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COVID-19: famotidine, histamine, mast cells, and mechanisms [eprint]

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.
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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, multisystem inflammatory syndrome in children: antibody-induced mast cell activation hypothesis

Published in:
J Pediatrics & Pediatr Med. 2020; 4(2): 1-7

Summary

Multisystem Inflammatory Syndrome in Children (MIS-C) is appearing in infants, children, and young adults in association with COVID-19 (coronavirus disease 2019) infections of SARS-CoV-2. Kawasaki Disease (KD) 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 observed symptoms for MIS-C and KD are consistent with Mast Cell Activation Syndrome (MCAS) characterized by inflammatory molecules released from activated mast cells. Based on the associations of KD with multiple viral and bacterial pathogens, we put forward the hypothesis that KD and MIS-C result from antibody activation of mast cells by Fc receptor-bound pathogen antibodies causing a hyperinflammatory response upon second pathogen exposure. Within this hypothesis, MIS-C may be atypical KD or a KD-like disease associated with SARS-CoV-2. We extend the mast cell hypothesis that increased histamine levels are inducing contraction of effector cells with impeded blood flow through cardiac capillaries. In some patients, pressure from impeded blood flow, within cardiac capillaries, may result in increased coronary artery blood pressure leading to aneurysms, a well-known complication in KD.
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Summary

Multisystem Inflammatory Syndrome in Children (MIS-C) is appearing in infants, children, and young adults in association with COVID-19 (coronavirus disease 2019) infections of SARS-CoV-2. Kawasaki Disease (KD) is one of the most common vasculitides of childhood. KD presents with similar symptoms to MIS-C especially in severe forms such as Kawasaki...

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Medical countermeasures analysis of 2019-nCoV and vaccine risks for antibody-dependent enhancement (ADE)

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.
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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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Large-scale Bayesian 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 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.
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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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A linear algebra approach to fast DNA mixture analysis using GPUs

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.
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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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Rapid sequence identification of potential pathogens using techniques from sparse linear algebra

Published in:
HST 2015, IEEE Int. Conf. on Technologies for Homeland Security, 14-16 April 2015.

Summary

The decreasing costs and increasing speed and accuracy of DNA sample collection, preparation, and sequencing has rapidly produced an enormous volume of genetic data. However, fast and accurate analysis of the samples remains a bottleneck. Here we present D4RAGenS, a genetic sequence identification algorithm that exhibits the Big Data handling and computational power of the Dynamic Distributed Dimensional Data Model (D4M). The method leverages linear algebra and statistical properties to increase computational performance while retaining accuracy by subsampling the data. Two run modes, Fast and Wise, yield speed and precision tradeoffs, with applications in biodefense and medical diagnostics. The D4RAGenS analysis algorithm is tested over several datasets, including three utilized for the Defense Threat Reduction Agency (DTRA) metagenomic algorithm contest.
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Summary

The decreasing costs and increasing speed and accuracy of DNA sample collection, preparation, and sequencing has rapidly produced an enormous volume of genetic data. However, fast and accurate analysis of the samples remains a bottleneck. Here we present D4RAGenS, a genetic sequence identification algorithm that exhibits the Big Data handling...

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Using a big data database to identify pathogens in protein data space [e-print]

Summary

Current metagenomic analysis algorithms require significant computing resources, can report excessive false positives (type I errors), may miss organisms (type II errors/false negatives), or scale poorly on large datasets. This paper explores using big data database technologies to characterize very large metagenomic DNA sequences in protein space, with the ultimate goal of rapid pathogen identification in patient samples. Our approach uses the abilities of a big data databases to hold large sparse associative array representations of genetic data to extract statistical patterns about the data that can be used in a variety of ways to improve identification algorithms.
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Summary

Current metagenomic analysis algorithms require significant computing resources, can report excessive false positives (type I errors), may miss organisms (type II errors/false negatives), or scale poorly on large datasets. This paper explores using big data database technologies to characterize very large metagenomic DNA sequences in protein space, with the ultimate...

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Genetic sequence matching using D4M big data approaches

Published in:
HPEC 2014: IEEE Conf. on High Performance Extreme Computing, 9-11 September 2014.

Summary

Recent technological advances in Next Generation Sequencing tools have led to increasing speeds of DNA sample collection, preparation, and sequencing. One instrument can produce over 600 Gb of genetic sequence data in a single run. This creates new opportunities to efficiently handle the increasing workload. We propose a new method of fast genetic sequence analysis using the Dynamic Distributed Dimensional Data Model (D4M) - an associative array environment for MATLAB developed at MIT Lincoln Laboratory. Based on mathematical and statistical properties, the method leverages big data techniques and the implementation of an Apache Acculumo database to accelerate computations one-hundred fold over other methods. Comparisons of the D4M method with the current gold-standard for sequence analysis, BLAST, show the two are comparable in the alignments they find. This paper will present an overview of the D4M genetic sequence algorithm and statistical comparisons with BLAST.
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Summary

Recent technological advances in Next Generation Sequencing tools have led to increasing speeds of DNA sample collection, preparation, and sequencing. One instrument can produce over 600 Gb of genetic sequence data in a single run. This creates new opportunities to efficiently handle the increasing workload. We propose a new method...

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Taming biological big data with D4M

Published in:
Lincoln Laboratory Journal, Vol. 20, No. 1, 2013, pp. 82-91.

Summary

The supercomputing community has taken up the challenge of "taming the beast" spawned by the massive amount of data available in the bioinformatics domain: How can these data be exploited faster and better? MIT Lincoln Laboratory computer scientists demonstrated how a new Laboratory-developed technology, the Dynamic Distributed Dimensional Data Model (D4M), can be used to accelerate DNA sequence comparison, a core operation in bioinformatics.
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Summary

The supercomputing community has taken up the challenge of "taming the beast" spawned by the massive amount of data available in the bioinformatics domain: How can these data be exploited faster and better? MIT Lincoln Laboratory computer scientists demonstrated how a new Laboratory-developed technology, the Dynamic Distributed Dimensional Data Model...

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Taming biological big data with D4M

Summary

The supercomputing community has taken up the challenge of "taming the beast" spawned by the massive amount of data available in the bioinformatics domain: How can these data be exploited faster and better? MIT Lincoln Laboratory computer scientists demonstrated how a new Laboratory-developed technology, the Dynamic Distributed Dimensional Data Model (D4M), can be used to accelerate DNA sequence comparison, a core operation in bioinformatics.
READ LESS

Summary

The supercomputing community has taken up the challenge of "taming the beast" spawned by the massive amount of data available in the bioinformatics domain: How can these data be exploited faster and better? MIT Lincoln Laboratory computer scientists demonstrated how a new Laboratory-developed technology, the Dynamic Distributed Dimensional Data Model...

READ MORE

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