检索结果-内蒙古大学图书馆

An integrative systems-biology approach defines mechanisms of Alzheimer’s disease neurodegeneration

Nature Communications 2025年第1期16卷 1-21页

作者： Leventhal, Matthew J. Zanella, Camila A. Kang, Byunguk Peng, Jiajie Gritsch, david Liao, Zhixiang Bukhari, Hassan Wang, Tao Pao, Ping-Chieh danquah, Serwah Benetatos, Joseph Nehme, Ralda Farhi, Samouil Tsai, Li-Huei dong, Xianjun Scherzer, Clemens R. Feany, Mel B. Fraenkel, Ernest MIT Ph.D. Program in Computational and Systems Biology Cambridge MA United States Department of Biological Engineering Massachusetts Institute of Technology Cambridge MA United States Broad Institute of Harvard and MIT Cambridge MA United States Department of Pathology Brigham and Women’s Hospital and Harvard Medical School Boston MA United States Spatial Technology Platform Broad Institute of Harvard and MIT Cambridge MA United States Precision Neurology Program Brigham and Women’s Hospital and Harvard Medical school Boston MA United States APDA Center for Advanced Parkinson’s Disease Research Brigham and Women’s Hospital and Harvard Medical School Boston MA United States Picower Institute for Learning and Memory Massachusetts Institute of Technology Cambridge MA United States Department of Brain and Cognitive Sciences Massachusetts Institute of Technology Cambridge MA United States Stanley Center for Psychiatric Research Broad Institute of Harvard and MIT Cambridge MA United States School of Computer Science Northwestern Polytechnical University Xi’an China Stephen and Denise Adams Center of Yale School of Medicine New Haven CT United States

despite years of intense investigation, the mechanisms underlying neuronal death in Alzheimer’s disease, remain incompletely understood. To define relevant pathways, we conducted an unbiased, genome-scale forward genetic screen for age-associated neurodegeneration in drosophila. We also measured proteomics, phosphoproteomics, and metabolomics in drosophila models of Alzheimer’s disease and identified Alzheimer’s genetic variants that modify gene expression in disease-vulnerable neurons in humans. We then used a network model to integrate these data with previously published Alzheimer’s disease proteomics, lipidomics and genomics. Here, we computationally predict and experimentally confirm how HNRNPA2B1 and MEPCE enhance toxicity of the tau protein, a pathological feature of Alzheimer’s disease. Furthermore, we demonstrated that the screen hits CSNK2A1 and NOTCH1 regulate dNA damage in drosophila and human stem cell-derived neural progenitor cells. Our study identifies candidate pathways that could be targeted to ameliorate neurodegeneration in Alzheimer’s disease. © The Author(s) 2025.

关键词：

来源：评论

学校读者我要写书评

暂无评论

Nhs: Network-based hierarchical segmentation for cryo-electron microscopy density maps

Nhs: Network-based hierarchical segmentation for cryo-electr...

引用

作者： Burger, Virginia Chennubhotla, Chakra Joint CMU-Pitt Ph.D. Program in Computational Biology University of Pittsburgh School of Medicine Pittsburgh PA United States Department of Computational and Systems Biology University of Pittsburgh School of Medicine Pittsburgh PA United States

Cryo-electron microscopy (cryo-EM) experiments yield low-resolution (3-30 Å) 3d-density maps of macromolecules. These density maps are segmented to identify structurally distinct proteins, protein domains, and subunits. Such partitioning aids the inference of protein motions and guides fitting of high-resolution atomistic structures. Cryo-EM density map segmentation has traditionally required tedious and subjective manual partitioning or semisupervised computational methods, whereas validation of resulting segmentations has remained an open problem in this field. We introduce a network-based hierarchical segmentation (Nhs) method, that provides a multi-scale partitioning, reflecting local and global clustering, while requiring no user input. This approach models each map as a graph, where map voxels constitute nodes and weighted edges connect neighboring voxels. Nhs initiates Markov diffusion (or random walk) on the weighted graph. As Markov probabilities homogenize through diffusion, an intrinsic segmentation emerges. We validate the segmentations with ground-truth maps based on atomistic models. When implemented on density maps in the 2010 Cryo-EM Modeling Challenge, Nhs efficiently and objectively partitions macromolecules into structurally and functionally relevant subregions at multiple scales. © 2012 Wiley Periodicals, Inc.

关键词： diffusion

来源：评论

学校读者我要写书评

暂无评论

Worm Perturb-Seq: massively parallel whole-animal RNAi and RNA-seq

引用

Nature Communications 2025年第1期16卷 1-21页

作者： Hefei Zhang Xuhang Li Shivani Nanda Albertha J. M. Walhout dongyuan Song Jingyi Jessica Li Onur Yukselen Alper Kucukural Manuel Garber Department of Systems Biology University of Massachusetts Chan Medical School Worcester MA USA Bioinformatics Interdepartmental Ph.D. Program University of California Los Angeles CA USA Department of Statistics and Data Science Department of Biostatistics Department of Computational Medicine and Department of Human Genetics University of California Los Angeles CA USA Via Scientific Inc. Cambridge MA USA Department of Genomics and Computational Biology University of Massachusetts Chan Medical School Worcester MA USA

Transcriptomes provide highly informative molecular phenotypes that, combined with gene perturbation, can connect genotype to phenotype. An ultimate goal is to perturb every gene and measure transcriptome changes, however, this is challenging, especially in whole animals. Here, we present ‘Worm Perturb-Seq (WPS)’, a method that provides high-resolution RNA-sequencing profiles for hundreds of replicate perturbations at a time in living animals. WPS introduces multiple experimental advances combining strengths of Caenhorhabditis elegans genetics and multiplexed RNA-sequencing with a novel analytical framework, EmpirdE. EmpirdE leverages the unique power of large transcriptomic datasets and improves statistical rigor by using gene-specific empirical null distributions to identify dEGs. We apply WPS to 103 nuclear hormone receptors (NHRs) and find a striking ‘pairwise modularity’ in which pairs of NHRs regulate shared target genes. We envision the advances of WPS to be useful not only for C. elegans, but broadly for other models, including human cells.

关键词：

来源：评论

学校读者我要写书评

暂无评论

Novel use of differential image velocity invariants to categorize ciliary motion defects

Novel use of differential image velocity invariants to categ...

引用

2011 Biomedical Sciences and Engineering Conference: Image Informatics and Analytics in Biomedicine, BSEC 2011

作者： Quinn, Shannon Francis, Richard Lo, Cecilia Chennubhotla, Chakra Joint Carnegie Mellon University University of Pittsburgh Ph.D. Program in Computational Biology United States Department of Developmental Biology United States Department of Computational and Systems Biology United States University of Pittsburgh School of Medicine Pittsburgh PA 15260 United States

ISBN: (纸本)9781612844107

Primary ciliary dyskinesia (PCd) is a disorder characterized by sinopulmonary disease arising from ciliary motion defects in respiratory epithelia. An essential first step in the diagnostic evaluation of PCd is the use of high-speed videomicroscopy to analyze ciliary beat patterns in nasal epithelia biopsies. This includes a quantitative assessment of ciliary beat frequency (CBF, where CBF of 11 Hz is referred to further diagnosis), followed by a visual examination of ciliary beat patterns to detect the presence of dyskinetic motions, such as stiff, incomplete, wavy and others. Both procedures lack standardized protocols, hence CBF is often counted manually by observing the ciliary image frames in slow motion, while a manual examination of beat patterns is subjective, cumbersome, and error-prone. We are building automated image analysis methods to address this problem. To this end, we report the use of image velocities for measuring CBF and demonstrate the effectiveness of the differential image velocity invariants, curl and deformation, in deconvolving the various motion defects. © 2011 IEEE.

关键词： defects

来源：评论

学校读者我要写书评

暂无评论

SPATIAL ATTENTION KINETIC NETWORK WITH E(N)-EQUIVARIANCE 11

SPATIAL ATTENTION KINETIC NETWORK WITH E(N)-EQUIVARIANCE

引用

11th International Conference on Learning Representations, ICLR 2023

作者： Wang, Yuanqing Chodera, John d. Computational and Systems Biology Program Sloan Kettering Institute Memorial Sloan Kettering Cancer Center New YorkNY10065 United States Ph.D. Program in Physiology Biophysics and System Biology Weill Cornell Medical College Cornell Univerisity New YorkNY10065 United States

Neural networks that are equivariant to rotations, translations, reflections, and permutations on n-dimensional geometric space have shown promise in physical modeling-from modeling potential energy surfaces to forecasting the time evolution of dynamical systems. Current state-of-the-art methods employ spherical harmonics to encode higher-order interactions among particles, which are computationally expensive. In this paper, we propose a simple alternative functional form that uses neurally parametrized linear combinations of edge vectors to achieve equivariance while still universally approximating node environments. Incorporating this insight, we design spatial attention kinetic networks with E(n)-equivariance, or SAKE, which are competitive in many-body system modeling tasks while being significantly faster. © 2023 11th International Conference on Learning Representations, ICLR 2023. All rights reserved.

关键词： dynamical systems

来源：评论

学校读者我要写书评

暂无评论

Novel use of differential image velocity invariants to categorize ciliary motion defects

Novel use of differential image velocity invariants to categ...

引用

Annual ORNL Biomedical Science & Engineering Conference (BSEC)

作者： Shannon Quinn Richard Francis Cecilia Lo Chakra Chennubhotla Program in Computational Biology Joint Carnegie Mellon University University of Pittsburgh USA Ph.D. Program in Computational Biology University of Pittsburgh University of Pittsburgh School of Medicine Pittsburgh PA Department of Developmental Biology University of Pittsburgh School of Medicine Pittsburgh PA USA Department of Computational and Systems Biology

关键词： Videos Pixel Optical imaging diseases Humans Medical diagnostic imaging

来源：评论

学校读者我要写书评

暂无评论

Categorical, low-dimensional decomposition of human odor space with non-negative matrix factorization

引用

Flavour 2014年第1期3卷 1-2页

作者： JB Castro SP Quinn A Ramanathan CS Chennubhotla Department of Psychology Bates College Lewiston USA Joint CMU-Pitt Ph.D. Program in Computational Biology University of Pittsburgh Pittsburgh USA Computational Data Analytics Group Oak Ridge National Laboratory Oak Ridge USA Department of Computational and Systems Biology University of Pittsburgh Pittsburgh USA

来源：评论

学校读者我要写书评

暂无评论

Single-cell manipulation and analysis using microfluidics, photomechanical actuation, and machine learning 19

Single-cell manipulation and analysis using microfluidics, p...

引用

Imaging, Manipulation, and Analysis of Biomolecules, Cells, and Tissues XIX 2021

作者： Chen, Yu-Chih Department of Computational and Systems Biology University of Pittsburgh School of Medicine 5115 Centre Avenue PittsburghPA15232 United States UPMC Hillman Cancer Center 5115 Centre Avenue PittsburghPA15232 United States Department of Bioengineering Swanson School of Engineering University of Pittsburgh 5115 Centre Avenue PittsburghPA15232 United States CMU-Pitt Ph.D. Program in Computational Biology 5115 Centre Avenue PittsburghPA15232 United States

ISBN: (数字)9781510641303

ISBN: (纸本)9781510641297

Cellular heterogeneity facilitating specialization of cells is essential to control normal physiological processes as well as drive pathogenesis of many diseases. While it remains common to measure population-averaged properties in biological studies, the assumption that all cells are identical can lead to incorrect or at least imprecise assessments. To better understand heterogeneous characteristics and responses of individual cells, single-cell analytic methods should be applied to profile individual cellular properties. Using micro-fabrication technology, we have developed high-throughput microfluidic platforms, that enable tracking of thousands of single cells on-chip. Building on the cell isolation capability, we innovated a photomechanical actuation method to selectively detach and retrieve target cells for downstream analysis. Irradiation of a nanosecond-pulsed laser is utilized to generate shear force for detaching target cells cultured on carbon nanotube–polydimethylsiloxane (CNT-PdMS) composite. This non-destructive cell retrieval method can preserve cell viability, membrane proteins, and mRNA expression levels, so we have successfully performed single-cell transcriptome analysis as well as functional studies on the retrieved target cells. In addition to cell tracking and retrieval, we applied machine learning techniques to correlate cellular morphological features with cellular functions including migration, cancer drug response, and tumor initiation. Machine made significantly better predictions than experienced researchers, and we found novel morphological features facilitating breakthroughs in mechanistic understanding. The integrated single-cell manipulation and analysis augmented with machine learning will change how we understand cell biology and ultimately improve how we treat diseases. © 2021 SPIE

关键词： Proteins

来源：评论

学校读者我要写书评

暂无评论

Tumor-derived interleukin-1 receptor antagonist exhibits immunosuppressive functions and promotes pancreatic cancer

引用

Cell and Bioscience 2023年第1期13卷 1页

作者： Fan, Yu-Ching Fong, Yu-Cin Kuo, Chun-Tse Li, Chia-Wei Chen, Wei-Yu Lin, Jian-da Bürtin, Florian Linnebacher, Michael Bui, Quoc Thang Lee, Kuan-der Tsai, Yuan-Chin Ph.D. Program for Cancer Molecular Biology and Drug Discovery College of Medical Science and Technology Taipei Medical University and Academia Sinica Taipei Taiwan Graduate Institute of Cancer Biology and Drug Discovery College of Medical Science and Technology Taipei Medical University Taipei Taiwan Institute of Biomedical Sciences Academia Sinica Taipei Taiwan Department of Pathology Wan Fang Hospital Taipei Medical University Taipei Taiwan Department of Pathology School of Medicine College of Medicine Taipei Medical University Taipei Taiwan Department of Biochemical Science and Technology College of Life Science National Taiwan University Taipei City 10617 Taiwan Center for Computational and Systems Biology National Taiwan University Taipei City 10617 Taiwan Clinic of General Surgery University Medical Center Rostock Schillingallee 35 Rostock 18057 Germany Clinic of General Surgery Molecular Oncology and Immunotherapy University Medical Center Rostock Schillingallee 69 Rostock 18057 Germany International Ph.D. Program for Cell Therapy and Regeneration Medicine (IPCTRM) School of Medicine College of Medicine Taipei Medical University Taipei Taiwan Department of Post-Baccalaureate Medicine College of Medicine Natioanl Chung Hsing University Taichung Taiwan Cell Therapy and Regenerative Medicine Center and Comprehensive Cancer Center Taichung Veterans General Hospital Taichung Taiwan Ph.D. Program for Cancer Molecular Biology and Drug Discovery College of Medical Science and Technology Taipei Medical University Taipei Taiwan

Background: Pancreatic ductal adenocarcinoma (PdA) is a pernicious disease characterized by an immunosuppressive milieu that is unresponsive to current immunotherapies. Interleukin-1 receptor antagonist (IL-1Ra) is a natural anti-inflammatory cytokine;however, its contribution to cancer pathogenesis and immunosuppression remains elusive. In this research, we investigated the role and mechanism of IL-1Ra in malignant progression of PdA. Results: Through analyzing clinical dataset and examining the pathological tumor tissues and serum samples, we have demonstrated that IL-1Ra expression is elevated in human PdA and positively associated with malignant progression of PdA. To study the biological function of IL-1Ra in tumors, we generated a set of mouse pancreatic cancer cell lines with a knockout (KO) of the Il1rn gene, encoding IL-1Ra, and compared the tumor growth rates in immune-competent and immune-deficient mice. We found that the Il1rn KO cells exhibited greater tumor inhibition in immune-competent mice, highlighting the crucial role of a functional immune system in Il1rn KO-mediated anti-tumor response. Consistently, we found an increase in Cd8⁺ T cells and a decrease in Cd11b⁺Ly6G⁻ immunosuppressive mononuclear population in the tumor microenvironment of Il1rn KO-derived tumors. To monitor the inhibitory effects of IL-1Ra on immune cells, we utilized a luciferase-based reporter Cd4⁺ T cell line and splenocytes, which were derived from transgenic mice expressing ovalbumin-specific T cell receptors in Cd8⁺ T cells, and mice immunized with ovalbumin. We showed that IL-1Ra suppressed T cell receptor signaling and inhibited antigen-specific interferon-γ (IFN-γ) secretion and cytolytic activity in splenocytes. Conclusions: Our findings illustrate the immunosuppressive properties of the natural anti-inflammatory cytokine IL-1Ra, and provide a rationale for considering IL-1Ra-targeted therapies in the treatment of

关键词： IFN-γ Immunosuppression interleukin-1 receptor antagonist Pancreatic adenocarcinoma Patient-derived xenograft Tumor microenvironment

来源：评论

学校读者我要写书评

暂无评论

Cell phenotypic transition proceeds through concerted reorganization of gene regulatory network

arXiv

引用

arXiv 2021年

作者： Wang, Weikang Poe, dante Ni, Ke Xing, Jianhua Department of Computational and Systems Biology University of Pittsburgh PittsburghPA15232 United States Joint CMU-Pitt Ph.D. Program in Computational Biology University of Pittsburgh PittsburghPA United States Department of Physics and Astronomy University of Pittsburgh PittsburghPA15232 United States UPMC-Hillman Cancer Center University of Pittsburgh PittsburghPA United States

phenotype transition takes place in many biological processes such as differentiation, and understanding how a cell reprograms its global gene expression profile is a problem of rate theories. A cell phenotype transition accompanies with switching of expression rates of clusters of genes, analogous to domain flipping in an Ising system. Here through analyzing single cell RNA sequencing data in the framework of transition path theory, we set to study how such a genome-wide expression program switching proceeds in three different cell transition processes. For each process after reconstructing a Markov transition model in the cell state space, we formed an ensemble of shortest paths connecting the initial and final cell states, reconstructed a reaction coordinate describing the transition progression, and inferred the gene regulation network (GRN) along the reaction coordinate. In all three processes we observed common pattern that the frustration of gene regulatory network (GRN), defined as overall confliction between the regulation received by genes and their expression states, first increases then decreases when approaching a new phenotype. The results support a mechanism of concerted silencing of genes that are active in the initial phenotype and activation of genes that are active in the final phenotype. © 2021, CC BY.

关键词： Ising model

来源：评论

学校读者我要写书评

暂无评论

建议与咨询留下您的常用邮箱和电话号码，以便我们向您反馈解决方案和替代方法

时间限定

文献类型

馆藏选择

核心期刊

语言

文献类型

帮助

文字说明：

检索规则说明：

检索范例：

分类表

所选分类

限定检索结果

文献类型

馆藏范围

日期分布

学科分类号

主题

机构

作者

语言

请选择保存的检索档案：

请选择收藏分类：

通借通还

建议与咨询 留下您的常用邮箱和电话号码，以便我们向您反馈解决方案和替代方法

时间限定

文献类型

馆藏选择

核心期刊

语言

文献类型

帮助

文字说明：

检索规则说明：

检索范例：

分类表

所选分类

限定检索结果

文献类型

馆藏范围

日期分布

学科分类号

主题

机构

作者

语言

请选择保存的检索档案： 新增检索档案 确定 取消

请选择收藏分类： 新增自定义分类 确定 取消

通借通还

建议与咨询留下您的常用邮箱和电话号码，以便我们向您反馈解决方案和替代方法

请选择保存的检索档案：

请选择收藏分类：