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A β-Globin Locus-Intrinsic Epigenetic Mechanism Underlies Fetal Globin Production in F-Cells

BLOOD 2020年 136卷 16-17页

作者： Khandros, Eugene Huang, Peng Peslak, Scott A. Sharma, Malini Abdulmalik, Osheiza Giardine, Belinda Zhang, Zhe Keller, Cheryl A. Hardison, Ross C. Blobel, Gerd A. Division of Hematology Children's Hospital of Philadelphia Philadelphia PA Department of Medicine Division of Hematology/Oncology Hospital of the University of Pennsylvania Philadelphia PA Department of Biochemistry and Molecular Biology Center for Computational Biology & Bioinformatics The Pennsylvania State University University Park PA Department of Biomedical and Health Informatics Children's Hospital of Philadelphia Philadelphia PA

Upregulation of fetal hemoglobin (HbF, α 2 γ 2 ) by reversing the developmental switch to adult HbA (α 2 β 2 ) is a key approach for both pharmacologic and gene targeting therapies in the treatment of sickle cell disease (SCD) and β-thalassemia. HbF expression in healthy individuals, patients with SCD, and those treated with hydroxyurea is restricted to a subset of red blood cells known as F-cells; effective SCD therapy requires increasing the proportion of F-cells expressing sufficient HbF to block sickling. Although these cells have been observed since the 1950s, there have not been previous direct comparisons of F-cells to matched HbF-low A-cells from the same individual. Fetal erythroblasts have distinct global transcriptional programs and distinct long-range chromatin looping at the β-globin locus when compared to adult erythroblasts. An important question is therefore whether F-cells are formed through reversion to a fetal-like state at the transcriptional and epigenetic level. To address this clinically important question, we previously reported development of new techniques for the purification of stage-matched F- and A-erythroblasts from primary human CD34 + cell erythroid cultures and their downstream analysis (Khandros et al, Blood 2020). We demonstrated that F-cells in primary erythroid cultures have minimal transcriptional differences with A-cells and that the few differentially expressed transcripts do not overlap with fetal-specific transcripts. Furthermore, treatment with hydroxyurea or pomalidomide did not enhance transcriptional differences between F- and A-cells. Surprisingly, we did not find differences in the expression of any known HbF regulators such as BCL11A, LRF, or NuRD complex members that would account for differential HbF expression. Based on these findings, we hypothesized that F-cells are distinguished by epigenetic variation specifically at the β-globin locus. Given that fetal erythroblasts differ from adult erythroblasts in the chro

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The anatomic determinants of conductive hearing loss secondary to tympanic membrane perforation

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Journal of Otology 2017年第3期12卷 125-131页

作者： David J.Carpenter Debara L.Tucci David M.Kaylie Dennis O.Frank-Ito Division of Head and Neck Surgery & Communication Sciences Department of Surgery Duke University Medical Center Durham NC USA Computational Biology & Bioinformatics PhD Program Duke University Durham NC USA Department of Mechanical Engineering and Materials Science Duke University Durham NC USA

Objectives: Recent studies have introduced middle ear volume(MEV) as a novel determinant of perforation-induced conductive hearing loss(CHL) in a mechanism driven by trans-tympanic membrane pressure differences. The primary aims of this preliminary report are to: 1) correlate CHL with perforation size; 2) describe the relationship between CHL and MEV; and 3) compare CHL across a range of cholesteatoma ***: A retrospective pilot study was performed in 31 subjects with audiometry indicative of conductive hearing loss, temporal bone CT scans,and no prior middle ear surgery. Perforation size and MEV were analyzed with respect to CHL in a cohort of 10 perforated ears with no cholesteatoma. CHLs were compared in 3 groups defined by extent of cholesteatoma ***: Ears with large and small perforations showed mean ABG values of 32.0 ± 15.7 dB and 16.0 ± 16.4 dB, respectively. A direct relationship was observed between MEV and CHL for ears with large perforations across all frequencies, whereas this relationship for small perforations was frequency-dependent. Finally, a statistically significant increase in CHL was found across ears with increasing cholesteatoma involvement at 1000 Hz(X^2(2) = 9.786, p = 0.008),2000 Hz(x^2(2) = 8.455, p = 0.015),and 4000 Hz(x^2(2)= 8.253, p = 0.016).Conclusions: These pilot data suggest that greater perforation-induced conductive hearing losses may be associated with larger perforation sizes and cholesteatoma. The correlation between MEV and CHL may require additional study.

关键词： Perforation-induced hearing loss Conductive hearing loss Middle ear volume Three-dimensional volume reconstruction

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Representation of K-mer Sets Using Spectrum-Preserving String Sets 24th

Representation of K-mer Sets Using Spectrum-Preserving Strin...

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24th Annual Conference on Research in computational Molecular biology, RECOMB 2020

作者： Rahman, Amatur Medvedev, Paul Department of Computer Science and Engineering The Pennsylvania State University State College United States Department of Biochemistry and Molecular Biology The Pennsylvania State University State College United States Center for Computational Biology and Bioinformatics The Pennsylvania State University State College United States

ISBN: (纸本)9783030452568

Given the popularity and elegance of k-mer based tools, finding a space-efficient way to represent a set of k-mers is important for improving the scalability of bioinformatics analyses. One popular approach is to convert the set of k-mers into the more compact set of unitigs. We generalize this approach and formulate it as the problem of finding a smallest spectrum-preserving string set (SPSS) representation. We show that this problem is equivalent to finding a smallest path cover in a compacted de Bruijn graph. Using this reduction, we prove a lower bound on the size of the optimal SPSS and propose a greedy method called UST that results in a smaller representation than unitigs and is nearly optimal with respect to our lower bound. We demonstrate the usefulness of the SPSS formulation with two applications of UST. The first one is a compression algorithm, UST-Compress, which we show can store a set of k-mers using an order-of-magnitude less disk space than other lossless compression tools. The second one is an exact static k-mer membership index, UST-FM, which we show improves index size by 10–44% compared to other state-of-the-art low memory indices. Our tool is publicly available at: https://***/medvedevgroup/UST/. © Springer Nature Switzerland AG 2020.

关键词： Computers

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De Novo Clustering of Long-Read Transcriptome Data Using a Greedy, Quality-Value Based Algorithm 1

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23rd International Conference on Research in computational Molecular biology, RECOMB 2019

作者： Sahlin, Kristoffer Medvedev, Paul Department of Computer Science and Engineering Pennsylvania State University State College United States Department of Biochemistry and Molecular Biology Pennsylvania State University State College United States Center for Computational Biology and Bioinformatics Pennsylvania State University State College United States

ISBN: (数字)9783030170837

ISBN: (纸本)9783030170820

Long-read sequencing of transcripts with PacBio Iso-Seq and Oxford Nanopore Technologies has proven to be central to the study of complex isoform landscapes in many organisms. However, current de novo transcript reconstruction algorithms from long-read data are limited, leaving the potential of these technologies unfulfilled. A common bottleneck is the dearth of scalable and accurate algorithms for clustering long reads according to their gene family of origin. To address this challenge, we develop isONclust, a clustering algorithm that is greedy (in order to scale) and makes use of quality values (in order to handle variable error rates). We test isONclust on three simulated and five biological datasets, across a breadth of organisms, technologies, and read depths. Our results demonstrate that isONclust is a substantial improvement over previous approaches, both in terms of overall accuracy and/or scalability to large datasets. Our tool is available at https://***/ksahlin/isONclust. © 2019, Springer Nature Switzerland AG.

关键词： Large dataset

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Identifying Comparative Structures in Biomedical Text 16

Identifying Comparative Structures in Biomedical Text

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16th SIGBioMed Workshop on Biomedical Natural Language Processing, BioNLP 2017

作者： Gupta, Samir Ashique Mahmood, A.S.M. Ross, Karen E. Wu, Cathy H. Vijay-Shanker, K. Department of Computer and Information Sciences University of Delaware NewarkDE United States Center for Bioinformatics and Computational Biology University of Delaware NewarkDE United States Department of Biochemistry and Molecular and Cellular Biology Georgetown University Medical Center WashingtonDC United States

ISBN: (纸本)9781945626593

Comparison sentences are very commonly used by authors in biomedical literature to report results of experiments. In such comparisons, authors typically make observations under two different scenarios. In this paper, we present a system to automatically identify such comparative sentences and their components i.e. the compared entities, the scale of the comparison and the aspect on which the entities are being compared. Our methodology is based on dependencies obtained by applying a parser to extract a wide range of comparison structures. We evaluated our system for its effectiveness in identifying comparisons and their components. The system achieved a F-score of 0.87 for comparison sentence identification and 0.77-0.81 for identifying its components. © 2017 Association for computational Linguistics

关键词： Syntactics

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Visualization of Distribution of Pathogenicity Genomic Islands between Pathogenic, Nosocomial and Environmental Bacteria

Visualization of Distribution of Pathogenicity Genomic Islan...

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International Conference on Information Visualisation (IV)

作者： Oleg N. Reva Oliver Bezuidt Bioinformatics and Computational Biology Unit Biochemistry Department University of Pretoria Pretoria South Africa

The recurrent outbreaks of pathogens that possess new virulence factors and broad range antibiotic resistance gene cassettes reflect the importance of horizontal gene transfer (HGT) in the evolution of pathogenic bacteria. In many cases, the establishment of pathogens is mediated by the mobile genetic islands (GIs) which can easily be interchanged between bacterial taxa inhabiting the same or different environments. New computational tools to visualize and track down the network of distribution of GIs among bacteria are proposed in this work.

关键词： bioinformatics Genomics Microorganisms Biological cells DNA Visualization

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Atomistic mechanisms underlying the activation of the G protein-coupled sweet receptor heterodimer by sugar alcohol recognition (vol 9, 10205, 2019)

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SCIENTIFIC REPORTS 2019年第1期9卷 1-11页

作者： Mahalapbutr, Panupong Darai, Nitchakan Panman, Wanwisa Opasmahakul, Aunchan Kungwan, Nawee Hannongbua, Supot Rungrotmongkol, Thanyada Structural and Computational Biology Research Unit Department of Biochemistry Faculty of Science Chulalongkorn University Bangkok 10330 Thailand. Program in Biotechnology Faculty of Science Chulalongkorn University Bangkok 10330 Thailand. Multidisciplinary Program of Petrochemistry and Polymer Science Faculty of Science Chulalongkorn University Bangkok 10330 Thailand. Computational Chemistry Center of Excellent Department of Chemistry Faculty of Science Chulalongkorn University Bangkok 10330 Thailand. Department of Chemistry Faculty of Science Chiang Mai University Chiang Mai 50200 Thailand. Center of Excellence in Materials Science and Technology Chiang Mai University Chiang Mai 50200 Thailand. Structural and Computational Biology Research Unit Department of Biochemistry Faculty of Science Chulalongkorn University Bangkok 10330 Thailand. t.rungrotmongkol@***. Ph.D. Program in Bioinformatics and Computational Biology Faculty of Science Chulalongkorn University Bangkok 10330 Thailand. t.rungrotmongkol@***. Molecular Sensory Science Center Faculty of Science Chulalongkorn University Bangkok 10330 Thailand. t.rungrotmongkol@***.

The human T1R2-T1R3 sweet taste receptor (STR) plays an important role in recognizing various low-molecular-weight sweet-tasting sugars and proteins, resulting in the release of intracellular heterotrimeric G protein that in turn leads to the sweet taste perception. Xylitol and sorbitol, which are naturally occurring sugar alcohols (polyols) found in many fruits and vegetables, exhibit the potential caries-reducing effect and are widely used for diabetic patients as low-calorie sweeteners. In the present study, computational tools were applied to investigate the structural details of binary complexes formed between these two polyols and the T1R2-T1R3 heterodimeric STR. Principal component analysis revealed that the Venus flytrap domain (VFD) of T1R2 monomer was adapted by the induced-fit mechanism to accommodate the focused polyols, in which α-helical residues 233-268 moved significantly closer to stabilize ligands. This finding likely suggested that these structural transformations might be the important mechanisms underlying polyols-STR recognitions. The calculated free energies also supported the VFD of T1R2 monomer as the preferential binding site for such polyols, rather than T1R3 region, in accord with the lower number of accessible water molecules in the T1R2 pocket. The E302 amino acid residue in T1R2 was found to be the important recognition residue for polyols binding through a strongly formed hydrogen bond. Additionally, the binding affinity of xylitol toward the T1R2 monomer was significantly higher than that of sorbitol, making it a sweeter tasting molecule.

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Evolutionary direction of processed pseudogenes

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Science China(Life Sciences) 2016年第8期59卷 839-849页

作者： Guoqing Liu Xiangjun Cui Hong Li Lu Cai School of Life Science and Technology Inner Mongolia University of Science and TechnologyBaotou 014010China 1nstitute of Bioengineering and Technology lnner Mongolia University of Science and TechnologyBaotou 014010China School of Physical Science and Technology Inner Mongolia UniversityHohhot 010021China Computational Systems Biology Lab Department of Biochemistry and Molecular BiologyInstitute of BioinformaticsUniversity of GeorgiaAthens GA 30602USA

While some pseudogenes have been reported to play important roles in gene regulation, little is known about the possible relationship between pseudogene functions and evolutionary process of pseudogenes, or about the forces responsible for the pseudogene evolution. In this study, we characterized human processed pseudogenes in terms of evolutionary dynamics. Our results show that pseudogenes tend to evolve toward: lower GC content, strong dinucleotide bias, reduced abundance of transcription factor binding motifs and short palindromes, and decreased ability to form nucleosomes. We explored possible evolutionary forces that shaped the evolution pattern of pseudogenes, and concluded that mutations in pseudogenes are likely determined, at least partially, by neighbor-dependent mutational bias and recombination-associated selection.

关键词： GC content mutual information transcription factor binding motifs mutational bias recombination

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Modeling protein interaction network and mechanisms in exocytosis

Modeling protein interaction network and mechanisms in exocy...

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7th IEEE International Conference on bioinformatics and Bioengineering, BIBE

作者： Zhou, Wen Xia, Tian Tong, Jiansong Dickerson, Julie Su, Bo Gu, Xun Department of Mathematics Iowa State University Ames IA 50010 United States Program of Bioinformatics and Computational Biology Iowa State University Ames IA 50010 United States Department of Biochemistry Biophysics and Molecular Biology Iowa State University Ames IA 50010 United States Department of Genetics Development and Cell Biology Iowa State University Ames IA 50010 United States

ISBN: (纸本)1424415098

Exocytosis is an essential process in all eukaryotic cells that allows communication in cells through vesicles which contain a wide range of intracellular molecules such as hormones, matrix proteins and neurotransmitters. Recent studies have shown this process is regulated by molecular interactions among a group of well defined and conserved proteins. To gain insight into the dynamics of these interactions, we use protein interaction network modeling to investigate exocytotic system (particularly in endocrine) computationally and mathematically. The protein interactions are formulated into ordinary differential equations (ODE). We then apply a novel mathematic approach to estimate model parameters from experimental data for SNAREs-only network (with three key proteins), which is a subset of this system. Our approach is able to sense temporal changes in protein concentration and ratios of multiple proteins and precisely reconstruct the dynamical process of exocytosis, including vesicle docking, priming and fusion. Additionally, the model suggests that initial concentration of synaptic proteins plays a crucial role in efficiency of vesicle fusion, based on system stability analysis. ©2007 IEEE.

关键词： Proteins

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Mechanistic differences of antivirals revealed by microfluidics-based single-cell virology 21

Mechanistic differences of antivirals revealed by microfluid...

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21st International Conference on Miniaturized Systems for Chemistry and Life Sciences, MicroTAS 2017

作者： Liu, Wu Caglar, Mehmet U. Mao, Zhangming Wilke, Claus O. Huang, Tony Jun Cameron, Craig E. Department of Biochemistry and Molecular Biology Pennsylvania State University United States Materials Research Institute Pennsylvania State University United States Center for Computational Biology and Bioinformatics Institute for Cellular and Molecular Biology Department of Integrative Biology University of Texas Austin United States Department of Mechanical Engineering and Material Science Duke University United States

ISBN: (纸本)9780692941836

A multi-layer microfluidic platform was developed to track the dynamics of up to 5000 viral infection events at the single-cell level. After mixed with fluorescent protein-tagged poliovirus, single cells were trapped with an efficiency as high as 86.1%, and isolated into microwells to eliminate crosstalk. Fluorescence intensity of each single cell was monitored, and an analytic model was developed to describe the kinetics quantitatively. The effects of antivirals on viral replication were investigated and compared, unveiling insights into the antiviral mechanisms masked by traditional population-based assays. The practicality and great potential of this platform for single-cell virology were thus demonstrated. © 17CBMS-0001.

关键词： Microfluidics

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