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Correction to: CpG‑creating mutations are costly in many human viruses

Evolutionary Ecology 2020年第3期34卷 361-362页

作者： Caudill, Victoria R. Qin, Sarina Winstead, Ryan Kaur, Jasmeen Tisthammer, Kaho Pineda, E. Geo Solis, Caroline Cobey, Sarah Bedford, Trevor Carja, Oana Eggo, Rosalind M. Koelle, Katia Lythgoe, Katrina Regoes, Roland Roy, Scott Allen, Nicole Aviles, Milo Baker, Brittany A. Bauer, William Bermudez, Shannel Carlson, Corey Castellanos, Edgar Catalan, Francisca L. Chemel, Angeline Katia Elliot, Jacob Evans, Dwayne Fiutek, Natalie Fryer, Emily Goodfellow, Samuel Melvin Hecht, Mordecai Hopp, Kellen Hopson, E. Deshawn Jaberi, Amirhossein Kim, Jennifer Kinney, Christen Lao, Derek Le, Adrienne Lo, Jacky Lopez, Alejandro G. López, Andrea Lorenzo, Fernando G. Luu, Gordon T. Mahoney, Andrew R. Melton, Rebecca L. Nascimento, Gabriela Do Pradhananga, Anjani Rodrigues, Nicole S. Shieh, Annie Sims, Jasmine Singh, Rima Sulaeman, Hasan Thu, Ricky Tran, Krystal Tran, Livia Winters, Elizabeth J. Wong, Albert Pennings, Pleuni S. Department of Biology San Francisco State University San Francisco USA Department of Biology University of Oregon Eugene USA Quantitative Systems Biology Univeristy of California Merced USA Department of Ecology and Evolution University of Chicago Chicago USA Vaccine and Infectious Disease Division Fred Hutchinson Cancer Research Center Seattle USA Department of Computational Biology School of Computer Science Carnegie Mellon University Pittsburgh USA Department of Infectious Disease Epidemiology London School of Hygiene & Tropical Medicine London UK Department of Biology Emory University Atlanta USA Big Data Institute University of Oxford Oxford UK Department of Environmental Systems Science ETH Zurich Zurich Switzerland Department of Neurological Surgery University of California San Francisco USA Department of Organismic and Evolutionary Biology Harvard University Cambridge USA Department of Plant Biology Carnegie Institution for Science Stanford USA Health Sciences Center University of New Mexico Albuquerque USA UCSD Biomed Sciences PhD Program University of California San Diego USA Biochemistry Molecular Cellular and Developmental Biology Graduate Group University of California Davis USA UCSF Tetrad Graduate Program University of California San Francisco USA

In the original article, the co-author name "Jennifer Kim" has been inadvertently missed during the publication process. The complete author group is given in this correction.

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A Survey of Generative AI for de novo Drug Design: New Frontiers in Molecule and Protein Generation

arXiv

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arXiv 2024年

作者： Tang, Xiangru Dai, Howard Knight, Elizabeth Wu, Fang Li, Yunyang Li, Tianxiao Gerstein, Mark Department of Computer Science Yale University New HavenCT06520 United States School of Medicine Yale University New HavenCT06520 United States Computer Science Department Stanford University CA94305 United States Program in Computational Biology & Bioinformatics Yale University New HavenCT06520 United States Department of Molecular Biophysics & Biochemistry Yale University New HavenCT06520 United States Department of Statistics & Data Science Yale University New HavenCT06520 United States Department of Biomedical Informatics & Data Science Yale University New HavenCT06520 United States

Artificial intelligence (AI)-driven methods can vastly improve the historically costly drug design process, with various generative models already in widespread use. Generative models for de novo drug design, in particular, focus on the creation of novel biological compounds entirely from scratch, representing a promising future direction. Rapid development in the field, combined with the inherent complexity of the drug design process, creates a difficult landscape for new researchers to enter. In this survey, we organize de novo drug design into two overarching themes: small molecule and protein generation. Within each theme, we identify a variety of subtasks and applications, highlighting important datasets, benchmarks, and model architectures and comparing the performance of top models. We take a broad approach to AI-driven drug design, allowing for both micro-level comparisons of various methods within each subtask and macro-level observations across different fields. We discuss parallel challenges and approaches between the two applications and highlight future directions for AI-driven de novo drug design as a whole. An organized repository of all covered sources is available at https://***/gersteinlab/GenAI4Drug. © 2024, CC BY.

关键词： Proteins

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DIFFUSION CURVATURE FOR ESTIMATING LOCAL CURVATURE IN HIGH DIMENSIONAL DATA

arXiv

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arXiv 2022年

作者： Bhaskar, Dhananjay MacDonald, Kincaid Fasina, Oluwadamilola Thomas, Dawson Rieck, Bastian Adelstein, Ian Krishnaswamy, Smita Department of Genetics Yale School of Medicine New HavenCT United States Department of Mathematics Yale University New HavenCT United States Program for Applied Mathematics Yale University New HavenCT United States Department of Physics Yale University New HavenCT United States Institute of AI for Health Helmholtz Pioneer Campus Munich Germany Department of Computer Science Yale University New HavenCT United States Program for Computational Biology and Bioinformatics Yale University New HavenCT United States

We introduce a new intrinsic measure of local curvature on point-cloud data called diffusion curvature. Our measure uses the framework of diffusion maps, including the data diffusion operator, to structure point cloud data and define local curvature based on the laziness of a random walk starting at a point or region of the data. We show that this laziness directly relates to volume comparison results from Riemannian geometry. We then extend this scalar curvature notion to an entire quadratic form using neural network estimations based on the diffusion map of point-cloud data. We show applications of both estimations on toy data, single-cell data and on estimating local Hessian matrices of neural network loss landscapes. © 2022, CC BY.

关键词： Geometry

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Interpretable network propagation with application to expanding the repertoire of human proteins that interact with SARS-CoV-2

arXiv

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arXiv 2020年

作者： Law, Jeffrey N. Akers, Kyle Tasnina, Nure Della Santina, Catherine M. Deutsch, Shay Kshirsagar, Meghana Klein-Seetharaman, Judith Crovella, Mark Rajagopalan, Padmavathy Kasif, Simon Murali, T.M. Interdisciplinary Ph.D. Program in Genetics Bioinformatics and Computational Biology BlacksburgVA United States Department of Computer Science Virginia Tech BlacksburgVA United States Department of Biomedical Engineering Boston University BostonMA United States Department of Mathematics University of California Los AngelesCA United States AI for Good Lab Microsoft RedmondWA United States Department of Chemistry Colorado School of Mines GoldenCO United States Department of Computer Science Boston University BostonMA United States Department of Chemical Engineering Virginia Tech BlacksburgVA United States

Background: Network propagation has been widely used for nearly 20 years to predict gene functions and phenotypes. Despite the popularity of this approach, little attention has been paid to the question of provenance tracing in this context, e.g., determining how much any experimental observation in the input contributes to the score of every prediction. Results: We design a network propagation framework with two novel components and apply it to predict human proteins that directly or indirectly interact with SARS-CoV-2 proteins. First, we trace the provenance of each prediction to its experimentally validated sources, which in our case are human proteins experimentally determined to interact with viral proteins. Second, we design a technique that helps to reduce the manual adjustment of parameters by users. We find that for every top-ranking prediction, the highest contribution to its score arises from a direct neighbor in a human protein-protein interaction network. We further analyze these results to develop functional insights on SARS-CoV-2 that expand on known biology such as the connection between endoplasmic reticulum stress, HSPA5, and anti-clotting agents. Conclusions: We examine how our provenance tracing method can be generalized to a broad class of network-based algorithms. We provide a useful resource for the SARS-CoV-2 community that implicates many previously undocumented proteins with putative functional relationships to viral infection. This resource includes potential drugs that can be opportunistically repositioned to target these proteins. We also discuss how our overall framework can be extended to other, newly-emerging viruses. © 2020, CC BY-NC-SA.

关键词： SARS

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Graph Fourier MMD for Signals on Graphs

Graph Fourier MMD for Signals on Graphs

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International Conference on Sampling Theory and Applications (SampTA)

作者： Samuel Leone Aarthi Venkat Guillaume Huguet Alexander Tong Guy Wolf Smita Krishnaswamy Applied Math Program New Haven Connecticut Computational Biology & Bioinformatics Program Yale University New Haven Connecticut Dept. of Math. & Stat Mila - Quebec AI Institute Université de Montréal Montreal Canada Dept. of Comp. Sci. & Oper. Res. Mila-Quebec AI Institute Université de Montréal Montreal Canada Department of Computer Science Department of Genetics Yale University New Haven Connecticut

While numerous methods have been proposed for computing distances between probability distributions in Euclidean space, relatively little attention has been given to computing such distances for distributions on graphs. However, there has been a marked increase in data that either lies on graph (such as protein interaction networks) or can be modeled as a graph (single cell data), particularly in the biomedical sciences. Thus, it becomes important to find ways to compare signals defined on such graphs. Here, we propose Graph Fourier MMD (GFMMD), a novel distance between distributions and signals on graphs. GFMMD is defined via an optimal witness function that is both smooth on the graph and maximizes the difference in expectation between the pair of distributions on the graph. We find an analytical solution to this optimization problem as well as an embedding of distributions that results from this method. We also prove several properties of this method including scale invariance and applicability to disconnected graphs. We showcase it on graph benchmark datasets as well on single cell RNA-sequencing data analysis. In the latter, we use the GFMMD-based gene embeddings to find meaningful gene clusters. We also propose a novel type of score for gene selection called gene localization score which helps select genes for cellular state space characterization.

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Unsupervised extraction of phenotypes from cancer clinical notes for association studies

arXiv

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arXiv 2019年

作者： Stark, Stefan G. Hyland, Stephanie L. Pradier, Melanie F. Lehmann, Kjong-Van Wicki, Andreas Perez-Cruz, Fernando Vogt, Julia E. Rätsch, Gunnar Computational Biology Program Memorial Sloan Kettering Cancer Center New York United States Tri-Institutional Ph.D. Program in Computational Biology and Medicine Weill Cornell Medicine New York United States Department of Computer Science ETH Zürich Zürich Switzerland Medical Informatics Group University Hospital Zürich Zürich Switzerland Swiss Institute for Bioinformatics Zurich Switzerland Department of Biology ETH Zürich Zürich Switzerland Department of Signal Processing and Information Theory University Carlos III in Madrid Leganés Spain School of Engineering and Applied Sciences Harvard University CambridgeMA United States Department of Biomedicine University of Basel Basel Switzerland Tumorzentrum University Hospital Basel Basel Switzerland Swiss Data Science Center ETH Zürich and EPFL Lausanne Switzerland Department of Mathematics and Computer Science University of Basel Basel Switzerland

The recent adoption of Electronic Health Records (EHRs) by healthcare providers has introduced an important source of data that provides detailed and highly specific insights into patient phenotypes over large cohorts. These datasets, in combination with machine learning and statistical approaches, generate new opportunities for research and clinical care. However, many methods require the patient representations to be in structured formats, while the information in the EHR is often locked in unstructured text designed for human readability. In this work, we develop the methodology to automatically extract clinical features from clinical narratives from large EHR corpora without the need for prior knowledge. We consider medical terms and sentences appearing in clinical narratives as atomic information units. We propose an efficient clustering strategy suitable for the analysis of large text corpora and utilize the clusters to represent information about the patient compactly. Additionally, we define the sentences on ontologic and natural language vocabularies to automatically detect pertinent combinations of concepts present in the corpus, even when an ontology is not available. To demonstrate the utility of our approach, we perform an association study of clinical features with somatic mutation profiles from 4,007 cancer patients and their tumors. We apply the proposed algorithm to a dataset consisting of .65 thousand documents with a total of .3.2 million sentences. After correcting for cancer type and other confounding factors, we identify a total of 340 significant statistical associations between the presence of somatic mutations and clinical features. We annotated these associations according to their novelty and we report several known associations. We also propose 37 plausible, testable hypothesis for associations where the underlying biological mechanism does not appear to be known. These results illustrate that the automated discovery of clinical features

关键词： Diseases

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Identifying topologically associating domains using differential kernels

arXiv

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arXiv 2023年

作者： Maisuradze, Luka King, Megan C. Surovtsev, Ivan V. Mochrie, Simon G.J. Shattuck, Mark D. O’Hern, Corey S. Department of Molecular Biophysics and Biochemistry Yale University New HavenCT United States Department of Cell Biology Yale School of Medicine New HavenCT United States Department of Physics Yale University New HavenCT United States Benjamin Levich Institute Physics Department The City College of New York New YorkNY United States Department of Mechanical Engineering and Materials Science Yale University New HavenCT United States Graduate Program in Computational Biology and Bioinformatics Yale University New HavenCT United States

Chromatin is a polymer complex of DNA and proteins that regulates gene expression. The three-dimensional (3D) structure and organization of chromatin controls DNA transcription and replication. High-throughput chromatin conformation capture techniques generate Hi-C maps that can provide insight into the 3D structure of chromatin. Hi-C maps can be represented as a symmetric matrix Aij, where each element represents the average contact probability or number of contacts between chromatin loci i and j. Previous studies have detected topologically associating domains (TADs), or self-interacting regions in Aij within which the contact probability is greater than that outside the region. Many algorithms have been developed to identify TADs within Hi-C maps. However, most TAD identification algorithms are unable to identify nested or overlapping TADs and for a given Hi-C map there is significant variation in the location and number of TADs identified by different methods. We develop a novel method to identify TADs, KerTAD, using a kernel-based technique from computer vision and image processing that is able to accurately identify nested and overlapping TADs. We benchmark this method against state-of-the-art TAD identification methods on both synthetic and experimental data sets. We find that the new method consistently has higher true positive rates (TPR) and lower false discovery rates (FDR) than all tested methods for both synthetic and manually annotated experimental Hi-C maps. The TPR for KerTAD is also largely insensitive to increasing noise and sparsity, in contrast to the other methods. We also find that KerTAD is consistent in the number and size of TADs identified across replicate experimental Hi-C maps for several organisms. Thus, KerTAD will improve automated TAD identification and enable researchers to better correlate changes in TADs to biological phenomena, such as enhancer-promoter interactions and disease states. © 2023, CC BY.

关键词： Topology

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Characterizing the mechanical response of metallic glasses to uniaxial tension using a spring network model

arXiv

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arXiv 2023年

作者： Nawano, Aya Schroers, Jan Shattuck, Mark D. O’Hern, Corey S. Department of Mechanical Engineering and Materials Science Yale University New HavenCT06520 United States Benjamin Levich Institute and Physics Department The City College of New York New YorkNY10031 United States Department of Physics Yale University New HavenCT06520 United States Department of Applied Physics Yale University New HavenCT06520 United States Graduate Program in Computational Biology and Bioinformatics Yale University New HavenCT06520 United States

Metallic glasses are frequently used as structural materials. Therefore, it is important to develop methods to predict their mechanical response as a function of the microstructure prior to loading. We develop a novel coarse-grained spring network model, which describes the mechanical response of metallic glasses using an equivalent series network of springs, which can break and re-form to mimic atomic rearrangements during deformation. To validate the spring network model, we perform numerical simulations of quasistatic, uniaxial tensile deformation of Lennard-Jones and embedded atom method (EAM) potentials for Cu50Zr50 metallic glasses in the absence of large-scale shear band formation. We consider samples prepared using a wide range of cooling rates and with different amounts of crystalline order. We show that both the Lennard-Jones and EAM models possess qualitatively similar stress σ versus strain γ curves. By specifying five parameters in the spring network model (ultimate strength, strain at ultimate strength, slopes of σ(γ) at γ = 0 and at large strain, and strain at fracture where σ = 0), we can accurately describe the form of the stress-strain curves during uniaxial tension for the computational studies of Cu50Zr50, as well as recent experimental studies of several Zr-based metallic glasses. For the computational studies of Cu50Zr50, we find that the yield strain distribution is shifted to larger strains for slowly cooled glasses compared to rapidly cooled glasses. In addition, the average number of new springs and their rate of formation decreases with decreasing cooling rate. These effects offset each other at large strains, causing the stress-strain curve to become independent of the sample preparation protocol in this regime. In future studies, we will extract the parameters that define the spring network model directly from atomic rearrangements that occur during uniaxial deformation. © 2023, CC BY-NC-ND.

关键词： Metallic glass

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Communicationmachine Learning-Based QSAR and LB-PaCS-MD Guided Design of SARs-CoV-2 Main Protease Inhibitors

SSRN

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SSRN 2024年

作者： Toopradab, Borwornlak Xie, Wanting Duan, Lian Hengphasatporn, Kowit Harada, Ryuhei Sinsulpsiri, Silpsiri Shigeta, Yasuteru Shi, Liyi Maitarad, Phornphimon Rungrotmongkol, Thanyada Program in Bioinformatics and Computational Biology Graduate School Chulalongkorn University Bangkok10330 Thailand Center of Excellence in Biocatalyst and Sustainable Biotechnology Department of Biochemistry Faculty of Science Chulalongkorn University Bangkok10330 Thailand Research Center of Nano Science and Technology Department of Chemistry College of Science Shanghai University Shanghai200444 China University of Tsukuba 1-1-1 Tennodai Ibaraki Tsukuba305-8577 Japan Graduate School of Pure and Applied Sciences University of Tsukuba 1-1-1 Tennodai Ibaraki305–8571 Japan Emerging Industries Institute Shanghai University Zhejiang Jiaxing314006 China

The global outbreak of the COVID-19 pandemic caused by the SARS-CoV-2 virus had led to profound respiratory health implications. This study focused on designing organoselenium-based inhibitors targeting the SARS-CoV-2 main protease (Mpro). The ligand-binding pathway sampling method based on parallel cascade selection molecular dynamics (LB-PaCS-MD) simulations was employed to elucidate plausible paths and conformations of ebselen, a synthetic organoselenium drug, within the Mpro catalytic site. Ebselen effectively engaged the active site, adopting proximity to H41 and interacting through the benzoisoselenazole ring in a π-π T-shaped arrangement, with an additional π-sulfur interaction with C145. In addition, the ligand-based drug design using the QSAR with GFA-MLR, RF, and ANN models were employed for biological activity prediction. The QSAR-ANN model showed robust statistical performance, with an R2training exceeding 0.98 and an RMSEtest of 0.21, indicating its suitability for predicting biological activities. Integration the ANN model with the LB-PaCS-MD insights enabled the rational design of novel compounds anchored in the ebselen core structure, identifying promising candidates with favorable predicted IC50 values. The designed compounds exhibited suitable drug-like characteristics and adopted an active conformation similar to ebselen, inhibiting Mpro function. These findings represent a synergistic approach merging ligand and structure-based drug design;with the potential to guide experimental synthesis and enzyme assay testing. © 2024, The Authors. All rights reserved.

关键词： Coronavirus

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ζ-QVAE: A Quantum Variational Autoencoder utilizing Regularized Mixed-state Latent Representations

arXiv

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arXiv 2024年

作者： Wang, Gaoyuan Warrell, Jonathan Emani, Prashant S. Gerstein, Mark Program in Computational Biology and Bioinformatics Yale University New HavenCT06520 United States Department of Molecular Biophysics and Biochemistry Yale University New HavenCT06520 United States Department of Computer Science Yale University New HavenCT06520 United States Department of Statistics & Data Science Yale University New HavenCT06520 United States Department of Biomedical Informatics & Data Science Yale University New HavenCT06520 United States NEC Laboratories America PrincetonNJ08540 United States

A major challenge in near-term quantum computing is its application to large real-world datasets due to scarce quantum hardware resources. One approach to enabling tractable quantum models for such datasets involves compressing the original data to manageable dimensions while still representing essential information for downstream analysis. In classical machine learning, variational autoencoders (VAEs) facilitate efficient data compression, representation learning for subsequent tasks, and novel data generation. However, no model has been proposed that exactly captures all of these features for direct application to quantum data on quantum computers. Some existing quantum models for data compression lack regularization of latent representations, thus preventing direct use for generation and control of generalization. Others are hybrid models with only some internal quantum components, impeding direct training on quantum data. To bridge this gap, we present a fully quantum framework, ζ-QVAE, which encompasses all the capabilities of classical VAEs and can be directly applied for both classical and quantum data compression. Our model utilizes regularized mixed states to attain optimal latent representations. It accommodates various divergences for reconstruction and regularization. Furthermore, by accommodating mixed states at every stage, it can utilize the full-data density matrix and allow for a"global"training objective. Doing so, in turn, makes efficient optimization possible and has potential implications for private and federated learning. In addition to exploring the theoretical properties of ζ-QVAE, we demonstrate its performance on representative genomics and synthetic data. Our results consistently indicate that ζ-QVAE exhibits similar or better performance compared to matched classical models. © 2024, CC BY-NC-ND.

关键词： Large datasets

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