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Target genes discovery through copy number alteration analysis in human hepatocellular carcinoma

World Journal of Gastroenterology 2013年第47期19卷 8873-8879页

作者： De-Leung Gu Yen-Hsieh Chen Jou-Ho Shih Chi-Hung Lin Yuh-Shan Jou Chian-Feng Chen Institute of Biomedical Sciences Academia Sinica Institute of Microbiology and Immunology School of Life ScienceNational Yang-Ming University Bioinformatics Program Taiwan International Graduate ProgramAcademia Sinica Genome and Systems Biology Degree Program National Taiwan University VYM Genome Research Center National Yang-Ming University

High-throughput short-read sequencing of exomes and whole cancer genomes in multiple human hepatocellular carcinoma(HCC)cohorts confirmed previously identified frequently mutated somatic genes,such as TP53,CTNNB1 and AXIN1,and identified several novel genes with moderate mutation frequencies,including ARID1A,ARID2,MLL,MLL2,MLL3,MLL4,IRF2,ATM,CDKN2A,FGF19,PIK3CA,RPS6KA3,JAK1,KEAP1,NFE2L2,C16orf62,LEPR,RAC2,and *** classification of these mutated genes suggested that alterations in pathways participating in chromatin remodeling,Wnt/β-catenin signaling,JAK/STAT signaling,and oxidative stress play critical roles in HCC ***,because there are few druggable genes used in HCC therapy,the identification of new therapeutic targets through integrated genomic approaches remains an important *** a large amount of HCC genomic data genotyped by high density single nucleotide polymorphism arrays is deposited in the public domain,copy number alteration(CNA)analyses of these arrays is a cost-effective way to reveal target genes through profiling of recurrent and overlapping amplicons,homozygous deletions and potentially unbalanced chromosomal translocations accumulated during HCC ***,integration of CNAs with other high-throughput genomic data,such as aberrantly coding transcriptomes and non-coding gene expression in human HCC tissues and rodent HCC models,provides lines of evidence that can be used to facilitate the identification of novel HCC target genes with the potential of improving the survival of HCC patients.

关键词： Copy number alteration High-density single nucleotide polymorphism arrays Driver genes Hepatocellular carcinoma

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Transcriptional regulation by PHGDH drives amyloid pathology in Alzheimer's disease

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Cell 2025年

作者： Chen, Junchen Hadi, Fatemeh Wen, Xingzhao Zhao, Wenxin Xu, Ming Xue, Shuanghong Lin, Pei Calandrelli, Riccardo Richard, John Lalith Charles Song, Zhixuan Li, Jessica Amani, Alborz Liu, Yang Chen, Xu Zhong, Sheng Shu Chien-Gene Lay Department of Bioengineering University of California San Diego La Jolla San Diego CA United States Institute of Engineering in Medicine University of California San Diego La Jolla San Diego CA United States Program in Bioinformatics and Systems Biology University of California San Diego La Jolla San Diego CA United States School of Biological Sciences University of California San Diego La Jolla San Diego CA United States Department of Neurosciences University of California San Diego La Jolla San Diego CA United States Neuroscience Graduate Program University of California San Diego La Jolla San Diego CA United States

Virtually all individuals aged 65 or older develop at least early pathology of Alzheimer's disease (AD), yet most lack disease-causing mutations in APP, PSEN, or MAPT, and many do not carry the APOE4 risk allele. This raises questions about AD development in the general population. Although transcriptional dysregulation has not traditionally been a hallmark of AD, recent studies reveal significant epigenomic changes in late-onset AD (LOAD) patients. We show that altered expression of the LOAD biomarker phosphoglycerate dehydrogenase (PHGDH) modulates AD pathology in mice and human brain organoids independent of its enzymatic activity. PHGDH has an uncharacterized role in transcriptional regulation, promoting the transcription of inhibitor of nuclear factor kappa-B kinase subunit alpha (IKKa) and high-mobility group box 1 (HMGB1) in astrocytes, which suppress autophagy and accelerate amyloid pathology. A blood-brain-barrier-permeable small-molecule inhibitor targeting PHGDH's transcriptional function reduces amyloid pathology and improves AD-related behavioral deficits. These findings highlight transcriptional regulation in LOAD and suggest therapeutic strategies beyond targeting familial mutations. © 2025 The Author(s)

关键词： Alzheimer's disease amyloid pathology astrocyte biomarker LOAD PHGDH small molecule therapeutic candidate transcriptional regulation

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Plant biotic interactions

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Journal of Integrative Plant Biology 2016年第4期58卷 282-283页

作者： Hailing Jin Special Issue EditorUC President's Chair Director of Genetics Genomics and Bioinformatics Graduate ProgramCenter for Plant Cell BiologyInstitute for Integrative Genome BiologyUniversity of CaliforniaRiversideUSA

Plants are constantly under attack by pathogens,pests,and parasites,resulting in severe consequences on global food production and human *** pathogens and pests find their ways to invade and communicate with their hos... 详细信息

关键词： communicate constantly sophisticated consequences microbial fight biotic evolved pathogen volatile

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A Bayesian-based approach for extracting the pion charge radius from electron-electron scattering data

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Chinese Physics C 2021年第8期45卷 12-27页

作者： Alam A Hidayat Bens Pardamean Bioinformatics and Data Science Research Center Bina Nusantara UniversityJakarta 11480Indonesia Computer Science Department BINUS Graduate Program-Master of Computer ScienceBina Nusantara UniversityJakarta 11480Indonesia

In this study,we utilize a potentially versatile Bayesian parameter approach to compute the value of the pion charge radius and quantify its uncertainty from several experimental e^(+)e^(-) datasets for the pion vector form *** employ dispersion relations to model the pion vector form factor to extract the *** model selection is used to determine the order of polynomial appearing in the form factor formulation that can be supported by the data,adapting the computation of Bayes evidence and Bayesian effective complexity based on Occam's *** findings indicate that five out of six used datasets favor the nine-parameter model for radius extraction,and accordingly,we average the radii from the *** some inconsistencies with the most updated radius values,our approach may serve as a more intuitive method of addressing parameter estimations in dispersion theory.

关键词： Bayesian complexity dispersion hadron pion

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Data driven point packing for fast clustering

Data driven point packing for fast clustering

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IEEE Symposium on Computational Intelligence and bioinformatics and Computational Biology (CIBCB)

作者： Matthew Stoodley Daniel Ashlock Steffen Graether The Bioinformatics Program at the University of Guelph The Department of Mathematics and Statistics The Bioinformatics Program at the University of Guelph The Department of Molecular and Cellular Biology The Bioinformatics Program at the University of Guelph

Modern data acquisition has forced the field of large data on the scientific community. This papers gives a rapid technique for clustering data. The technique is based on an off-line process for packing points chosen from a data space. Once the off-line process has been run, the clustering may be re-run on different data sets of the same type in linear time. The clustering takes the form of a Voronoi tiling of the data space with the tile centres being the elements of the point packing. The data items within each tile form the clusters. The evolutionary algorithm is an adaptation of one, based on the Conway crossover operator, that has been used to create error correcting codes over the Levenstein metric; the tile centres are a form of code, but over the Euclidean metric. The technique generalizes smoothly to other metric spaces and may be used on any type of data for which a distance metric can be devised. The data set used in this study captures information about codon usage bias in human genes. The clustering is validated by looking for GO term over- representation in the clusters, with significant results.

关键词： Amino acids Clustering algorithms RNA DNA Measurement bioinformatics Hypercubes

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

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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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Noise response in monomolecular closed systems

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Journal of the Chinese Chemical Society 2023年第3期70卷 747-758页

作者： Fajiculay, Erickson Hsu, Chao-Ping Institute of Chemistry Academia Sinica Taipei Taiwan Bioinformatics Program Institute of Statistical Science Taiwan International Graduate Program Academia Sinica Taipei Taiwan Institute of Bioinformatics and Structure Biology National Tsinghua University Hsinchu City Taiwan Physics Division National Center for Theoretical Sciences Taipei Taiwan Genome and Systems Biology Degree Program National Taiwan University Taipei Taiwan

One of the primary interests in understanding biological systems is the interaction between noise and cellular regulation. Noise levels can be altered by rate constant perturbations, which may result in an imbalance of important biological functions. Although the theory of noise localization can estimate noise perturbation response, it is currently limited to open systems, where the majority of biological networks belong. However, during their lifetime, some components of biological systems participate in reactions that can be categorized under a closed system. Therefore, a counterpart theory for closed systems is desirable. In this work, steady-state perturbations of monomolecular closed systems and ways to estimate the response of noise as (co)variances are explored. We extend the structural sensitivity analysis for analyzing noise response patterns by using additional clues derived from multinomial assumptions. We identified scenarios in which this combination might fail in noise prediction, which we call noise flip, arising from the nonlinear dependence of variance upon composition. Nevertheless, theoretical intuition and simulation show that noise flip diminishes with increasing system size. This work provides an efficient and scalable means to estimate noise responses with potential applications in model discrimination, network-wide response scanning, and reconstruction. © 2023 The Chemical Society Located in Taipei & Wiley-VCH GmbH.

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SeqCP: A sequence-based algorithm for searching circularly permuted proteins

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Computational and Structural Biotechnology Journal 2023年 21卷 185-201页

作者： Chen, Chi-Chun Huang, Yu-Wei Huang, Hsuan-Cheng Lo, Wei-Cheng Lyu, Ping-Chiang Bioinformatics Program Institute of Information Science Taiwan International Graduate Program Academia Sinica Taipei115 Taiwan Institute of Bioinformatics and Structural Biology National Tsing Hua University Hsinchu300 Taiwan Institute of Bioinformatics and Systems Biology National Yang Ming Chiao Tung University Hsinchu300 Taiwan Institute of Biomedical Informatics National Yang Ming Chiao Tung University Taipei112 Taiwan Department of Biological Science and Technology National Yang Ming Chiao Tung University Hsinchu300 Taiwan The Center for Bioinformatics Research National Yang Ming Chiao Tung University Hsinchu Taiwan

Circular permutation (CP) is a protein sequence rearrangement in which the amino- and carboxyl-termini of a protein can be created in different positions along the imaginary circularized sequence. Circularly permutated proteins usually exhibit conserved three-dimensional structures and functions. By comparing the structures of circular permutants (CPMs), protein research and bioengineering applications can be approached in ways that are difficult to achieve by traditional mutagenesis. Most current CP detection algorithms depend on structural information. Because there is a vast number of proteins with unknown structures, many CP pairs may remain unidentified. An efficient sequence-based CP detector will help identify more CP pairs and advance many protein studies. For instance, some hypothetical proteins may have CPMs with known functions and structures that are informative for functional annotation, but existing structure-based CP search methods cannot be applied when those hypothetical proteins lack structural information. Despite the considerable potential for applications, sequence-based CP search methods have not been well developed. We present a sequence-based method, SeqCP, which analyzes normal and duplicated sequence alignments to identify CPMs and determine candidate CP sites for proteins. SeqCP was trained by data obtained from the Circular Permutation Database and tested with nonredundant datasets from the Protein Data Bank. It shows high reliability in CP identification and achieves an AUC of 0.9. SeqCP has been implemented into a web server available at: http://***/SeqCP/. © 2022 The Authors

关键词： Proteins

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Parallel sorting of biological sequences using the Intel RTM Concurrent Collections.

Parallel sorting of biological sequences using the Intel RTM...

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作者： Nembhard, Fitzroy D. Morgan State University.bComputer Science and Bioinformatics Program.

学位级别：M.S.

Performing analyses of and computations with biological sequence data, such as deoxyribonucleic acid DNA) and ribonucleic acid RNA), require a lot of processing time and memory using sequential algorithms. Today, programmers and scientists have developed and tested a few models for parallelizing and optimizing algorithms to improve results in bioinformatics. However, some of these approaches have not made efficient use of multi-core systems or computers with many processors. The IntelRTM Concurrent Collections is a software tool and library for transforming serial programs into semantically equivalent parallel programs. The IntelRTM Concurrent Collections approach is a new and unique technique for designing parallel programs. It overcomes the over-constraint nature of serial languages by providing a conclusive programming concept and allows for programs to be run efficiently on multi-core systems and computers with many processors. The main goals of this research are: to design a serial C/C＋＋ program for sorting biological sequences based on the Divide and Conquer methodology, to transform the serial C/C＋＋ program into a semantically equivalent parallel C/C＋＋ program using the IntelRTM Concurrent Collections, to compare and analyze execution times of the serial and parallel programs and to make appropriate conclusions on the suitability of the Divide and Conquer methodology for parallelization, to provide suggestions on the suitability of the IntelRTM Concurrent Collections technology for parallelization of serial algorithms, and to show the importance of parallelization of bioinformatics algorithms. The main results/achievements of this thesis research are: successful parallel sorting of biological sequences using the merge sort Divide and Conquer algorithm, successfully conducted experiments on the Intel RTM Many-core Testing Lab, which runs with the RedHat Enterprise Linux operating system and is comprised of 32 processors and 265GB RAM, proof that the IntelRTM C

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Predicting helix-helix interactions from residue contacts in membrane proteins

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bioinformatics 2009年第8期25卷 996-1003页

作者： Lo, Allan Chiu, Yi-Yuan Rødland, Einar Andreas Lyu, Ping-Chiang Sung, Ting-Yi Hsu, Wen-Lian Bioinformatics Program Taiwan International Graduate Program Academia Sinica Taipei Taiwan Institute of Bioinformatics and Structural Biology Department of Life Sciences National Tsing Hua University Hsinchu Taiwan Bioinformatics Laboratory Institute of Information Science Academia Sinica Taipei Taiwan Centre for Cancer Biomedicine University of Oslo NO-0027 Oslo Norway SAMBA Norwegian Computing Center Blindern NO-0314 Oslo P.O. Box 114 Norway

Motivation: Helix-helix interactions play a critical role in the structure assembly, stability and function of membrane proteins. On the molecular level, the interactions are mediated by one or more residue contacts. Although previous studies focused on helix-packing patterns and sequence motifs, few of them developed methods specifically for contact prediction. Results: We present a new hierarchical framework for contact prediction, with an application in membrane proteins. The hierarchical scheme consists of two levels: in the first level, contact residues are predicted from the sequence and their pairing relationships are further predicted in the second level. Statistical analyses on contact propensities are combined with other sequence and structural information for training the support vector machine classifiers. Evaluated on 52 protein chains using leave-one-out cross validation (LOOCV) and an independent test set of 14 protein chains, the two-level approach consistently improves the conventional direct approach in prediction accuracy, with 80% reduction of input for prediction. Furthermore, the predicted contacts are then used to infer interactions between pairs of helices. When at least three predicted contacts are required for an inferred interaction, the accuracy, sensitivity and specificity are 56%, 40% and 89%, respectively. Our results demonstrate that a hierarchical framework can be applied to eliminate false positives (FP) while reducing computational complexity in predicting contacts. Together with the estimated contact propensities, this method can be used to gain insights into helix-packing in membrane proteins. © 2009 The Author(s).

关键词： Computational Biology/methods* Databases, Protein Databases, Protein Membrane Proteins/chemistry* Membrane Proteins/metabolism Models, Biological Protein Structure, Secondary Reproducibility of Results

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