference towards non-glycolytic metabolism even when infected with HIV-1. We found that inhibiting non-glycolytic metabolism resulted in a significant decrease in HIV-1 infected GC Tfh cells. Second, we found that GC Tfh cells sharply upregulate proteins responsible for stopping controlled cell death. We found one of these proteins, BIRC5, was integral to GC Tfh survival of HIV-1 infection. Inhibition of BIRC5 led to overall decreases in surviving infected cells, as well as significant decreases in infected GC Tfh survival. In contrast, inhibition of BIRC5 had no effect on uninfected cells. Our results signify an important advancement in the study of HIV-1 reservoir and will help in developing novel therapeutics to eradicate rather than suppress HIV-1 in PLHIV.
An Extreme Learning Machine-based Pedestrian Detection Method
(Office of the Vice Chancellor for Research, 2013-04-05) Yang, Kai; Du, Eliza Y.; Delp, Edward J.; Jiang, Pingge; Jiang, Feng; Chen, Yaobin; Sherony, Rini; Takahashi, Hiroyuki
Pedestrian detection is a challenging task due to the high variance of pedestrians and fast changing background, especially for a single in-car camera system. Traditional HOG+SVM methods have two challenges: (1) false positives and (2) processing speed. In this paper, a new pedestrian detection method using multimodal HOG for pedestrian feature extraction and kernel based Extreme Learning Machine (ELM) for classification is presented. The experimental results using our naturalistic driving dataset show that the proposed method outperforms the traditional HOG+SVM method in both recognition accuracy and processing speed.
The glutathione peroxidase Gpx4 prevents lipid peroxidation and ferroptosis to sustain Treg cell activation and suppression of antitumor immunity
(Elsevier, 2021-06) Xu, Chengxian; Sun, Shaogang; Johnson, Travis; Qi, Rong; Zhang, Siyuan; Zhang, Jie; Yang, Kai; Pediatrics, School of Medicine
T regulatory (Treg) cells are crucial to maintain immune tolerance and repress antitumor immunity, but the mechanisms governing their cellular redox homeostasis remain elusive. We report that glutathione peroxidase 4 (Gpx4) prevents Treg cells from lipid peroxidation and ferroptosis in regulating immune homeostasis and antitumor immunity. Treg-specific deletion of Gpx4 impairs immune homeostasis without substantially affecting survival of Treg cells at steady state. Loss of Gpx4 results in excessive accumulation of lipid peroxides and ferroptosis of Treg cells upon T cell receptor (TCR)/CD28 co-stimulation. Neutralization of lipid peroxides and blockade of iron availability rescue ferroptosis of Gpx4-deficient Treg cells. Moreover, Gpx4-deficient Treg cells elevate generation of mitochondrial superoxide and production of interleukin-1β (IL-1β) that facilitates T helper 17 (TH17) responses. Furthermore, Treg-specific ablation of Gpx4 represses tumor growth and concomitantly potentiates antitumor immunity. Our studies establish a crucial role for Gpx4 in protecting activated Treg cells from lipid peroxidation and ferroptosis and offer a potential therapeutic strategy to improve cancer treatment.

Browsing by Author "Yang, Kai"

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