Publications
COVID-19: famotidine, histamine, mast cells, and mechanisms [eprint]
May 23, 2020
Journal Article
Published in:
Research Square, preprint, 23 May 2020.
Summary
SARS-CoV-2 infection is required for COVID-19, but many signs and symptoms of COVID-19 differ from common acute viral diseases. Currently, there are no pre- or post-exposure prophylactic COVID-19 medical countermeasures. Clinical data suggest that famotidine may mitigate COVID-19 disease, but both mechanism of action and rationale for dose selection remain obscure. We explore several plausible avenues of activity including antiviral and host-mediated actions. We propose that the principal famotidine mechanism of action for COVID-19 involves on-target histamine receptor H2 activity, and that development of clinical COVID-19 involves dysfunctional mast cell activation and histamine release.
Summary
SARS-CoV-2 infection is required for COVID-19, but many signs and symptoms of COVID-19 differ from common acute viral diseases. Currently, there are no pre- or post-exposure prophylactic COVID-19 medical countermeasures. Clinical data suggest that famotidine may mitigate COVID-19 disease, but both mechanism of action and rationale for dose selection remain...
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Kawasaki disease and multisystem inflammatory syndrome in children: an antibody-induced mast cell activation hypothesis [eprint]
May 12, 2020
Journal Article
Published in:
The Lancet, manuscript submitted May 2020.
Summary
Multisystem Inflammatory Syndrome in Children (MIS-C, previously designated as Pediatric Multisystem Inflammatory Syndrome - PMIS) is appearing in infants, children, and young adults in association with COVID-19 (coronavirus disease 2019) infections. Kawasaki Disease (KD, previously called mucocutaneous lymph node syndrome) is one of the most common vasculitides of childhood. KD presents with similar symptoms to MIS-C especially in severe forms such as Kawasaki Disease Shock Syndrome (KDSS). The cause of KD is currently unknown; KD has features similar to those associated with viral infection. The leading hypothesis is that a ubiquitous infectious agent can induce KD in a genetically susceptible patient. This hypothesis is supported by the presence of IgA plasma cells identified in inflamed tissues and coronary arteries of KD patients. Associations between KD and multiple pathogens have been reported, including: adenovirus, human bocavirus, coronavirus, human coronavirus 229E, human coronavirus (HCoV-NH) NL63, cytomegalovirus, dengue, enterovirus, Epstein–Barr virus, human herpesvirus 6, human lymphotropic virus, human rhinovirus, influenza, measles, parvovirus B19, parainfluenza virus type 2, respiratory syncytial virus (RSV), rotavirus, varicella zoster (chicken pox), torque teno virus, Staphylococcus aureus, and Streptococcus. Postinfluenza vaccination KD has also been reported. The seasonality and temporal clustering of KD further support an infectious etiology. A mild cold may precede the onset of KD and up to one third of patients have concurrent, confirmed infections at the time of KD diagnosis. The aggregate of these pathogen associations with KD support the rejection of the hypothesis that KD is caused by a single infectious agent. The alternative hypothesis is that KD is associated with multiple infectious agents. We hypothesize that MIS-C may be atypical KD or a KD-like disease associated with SARS-CoV-2 as a result of antibody dependent enhancement activation of mast cells. We further hypothesize that KD and MIS-C may be induced in part by histamine and other inflammatory molecules released from activation of mast cells by Fc receptor bound pathogen antibodies resulting in a hyperinflammatory response.
Summary
Multisystem Inflammatory Syndrome in Children (MIS-C, previously designated as Pediatric Multisystem Inflammatory Syndrome - PMIS) is appearing in infants, children, and young adults in association with COVID-19 (coronavirus disease 2019) infections. Kawasaki Disease (KD, previously called mucocutaneous lymph node syndrome) is one of the most common vasculitides of childhood. KD...
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Medical countermeasures analysis of 2019-nCoV and vaccine risks for antibody-dependent enhancement (ADE)
March 8, 2020
Journal Article
Published in:
https://www.preprints.org/manuscript/202003.0138/v1
Summary
Background: In 80% of patients, COVID-19 presents as mild disease. 20% of cases develop severe (13%) or critical (6%) illness. More severe forms of COVID-19 present as clinical severe acute respiratory syndrome, but include a T-predominant lymphopenia, high circulating levels of proinflammatory cytokines and chemokines, accumulation of neutrophils and macrophages in lungs, and immune dysregulation including immunosuppression. Methods: All major SARS-CoV-2 proteins were characterized using an amino acid residue variation analysis method. Results predict that most SARS-CoV-2 proteins are evolutionary constrained, with the exception of the spike (S) protein extended outer surface. Results were interpreted based on known SARS-like coronavirus virology and pathophysiology, with a focus on medical countermeasure development implications. Findings: Non-neutralizing antibodies to variable S domains may enable an alternative infection pathway via Fc receptor-mediated uptake. This may be a gating event for the immune response dysregulation observed in more severe COVID-19 disease. Prior studies involving vaccine candidates for FCoV SARS-CoV-1 and Middle East Respiratory Syndrome coronavirus (MERS-CoV) demonstrate vaccination-induced antibody-dependent enhancement of disease (ADE), including infection of phagocytic antigen presenting cells (APC). T effector cells are believed to play an important role in controlling coronavirus infection; pan-T depletion is present in severe COVID-19 disease and may be accelerated by APC infection. Sequence and structural conservation of S motifs suggests that SARS and MERS vaccine ADE risks may foreshadow SARS-CoV-2 S-based vaccine risks. Autophagy inhibitors may reduce APC infection and T-cell depletion. Amino acid residue variation analysis identifies multiple constrained domains suitable as T cell vaccine targets. Evolutionary constraints on proven antiviral drug targets present in SARS-CoV-1 and SARS-CoV-2 may reduce risk of developing antiviral drug escape mutants. Interpretation: Safety testing of COVID-19 S protein-based B cell vaccines in animal models is strongly encouraged prior to clinical trials to reduce risk of ADE upon virus exposure.
Summary
Background: In 80% of patients, COVID-19 presents as mild disease. 20% of cases develop severe (13%) or critical (6%) illness. More severe forms of COVID-19 present as clinical severe acute respiratory syndrome, but include a T-predominant lymphopenia, high circulating levels of proinflammatory cytokines and chemokines, accumulation of neutrophils and macrophages...
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AI enabling technologies: a survey
May 8, 2019
Journal Article
Published in:
https://arxiv.org/abs/1905.03592
Summary
Artificial Intelligence (AI) has the opportunity to revolutionize the way the United States Department of Defense (DoD) and Intelligence Community (IC) address the challenges of evolving threats, data deluge, and rapid courses of action. Developing an end-to-end artificial intelligence system involves parallel development of different pieces that must work together in order to provide capabilities that can be used by decision makers, warfighters and analysts. These pieces include data collection, data conditioning, algorithms, computing, robust artificial intelligence, and human-machine teaming. While much of the popular press today surrounds advances in algorithms and computing, most modern AI systems leverage advances across numerous different fields. Further, while certain components may not be as visible to end-users as others, our experience has shown that each of these interrelated components play a major role in the success or failure of an AI system. This article is meant to highlight many of these technologies that are involved in an end-to-end AI system. The goal of this article is to provide readers with an overview of terminology, technical details and recent highlights from academia, industry and government. Where possible, we indicate relevant resources that can be used for further reading and understanding.
Summary
Artificial Intelligence (AI) has the opportunity to revolutionize the way the United States Department of Defense (DoD) and Intelligence Community (IC) address the challenges of evolving threats, data deluge, and rapid courses of action. Developing an end-to-end artificial intelligence system involves parallel development of different pieces that must work together...
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Large-scale Bayesian kinship analysis
September 25, 2018
Conference Paper
Published in:
IEEE High Performance Extreme Computing Conf., HPEC, 25-27 September 2018.
Summary
Kinship prediction in forensics is limited to first degree relatives due to the small number of short tandem repeat loci characterized. The Genetic Chain Rule for Probabilistic Kinship Estimation can leverage large panels of single nucleotide polymorphisms (SNPs) or sets of sequence linked SNPs, called haploblocks, to estimate more distant relationships between individuals. This method uses allele frequencies and Markov Chain Monte Carlo methods to determine kinship probabilities. Allele frequencies are a crucial input to this method. Since these frequencies are estimated from finite populations and many alleles are rare, a Bayesian extension to the algorithm has been developed to determine credible intervals for kinship estimates as a function of the certainty in allele frequency estimates. Generation of sufficiently large samples to accurately estimate credible intervals can take significant computational resources. In this paper, we leverage hundreds of compute cores to generate large numbers of Dirichlet random samples for Bayesian kinship prediction. We show that it is possible to generate 2,097,152 random samples on 32,768 cores at a rate of 29.68 samples per second. The ability to generate extremely large number of samples enables the computation of more statistically significant results from a Bayesian approach to kinship analysis.
Summary
Kinship prediction in forensics is limited to first degree relatives due to the small number of short tandem repeat loci characterized. The Genetic Chain Rule for Probabilistic Kinship Estimation can leverage large panels of single nucleotide polymorphisms (SNPs) or sets of sequence linked SNPs, called haploblocks, to estimate more distant...
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Simulation approach to sensor placement using Unity3D
September 25, 2018
Conference Paper
Published in:
IEEE High Performance Extreme Computing Conf., HPEC, 25-27 September 2018.
Summary
3D game simulation engines have demonstrated utility in the areas of training, scientific analysis, and knowledge solicitation. This paper will make the case for the use of 3D game simulation engines in the field of sensor placement optimization. Our study used a series of parallel simulations in the Unity3D simulation framework to answer the questions: how many sensors of various modalities are required and where they should be placed to meet a desired threat detection threshold? The result is a framework that not only answers this sensor placement question, but can be easily expanded to differing optimization criteria as well as answer how a particular configuration responds to differing crowd flows or informed/non-informed adversaries. Additionally, we demonstrate the scalability of this framework by running parallel instances on a supercomputing grid and illustrate the processing speed gained.
Summary
3D game simulation engines have demonstrated utility in the areas of training, scientific analysis, and knowledge solicitation. This paper will make the case for the use of 3D game simulation engines in the field of sensor placement optimization. Our study used a series of parallel simulations in the Unity3D simulation...
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A cloud-based brain connectivity analysis tool
September 12, 2017
Conference Paper
Published in:
HPEC 2017: IEEE Conf. on High Performance Extreme Computing, 12-14 September 2017.
Summary
With advances in high throughput brain imaging at the cellular and sub-cellular level, there is growing demand for platforms that can support high performance, large-scale brain data processing and analysis. In this paper, we present a novel pipeline that combines Accumulo, D4M, geohashing, and parallel programming to manage large-scale neuron connectivity graphs in a cloud environment. Our brain connectivity graph is represented using vertices (fiber start/end nodes), edges (fiber tracks), and the 3D coordinates of the fiber tracks. For optimal performance, we take the hybrid approach of storing vertices and edges in Accumulo and saving the fiber track 3D coordinates in flat files. Accumulo database operations offer low latency on sparse queries while flat files offer high throughput for storing, querying, and analyzing bulk data. We evaluated our pipeline by using 250 gigabytes of mouse neuron connectivity data. Benchmarking experiments on retrieving vertices and edges from Accumulo demonstrate that we can achieve 1-2 orders of magnitude speedup in retrieval time when compared to the same operation from traditional flat files. The implementation of graph analytics such as Breadth First Search using Accumulo and D4M offers consistent good performance regardless of data size and density, thus is scalable to very large dataset. Indexing of neuron subvolumes is simple and logical with geohashing-based binary tree encoding. This hybrid data management backend is used to drive an interactive web-based 3D graphical user interface, where users can examine the 3D connectivity map in a Google Map-like viewer. Our pipeline is scalable and extensible to other data modalities.
Summary
With advances in high throughput brain imaging at the cellular and sub-cellular level, there is growing demand for platforms that can support high performance, large-scale brain data processing and analysis. In this paper, we present a novel pipeline that combines Accumulo, D4M, geohashing, and parallel programming to manage large-scale neuron...
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A linear algebra approach to fast DNA mixture analysis using GPUs
September 12, 2017
Conference Paper
Published in:
HPEC 2017: IEEE Conf. on High Performance Extreme Computing, 12-14 September 2017.
Summary
Analysis of DNA samples is an important step in forensics, and the speed of analysis can impact investigations. Comparison of DNA sequences is based on the analysis of short tandem repeats (STRs), which are short DNA sequences of 2-5 base pairs. Current forensics approaches use 20 STR loci for analysis. The use of single nucleotide polymorphisms (SNPs) has utility for analysis of complex DNA mixtures. The use of tens of thousands of SNPs loci for analysis poses significant computational challenges because the forensic analysis scales by the product of the loci count and number of DNA samples to be analyzed. In this paper, we discuss the implementation of a DNA sequence comparison algorithm by re-casting the algorithm in terms of linear algebra primitives. By developing an overloaded matrix multiplication approach to DNA comparisons, we can leverage advances in GPU hardware and algorithms for Dense Generalized Matrix-Multiply (DGEMM) to speed up DNA sample comparisons. We show that it is possible to compare 2048 unknown DNA samples with 20 million known samples in under 6 seconds using a NVIDIA K80 GPU.
Summary
Analysis of DNA samples is an important step in forensics, and the speed of analysis can impact investigations. Comparison of DNA sequences is based on the analysis of short tandem repeats (STRs), which are short DNA sequences of 2-5 base pairs. Current forensics approaches use 20 STR loci for analysis...
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Detecting virus exposure during the pre-symptomatic incubation period using physiological data
March 3, 2017
Journal Article
Published in:
Science Translational Medicine (submitted), 3 March 2017.
Summary
Early pathogen exposure detection allows better patient care and faster implementation of public health measures (patient isolation, contact tracing). Existing exposure detection most frequently relies on overt clinical symptoms, namely fever, during the infectious prodromal period. We have developed a robust machine learning method to better detect asymptomatic states during the incubation period using subtle, sub-clinical physiological markers. Using high-resolution physiological data from non-human primate studies of Ebola and Marburg viruses, we pre-processed the data to reduce short-term variability and normalize diurnal variations, then provided these to a supervised random forest classification algorithm. In most subjects detection is achieved well before the onset of fever; subject cross-validation lead to 52±14h mean early detection (at >0.90 area under the receiver-operating characteristic curve). Cross-cohort tests across pathogens and exposure routes also lead to successful early detection (28±16h and 43±22h, respectively). We discuss which physiological indicators are most informative for early detection and options for extending this capability to lower data resolution and wearable, non-invasive sensors.
Summary
Early pathogen exposure detection allows better patient care and faster implementation of public health measures (patient isolation, contact tracing). Existing exposure detection most frequently relies on overt clinical symptoms, namely fever, during the infectious prodromal period. We have developed a robust machine learning method to better detect asymptomatic states during...
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Benchmarking SciDB data import on HPC systems
September 13, 2016
Conference Paper
Published in:
HPEC 2016: IEEE Conf. on High Performance Extreme Computing, 13-15 September 2016.
Summary
SciDB is a scalable, computational database management system that uses an array model for data storage. The array data model of SciDB makes it ideally suited for storing and managing large amounts of imaging data. SciDB is designed to support advanced analytics in database, thus reducing the need for extracting data for analysis. It is designed to be massively parallel and can run on commodity hardware in a high performance computing (HPC) environment. In this paper, we present the performance of SciDB using simulated image data. The Dynamic Distributed Dimensional Data Model (D4M) software is used to implement the benchmark on a cluster running the MIT SuperCloud software stack. A peak performance of 2.2M database inserts per second was achieved on a single node of this system. We also show that SciDB and the D4M toolbox provide more efficient ways to access random sub-volumes of massive datasets compared to the traditional approaches of reading volumetric data from individual files. This work describes the D4M and SciDB tools we developed and presents the initial performance results. This performance was achieved by using parallel inserts, a in-database merging of arrays as well as supercomputing techniques, such as distributed arrays and single-program-multiple-data programming.
Summary
SciDB is a scalable, computational database management system that uses an array model for data storage. The array data model of SciDB makes it ideally suited for storing and managing large amounts of imaging data. SciDB is designed to support advanced analytics in database, thus reducing the need for extracting...
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