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arXiv 2021年

作者： Aizenbud, Yariv Jaffe, Ariel Wang, Meng Hu, Amber Amsel, Noah Nadler, Boaz Chang, Joseph T. Kluger, Yuval Program in Applied Mathematics Yale University New HavenCT06511 United States Department of Computer Science Weizmann Institute of Science Rehovot76100 Israel Department of Statistics Yale University New HavenCT06520 United States Interdepartmental Program in Computational Biology and Bioinformatics Yale University New HavenCT06511 United States Department of Pathology Yale University New HavenCT06511 United States

Modeling the distribution of high dimensional data by a latent tree graphical model is a prevalent approach in multiple scientific domains. A common task is to infer the underlying tree structure, given only observations of its terminal nodes. Many algorithms for tree recovery are computationally intensive, which limits their applicability to trees of moderate size. For large trees, a common approach, termed divide-and-conquer, is to recover the tree structure in two steps. First, recover the structure separately of multiple, possibly random subsets of the terminal nodes. Second, merge the resulting subtrees to form a full tree. Here, we develop Spectral Top-Down Recovery (STDR), a deterministic divide-and-conquer approach to infer large latent tree models. Unlike previous methods, STDR partitions the terminal nodes in a non random way, based on the Fiedler vector of a suitable Laplacian matrix related to the observed nodes. We prove that under certain conditions, this partitioning is consistent with the tree structure. This, in turn, leads to a significantly simpler merging procedure of the small subtrees. We prove that STDR is statistically consistent and bound the number of samples required to accurately recover the tree with high probability. Using simulated data from several common tree models in phylogenetics, we demonstrate that STDR has a significant advantage in terms of runtime, with improved or similar accuracy. Copyright © 2021, The Authors. All rights reserved.

关键词： Recovery

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A meta-analysis of Boolean network models reveals design principles of gene regulatory networks

arXiv

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arXiv 2020年

作者： Kadelka, Claus Butrie, Taras-Michael Hilton, Evan Kinseth, Jack Schmidt, Addison Serdarevic, Haris Department of Mathematics Iowa State University AmesIA50011 United States Department of Aerospace Engineering Iowa State University AmesIA50011 United States Department of Computer Science Iowa State University AmesIA50011 United States Bioinformatics and Computational Biology Program Iowa State University AmesIA50011 United States

Gene regulatory networks (GRNs) play a central role in cellular decision-making. Understanding their structure and how it impacts their dynamics constitutes thus a fundamental biological question. GRNs are frequently modeled as Boolean networks, which are intuitive, simple to describe, and can yield qualitative results even when data is sparse. We assembled the largest repository of expert-curated Boolean GRN models. A meta-analysis of this diverse set of models reveals several design principles. GRNs exhibit more canalization, redundancy and stable dynamics than expected. Moreover, they are enriched for certain recurring network motifs. This raises the important question why evolution favors these design mechanisms. Copyright © 2020, The Authors. All rights reserved.

关键词： Decision making

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Inhibition of topoisomerase IIα and induction of DNA damage in cholangiocarcinoma cells by altholactone and its halogenated benzoate derivatives

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Biomedicine and Pharmacotherapy 2020年 127卷 110149-110149页

作者： Kitdumrongthum, Sarunya Reabroi, Somrudee Suksen, Kanoknetr Tuchinda, Patoomratana Munyoo, Bamroong Mahalapbutr, Panupong Rungrotmongkol, Thanyada Ounjai, Puey Chairoungdua, Arthit Toxicology Graduate Program Faculty of Science Mahidol University Bangkok Thailand Excellent Center for Drug Discovery (ECDD) Mahidol University Bangkok Thailand Department of Pharmacology Faculty of Science Mahidol University Bangkok Thailand Department of Physiology Faculty of Science Mahidol University Bangkok Thailand Department of Chemistry Faculty of Science Mahidol University Bangkok Thailand Structural and Computational Biology Research Unit Department of Biochemistry Faculty of Science Chulalongkorn University Bangkok Thailand Program in Bioinformatics and Computational Biology Graduate School Chulalongkorn University Bangkok Thailand Department of Biology Faculty of Science Mahidol University Bangkok Thailand

Topoisomerase IIα enzyme (Topo IIα) plays a critical function in DNA replication process and is considered to be a promising target of anti-cancer drugs. In the present study, we reported that the altholactone derivatives modified by adding a halogenated benzoate group showed greater inhibitory activity on Topo IIα enzyme in cell-free system concomitant with cytotoxicity against the CCA cell lines (KKU-M055 and KKU-M213) than those of the parent altholactone. However, the cytotoxic activities of four halogenated benzoate altholactone derivatives including iodo-, fluoro-, chloro-, and bromobenzoate derivatives (compound 1, 2, 3, and 4, respectively) were of equal potency. The fluorobenzoate derivative (compound 2) was chosen for investigating the underlying mechanism in CCA cells. Compound 2 arrested CCA cell cycle at sub G1 phase and induced apoptotic cell death. It markedly inhibited Topo IIα protein expression in both KKU-M055 and KKU-M213 cells, which was accompanied by DNA double-strand breaks demonstrated by an increase in phosphorylated H2A.X protein. Interestingly, KKU-M055 cells, which express higher Topo IIα mRNA compared to KKU-M213 cells, showed greater sensitivity to the compound, indicating the selectivity of the compound to Topo IIα enzyme. By computational docking analysis, the binding affinity of altholactone (-52.5 kcal/mol) and compound 2 (-56.7 kcal/mol) were similar to that of the Topo II poison salvicine (-53.7 kcal/mol). The aromatic moiety of both altholactones embedded in a hydrophobic pocket of Topo II ATPase domain. In addition, compound 2 induced the formation of linear DNA in Topo II-mediated cleavage assay. Collectively, our results demonstrate that the addition of fluorobenzoyl group to altholactone enhances potency and selectivity to inhibit type IIα topoisomerases. Atholactone and fluorobenzoate derivative act as Topo II cleavage complexes stabilizing compounds or Topo II poisons preferentially through binding at ATPase domain of Topo

关键词： Altholactone Cholangiocarcinoma Halogenated benzoate Topoisomerase IIα

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Machine learning for early prediction of circulatory failure in the intensive care unit

arXiv

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arXiv 2019年

作者： Hyland, Stephanie L. Faltys, Martin Hüser, Matthias Lyu, Xinrui Gumbsch, Thomas Esteban, Cristóbal Bock, Christian Horn, Max Moor, Michael Rieck, Bastian Zimmermann, Marc Bodenham, Dean Borgwardt, Karsten Rätsch, Gunnar Merz, Tobias M. Department of Computer Science ETH Zürich Zürich Switzerland Computational Biology Program Memorial Sloan Kettering Cancer Center New York United States Tri-Institutional PhD Program in Computational Biology and Medicine Weill Cornell Medicine New York United States Medical Informatics Group Zürich University Hospital Zürich Switzerland Department of Intensive Care Medicine University Hospital University of Bern Bern Switzerland Department of Biosystems and Engineering ETH Zürich Basel Switzerland Department of Biology ETH Zürich Zürich Switzerland Swiss Institute for Bioinformatics Lausanne Switzerland Cardiovascular Intensive Care Unit Auckland City Hospital Auckland New Zealand

Intensive care clinicians are presented with large quantities of patient information and measurements from a multitude of monitoring systems. The limited ability of humans to process such complex information hinders physicians to readily recognize and act on early signs of patient deterioration. We used machine learning to develop an early warning system for circulatory failure based on a high-resolution ICU database with 240 patient-years of data. This automatic system predicts 90.0% of circulatory failure events (prevalence 3.1%), with 81.8% identified more than two hours in advance, resulting in an area under the receiver operating characteristic curve of 94.0% and area under the precision recall curve of 63.0%. The model was externally validated in a large independent patient cohort. Copyright © 2019, The Authors. All rights reserved.

关键词： Intensive care units

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Core packing of well-defined x-ray and NMR structures is the same

arXiv

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arXiv 2022年

作者： Grigas, Alex T. Liu, Zhuoyi Regan, Lynne O’Hern, Corey S. Graduate Program in Computational Biology and Bioinformatics Yale University New HavenCT06520 United States Integrated Graduate Program in Physical and Engineering Biology Yale University New HavenCT06520 United States Department of Mechanical Engineering and Materials Science Yale University New HavenCT06520 United States Institute of Quantitative Biology Biochemistry and Biotechnology Centre for Synthetic and Systems Biology School of Biological Sciences University of Edinburgh United Kingdom Department of Physics Yale University New HavenCT06520 United States Department of Applied Physics Yale University New HavenCT06520 United States

Numerous studies have investigated the differences and similarities between protein structures determined by solution NMR spectroscopy and those determined by x-ray crystallography. A fundamental question is whether any observed differences are due to differing methodologies, or to differences in the behavior of proteins in solution versus in the crystalline state. Here, we compare the properties of the hydrophobic cores of high-resolution protein crystal structures and those in NMR structures, determined using increasing numbers and types of restraints. Prior studies have reported that many NMR structures have denser cores compared to those of high-resolution x-ray crystal structures. Our current work investigates this result in more detail, and finds that these NMR structures tend to violate basic features of protein stereochemistry, such as small non-bonded atomic overlaps and few Ramachandran and side chain dihedral angle outliers. We find that NMR structures solved with more restraints, and which do not significantly violate stereochemistry, have hydrophobic cores that have a similar size and packing fraction as their counterparts determined by x-ray crystallography at high-resolution. These results lead us to conclude that, at least regarding the core packing properties, high-quality structures determined by NMR and x-ray crystallography are the same, and the differences reported earlier are most likely a consequence of methodology, rather than fundamental differences between the protein in the two different environments. Significance: Dense packing of hydrophobic residues is key to protein structure and stability. Previously, it has been noted that structures solved by NMR spectroscopy have denser cores than x-ray crystal structures. Here, we calculate the core size and packing fraction of NMR structures with experimental restraints in the PDB. Their cores are typically smaller, but denser. However, NMR structures with accurate stereochemistry possess core pa

关键词： X ray crystallography

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Comprehensive analysis of the pseudogenes of glycolytic enzymes in vertebrates: The anomalously high number of GAPDH pseudogenes highlights a recent burst of retrotrans-positional activity

引用

BMC Genomics 2009年第1期10卷 480-480页

作者： Liu, Yuen-Jong Zheng, Deyou Balasubramanian, Suganthi Carriero, Nicholas Khurana, Ekta Robilotto, Rebecca Gerstein, Mark B. Department of Surgery Beth Israel Deaconess Medical Center Harvard Medical School Boston MA 110 Francis Street United States Department of Molecular Biophysics and Biochemistry Yale University New Haven CT 06520 P.O. Box 208114 United States Albert Einstein College of Medicine of Yeshiva University Department of Neurology Rose F. Kennedy Center Bronx NY 10461 1410 Pelham Parkway South United States Program in Computational Biology and Bioinformatics Yale University New Haven CT 06520 United States Department of Computer Science Yale University New Haven CT 06520 Bass 432 266 Whitney Avenue United States

Background: Pseudogenes provide a record of the molecular evolution of genes. As glycolysis is such a highly conserved and fundamental metabolic pathway, the pseudogenes of glycolytic enzymes comprise a standardized genomic measuring stick and an ideal platform for studying molecular evolution. One of the glycolytic enzymes, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), has already been noted to have one of the largest numbers of associated pseudogenes, among all proteins. Results: We assembled the first comprehensive catalog of the processed and duplicated pseudogenes of glycolytic enzymes in many vertebrate model-organism genomes, including human, chimpanzee, mouse, rat, chicken, zebrafish, pufferfish, fruitfly, and worm (available at http://***/glycolysis/). We found that glycolytic pseudogenes are predominantly processed, i.e. retrotransposed from the mRNA of their parent genes. Although each glycolytic enzyme plays a unique role, GAPDH has by far the most pseudogenes, perhaps reflecting its large number of non-glycolytic functions or its possession of a particularly retrotranspositionally active sub-sequence. Furthermore, the number of GAPDH pseudogenes varies significantly among the genomes we studied: none in zebrafish, pufferfish, fruitfly, and worm, 1 in chicken, 50 in chimpanzee, 62 in human, 331 in mouse, and 364 in rat. Next, we developed a simple method of identifying conserved syntenic blocks (consistently applicable to the wide range of organisms in the study) by using orthologous genes as anchors delimiting a conserved block between a pair of genomes. This approach showed that few glycolytic pseudogenes are shared between primate and rodent lineages. Finally, by estimating pseudogene ages using Kimura's two-parameter model of nucleotide substitution, we found evidence for bursts of retrotranspositional activity approximately 42, 36, and 26 million years ago in the human, mouse, and rat lineages, respectively. Conclusion: Overall, we pe

关键词： Glycolytic Enzyme Segmental Duplication Chimpanzee Genome Assembly Version ENSEMBL Release

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A FLOW ARTIST FOR HIGH-DIMENSIONAL CELLULAR DATA

arXiv

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arXiv 2023年

作者： MacDonald, Kincaid Bhaskar, Dhananjay Thampakkul, Guy Nguyen, Nhi Zhang, Joia Perlmutter, Michael Adelstein, Ian Krishnaswamy, Smita Department of Mathematics Yale University United States Department of Genetics Yale School of Medicine United States Department of Computer Science Yale University United States Department of Mathematics Pomona College United States Applied Mathematics Program Yale University United States Department of Statistics University of Washington United States Department of Mathematics Boise State University United States Computational Biology and Bioinformatics Program Yale University United States

We consider the problem of embedding point cloud data sampled from an underlying manifold with an associated flow or velocity. Such data arises in many contexts where static snapshots of dynamic entities are measured, including in high-throughput biology such as single-cell transcriptomics. Existing embedding techniques either do not utilize velocity information or embed the coordinates and velocities independently, i.e., they either impose velocities on top of an existing point embedding or embed points within a prescribed vector field. Here we present FlowArtist, a neural network that embeds points while jointly learning a vector field around the points. The combination allows FlowArtist to better separate and visualize velocity-informed structures. Our results, on toy datasets and single-cell RNA velocity data, illustrate the value of utilizing coordinate and velocity information in tandem for embedding and visualizing high-dimensional data. © 2023, CC BY.

关键词： RNA

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Metabolic energy expenditure for time-varying isometric forces

arXiv

引用

arXiv 2024年

作者： Muralidhar, Sriram Sekaripuram Heitman, Kristen Walcott, Samuel C. Srinivasan, Manoj Mechanical and Aerospace Engineering The Ohio State University ColumbusOH43201 United States School of Health and Rehabilitation Sciences The Ohio State University ColumbusOH43201 United States Mathematical Sciences and Bioinformatics and Computational Biology Worcester Polytechnic Institute WorcesterMA01609 United States Program in Biophysics The Ohio State University ColumbusOH43201 United States

Muscles consume metabolic energy (ATP) to produce force. A mathematical model for energy expen- diture can be useful in estimating real-time costs of movements or to predict energy optimal movements. Metabolic cost models developed so far have predominantly aimed at dynamic movement tasks, where me- chanical work dominates. Further, while it is known that both force magnitude and rate of change of force (force rate) affect metabolic cost, it is not known how these terms interact, or if the force rate dependence can be a consequence of the force dependence. Here, we performed extensive human subject experiments, involving each subject over 5 hours of metabolic trials, which systematically changed the mean forces and forces rates so as to characterize a holistic relation for metabolic cost based on both force and force rate - or analogously, torque and torque rate. Our experiments involved humans producing symmetric or asym- metric sinusoidal forces with different means, amplitudes, frequencies, and rise and fall periods. We showed that the metabolic cost can be well-approximated by a sum of power law functions of torque and torque rate. We found that the metabolic cost scales non-linearly with joint torque (with exponent 1 = 1.36) and non-linearly with torque rate (with exponent 2 = 2.5). Surprisingly, the data suggested that the cost was roughly four times higher for decreasing the torque than increasing, mirroring the analogous ratio between the cost of positive and negative work. Using these metabolic cost relations, we show that if the metabolic cost scales with particular exponents with muscle force and force rates, the same exponents will be observed in multi-joint tasks with multiple muscles. Our new metabolic cost model involving both force and force rate will potentially allow better predictions of energy optimal movements and thus inform wearable robot design and analysis. © 2024, CC BY.

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Ciwars: A Web Server for Antibiotic Resistance Surveillance Using Longitudinal Metagenomic Data

SSRN

引用

SSRN 2024年

作者： Emon, Muhit Islam Cheung, Yat Fei Stoll, James Rumi, Monjura Afrin Brown, Connor Choi, Joung Min Moumi, Nazifa Ahmed Ahmed, Shafayat Song, Haoqiu Sein, Justin Yao, Shunyu Khan, Ahmad Gupta, Suraj Kulkarni, Rutwik Butt, Ali Vikesland, Peter Pruden, Amy Zhang, Liqing Department of Computer Science Virginia Tech BlacksburgVA24060 United States Fralin Life Science Institute Virginia Tech BlacksburgVA24060 United States Department of Civil and Environmental Engineering Virginia Tech BlacksburgVA24060 United States The Interdisciplinary PhD Program in Genetics Bioinformatics and Computational Biology Virginia Tech BlacksburgVA24060 United States

The rise of antibiotic resistance (AR) poses substantial threats to human and animal health, food security, and economic stability. Wastewater-based surveillance (WBS) has emerged as a powerful strategy for population-level AR monitoring, providing valuable data to guide public health and policy decisions. Metagenomic sequencing is especially promising, as it can yield comprehensive profiles of antibiotic resistance genes (ARGs) and other genes relevant to AR in a single run. However, online analytical platforms to facilitate continuous AR monitoring through longitudinal metagenomic data are lacking. To address this, we introduce Cyberinfrastructure for Waterborne Antibiotic Resistance Surveillance (CIWARS), a web server configured for characterizing key AR trends from longitudinal metagenomic WBS data. CIWARS offers comprehensive ARG and taxonomic profiling, along with detection of anomalous AR indicators over time, aiding in identifying potential events of concern, such as the emergence of resistant strains or outbreaks. Through interactive temporal data visualization, CIWARS enables AR monitoring and demonstrates its potential for informing effective and timely interventions to mitigate the spread and transmission of AR. CIWARS is broadly applicable to longitudinal metagenomic data from any environment and thus could be a valuable tool to support global efforts to combat the evolution and spread of AR, while also guiding agricultural and public health efforts aimed at optimizing antibiotic use when it is needed. The web server is freely available at https://***/. © 2024, The Authors. All rights reserved.

关键词： Gene encoding

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Pseudo-perplexity in One Fell Swoop for Protein Fitness Estimation

arXiv

引用

arXiv 2024年

作者： Kantroo, Pranav Wagner, Günter P. Machta, Benjamin B. Computational Biology and Bioinformatics Program Yale University New HavenCT06520 United States Emeritus Department of Ecology and Evolutionary Biology Yale University New HavenCT06520 United States Department of Evolutionary Biology University of Vienna Djerassi Platz 1 ViennaA-1030 Austria Hagler Institute for Advanced Studies Texas A&M College StationTX77843 United States Department of Physics Yale University New HavenCT06520 United States Quantitative Biology Institute Yale University New HavenCT06520 United States

Protein language models trained on the masked language modeling objective learn to predict the identity of hidden amino acid residues within a sequence using the remaining observable sequence as context. They do so by embedding the residues into a high dimensional space that encapsulates the relevant contextual cues. These embedding vectors serve as an informative context-sensitive representation that not only aids with the defined training objective, but can also be used for other tasks by downstream models. We propose a scheme to use the embeddings of an unmasked sequence to estimate the corresponding masked probability vectors for all the positions in a single forward pass through the language model. This One Fell Swoop (OFS) approach allows us to efficiently estimate the pseudo-perplexity of the sequence, a measure of the model's uncertainty in its predictions, that can also serve as a fitness estimate. We find that ESM2 OFS pseudo-perplexity performs nearly as well as the true pseudo-perplexity at fitness estimation, and more notably it defines a new state of the art on the ProteinGym Indels benchmark. The strong performance of the fitness measure prompted us to investigate if it could be used to detect the elevated stability reported in reconstructed ancestral sequences. We find that this measure ranks ancestral reconstructions as more fit than extant sequences. Finally, we show that the computational efficiency of the technique allows for the use of Monte Carlo methods that can rapidly explore functional sequence space. © 2024, CC BY.

关键词： Embeddings

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