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Article ; Online: Aquila enables reference-assisted diploid personal genome assembly and comprehensive variant detection based on linked reads.

Zhou, Xin / Zhang, Lu / Weng, Ziming / Dill, David L / Sidow, Arend

2021 Volume 12, Issue 1, Page(s) 1077

Abstract: We introduce Aquila, a new approach to variant discovery in personal genomes, which is critical for uncovering the genetic contributions to health and disease. Aquila uses a reference sequence and linked-read data to generate a high quality diploid ... ...

Abstract	We introduce Aquila, a new approach to variant discovery in personal genomes, which is critical for uncovering the genetic contributions to health and disease. Aquila uses a reference sequence and linked-read data to generate a high quality diploid genome assembly, from which it then comprehensively detects and phases personal genetic variation. The contigs of the assemblies from our libraries cover >95% of the human reference genome, with over 98% of that in a diploid state. Thus, the assemblies support detection and accurate genotyping of the most prevalent types of human genetic variation, including single nucleotide polymorphisms (SNPs), small insertions and deletions (small indels), and structural variants (SVs), in all but the most difficult regions. All heterozygous variants are phased in blocks that can approach arm-level length. The final output of Aquila is a diploid and phased personal genome sequence, and a phased Variant Call Format (VCF) file that also contains homozygous and a few unphased heterozygous variants. Aquila represents a cost-effective approach that can be applied to cohorts for variation discovery or association studies, or to single individuals with rare phenotypes that could be caused by SVs or compound heterozygosity.
MeSH term(s)	Animals ; Computational Biology/methods ; Diploidy ; Genomics/methods ; High-Throughput Nucleotide Sequencing/methods ; Humans ; Polymorphism, Single Nucleotide ; Reproducibility of Results ; Whole Genome Sequencing/methods
Language	English
Publishing date	2021-02-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-021-21395-x
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Aquila_stLFR: diploid genome assembly based structural variant calling package for stLFR linked-reads.

Liu, Yichen Henry / Grubbs, Griffin L / Zhang, Lu / Fang, Xiaodong / Dill, David L / Sidow, Arend / Zhou, Xin

Bioinformatics advances

2021 Volume 1, Issue 1, Page(s) vbab007

Abstract: Motivation: Identifying structural variants (SVs) is critical in health and disease, however, detecting them remains a challenge. Several linked-read sequencing technologies, including 10X Genomics, TELL-Seq and single tube long fragment read (stLFR), ... ...

Abstract	Motivation: Identifying structural variants (SVs) is critical in health and disease, however, detecting them remains a challenge. Several linked-read sequencing technologies, including 10X Genomics, TELL-Seq and single tube long fragment read (stLFR), have been recently developed as cost-effective approaches to reconstruct multi-megabase haplotypes (phase blocks) from sequence data of a single sample. These technologies provide an optimal sequencing platform to characterize SVs, though few computational algorithms can utilize them. Thus, we developed Aquila_stLFR, an approach that resolves SVs through haplotype-based assembly of stLFR linked-reads. Results: Aquila_stLFR first partitions long fragment reads into two haplotype-specific blocks with the assistance of the high-quality reference genome, by taking advantage of the potential phasing ability of the linked-read itself. Each haplotype is then assembled independently, to achieve a complete diploid assembly to finally reconstruct the genome-wide SVs. We benchmarked Aquila_stLFR on a well-studied sample, NA24385, and showed Aquila_stLFR can detect medium to large size deletions (50 bp-10 kb) with high sensitivity and medium-size insertions (50 bp-1 kb) with high specificity. Availability and implementation: Source code and documentation are available on https://github.com/maiziex/Aquila_stLFR. Supplementary information: Supplementary data are available at
Language	English
Publishing date	2021-06-16
Publishing country	England
Document type	Journal Article
ISSN	2635-0041
ISSN (online)	2635-0041
DOI	10.1093/bioadv/vbab007
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Article ; Online: Mebendazole for Differentiation Therapy of Acute Myeloid Leukemia Identified by a Lineage Maturation Index.

Li, Yulin / Thomas, Daniel / Deutzmann, Anja / Majeti, Ravindra / Felsher, Dean W / Dill, David L

Scientific reports

2019 Volume 9, Issue 1, Page(s) 16775

Abstract: Accurate assessment of changes in cellular differentiation status in response to drug treatments or genetic perturbations is crucial for understanding tumorigenesis and developing novel therapeutics for human cancer. We have developed a novel ... ...

Abstract	Accurate assessment of changes in cellular differentiation status in response to drug treatments or genetic perturbations is crucial for understanding tumorigenesis and developing novel therapeutics for human cancer. We have developed a novel computational approach, the Lineage Maturation Index (LMI), to define the changes in differentiation state of hematopoietic malignancies based on their gene expression profiles. We have confirmed that the LMI approach can detect known changes of differentiation state in both normal and malignant hematopoietic cells. To discover novel differentiation therapies, we applied this approach to analyze the gene expression profiles of HL-60 leukemia cells treated with a small molecule drug library. Among multiple drugs that significantly increased the LMIs, we identified mebendazole, an anti-helminthic clinically used for decades with no known significant toxicity. We tested the differentiation activity of mebendazole using primary leukemia blast cells isolated from human acute myeloid leukemia (AML) patients. We determined that treatment with mebendazole induces dramatic differentiation of leukemia blast cells as shown by cellular morphology and cell surface markers. Furthermore, mebendazole treatment significantly extended the survival of leukemia-bearing mice in a xenograft model. These findings suggest that mebendazole may be utilized as a low toxicity therapeutic for human acute myeloid leukemia and confirm the LMI approach as a robust tool for the discovery of novel differentiation therapies for cancer.
MeSH term(s)	Animals ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/pharmacology ; Cell Differentiation/drug effects ; Cell Lineage/drug effects ; Cell Proliferation/drug effects ; Computational Biology ; Drug Repositioning ; Gene Expression Profiling/methods ; Gene Expression Regulation, Neoplastic ; HL-60 Cells ; Humans ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/genetics ; Mebendazole/administration & dosage ; Mebendazole/pharmacology ; Mice ; Small Molecule Libraries/pharmacology ; Xenograft Model Antitumor Assays
Chemical Substances	Antineoplastic Agents ; Small Molecule Libraries ; Mebendazole (81G6I5V05I)
Language	English
Publishing date	2019-11-14
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-019-53290-3
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Towards in vivo estimation of reaction kinetics using high-throughput metabolomics data: a maximum likelihood approach.

Zhang, Weiruo / Kolte, Ritesh / Dill, David L

BMC systems biology

2015 Volume 9, Page(s) 66

Abstract: Background: High-throughput assays such as mass spectrometry have opened up the possibility for large-scale in vivo measurements of the metabolome. This data could potentially be used to estimate kinetic parameters for many metabolic reactions. However, ...

Abstract	Background: High-throughput assays such as mass spectrometry have opened up the possibility for large-scale in vivo measurements of the metabolome. This data could potentially be used to estimate kinetic parameters for many metabolic reactions. However, high-throughput in vivo measurements have special properties that are not taken into account in existing methods for estimating kinetic parameters, including significant relative errors in measurements of metabolite concentrations and reaction rates, and reactions with multiple substrates and products, which are sometimes reversible. A new method is needed to estimate kinetic parameters taking into account these factors. Results: A new method, InVEst (In Vivo Estimation), is described for estimating reaction kinetic parameters, which addresses the specific challenges of in vivo data. InVEst uses maximum likelihood estimation based on a model where all measurements have relative errors. Simulations show that InVEst produces accurate estimates for a reversible enzymatic reaction with multiple reactants and products, that estimated parameters can be used to predict the effects of genetic variants, and that InVEst is more accurate than general least squares and graphic methods on data with relative errors. InVEst uses the bootstrap method to evaluate the accuracy of its estimates. Conclusions: InVEst addresses several challenges of in vivo data, which are not taken into account by existing methods. When data have relative errors, InVEst produces more accurate and robust estimates. InVEst also provides useful information about estimation accuracy using bootstrapping. It has potential applications of quantifying the effects of genetic variants, inference of the target of a mutation or drug treatment and improving flux estimation.
MeSH term(s)	Algorithms ; Computer Simulation ; Kinetics ; Likelihood Functions ; Metabolomics ; Models, Biological ; Systems Biology/methods
Language	English
Publishing date	2015-10-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1752-0509
ISSN (online)	1752-0509
DOI	10.1186/s12918-015-0214-7
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Article: Towards Program Optimization through Automated Analysis of Numerical Precision.

Linderman, Michael D / Ho, Matthew / Dill, David L / Meng, Teresa H / Nolan, Garry P

Proceedings of the ... CGO : International Symposium on Code Generation and Optimization. International Symposium on Code Generation and Optimization

2017 Volume 2010, Page(s) 230–237

Abstract: Reducing the arithmetic precision of a computation has real performance implications, including increased speed, decreased power consumption, and a smaller memory footprint. For some architectures, e.g., GPUs, there can be such a large performance ... ...

Abstract	Reducing the arithmetic precision of a computation has real performance implications, including increased speed, decreased power consumption, and a smaller memory footprint. For some architectures, e.g., GPUs, there can be such a large performance difference that using reduced precision is effectively a requirement. The tradeoff is that the accuracy of the computation will be compromised. In this paper we describe a proof assistant and associated static analysis techniques for efficiently bounding numerical and precision-related errors. The programmer/compiler can use these bounds to numerically verify and optimize an application for different input and machine configurations. We present several case study applications that demonstrate the effectiveness of these techniques and the performance benefits that can be achieved with rigorous precision analysis.
Language	English
Publishing date	2017-04-22
Publishing country	United States
Document type	Journal Article
ISSN	2164-2397
ISSN	2164-2397
DOI	10.1145/1772954.1772987
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Article ; Online: The Move Prover

Zhong, Jingyi Emma / Cheang, Kevin / Qadeer, Shaz / Grieskamp, Wolfgang / Blackshear, Sam / Park, Junkil / Zohar, Yoni / Barrett, Clark / Dill, David L.

Computer Aided Verification

Abstract: The Libra blockchain is designed to store billions of dollars in assets, so the security of code that executes transactions is important. The Libra blockchain has a new language for implementing transactions, called “Move.” This paper describes the Move ... ...

Abstract	The Libra blockchain is designed to store billions of dollars in assets, so the security of code that executes transactions is important. The Libra blockchain has a new language for implementing transactions, called “Move.” This paper describes the Move Prover, an automatic formal verification system for Move. We overview the unique features of the Move language and then describe the architecture of the Prover, including the language for formal specification and the translation to the Boogie intermediate verification language .
Keywords	covid19
Publisher	PMC
Document type	Article ; Online
DOI	10.1007/978-3-030-53288-8_7
Database	COVID19

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Book ; Online: Resources

Blackshear, Sam / Dill, David L. / Qadeer, Shaz / Barrett, Clark W. / Mitchell, John C. / Padon, Oded / Zohar, Yoni

A Safe Language Abstraction for Money

2020

Abstract: Smart contracts are programs that implement transactions on modern blockchain platforms. In this rapidly evolving environment, smart-contract programming languages must allow users to write programs that flexibly manage and transfer assets, while ... ...

Abstract	Smart contracts are programs that implement transactions on modern blockchain platforms. In this rapidly evolving environment, smart-contract programming languages must allow users to write programs that flexibly manage and transfer assets, while providing strong protection against sophisticated attacks. Addressing this need, we present flexible and reliable abstractions for programming with digital currency in the Move language. Move uses novel linear resource types with C++11/Rust-style move semantics as an explicit representation to represent assets such as money. When a resource variable is assigned to a new variable, the variable previously holding it must be invalidated. When combined with other abstraction features of Move, linearity ensures resource conservation: assets represented by resources can only be created or deleted by authorized parties, and cannot be duplicated or lost by others possessing them. We present an executable bytecode language with move semantics and show that it satisfies a set of resource safety guarantees. Comment: 14 pages, 7 figures
Keywords	Computer Science - Programming Languages
Subject code	005
Publishing date	2020-04-10
Publishing country	us
Document type	Book ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Book ; Online: Learning a SAT Solver from Single-Bit Supervision

Selsam, Daniel / Lamm, Matthew / Bünz, Benedikt / Liang, Percy / de Moura, Leonardo / Dill, David L.

2018

Abstract: We present NeuroSAT, a message passing neural network that learns to solve SAT problems after only being trained as a classifier to predict satisfiability. Although it is not competitive with state-of-the-art SAT solvers, NeuroSAT can solve problems that ...

Abstract	We present NeuroSAT, a message passing neural network that learns to solve SAT problems after only being trained as a classifier to predict satisfiability. Although it is not competitive with state-of-the-art SAT solvers, NeuroSAT can solve problems that are substantially larger and more difficult than it ever saw during training by simply running for more iterations. Moreover, NeuroSAT generalizes to novel distributions; after training only on random SAT problems, at test time it can solve SAT problems encoding graph coloring, clique detection, dominating set, and vertex cover problems, all on a range of distributions over small random graphs.
Keywords	Computer Science - Artificial Intelligence ; Computer Science - Machine Learning ; Computer Science - Logic in Computer Science
Publishing date	2018-02-10
Publishing country	us
Document type	Book ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Timing robustness in the budding and fission yeast cell cycles.

Mangla, Karan / Dill, David L / Horowitz, Mark A

PloS one

2010 Volume 5, Issue 2, Page(s) e8906

Abstract: Robustness of biological models has emerged as an important principle in systems biology. Many past analyses of Boolean models update all pending changes in signals simultaneously (i.e., synchronously), making it impossible to consider robustness to ... ...

Abstract	Robustness of biological models has emerged as an important principle in systems biology. Many past analyses of Boolean models update all pending changes in signals simultaneously (i.e., synchronously), making it impossible to consider robustness to variations in timing that result from noise and different environmental conditions. We checked previously published mathematical models of the cell cycles of budding and fission yeast for robustness to timing variations by constructing Boolean models and analyzing them using model-checking software for the property of speed independence. Surprisingly, the models are nearly, but not totally, speed-independent. In some cases, examination of timing problems discovered in the analysis exposes apparent inaccuracies in the model. Biologically justified revisions to the model eliminate the timing problems. Furthermore, in silico random mutations in the regulatory interactions of a speed-independent Boolean model are shown to be unlikely to preserve speed independence, even in models that are otherwise functional, providing evidence for selection pressure to maintain timing robustness. Multiple cell cycle models exhibit strong robustness to timing variation, apparently due to evolutionary pressure. Thus, timing robustness can be a basis for generating testable hypotheses and can focus attention on aspects of a model that may need refinement.
MeSH term(s)	Algorithms ; Cell Cycle/genetics ; Cell Cycle/physiology ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/physiology ; Fungal Proteins/genetics ; Fungal Proteins/physiology ; Gene Expression Regulation, Fungal ; Gene Regulatory Networks ; Models, Biological ; Mutation ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/physiology ; Schizosaccharomyces/genetics ; Schizosaccharomyces/physiology ; Signal Transduction/genetics ; Signal Transduction/physiology ; Software ; Time Factors
Chemical Substances	Cell Cycle Proteins ; Fungal Proteins
Language	English
Publishing date	2010-02-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0008906
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: A geographically-diverse collection of 418 human gut microbiome pathway genome databases.

Hahn, Aria S / Altman, Tomer / Konwar, Kishori M / Hanson, Niels W / Kim, Dongjae / Relman, David A / Dill, David L / Hallam, Steven J

Scientific data

2017 Volume 4, Page(s) 170035

Abstract: Advances in high-throughput sequencing are reshaping how we perceive microbial communities inhabiting the human body, with implications for therapeutic interventions. Several large-scale datasets derived from hundreds of human microbiome samples sourced ... ...

Abstract	Advances in high-throughput sequencing are reshaping how we perceive microbial communities inhabiting the human body, with implications for therapeutic interventions. Several large-scale datasets derived from hundreds of human microbiome samples sourced from multiple studies are now publicly available. However, idiosyncratic data processing methods between studies introduce systematic differences that confound comparative analyses. To overcome these challenges, we developed GutCyc, a compendium of environmental pathway genome databases (ePGDBs) constructed from 418 assembled human microbiome datasets using MetaPathways, enabling reproducible functional metagenomic annotation. We also generated metabolic network reconstructions for each metagenome using the Pathway Tools software, empowering researchers and clinicians interested in visualizing and interpreting metabolic pathways encoded by the human gut microbiome. For the first time, GutCyc provides consistent annotations and metabolic pathway predictions, making possible comparative community analyses between health and disease states in inflammatory bowel disease, Crohn's disease, and type 2 diabetes. GutCyc data products are searchable online, or may be downloaded and explored locally using MetaPathways and Pathway Tools.
MeSH term(s)	Crohn Disease/microbiology ; Databases, Genetic ; Diabetes Mellitus, Type 2/microbiology ; Gastrointestinal Microbiome ; Geography, Medical ; Humans ; Inflammatory Bowel Diseases/microbiology ; Metabolic Networks and Pathways ; Metagenome ; Metagenomics
Language	English
Publishing date	2017-04-11
Publishing country	England
Document type	Dataset ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2775191-0
ISSN	2052-4463 ; 2052-4463
ISSN (online)	2052-4463
ISSN	2052-4463
DOI	10.1038/sdata.2017.35
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