Publications by authors named "Robin Armstrong"

9 Publications

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Early multidrug treatment of SARS-CoV-2 infection (COVID-19) and reduced mortality among nursing home (or outpatient/ambulatory) residents.

Med Hypotheses 2021 Jun 5;153:110622. Epub 2021 Jun 5.

Concerned Ontario Doctors, Toronto, ON, Canada. Electronic address:

The outbreak of COVID-19 from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread all over the world with tremendous morbidity and mortality in the elderly. In-hospital treatment addresses the multifaceted nature of the illness including initial viral replication, cytokine storm, and endothelial injury with thrombosis. We identified nine reports of early treatment outcomes in COVID-19 nursing home patients. Multi-drug therapy including hydroxychloroquine with one or more anti-infectives, corticosteroids, and antithrombotic anti-blood clotting agents can be extended to seniors in the nursing home setting without hospitalization. Data from nine studies found hydroxychloroquine-based multidrug regimens were associated with a statistically significant > 60% reduction in mortality. Going forward, we conclude that early empiric treatment for the elderly with COVID-19 in the nursing home setting (or similar congregated settings with elderly residents/patients e.g. LTF or ALF) has a reasonable probability of success and acceptable safety. This group remains our highest at-risk group and warrants acute treatment focus prior to symptoms worsening. Given the rapidity and severity of SARS-CoV-2 outbreaks in nursing homes, in-center treatment of acute COVID-19 patients is a reasonable strategy to reduce the risks of hospitalization and death. If elderly high-risk patients in such congregated nursing home type settings are allowed to worsen with no early treatment, they may be too sick and fragile to benefit from in-hospital therapeutics and are at risk for pulmonary failure, life-ending micro-thrombi of the lungs, kidneys etc. The issue is timing of therapeutics, and we argue that early treatment before hospitalization, is the right time and can potentially save lives, especially among our higher-risk elderly populations hit hardest by severe illness and death from COVID-19. We must reiterate, we are talking about 'early' treatment before the disease is far along in the disease sequelae where the patient then needs hospitalization and aggressive interventions. We are referring to the initial days e.g. day one, post infection when symptoms emerge or there is strong clinical suspicion. This early therapeutic option deserves serious and urgent consideration by the medical establishment and respective decision-makers. Doctors must be allowed their clinical discretion in how they optimally treat their patients. Doctors must be brave and trust their skilled judgements and do all to save the lives of their patients. We therefore hypothesize that early outpatient ambulatory treatment, once initiated as soon as symptoms begin in high-risk positive persons, would significantly reduce hospitalizations and prevent deaths. Specifically, the provision of early multi-drug sequenced therapy with repurposed drugs will reduce hospitalization and death in elderly patients being cared for in long-term-care facilities. The most important implications of our hypothesis are: 1) hospitalizations and deaths would be reduced 2) transmission would be reduced due to the mitigation of symptoms and 3) recovery following infection and treatment provides for natural exposure immunity that is broad based, durable, and robust (helping towards natural immunity within the population). The end result is reduced strain on hospitals and systems that would allow for other non-COVID illnesses to receive care.
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http://dx.doi.org/10.1016/j.mehy.2021.110622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178530PMC
June 2021

Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19).

Rev Cardiovasc Med 2020 12;21(4):517-530

Emergency Medicine, Phoenix, 85016, AZ, USA.

The SARS-CoV-2 virus spreading across the world has led to surges of COVID-19 illness, hospitalizations, and death. The complex and multifaceted pathophysiology of life-threatening COVID-19 illness including viral mediated organ damage, cytokine storm, and thrombosis warrants early interventions to address all components of the devastating illness. In countries where therapeutic nihilism is prevalent, patients endure escalating symptoms and without early treatment can succumb to delayed in-hospital care and death. Prompt early initiation of sequenced multidrug therapy (SMDT) is a widely and currently available solution to stem the tide of hospitalizations and death. A multipronged therapeutic approach includes 1) adjuvant nutraceuticals, 2) combination intracellular anti-infective therapy, 3) inhaled/oral corticosteroids, 4) antiplatelet agents/anticoagulants, 5) supportive care including supplemental oxygen, monitoring, and telemedicine. Randomized trials of individual, novel oral therapies have not delivered tools for physicians to combat the pandemic in practice. No single therapeutic option thus far has been entirely effective and therefore a combination is required at this time. An urgent immediate pivot from single drug to SMDT regimens should be employed as a critical strategy to deal with the large numbers of acute COVID-19 patients with the aim of reducing the intensity and duration of symptoms and avoiding hospitalization and death.
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http://dx.doi.org/10.31083/j.rcm.2020.04.264DOI Listing
December 2020

Rif1 Functions in a Tissue-Specific Manner To Control Replication Timing Through Its PP1-Binding Motif.

Genetics 2020 05 6;215(1):75-87. Epub 2020 Mar 6.

Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee 37232

Replication initiation in eukaryotic cells occurs asynchronously throughout S phase, yielding early- and late-replicating regions of the genome, a process known as replication timing (RT). RT changes during development to ensure accurate genome duplication and maintain genome stability. To understand the relative contributions that cell lineage, cell cycle, and replication initiation regulators have on RT, we utilized the powerful developmental systems available in We generated and compared RT profiles from mitotic cells of different tissues and from mitotic and endocycling cells of the same tissue. Our results demonstrate that cell lineage has the largest effect on RT, whereas switching from a mitotic to an endoreplicative cell cycle has little to no effect on RT. Additionally, we demonstrate that the RT differences we observed in all cases are largely independent of transcriptional differences. We also employed a genetic approach in these same cell types to understand the relative contribution the eukaryotic RT control factor, Rif1, has on RT control. Our results demonstrate that Rif1 can function in a tissue-specific manner to control RT. Importantly, the Protein Phosphatase 1 (PP1) binding motif of Rif1 is essential for Rif1 to regulate RT. Together, our data support a model in which the RT program is primarily driven by cell lineage and is further refined by Rif1/PP1 to ultimately generate tissue-specific RT programs.
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http://dx.doi.org/10.1534/genetics.120.303155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198277PMC
May 2020

Phasing in heterochromatin during development.

Genes Dev 2019 04;33(7-8):379-381

Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.

Constitutive heterochromatin is a prevalent feature of eukaryotic genomes important for promoting cell differentiation and maintaining genome stability. During animal reproduction, constitutive heterochromatin is disassembled in gametes prior to formation of the zygote and then subsequently re-established as development ensues and cells differentiate. Despite progress in understanding the mechanisms that maintain heterochromatin in differentiated cell types, how constitutive heterochromatin is assembled de novo during early development remains poorly understood. In this issue of , Seller and colleagues (pp. 403-417) develop a new technology for inhibiting maternal gene function to identify the H3K9 methyltransferase necessary for initiating constitutive heterochromatin formation during early embryogenesis.
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http://dx.doi.org/10.1101/gad.324731.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446546PMC
April 2019

H3K9 Promotes Under-Replication of Pericentromeric Heterochromatin in Drosophila Salivary Gland Polytene Chromosomes.

Genes (Basel) 2019 01 29;10(2). Epub 2019 Jan 29.

Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC 27599, USA.

Chromatin structure and its organization contributes to the proper regulation and timing of DNA replication. Yet, the precise mechanism by which chromatin contributes to DNA replication remains incompletely understood. This is particularly true for cell types that rely on polyploidization as a developmental strategy for growth and high biosynthetic capacity. During larval development, cells of the salivary gland undergo endoreplication, repetitive rounds of DNA synthesis without intervening cell division, resulting in ploidy values of ~1350C. S phase of these endocycles displays a reproducible pattern of early and late replicating regions of the genome resulting from the activity of the same replication initiation factors that are used in diploid cells. However, unlike diploid cells, the latest replicating regions of polyploid salivary gland genomes, composed primarily of pericentric heterochromatic enriched in H3K9 methylation, are not replicated each endocycle, resulting in under-replicated domains with reduced ploidy. Here, we employ a histone gene replacement strategy in to demonstrate that mutation of a histone residue important for heterochromatin organization and function (H3K9) but not mutation of a histone residue important for euchromatin function (H4K16), disrupts proper endoreplication in salivary gland polyploid genomes thereby leading to DNA copy gain in pericentric heterochromatin. These findings reveal that H3K9 is necessary for normal levels of under-replication of pericentric heterochromatin and suggest that under-replication at pericentric heterochromatin is mediated through H3K9 methylation.
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http://dx.doi.org/10.3390/genes10020093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409945PMC
January 2019

Chromatin conformation and transcriptional activity are permissive regulators of DNA replication initiation in .

Genome Res 2018 11 2;28(11):1688-1700. Epub 2018 Oct 2.

Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.

Chromatin structure has emerged as a key contributor to spatial and temporal control over the initiation of DNA replication. However, despite genome-wide correlations between early replication of gene-rich, accessible euchromatin and late replication of gene-poor, inaccessible heterochromatin, a causal relationship between chromatin structure and replication initiation remains elusive. Here, we combined histone gene engineering and whole-genome sequencing in to determine how perturbing chromatin structure affects replication initiation. We found that most pericentric heterochromatin remains late replicating in mutants, even though pericentric heterochromatin is depleted of HP1a, more accessible, and transcriptionally active. These data indicate that HP1a loss, increased chromatin accessibility, and elevated transcription do not result in early replication of heterochromatin. Nevertheless, a small amount of pericentric heterochromatin with increased accessibility replicates earlier in mutants. Transcription is de-repressed in these regions of advanced replication but not in those regions of the mutant genome that replicate later, suggesting that transcriptional repression may contribute to late replication. We also explored relationships among chromatin, transcription, and replication in euchromatin by analyzing mutants. In the X Chromosome gene expression is up-regulated twofold and replicates earlier in XY males than it does in XX females. We found that mutation prevents normal male development and abrogates hyperexpression and earlier replication of the male X, consistent with previously established genome-wide correlations between transcription and early replication. In contrast, females are viable and fertile, indicating that H4K16 modification is dispensable for genome replication and gene expression.
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http://dx.doi.org/10.1101/gr.239913.118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6211642PMC
November 2018

Drosophila DNA polymerase theta utilizes both helicase-like and polymerase domains during microhomology-mediated end joining and interstrand crosslink repair.

PLoS Genet 2017 May 25;13(5):e1006813. Epub 2017 May 25.

Department of Biology, Tufts University, Medford, Massachusetts.

Double strand breaks (DSBs) and interstrand crosslinks (ICLs) are toxic DNA lesions that can be repaired through multiple pathways, some of which involve shared proteins. One of these proteins, DNA Polymerase θ (Pol θ), coordinates a mutagenic DSB repair pathway named microhomology-mediated end joining (MMEJ) and is also a critical component for bypass or repair of ICLs in several organisms. Pol θ contains both polymerase and helicase-like domains that are tethered by an unstructured central region. While the role of the polymerase domain in promoting MMEJ has been studied extensively both in vitro and in vivo, a function for the helicase-like domain, which possesses DNA-dependent ATPase activity, remains unclear. Here, we utilize genetic and biochemical analyses to examine the roles of the helicase-like and polymerase domains of Drosophila Pol θ. We demonstrate an absolute requirement for both polymerase and ATPase activities during ICL repair in vivo. However, similar to mammalian systems, polymerase activity, but not ATPase activity, is required for ionizing radiation-induced DSB repair. Using a site-specific break repair assay, we show that overall end-joining efficiency is not affected in ATPase-dead mutants, but there is a significant decrease in templated insertion events. In vitro, Pol θ can efficiently bypass a model unhooked nitrogen mustard crosslink and promote DNA synthesis following microhomology annealing, although ATPase activity is not required for these functions. Together, our data illustrate the functional importance of the helicase-like domain of Pol θ and suggest that its tethering to the polymerase domain is important for its multiple functions in DNA repair and damage tolerance.
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http://dx.doi.org/10.1371/journal.pgen.1006813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5466332PMC
May 2017

Methylation of histone H4 lysine 20 by PR-Set7 ensures the integrity of late replicating sequence domains in Drosophila.

Nucleic Acids Res 2016 09 29;44(15):7204-18. Epub 2016 Apr 29.

Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA

The methylation state of lysine 20 on histone H4 (H4K20) has been linked to chromatin compaction, transcription, DNA repair and DNA replication. Monomethylation of H4K20 (H4K20me1) is mediated by the cell cycle-regulated histone methyltransferase PR-Set7. PR-Set7 depletion in mammalian cells results in defective S phase progression and the accumulation of DNA damage, which has been partially attributed to defects in origin selection and activation. However, these studies were limited to only a handful of mammalian origins, and it remains unclear how PR-Set7 and H4K20 methylation impact the replication program on a genomic scale. We employed genetic, cytological, and genomic approaches to better understand the role of PR-Set7 and H4K20 methylation in regulating DNA replication and genome stability in Drosophila cells. We find that deregulation of H4K20 methylation had no impact on origin activation throughout the genome. Instead, depletion of PR-Set7 and loss of H4K20me1 results in the accumulation of DNA damage and an ATR-dependent cell cycle arrest. Coincident with the ATR-dependent cell cycle arrest, we find increased DNA damage that is specifically limited to late replicating regions of the Drosophila genome, suggesting that PR-Set7-mediated monomethylation of H4K20 is critical for maintaining the genomic integrity of late replicating domains.
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http://dx.doi.org/10.1093/nar/gkw333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5009726PMC
September 2016

Nurses' knowledge of error in blood pressure measurement technique.

Int J Nurs Pract 2002 Jun;8(3):118-26

Hypertension Unit, Greenslopes Private Hospital, Queensland, Australia.

Errors in measuring blood pressure may have significant impact on the investigation and treatment of patients. Errors arise from faults in measurement technique or the equipment used. In Australia, blood pressure measurement technique is taught to nurses during their undergraduate education and may not be reviewed again. This observational, descriptive study surveyed clinical nurses at a metropolitan teaching hospital at shift hand-over time. Participation was voluntary and anonymous by 78 nurses who answered a questionnaire to determine the need and focus for updating blood pressure measurement technique. Sixty-one per cent of participants conformed to currently accepted practice in identifying systolic blood pressure, and 71% diastolic blood pressure; 54% correctly interpreted a description of blood pressure sounds containing an auscultatory gap. Correct answers for assessment of faulty equipment were given by 58%, assessing cuff size by 57%, arm position for seated measurement by 14%, determination of inflation pressure by 29% and deflation rate 62%. Incidence of terminal digit preference was 32%. These findings indicate that knowledge of participants was inadequate to perform blood pressure measurement in a standardized manner, and prevent introduced error.
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http://dx.doi.org/10.1046/j.1440-172x.2002.00348.xDOI Listing
June 2002
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