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STAT5 and STAT3 balance shapes dendritic cell function and tumour immunity

Nature 2025年 1-10页

作者： Zhou, Jiajia Tison, Kole Zhou, Haibin Bai, Longchuan Acharyya, Ranjan Kumar McEachern, Donna Metwally, Hoda Wang, Yu Pitter, Michael Choi, Jae Eun Vatan, Linda Liao, Peng Yu, Jiali Lin, Heng Jiang, Long Wei, Shuang Gao, Xue Grove, Sara Parolia, Abhijit Cieslik, Marcin Kryczek, Ilona Green, Michael D. Lin, Jian-Xin Chinnaiyan, Arul M. Leonard, Warren J. Wang, Shaomeng Zou, Weiping Department of Surgery University of Michigan Medical School Ann Arbor MI United States Center of Excellence for Cancer Immunology and Immunotherapy University of Michigan Rogel Cancer Center Ann Arbor MI United States Graduate Program in Immunology University of Michigan Ann Arbor MI United States Department of Computational Medicine and Bioinformatics University of Michigan Medical School Ann Arbor MI United States Division of Hematology and Oncology Department of Internal Medicine University of Michigan Medical School Ann Arbor MI United States Department of Pathology University of Michigan Medical School Ann Arbor MI United States Michigan Center for Translational Pathology University of Michigan Medical School Ann Arbor MI United States Department of Radiation Oncology University of Michigan Medical School Ann Arbor MI United States Laboratory of Molecular Immunology and the Immunology Center National Heart Lung and Blood Institute National Institutes of Health Bethesda MD United States Howard Hughes Medical Institute University of Michigan Medical School Ann Arbor MI United States University of Michigan Rogel Cancer Center University of Michigan Ann Arbor MI United States Graduate Program in Cancer Biology University of Michigan Ann Arbor MI United States Department of Pharmacology University of Michigan Medical School Ann Arbor MI United States Department of Medicinal Chemistry College of Pharmacy University of Michigan Ann Arbor MI United States

Immune checkpoint blockade (ICB) has transformed cancer therapy1,2. The efficacy of immunotherapy depends on dendritic cell-mediated tumour antigen presentation, T cell priming and activation3,4. However, the relation...

Immune checkpoint blockade (ICB) has transformed cancer therapy^1,2. The efficacy of immunotherapy depends on dendritic cell-mediated tumour antigen presentation, T cell priming and activation^3,4. However, the relationship between the key transcription factors in dendritic cells and ICB efficacy remains unknown. Here we found that ICB reprograms the interplay between the STAT3 and STAT5 transcriptional pathways in dendritic cells, thereby activating T cell immunity and enabling ICB efficacy. Mechanistically, STAT3 restrained the JAK2 and STAT5 transcriptional pathway, determining the fate of dendritic cell function. As STAT3 is often activated in the tumour microenvironment⁵, we developed two distinct PROTAC (proteolysis-targeting chimera) degraders of STAT3, SD-36 and SD-2301. STAT3 degraders effectively degraded STAT3 in dendritic cells and reprogrammed the dendritic cell–transcriptional network towards immunogenicity. Furthermore, STAT3 degrader monotherapy was efficacious in treatment of advanced tumours and ICB-resistant tumours without toxicity in mice. Thus, the crosstalk between STAT3 and STAT5 transcriptional pathways determines the dendritic cell phenotype in the tumour microenvironment and STAT3 degraders hold promise for cancer immunotherapy. © The Author(s) 2025.

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Modularity detection in protein-protein interaction networks

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BMC Research Notes 2011年第1期4卷 1-6页

作者： Narayanan, Tejaswini Gersten, Merril Subramaniam, Shankar Grama, Ananth Department of Electrical and Computer Engineering University of California San Diego United States Graduate Program in Bioinformatics and Systems Biology University of California San Diego United States Department of Bioengineering University of California San Diego United States Department of Computer Science Purdue University West Lafayette IN United States

Background: Many recent studies have investigated modularity in biological networks, and its role in functional and structural characterization of constituent biomolecules. A technique that has shown considerable promise in the domain of modularity detection is the Newman and Girvan (NG) algorithm, which relies on the number of shortest-paths across pairs of vertices in the network traversing a given edge, referred to as the betweenness of that edge. The edge with the highest betweenness is iteratively eliminated from the network, with the betweenness of the remaining edges recalculated in every iteration. This generates a complete dendrogram, from which modules are extracted by applying a quality metric called modularity denoted by Q. This exhaustive computation can be prohibitively expensive for large networks such as Protein-Protein Interaction Networks. In this paper, we present a novel optimization to the modularity detection algorithm, in terms of an efficient termination criterion based on a target edge betweenness value, using which the process of iterative edge removal may be terminated. Results: We validate the robustness of our approach by applying our algorithm on real-world protein-protein interaction networks of Yeast, *** and Drosophila, and demonstrate that our algorithm consistently has significant computational gains in terms of reduced runtime, when compared to the NG algorithm. Furthermore, our algorithm produces modules comparable to those from the NG algorithm, qualitatively and quantitatively. We illustrate this using comparison metrics such as module distribution, module membership cardinality, modularity Q, and Jaccard Similarity Coefficient. Conclusions: We have presented an optimized approach for efficient modularity detection in networks. The intuition driving our approach is the extraction of holistic measures of centrality from graphs, which are representative of inherent modular structure of the underlying network, and the applic

关键词： Biological Network Jaccard Index Input Network High Betweenness Jaccard Similarity Coefficient

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Lymphatic endothelial mTORC1 instructs metabolic and developmental signaling during lymphangiogenesis

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Developmental Cell 2025年

作者： Han, Fei Simeroth, Summer Zhu, Jie Gryniuk, Irma Pranay, Atul Chen, Weiqing Wang, Yuan Cai, Yuanyuan Shen, Zhiyuan Wang, Guangyu Griffin, Courtney T. Xia, Lijun Yu, Pengchun Cardiovascular Biology Research Program Oklahoma Medical Research Foundation Oklahoma City 73104 OK United States Department of Cell Biology University of Oklahoma Health Sciences Center Oklahoma City 73104 OK United States Aging and Metabolism Research Program Oklahoma Medical Research Foundation Oklahoma City 73104 OK United States Center for Bioinformatics and Computational Biology Houston Methodist Research Institute Houston TX United States Department of Physiology Biophysics & Systems Biology Weill Cornell Graduate School of Medical Science Weill Cornell Medicine Cornell University New York NY United States Department of Radiation Oncology Rutgers Cancer Institute and Robert Wood Johnson Medical School Rutgers University New Brunswick NJ United States Center for Cardiovascular Regeneration Houston Methodist Research Institute Houston TX United States Center for RNA Therapeutics Houston Methodist Research Institute Houston TX United States Department of Cardiothoracic Surgery Weill Cornell Medicine Cornell University New York NY United States Department of Biochemistry and Physiology University of Oklahoma Health Sciences Center Oklahoma City OK United States

The lymphatic vasculature comprises lymphatic capillaries and collecting vessels. To support lymphatic development, lymphatic endothelial cells (LECs) utilize nutrients to fuel lymphangiogenic processes. Meanwhile, LECs maintain constant prospero homeobox 1 (PROX1) expression critical for lymphatic specification. However, molecular mechanisms orchestrating nutrient metabolism while sustaining PROX1 levels in LECs remain unclear. Here, we show that loss of RAPTOR, an indispensable mechanistic target of rapamycin complex 1 (mTORC1) component, downregulates PROX1 and impairs lymphatic capillary growth and differentiation of collecting lymphatics in mice. Mechanistically, mTORC1 inhibition in mouse and human LECs causes Myc reduction, which decreases hexokinase 2 (HK2) and glutaminase (GLS), inhibiting glycolysis and glutaminolysis. Myc or HK2/GLS ablation impedes lymphatic capillary and collecting vessel formation. Interestingly, mTORC1 regulation of PROX1 is independent of Myc-HK2/GLS signaling. Moreover, genetic interaction analysis indicates that Myc and PROX1 play crucial roles in mTORC1-regulated lymphatic development. Collectively, our findings identify mTORC1 as a key regulator of metabolic programs and PROX1 expression during lymphangiogenesis. © 2025 Elsevier Inc.

关键词： glutaminase glutaminolysis glycolysis hexokinase 2 lymphangiogenesis lymphatic endothelial cell lymphatic vessel mTORC1 Myc PROX1

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Relabeling Metabolic Pathway Data with Groups to Improve Prediction Outcomes 11th

Relabeling Metabolic Pathway Data with Groups to Improve P...

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11th International Conference on Computational Advances in Bio and Medical Sciences, ICCABS 2021

作者： Basher, Abdur Rahman M. A. Hallam, Steven J. Graduate Program in Bioinformatics University of British Columbia VancouverBCV5Z 4S6 Canada Department of Microbiology & Immunology University of British Columbia VancouverBCV6T 1Z3 Canada

ISBN: (纸本)9783031175305

Metabolic pathway inference from genomic sequence information is an integral scientific problem with wide ranging applications in the life sciences. As sequencing throughput increases, scalable and performative methods for pathway prediction at different levels of genome complexity and completion become compulsory. In this paper, we present reMap (relabeling metabolic pathway data with groups) a simple, and yet, generic framework, that performs relabeling examples to a different set of labels, characterized as groups. A pathway group is comprised of a subset of statistically correlated pathways that can be further distributed between multiple pathway groups. This has important implications for pathway prediction, where a learning algorithm can revisit a pathway multiple times across groups to improve sensitivity. The relabeling process in reMap is achieved through an alternating feedback process. In the first feed-forward phase, a minimal subset of pathway groups is picked to label each example. In the second feed-backward phase, reMap’s internal parameters are updated to increase the accuracy of mapping examples to pathway groups. The resulting pathway group dataset is then be used to train a multi-label learning algorithm. reMap’s effectiveness was evaluated on metabolic pathway prediction where resulting performance metrics equaled or exceeded other prediction methods on organismal genomes. © 2022, The Author(s), under exclusive license to Springer Nature Switzerland AG.

关键词： Forecasting

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Machine Learning Approach for Single Nucleotide Polymorphism Selection in Genetic Testing Results 8

Machine Learning Approach for Single Nucleotide Polymorphism...

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8th International Conference on Computer Science and Computational Intelligence, ICCSCI 2023

作者： Trinugroho, Joko Pebrianto Hidayat, Alam Ahmad Isnan, Mahmud Pardamean, Bens Bioinformatics and Data Science Research Center Bina Nusantara University Jakarta11480 Indonesia Department of Mathematics School of Computer Science Bina Nusantara University Jakarta11480 Indonesia Computer Science Department BINUS Graduate Program Bina Nusantara University Jakarta11480 Indonesia

Lactose intolerance is a type of digestive problem that may threaten the population because milk and dairy products compose of nutrients that are essential for human body. Genetic tests possess a great potential to detect lactose intolerance as it can be used in children and even infants. However, a new approach to analyze the genetic test results is needed to elucidate the Single Nucleotide Polymorphisms (SNPs) that are related to lactose intolerance. In this work, we utilized the machine learning based feature selection to select the SNPs associated with lactose tolerance trait from genotyping samples of direct-to-customer (DTCG genetic tests, obtained from the public database. Recursive Feature Elimination (RFE) with XGBoost model was used to perform feature selection. We also compared three different models, such as XGBoost, support vector machine (SVM), and random forest (RF) for training the selected features. Our findings revealed that 20 SNPs (out of 3501) were chosen, with rs4394668 as the most important variables (F-score 0.009). Furthermore, when compared to the RF and SVM models, the XGBoost model had the highest accuracy (0.87). Further studies should be undertaken to elucidate how the selected SNPs may lead to the lactose intolerance trait. © 2023 The Authors. Published by Elsevier B.V.

关键词： feature selection genetic test lactose intolerance SNP

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Redesign of high-affinity nonspecific nucleases with altered sequence preference

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Journal of the American Chemical Society 2009年第47期131卷 17345-17353页

作者： Wang, Yi-Ting Wright, Jon D. Doudeva, Lyudmila G. Jhang, Hua-Ci Lim, Carmay Yuan, Hanna S. Institute of Molecular Biology Academia Sinica Taipei Taiwan Institute of Biomedical Sciences Academia Sinica Taipei Taiwan Institute of Chemical Biology and Molecular Biophysics Taiwan International Graduate Program Academia Sinica Taipei Taiwan Institute of Bioinformatics and Structural Biology Department of Chemistry National Tsing Hua University HsinChu Taiwan Institute of Biochemistry and Molecular Biology National Taiwan University Taipei Taiwan

It is of crucial importance to elucidate the underlying principles that govern the binding affinity and selectivity between proteins and DNA. Here we use the nuclease domain of Colicin E7 (nColE7) as a model system to generate redesigned nucleases with improved DNA-binding affinities. ColE7 is a bacterial toxin, bearing a nonspecific endonuclease domain with a preference for hydrolyzing DNA phosphodiester bonds at the 3O-side after thymine and adenine;i.e., it prefers Thy and Ade at the -1 site. Using systematic computational screening, six nColE7 mutants were predicted to bind DNA with high affinity. Five of the redesigned single-point mutants were constructed and purified, and four mutants had a 3- to 5-fold higher DNA binding affinity than wild-type nColE7 as measured by fluorescence kinetic assays. Moreover, three of the designed mutants, D493N, D493Q, and D493R, digested DNA with an increased preference for guanine at +3 sites compared to the wild-type enzyme, as shown by DNA footprint assays. X-ray structure determination of the ColE7 mutant D493Q-DNA complex in conjunction with structural and free energy decomposition analyses provides a physical basis for the improved protein-DNA interactions: Replacing D493 at the protein-DNA interface with an amino acid residue that can maintain the native hydrogen bonds removes the unfavorable electrostatic repulsion between the negatively charged carboxylate and DNA phosphate groups. These results show that computational screening combined with biochemical, structural, and free energy analyses provide a useful means for generating redesigned nucleases with a higher DNA-binding affinity and altered sequence preferences in DNA cleavage. © 2009 American Chemical Society.

关键词： DNA

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Non-Coding RNA Analysis Using the Rfam Database

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Current Protocols in bioinformatics 2018年第1期62卷 e51-e51页

作者： Kalvari, Ioanna Nawrocki, Eric P. Argasinska, Joanna Quinones-Olvera, Natalia Finn, Robert D. Bateman, Alex Petrov, Anton I. European Molecular Biology Laboratory European Bioinformatics Institute Wellcome Genome Campus Hinxton Cambridge United Kingdom National Center for Biotechnology Information National Institutes of Health Department of Health and Human Services Bethesda MD United States Systems Biology Graduate Program Harvard University Cambridge MA United States

Rfam is a database of non-coding RNA families in which each family is represented by a multiple sequence alignment, a consensus secondary structure, and a covariance model. Using a combination of manual and literature-based curation and a custom software pipeline, Rfam converts descriptions of RNA families found in the scientific literature into computational models that can be used to annotate RNAs belonging to those families in any DNA or RNA sequence. Valuable research outputs that are often locked up in figures and supplementary information files are encapsulated in Rfam entries and made accessible through the Rfam Web site. The data produced by Rfam have a broad application, from genome annotation to providing training sets for algorithm development. This article gives an overview of how to search and navigate the Rfam Web site, and how to annotate sequences with RNA families. The Rfam database is freely available at http://***. © 2018 by John Wiley & Sons, Inc. Copyright © 2018 John Wiley & Sons, Inc.

关键词： genome annotation Infernal non-coding RNA Rfam RNA family

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Comparative Analysis of CNN Models for Multiclass Detection on Colon Disease 9

Comparative Analysis of CNN Models for Multiclass Detection ...

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9th International Conference on Information Technology and Digital Applications, ICITDA 2024

作者： Sulistyawan, Jason Sebastian Nugroho, Kuncahyo Setyo Isnan, Mahmud Pardamean, Bens Binus Graduate Program Bina Nusantara University Computer Science Department Jakarta11480 Indonesia Bioinformatics and Data Science Research Center Bina Nusantara University Jakarta11480 Indonesia School of Computer Science Bina Nusantara University Computer Science Department Jakarta11480 Indonesia

ISBN: (纸本)9798331510732

Gastrointestinal diseases are significant health concerns that mostly affect the digestive and biliary tracts. These can only be observed internally through endoscopy, or a modern approach named Wireless Capsule Endoscopy. Though the approach has proven to work, the process relies heavily on medical experts, which is prone to error when given a considerably large load. The use of deep learning in detecting diseases with images has been proven to work in various cases and can be implemented for gastrointestinal diseases. This study compared four deep learning models based on Convolutional Neural Network architectures consisting of the VGG16, ResNet152V2, InceptionV3, and Xception for classifying colon disease images. The experiment showed that the ResNet152V2 performed the best, compared to the other three with a testing accuracy score of 0.9837. On the other hand, the VGG16 had the lowest performance with around accuracy score of 0.89 while the Xception and InceptionV3models yielded similar accuracy scores of 0.9587 and 0.9549, respectively. The results highlight the effectiveness of ResNet152V2 in handling the complexity of colon disease detection © 2024 IEEE.

关键词： Convolutional neural networks

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Automatic question generation for bahasa indonesia examination using copynet 9th

Automatic question generation for bahasa indonesia examinati...

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9th International Conference on Computer Science and Computational Intelligence, ICCSCI 2024

作者： Henry, Matthew Martianus Elwirehardja, Gregorius Natanael Pardamean, Bens Bioinformatics and Data Science Research Center Bina Nusantara University Jakarta11480 Indonesia Computer Science Department School of Computer Science Bina Nusantara University Jakarta11480 Indonesia Computer Science Department BINUS Graduate Program Bina Nusantara University Jakarta11480 Indonesia

In educational institutions, an educator is responsible for assessing the student's knowledge grasp through examination. Creating exam questions, even the low-level factoid questions, is time-consuming, especially for inexperienced educators. Therefore, this study aims to create a sequence-to-sequence model using CopyNet by exploiting its copying mechanism advantage to automatically generate Bahasa Indonesia factoid questions to ease the educator's burden. Indonesian records in the TyDi QA dataset are used as the model input. GRU and Bi-GRU are employed as the CopyNet encoder, while LSTM is used as the CopyNet decoder. The model that utilizes GRU as the encoder achieves BLEU1, BLEU2, BLEU3, BLEU4, and ROUGE-L scores of 0.28, 0.19, 0.14, 0.1, and 0.32, respectively. Bi-GRU utilization as the model encoder achieves BLEU1, BLEU2, BLEU3, BLEU4, and ROUGE-L scores of 0.26, 0.17, 0.12, 0.09, and 0.30, respectively. Models using either encoder still achieve low scores. However, compared with the previous work, the result is still on par regarding the BLEU score. Further examination found that the generated questions do not adhere to semantic and syntactical correctness. Adding more records to the dataset and utilizing a more advanced architecture like CopyBERT are encouraged to improve the model performance in future work. Despite the result, this study has shown that CopyNet, primarily designed for text summarization or single-turn dialogue, can be tailored for factoid question generation. © 2024 The Authors.

关键词： Semantics

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Automatic Multiple Choice Question Generation: A Systematic Literature Review 9

Automatic Multiple Choice Question Generation: A Systematic ...

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9th International Conference on Information Technology and Digital Applications, ICITDA 2024

作者： Henry, Matthew Martianus Heryanto, Nur Adhianti Isnan, Mahmud Nugroho, Kuncahyo Setyo Pardamean, Bens Bina Nusantara University Bioinformatics and Data Science Research Center Jakarta11480 Indonesia School of Computer Science Bina Nusantara University Computer Science Department Jakarta11480 Indonesia Bina Nusantara University Binus Graduate Program Computer Science Department Jakarta11480 Indonesia

ISBN: (纸本)9798331510732

Despite their drawbacks, multiple-choice questions (MCQ) have been widely used to assess the students' understanding of lectures through examinations. The development of automatic MCQ generation is beneficial, especially for educators. As a starting point for further development, a Systematic Literature Review (SLR) is conducted to uncover current trends, future challenges, and opportunities in automatic MCQ generation. Previously, an SLR was conducted, but it lacks coverage of the utilization of transformer-based models. This SLR covers the development of automatic MCQ generation using either traditional or advanced approaches such as Transformers. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses framework was used to gather the data from Scopus, IEEE Xplore, SpringerLink, arXiv, and Semantic Scholar. The included articles must be open-access computer science conference papers or journal articles and written in English less than five years ago. Four independent reviewers analyzed the research workflow, evaluation metric, and dataset used in each study. There are 18 included studies, where 17% (n = 3) studies are from 2024, 33% (n = 6) studies are from 2023, 22% (n = 4) studies are from 2022, 11% (n = 2) studies are from 2021, and 17% (n = 3) studies are from 2020. There are 33% (n = 6) of the studies used the traditional feature-based engineering approach, 39% (n = 7) of the studies used the Transformer-based model fine-tuning approach, and the remaining used novel approaches. The study found that BERT variants are the most utilized Transformer-based model in automatic MCQ. The research notes some challenges, but also open various opportunities for further research, including Large Language Model (LLM) utilization for automatic MCQ generation, the utilization BERT-based models for standardized machine-learned evaluation metrics, and the initiative for the creation of an MCQ dataset benchmark. © 2024 IEEE.

关键词： Semantics

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