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KLF2 maintains lineage fidelity and suppresses CD8 T cell exhaustion during acute LCMV infection

science (New York, N.Y.) 2025年第6735期387卷 eadn2337页

作者： Fagerberg, Eric Attanasio, John Dien, Christine Singh, Jaiveer Kessler, Emily A. Abdullah, Leena Shen, Jian Hunt, Brian G. Connolly, Kelli A. De Brouwer, Edward He, Jiaming Iyer, Nivedita R. Buck, Jessica Borr, Emily R. Damo, Martina Foster, Gena G. Giles, Josephine R. Huang, Yina H. Tsang, John S. Krishnaswamy, Smita Cui, Weiguo Joshi, Nikhil S. Department of Immunobiology Yale University School of Medicine New Haven CT United States Program in Computational Biology & Bioinformatics Yale University New Haven CT United States Department of Microbiology and Immunology Geisel School of Medicine at Dartmouth NH United States Department of Pathology Feinberg School of Medicine at Northwestern University Chicago IL United States Department of Genetics and Computer Science Yale University School of Medicine New Haven CT United States Department of Medicine University of Chicago Chicago IL United States Section of Hematology Department of Internal Medicine Yale University School of Medicine New Haven CT United States Department of Systems Pharmacology and Translational Therapeutics University of Pennsylvania Philadelphia PA United States Institute for Immunology Perelman School of Medicine University of Pennsylvania Philadelphia PA United States Parker Institute for Cancer Immunotherapy Perelman School of Medicine University of Pennsylvania Philadelphia PA United States Yale Center for Systems and Engineering Immunology Yale University School of Medicine New Haven CT United States New Haven CT United States Department of Biomedical Engineering Yale University New Haven CT United States Computational Biology and Bioinformatics Program Yale University CT USA New Haven United States Applied Math Program Yale University New Haven CT United States

Naïve CD8 T cells have the potential to differentiate into a spectrum of functional states during an immune response. How these developmental decisions are made and what mechanisms exist to suppress differentiation toward alternative fates remains unclear. We employed in vivo CRISPR-Cas9-based perturbation sequencing to assess the role of ~40 transcription factors (TFs) and epigenetic modulators in T cell fate decisions. Unexpectedly, we found that knockout of the TF Klf2 resulted in aberrant differentiation to exhausted-like CD8 T cells during acute infection. KLF2 was required to suppress the exhaustion-promoting TF TOX and to enable the TF TBET to drive effector differentiation. KLF2 was also necessary to maintain a polyfunctional tumor-specific progenitor state. Thus, KLF2 provides effector CD8 T cell lineage fidelity and suppresses the exhaustion program.

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Cholesterol allosteric modulation of the oxytocin receptor

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Biophysical Journal 2025年

作者： Marlow, Brennica Vogel, Alexander Kuenze, Georg Pankonin, Maik Reinhardt, Franziska Stadler, Peter F. Hildebrand, Peter W. Meiler, Jens Center for Structural Biology Vanderbilt University Nashville TN United States Institute for Drug Discovery Medical Faculty Leipzig University Leipzig Germany Center for Scalable Data Analytics and Artificial Intelligence ScaDS.AI Leipzig University Leipzig Germany Interdisciplinary Center for Bioinformatics Leipzig University Leipzig Germany Chemical and Physical Biology Program Vanderbilt University Nashville TN United States Department of Chemistry Vanderbilt University Nashville TN United States Institute of Medical Physics and Biophysics Medical Faculty Leipzig University Leipzig Germany Bioinformatics Group Institute of Computer Science Interdisciplinary Center of Bioinformatics Leipzig University Leipzig Germany Max-Planck-Institute for Mathematics in the Sciences Leipzig Germany Institute of Theoretical Chemistry University of Vienna Wien Austria Facultad de Ciencias Universidad National de Colombia Sede Bogota Colombia Santa Fe Institute New Mexico Santa Fe Mexico

G-protein coupled receptors are critical components in cellular signaling, mediating various physiological responses to external stimuli. Here, we investigate the intricate relationship between cholesterol and the oxytocin receptor (OXTR), focusing on the binding mechanisms and the allosteric cross talk of bound cholesterol to the orthosteric ligand binding pocket. Utilizing molecular docking and molecular dynamics simulations, we identify cholesterol binding sites both on the agonist-bound and antagonist-bound state, which show differing distributions and residence times of the cholesterol molecules. Importantly, both methods converge on several key sites, demonstrating strong predictive overlap. Notably, one such site, and several sites detected by our molecular dynamics approach, also coincide with electron density observed in an experimental cryo-EM map, providing orthogonal validation for computational predictions. Allosteric network analysis uncovers the distinct pathways through which cholesterol may affect ligand-mediated receptor signaling, highlighting the significance of one site on the extracellular leaflet between TM4 and TM5, and two sites on the intracellular leaflet between TM2, TM3, and TM4 and between TM4 and TM5 in transmitting allosteric signals to the orthosteric pocket. These findings provide insights into the impact of cholesterol on OXTR function, emphasizing specific binding sites and signaling paths for further experimental exploration. © 2025 Biophysical Society

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A Drug-Induced Liver Injury Prediction Model using Transcriptional Response Data with Graph Neural Network

A Drug-Induced Liver Injury Prediction Model using Transcrip...

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International Conference on Big Data and Smart Computing (BIGCOMP)

作者： Doyeong Hwang Minji Jeon Jaewoo Kang Department of Computer Science and Engineering Korea University Seoul Republic of Korea Interdisciplinary Graduate Program in Bioinformatics Korea University Seoul Republic of Korea

ISBN: (数字)9781728160344

ISBN: (纸本)9781728160351

Drug-Induced Liver Injury (DILI) is a major cause of failed drug candidates in clinical trials and withdrawal of approved drugs from the market. Therefore, machine learning-based DILI prediction can be key in increasing the success rate of drug discovery because drug candidates that are predicted to potentially induce liver injury can be rejected before clinical trials. However, existing DILI prediction models mainly focus on the chemical structures of drugs. Since we cannot determine whether a drug will cause liver injury based solely on its structure, DILI prediction based on the transcriptional effect of a drug on a cell is necessary. In this paper, we propose GLIT which is a model that uses transcriptional response data and chemical structures and can be used for drug-induced liver injury prediction. GLIT learns the embedding vectors of drug structures and drug-induced gene expression profiles using graph attention networks in a biological knowledge graph for predicting DILI. GLIT outperformed a baseline model that uses only drug structure information by 7% and 19.2% in terms of correct classification rate (CCR) and Matthews correlation coefficient (MCC), respectively. In addition, we conducted a literature survey to confirm whether the class labels of drugs, in the unknown DILI class, predicted by GLIT are correct.

关键词： Drugs Gene expression Neural networks Injuries Liver Predictive models Biological system modeling

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Development of Machine Learning Models for Predicting Radiation Dermatitis in Breast Cancer Patients Using Clinical Risk Factors, Patient-Reported Outcomes, and Serum Cytokine Biomarkers

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Clinical Breast Cancer 2025年

作者： Lin, Neil Abbas-Aghababazadeh, Farnoosh Su, Jie Wu, Alison J. Lin, Cherie Shi, Wei Xu, Wei Haibe-Kains, Benjamin Liu, Fei-Fei Kwan, Jennifer Y.Y. Institute of Medical Science Temerty Faculty of Medicine University of Toronto Toronto Canada Temerty Faculty of Medicine University of Toronto Toronto Canada Princess Margaret Bioinformatics and Computational Genomics Laboratory University Health Network Toronto Canada Biostatistics Division Princess Margaret Cancer Centre Toronto Canada Research Institute Princess Margaret Cancer Centre Toronto Canada Department of Computer Science University of Toronto Toronto Canada Ontario Institute for Cancer Research Toronto Canada Vector Institute for Artificial Intelligence Toronto Canada Department of Radiation Oncology Temerty Faculty of Medicine University of Toronto Toronto Canada Department of Medical Biophysics Temerty Faculty of Medicine University of Toronto Toronto Canada Radiation Medicine Program Princess Margaret Cancer Centre Toronto Canada

Background: Radiation dermatitis (RD) is a significant side effect of radiotherapy experienced by breast cancer patients. Severe symptoms include desquamation or ulceration of irradiated skin, which impacts quality of life and increases healthcare costs. Early identification of patients at risk for severe RD can facilitate preventive management and reduce severe symptoms. This study evaluated the utility of subjective and objective factors, such as patient-reported outcomes (PROs) and serum cytokines, for predicting RD in breast cancer patients. The performance of machine learning (ML) and logistic regression-based models were compared. Patients and Methods: Data from 147 breast cancer patients who underwent radiotherapy was analyzed to develop prognostic models. ML algorithms, including neural networks, random forest, XGBoost, and logistic regression, were employed to predict clinically significant Grade 2+ RD. Clinical factors, PROs, and cytokine biomarkers were incorporated into the risk models. Model performance was evaluated using nested cross-validation with separate loops for hyperparameter tuning and calculating performance metrics. Results: Feature selection identified 18 predictors of Grade 2+ RD including smoking, radiotherapy boost, reduced motivation, and the cytokines interleukin-4, interleukin-17, interleukin-1RA, interferon-gamma, and stromal cell-derived factor-1a. Incorporating these predictors, the XGBoost model achieved the highest performance with an area under the curve (AUC) of 0.780 (95% CI: 0.701-0.854). This was not significantly improved over the logistic regression model, which demonstrated an AUC of 0.714 (95% CI: 0.629-0.798). Conclusion: Clinical risk factors, PROs, and serum cytokine levels provide complementary prognostic information for predicting severe RD in breast cancer patients undergoing radiotherapy. ML and logistic regression models demonstrated comparable performance for predicting clinically significant RD with AUC>0.70. ©

关键词： Cancer survivorship Oncology Predictive modeling Radiotherapy Skin toxicity

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Spectral Top-Down Recovery of Latent Tree Models

arXiv

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arXiv 2021年

作者： Aizenbud, Yariv Jaffe, Ariel Wang, Meng Hu, Amber Amsel, Noah Nadler, Boaz Chang, Joseph T. Kluger, Yuval Program in Applied Mathematics Yale University New HavenCT06511 United States Department of Computer Science Weizmann Institute of Science Rehovot76100 Israel Department of Statistics Yale University New HavenCT06520 United States Interdepartmental Program in Computational Biology and Bioinformatics Yale University New HavenCT06511 United States Department of Pathology Yale University New HavenCT06511 United States

Modeling the distribution of high dimensional data by a latent tree graphical model is a prevalent approach in multiple scientific domains. A common task is to infer the underlying tree structure, given only observations of its terminal nodes. Many algorithms for tree recovery are computationally intensive, which limits their applicability to trees of moderate size. For large trees, a common approach, termed divide-and-conquer, is to recover the tree structure in two steps. First, recover the structure separately of multiple, possibly random subsets of the terminal nodes. Second, merge the resulting subtrees to form a full tree. Here, we develop Spectral Top-Down Recovery (STDR), a deterministic divide-and-conquer approach to infer large latent tree models. Unlike previous methods, STDR partitions the terminal nodes in a non random way, based on the Fiedler vector of a suitable Laplacian matrix related to the observed nodes. We prove that under certain conditions, this partitioning is consistent with the tree structure. This, in turn, leads to a significantly simpler merging procedure of the small subtrees. We prove that STDR is statistically consistent and bound the number of samples required to accurately recover the tree with high probability. Using simulated data from several common tree models in phylogenetics, we demonstrate that STDR has a significant advantage in terms of runtime, with improved or similar accuracy. Copyright © 2021, The Authors. All rights reserved.

关键词： Recovery

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TargetNet: Functional microRNA target prediction with deep neural networks

arXiv

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arXiv 2021年

作者： Min, Seonwoo Lee, Byunghan Yoon, Sungroh Department of Electrical and Computer Engineering Seoul National University Seoul08826 Korea Republic of LG AI Research Seoul07796 Korea Republic of Department of Electronic and IT Media Engineering Seoul National University of Science and Technology Seoul01811 Korea Republic of Interdisciplinary Program in Artificial Intelligence and Interdisciplinary Program in Bioinformatics Seoul National University Seoul08826 Korea Republic of

Motivation: MicroRNAs (miRNAs) play pivotal roles in gene expression regulation by binding to target sites of messenger RNAs (mRNAs). While identifying functional targets of miRNAs is of utmost importance, their prediction remains a great challenge. Previous computational algorithms have major limitations. They use conservative candidate target site (CTS) selection criteria mainly focusing on canonical site types, rely on laborious and time-consuming manual feature extraction, and do not fully capitalize on the information underlying miRNA-CTS interactions. Results: In this paper, we introduce TargetNet, a novel deep learning-based algorithm for functional miRNA target prediction. To address the limitations of previous approaches, TargetNet has three key components: (1) relaxed CTS selection criteria accommodating irregularities in the seed region, (2) a novel miRNA-CTS sequence encoding scheme incorporating extended seed region alignments, and (3) a deep residual network-based prediction model. The proposed model was trained with miRNA-CTS pair datasets and evaluated with miRNA-mRNA pair datasets. TargetNet advances the previous state-of-theart algorithms used in functional miRNA target classification. Furthermore, it demonstrates great potential for distinguishing high-functional miRNA targets. © 2021, CC BY-NC-ND.

关键词： RNA

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Predicting Protein Interaction Network Perturbation by Alternative Splicing with Semi-Supervised Learning

SSRN

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SSRN 2020年

作者： Narykov, Oleksandr Johnson, Nathan Korkin, Dmitry Department of Computer Science Bioinformatics and Computational Biology Program Worcester Polytechnic Institute WorcesterMA United States Harvard Program in Therapeutic Sciences Harvard Medical School Breast Tumor Immunology Laboratory Dana-Farber Cancer Institute BostonMA United States Department of Computer Science Bioinformatics and Computational Biology Program Worcester Polytechnic Institute WorcesterMA United States

Alternative splicing introduces a new layer of protein diversity and complexity in regulating cellular functions that can be specific to the tissue and cell type, physiological state of a cell, or disease phenotype. In particular, recent high-throughput experimental studies have illuminated the functional role of splicing events through rewiring protein-protein interactions, yet the extent to which the macromolecular interactions are affected by alternative splicing has to be fully understood. In silico methods provide a fast and cheap alternative to interrogating functional characteristics of thousands of alternatively spliced isoforms. Here we develop an accurate feature-based machine learning approach that predicts if a protein-protein interaction carried out by a reference isoform is perturbed by an alternatively spliced isoform. Our method called ALTernatively Spliced INteractions prediction (ALT-IN) Tool was compared with the state-of-the-art PPI prediction tools and showed superior performance, achieving 0.92 in precision and recall values. © 2020, The Authors. All rights reserved.

关键词： Forecasting

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Gene knockout inference with variational graph autoencoder learning single-cell gene regulatory networks

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Nucleic acids research 2023年第13期51卷 6578-6592页

作者： Yongjian Yang Guanxun Li Yan Zhong Qian Xu Bo-Jia Chen Yu-Te Lin Robert S Chapkin James J Cai Department of Electrical and Computer Engineering Texas A&M University College Station TX 77843 USA. Department of Statistics Texas A&M University College Station TX 77843 USA. Key Laboratory of Advanced Theory and Application in Statistics and Data Science-MOE School of Statistics East China Normal University 3663 North Zhongshan Road Shanghai 200062 China. Department of Veterinary Integrative Biosciences Texas A&M University College Station TX 77843 USA. Graduate Institute of Microbiology and Public Health College of Veterinary Medicine National Chung Hsing University Taichung 402 Taiwan. Graduate Institute of Biomedical Electronics and Bioinformatics National Taiwan University Taipei Taiwan. Program in Integrative & Complex Diseases Department of Nutrition Texas A&M University College Station TX 77843 USA. Interdisciplinary Program of Genetics Texas A&M University College Station TX 77843 USA.

In this paper, we introduce Gene Knockout Inference (GenKI), a virtual knockout (KO) tool for gene function prediction using single-cell RNA sequencing (scRNA-seq) data in the absence of KO samples when only wild-type (WT) samples are available. Without using any information from real KO samples, GenKI is designed to capture shifting patterns in gene regulation caused by the KO perturbation in an unsupervised manner and provide a robust and scalable framework for gene function studies. To achieve this goal, GenKI adapts a variational graph autoencoder (VGAE) model to learn latent representations of genes and interactions between genes from the input WT scRNA-seq data and a derived single-cell gene regulatory network (scGRN). The virtual KO data is then generated by computationally removing all edges of the KO gene-the gene to be knocked out for functional study-from the scGRN. The differences between WT and virtual KO data are discerned by using their corresponding latent parameters derived from the trained VGAE model. Our simulations show that GenKI accurately approximates the perturbation profiles upon gene KO and outperforms the state-of-the-art under a series of evaluation conditions. Using publicly available scRNA-seq data sets, we demonstrate that GenKI recapitulates discoveries of real-animal KO experiments and accurately predicts cell type-specific functions of KO genes. Thus, GenKI provides an in-silico alternative to KO experiments that may partially replace the need for genetically modified animals or other genetically perturbed systems.

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Implications of self-identified race, ethnicity, and genetic ancestry on genetic association studies in biobanks within health systems

arXiv

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arXiv 2024年

作者： Johnson, Ruth Pasaniuc, Bogdan Department of Biomedical Informatics Harvard Medical School BostonMA02115 United States Department of Computer Science University of California Los Angeles Los AngelesCA90095 United States Bioinformatics Interdepartmental Program University of California Los Angeles Los AngelesCA90095 United States Department of Pathology Laboratory Medicine David Geffen School of Medicine University of California Los Angeles Los AngelesCA90095 United States Department of Human Genetics David Geffen School of Medicine University of California Los Angeles Los AngelesCA90095 United States Department of Computational Medicine David Geffen School of Medicine University of California Los Angeles Los AngelesCA90095 United States Institute of Precision Health University of California Los Angeles Los AngelesCA90095 United States

Precision medicine aims to create biomedical solutions tailored to specific factors that affect disease risk and treatment responses within the population. The success of the genomics era and recent widespread availability of electronic health records (EHR) has ushered in a new wave of genomic biobanks connected to EHR databases (EHR-linked biobanks). This perspective aims to discuss how race, ethnicity, and genetic ancestry are currently utilized to study common disease variation through genetic association studies. Although genetic ancestry plays a significant role in shaping the genetic landscape underlying disease risk in humans, the overall risk of a disease is caused by a complex combination of environmental, sociocultural, and genetic factors. When using EHR-linked biobanks to interrogate underlying disease etiology, it is also important to be aware of how the biases associated with commonly used descent-associated concepts such as race and ethnicity can propagate to downstream analyses. We intend for this resource to support researchers who perform or analyze genetic association studies in the EHR-linked biobank setting such as those involved in consortium-wide biobanking efforts. We provide background on how race, ethnicity, and genetic ancestry play a role in current association studies, highlight considerations where there is no consensus about best practices, and provide transparency about the current shortcomings. © 2024, CC BY.

关键词： Genome

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Detecting Hemileia vastatrix using Vision AI as Supporting to Food Security for Smallholder Coffee Commodities

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IOP Conference Series: Earth and Environmental science 2022年第1期998卷

作者： Teddy Suparyanto Erick Firmansyah Tjeng Wawan Cenggoro Digdo Sudigyo Bens Pardamean Faculty of Agricultural Technology Institute of Agriculture STIPER Yogyakarta Indonesia 55282 Bioinformatics & Data Science Research Center Bina Nusantara University Jakarta Indonesia 11480 Computer Science Department School of Computer Science Bina Nusantara University Jakarta Indonesia 11480 Computer Science Department BINUS Graduate Program - Master of Computer Science Program Bina Nusantara University Jakarta Indonesia 11480

The loss of food crops during the COVID-19 pandemic threatens food security in Indonesia as one of the world's top coffee producers. This affects the insecurity of coffee commodities which is influenced by several factors other than the pandemic such as pests, plant diseases, and extreme weather. Plant diseases, such as leaf rust, are a significant factor in the insecurity problem in coffee commodities. The fungus Hemileia vastatrix B et Br causes leaf rust disease, which is a pest that frequently damages coffee plants. This disease not only interferes with plant growth but also causes a decrease in coffee quality and quantity. This initial research aims to carry out early prevention of these diseases as supporting to food security in smallholder coffee commodities. An AI-based visual detection application is the result of this research. We collected 100 images of coffee leaves from various coffee plants. The image is reshaped to 256 x 256 pixels and randomly trimmed to 224 x 224 pixels to fulfill the size requirements of a standard Deep Learning technique. Each image was classified into two classes by a plant pest and disease specialist. The dataset was divided into training, validation, and testing series with a ratio of 60:20:20 for training procedures. The Convolutional Neural Network (CNN) research method used a variation of the ResNet CNN model with 18 layers. The best model validation was 59%.

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