Publications by authors named "Mark Bailey"

246 Publications

Revisiting mouse minute virus inactivation by high temperature short time treatment.

Biotechnol Bioeng 2021 Aug 8;118(8):2967-2976. Epub 2021 Jun 8.

Bioproduct Research and Development, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USA.

In recent years, high temperature short time (HTST) treatment technology has been increasingly adopted for medium treatment to mitigate the potential risk of viral contamination in mammalian cell culture GMP manufacturing facilities. Mouse minute virus (MMV), also called minute virus of mice (MVM), implicated in multiple viral contamination events is commonly used as a relevant model virus to assess the effectiveness of HTST treatment of cell culture media. However, results from different studies vary broadly in inactivation kinetics as well as log reduction factors (LRFs) achieved under given treatment conditions. To determine whether the reported discrepancies stemmed from differences in MMV strains, laboratory-scale HTST devices, medium matrices, and/or experimental designs, we have taken a collaborative approach to systematically assess the effectiveness of HTST treatment for MMV inactivation. This effort was conceptualized based on a media treatment gap analysis conducted by the Consortium on Adventitious Agent Contamination in Biomanufacturing (CAACB) under the MIT Center for Biomedical Innovation (CBI). Specifically, two different MMV strains were used to evaluate the effectiveness of HTST at various treatment conditions with regard to exposure temperature and hold time duration by two independent laboratories within two different companies. To minimize experimental variations, the two sites used the same batches of MMV stocks, the same commercially purchased medium, and the same model of thermocyclers as the laboratory-scale HTST device. The two independent laboratories yielded similar MMV inactivation kinetics and comparable LRF. No significant differences were observed between the two MMV strains evaluated, suggesting that the variations from prior studies were likely due to differences in equipment, medium matrices, or other factors. The data presented here indicate that MMV inactivation by HTST treatment obeys first-order kinetics and can be mathematically modeled using an Arrhenius equation. The model-based extrapolation provides a quantitative estimate of MMV inactivation by the current industry standard HTST condition (102°C for a hold time of 10 s) used for medium treatment. Finally, based on the data from the current study and the industry experience, it is recommended that any alternative virus barrier technologies adopted for medium treatment should provide a clearance of at least 3.0 LRF based on a worst-case model virus to effectively mitigate potential risks of viral contamination.
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http://dx.doi.org/10.1002/bit.27805DOI Listing
August 2021

Reversible Nutritional Deficiency-Related Conjunctival Xerosis and Optic Neuropathy Secondary to an Exclusively Potato-Based Diet.

J Neuroophthalmol 2021 Apr 14. Epub 2021 Apr 14.

Baylor College of Medicine (MDB, AGL), Houston, Texas; Department of Ophthalmology (PM, SR, AGL), Blanton Eye Institute, Houston Methodist Hospital, Houston, Texas; Houston Methodist Research Institute (AGL), Houston Methodist Hospital, Houston, Texas; Departments of Ophthalmology, Neurology, and Neurosurgery (AGL), Weill Cornell Medicine, New York, New York; Department of Ophthalmology (AGL), University of Texas Medical Branch, Galveston, Texas; University of Texas Maryland Anderson Cancer Center (AGL), Houston, Texas; Texas A and M College of Medicine (AGL), Bryan, Texas; and Department of Ophthalmology (AGL), the University of Iowa Hospitals and Clinics, Iowa City, Iowa.

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http://dx.doi.org/10.1097/WNO.0000000000001217DOI Listing
April 2021

Niche and local geography shape the pangenome of wastewater- and livestock-associated Enterobacteriaceae.

Sci Adv 2021 Apr 9;7(15). Epub 2021 Apr 9.

Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.

and other Enterobacteriaceae are diverse species with "open" pangenomes, where genes move intra- and interspecies via horizontal gene transfer. However, most analyses focus on clinical isolates. The pangenome dynamics of natural populations remain understudied, despite their suggested role as reservoirs for antimicrobial resistance (AMR) genes. Here, we analyze near-complete genomes for 827 Enterobacteriaceae (553 and 274 non- spp.) with 2292 circularized plasmids in total, collected from 19 locations (livestock farms and wastewater treatment works in the United Kingdom) within a 30-km radius at three time points over a year. We find different dynamics for chromosomal and plasmid-borne genes. Plasmids have a higher burden of AMR genes and insertion sequences, and AMR-gene-carrying plasmids show evidence of being under stronger selective pressure. Environmental niche and local geography both play a role in shaping plasmid dynamics. Our results highlight the importance of local strategies for controlling the spread of AMR.
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http://dx.doi.org/10.1126/sciadv.abe3868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034854PMC
April 2021

Sex-stratified genome-wide association study of multisite chronic pain in UK Biobank.

PLoS Genet 2021 Apr 8;17(4):e1009428. Epub 2021 Apr 8.

School of Life Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom.

Chronic pain is highly prevalent worldwide and imparts a significant socioeconomic and public health burden. Factors influencing susceptibility to, and mechanisms of, chronic pain development, are not fully understood, but sex is thought to play a significant role, and chronic pain is more prevalent in women than in men. To investigate sex differences in chronic pain, we carried out a sex-stratified genome-wide association study of Multisite Chronic Pain (MCP), a derived chronic pain phenotype, in UK Biobank on 178,556 men and 209,093 women, as well as investigating sex-specific genetic correlations with a range of psychiatric, autoimmune and anthropometric phenotypes and the relationship between sex-specific polygenic risk scores for MCP and chronic widespread pain. We also assessed whether MCP-associated genes showed expression pattern enrichment across tissues. A total of 123 SNPs at five independent loci were significantly associated with MCP in men. In women, a total of 286 genome-wide significant SNPs at ten independent loci were discovered. Meta-analysis of sex-stratified GWAS outputs revealed a further 87 independent associated SNPs. Gene-level analyses revealed sex-specific MCP associations, with 31 genes significantly associated in females, 37 genes associated in males, and a single gene, DCC, associated in both sexes. We found evidence for sex-specific pleiotropy and risk for MCP was found to be associated with chronic widespread pain in a sex-differential manner. Male and female MCP were highly genetically correlated, but at an rg of significantly less than 1 (0.92). All 37 male MCP-associated genes and all but one of 31 female MCP-associated genes were found to be expressed in the dorsal root ganglion, and there was a degree of enrichment for expression in sex-specific tissues. Overall, the findings indicate that sex differences in chronic pain exist at the SNP, gene and transcript abundance level, and highlight possible sex-specific pleiotropy for MCP. Results support the proposition of a strong central nervous-system component to chronic pain in both sexes, additionally highlighting a potential role for the DRG and nociception.
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http://dx.doi.org/10.1371/journal.pgen.1009428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8031124PMC
April 2021

In vitro toxicity of fibrous glaucophane.

Toxicology 2021 04 3;454:152743. Epub 2021 Mar 3.

Department of Chemical and Geological Sciences, University of Modena and Reggio Emilia, Modena, Italy. Electronic address:

The health hazard represented by the exposure to asbestos may also concern other minerals with asbestos-like crystal habit. One of these potentially hazardous minerals is fibrous glaucophane. Fibrous glaucophane is a major component of blueschist rocks of California (USA) currently mined for construction purposes. Dust generated by the excavation activities might potentially expose workers and the general public. The aim of this study was to determine whether fibrous glaucophane induces in vitro toxicity effects on lung cells by assessing the biological responses of cultured human pleural mesothelial cells (Met-5A) and THP-1 derived macrophages exposed for 24 h and 48 h to glaucophane fibres. Crocidolite asbestos was tested for comparison. The experimental configuration of the in vitro tests included a cell culture without fibres (i.e., control), cell cultures treated with 50 μg/mL (i.e., 15.6 μg/cm) of crocidolite fibres and 25-50-100 μg/mL (i.e., 7.8-15.6-31.2 μg/cm) of glaucophane fibres. Results showed that fibrous glaucophane may induce a decrease in cell viability and an increase in extra-cellular lactate dehydrogenase release in the tested cell cultures in a concentration dependent mode. Moreover, it was found that fibrous glaucophane has a potency to cause oxidative stress. The biological reactivity of fibrous glaucophane confirms that it is a toxic agent and, although it apparently induces lower toxic effects compared to crocidolite, exposure to this fibre may be responsible for the development of lung diseases in exposed unprotected workers and population.
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http://dx.doi.org/10.1016/j.tox.2021.152743DOI Listing
April 2021

Genomic network analysis of environmental and livestock F-type plasmid populations.

ISME J 2021 Mar 1. Epub 2021 Mar 1.

Nuffield Department of Medicine, University of Oxford, Oxford, UK.

F-type plasmids are diverse and of great clinical significance, often carrying genes conferring antimicrobial resistance (AMR) such as extended-spectrum β-lactamases, particularly in Enterobacterales. Organising this plasmid diversity is challenging, and current knowledge is largely based on plasmids from clinical settings. Here, we present a network community analysis of a large survey of F-type plasmids from environmental (influent, effluent and upstream/downstream waterways surrounding wastewater treatment works) and livestock settings. We use a tractable and scalable methodology to examine the relationship between plasmid metadata and network communities. This reveals how niche (sampling compartment and host genera) partition and shape plasmid diversity. We also perform pangenome-style analyses on network communities. We show that such communities define unique combinations of core genes, with limited overlap. Building plasmid phylogenies based on alignments of these core genes, we demonstrate that plasmid accessory function is closely linked to core gene content. Taken together, our results suggest that stable F-type plasmid backbone structures can persist in environmental settings while allowing dramatic variation in accessory gene content that may be linked to niche adaptation. The association of F-type plasmids with AMR may reflect their suitability for rapid niche adaptation.
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http://dx.doi.org/10.1038/s41396-021-00926-wDOI Listing
March 2021

SUMO enables substrate selectivity by mitogen-activated protein kinases to regulate immunity in plants.

Proc Natl Acad Sci U S A 2021 Mar;118(10)

Department of Biosciences, Durham University, DH1 3LE Durham, United Kingdom;

The versatility of mitogen-activated protein kinases (MAPKs) in translating exogenous and endogenous stimuli into appropriate cellular responses depends on its substrate specificity. In animals, several mechanisms have been proposed about how MAPKs maintain specificity to regulate distinct functional pathways. However, little is known of mechanisms that enable substrate selectivity in plant MAPKs. Small ubiquitin-like modifier (SUMO), a posttranslational modification system, plays an important role in plant development and defense by rapid reprogramming of cellular events. In this study we identified a functional SUMO interaction motif (SIM) in MPK3 and MPK6 that reveals a mechanism for selective interaction of MPK3/6 with SUMO-conjugated WRKY33, during defense. We show that WRKY33 is rapidly SUMOylated in response to infection and flg22 elicitor treatment. SUMOylation mediates WRKY33 phosphorylation by MPKs and consequent transcription factor activity. Disruption of either WRKY33 SUMO or MPK3/6 SIM sites attenuates their interaction and inactivates WRKY33-mediated defense. However, MPK3/6 SIM mutants show normal interaction with a non-SUMOylated form of another transcription factor, SPEECHLESS, unraveling a role for SUMOylation in differential substrate selectivity by MPKs. We reveal that the SUMO proteases, SUMO PROTEASE RELATED TO FERTILITY1 (SPF1) and SPF2 control WRKY33 SUMOylation and demonstrate a role for these SUMO proteases in defense. Our data reveal a mechanism by which MPK3/6 prioritize molecular pathways by differentially selecting substrates using the SUMO-SIM module during defense responses.
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http://dx.doi.org/10.1073/pnas.2021351118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958252PMC
March 2021

Influenza hemagglutinin-specific IgA Fc-effector functionality is restricted to stalk epitopes.

Proc Natl Acad Sci U S A 2021 02;118(8)

Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029;

In this study, we utilized a panel of human immunoglobulin (Ig) IgA monoclonal antibodies isolated from the plasmablasts of eight donors after 2014/2015 influenza virus vaccination (Fluarix) to study the binding and functional specificities of this isotype. In this cohort, isolated IgA monoclonal antibodies were primarily elicited against the hemagglutinin protein of the H1N1 component of the vaccine. To compare effector functionalities, an H1-specific subset of antibodies targeting distinct epitopes were expressed as monomeric, dimeric, or secretory IgA, as well as in an IgG1 backbone. When expressed with an IgG Fc domain, all antibodies elicited Fc-effector activity in a primary polymorphonuclear cell-based assay which differs from previous observations that found only stalk-specific antibodies activate the low-affinity FcγRIIIa. However, when expressed with IgA Fc domains, only antibodies targeting the stalk domain showed Fc-effector activity in line with these previous findings. To identify the cause of this discrepancy, we then confirmed that IgG signaling through the high-affinity FcγI receptor was not restricted to stalk epitopes. Since no corresponding high-affinity Fcα receptor exists, the IgA repertoire may therefore be limited to stalk-specific epitopes in the context of Fc receptor signaling.
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http://dx.doi.org/10.1073/pnas.2018102118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923359PMC
February 2021

The overlap of genetic susceptibility to schizophrenia and cardiometabolic disease can be used to identify metabolically different groups of individuals.

Sci Rep 2021 01 12;11(1):632. Epub 2021 Jan 12.

Institute of Health and Wellbeing, University of Glasgow, Room 111, Public Health, 1 Lilybank Gardens, Glasgow, G12 8RZ, UK.

Understanding why individuals with severe mental illness (Schizophrenia, Bipolar Disorder and Major Depressive Disorder) have increased risk of cardiometabolic disease (including obesity, type 2 diabetes and cardiovascular disease), and identifying those at highest risk of cardiometabolic disease are important priority areas for researchers. For individuals with European ancestry we explored whether genetic variation could identify sub-groups with different metabolic profiles. Loci associated with schizophrenia, bipolar disorder and major depressive disorder from previous genome-wide association studies and loci that were also implicated in cardiometabolic processes and diseases were selected. In the IMPROVE study (a high cardiovascular risk sample) and UK Biobank (general population sample) multidimensional scaling was applied to genetic variants implicated in both psychiatric and cardiometabolic disorders. Visual inspection of the resulting plots used to identify distinct clusters. Differences between these clusters were assessed using chi-squared and Kruskall-Wallis tests. In IMPROVE, genetic loci associated with both schizophrenia and cardiometabolic disease (but not bipolar disorder or major depressive disorder) identified three groups of individuals with distinct metabolic profiles. This grouping was replicated within UK Biobank, with somewhat less distinction between metabolic profiles. This work focused on individuals of European ancestry and is unlikely to apply to more genetically diverse populations. Overall, this study provides proof of concept that common biology underlying mental and physical illness may help to stratify subsets of individuals with different cardiometabolic profiles.
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http://dx.doi.org/10.1038/s41598-020-79964-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804422PMC
January 2021

The Arabidopsis NOT4A E3 ligase promotes PGR3 expression and regulates chloroplast translation.

Nat Commun 2021 01 11;12(1):251. Epub 2021 Jan 11.

School of Biosciences, University of Birmingham, Edgbaston, B15 2TT, UK.

Chloroplast function requires the coordinated action of nuclear- and chloroplast-derived proteins, including several hundred nuclear-encoded pentatricopeptide repeat (PPR) proteins that regulate plastid mRNA metabolism. Despite their large number and importance, regulatory mechanisms controlling PPR expression are poorly understood. Here we show that the Arabidopsis NOT4A ubiquitin-ligase positively regulates the expression of PROTON GRADIENT REGULATION 3 (PGR3), a PPR protein required for translating several thylakoid-localised photosynthetic components and ribosome subunits within chloroplasts. Loss of NOT4A function leads to a strong depletion of cytochrome bf and NAD(P)H dehydrogenase (NDH) complexes, as well as plastid 30 S ribosomes, which reduces mRNA translation and photosynthetic capacity, causing pale-yellow and slow-growth phenotypes. Quantitative transcriptome and proteome analysis of the not4a mutant reveal it lacks PGR3 expression, and that its molecular defects resemble those of a pgr3 mutant. Furthermore, we show that normal plastid function is restored to not4a through transgenic PGR3 expression. Our work identifies NOT4A as crucial for ensuring robust photosynthetic function during development and stress-response, through promoting PGR3 production and chloroplast translation.
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http://dx.doi.org/10.1038/s41467-020-20506-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801604PMC
January 2021

Treatment of sleep disturbance following stroke and traumatic brain injury: a systematic review of conservative interventions.

Disabil Rehabil 2020 Dec 11:1-13. Epub 2020 Dec 11.

Barts Health NHS Trust, Newham University Hospital, London, UK.

Purpose: Sleep disorders are common following stroke and traumatic brain injury. We present a systematic review of the literature investigating conservative interventions to improve sleep in these populations.

Materials And Methods: The PRISMA statement was used. Embase, PubMed, and the Cochrane library were searched for all experimental studies published prior to 28th March 2020 that assessed conservative interventions to improve the sleep or sleep disorders of adults with a history of stroke or traumatic brain injury (TBI). Two authors reviewed publications of interest and risk of bias assessments were performed using the Cochrane Risk of Bias Tool or the Methodological Index for Non-Randomised Studies instrument.

Results: Twenty-three publications were included in this systematic review. Meta-analyses were not performed due to study heterogeneity. Psychotherapy-based approaches might be useful for sleep disturbance after TBI and acupuncture may help improve insomnia or sleep disturbance following stroke or TBI, respectively. The evidence was less clear for morning bright light therapy and exercise. Limitations included a single author performing primary searches, only English publications, the reporting of secondary outcome measures, and sleep disorder diagnoses.

Conclusions: Some conservative interventions might be useful for improving sleep disturbance or disorders in these populations, but further research is required.IMPLICATIONS FOR REHABILITATIONSleep disturbance is common following stroke and traumatic brain injury, with insomnia and obstructive sleep apnoea being the most frequently diagnosed sleep disorders.Psychotherapy-based approaches might be useful for sleep disturbance after TBI and acupuncture may help improve insomnia or sleep disturbance following stroke or TBI, respectively.Morning bright light therapy appeared to be more beneficial for fatigue rather than sleep disturbance after TBI, and the evidence for exercise was less clear.
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http://dx.doi.org/10.1080/09638288.2020.1856948DOI Listing
December 2020

Contrasting community assembly processes structure lotic bacteria metacommunities along the river continuum.

Environ Microbiol 2021 01 10;23(1):484-498. Epub 2020 Dec 10.

UK Centre for Ecology & Hydrology, Wallingford, Oxfordshire, OX10 8BB, UK.

The heterogeneous nature of lotic habitats plays an important role in the complex ecological and evolutionary processes that structure the microbial communities within them. Due to such complexity, our understanding of lotic microbial ecology still lacks conceptual frameworks for the ecological processes that shape these communities. We explored how bacterial community composition and underlying ecological assembly processes differ between lotic habitats by examining community composition and inferring community assembly processes across four major habitat types (free-living, particle-associated, biofilm on benthic stones and rocks, and sediment). This was conducted at 12 river sites from headwater streams to the main river in the River Thames, UK. Our results indicate that there are distinct differences in the bacterial communities between four major habitat types, with contrasting ecological processes shaping their community assembly processes. While the mobile free-living and particle-associated communities were consistently less diverse than the fixed sediment and biofilm communities, the latter two communities displayed higher homogeneity across the sampling sites. This indicates that the relative influence of deterministic environmental filtering is elevated in sediment and biofilm communities compared with free-living and particle-associated communities, where stochastic processes play a larger role.
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http://dx.doi.org/10.1111/1462-2920.15337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898806PMC
January 2021

Leaf shape in is a complex, omnigenic trait.

Ecol Evol 2020 Nov 13;10(21):11922-11940. Epub 2020 Oct 13.

Department of Plant Physiology Umeå Plant Science Centre Umeå University Umeå Sweden.

Leaf shape is a defining feature of how we recognize and classify plant species. Although there is extensive variation in leaf shape within many species, few studies have disentangled the underlying genetic architecture. We characterized the genetic architecture of leaf shape variation in Eurasian aspen ( L.) by performing genome-wide association study (GWAS) for physiognomy traits. To ascertain the roles of identified GWAS candidate genes within the leaf development transcriptional program, we generated RNA-Seq data that we used to perform gene co-expression network analyses from a developmental series, which is publicly available within the PlantGenIE resource. We additionally used existing gene expression measurements across the population to analyze GWAS candidate genes in the context of a population-wide co-expression network and to identify genes that were differentially expressed between groups of individuals with contrasting leaf shapes. These data were integrated with expression GWAS (eQTL) results to define a set of candidate genes associated with leaf shape variation. Our results identified no clear adaptive link to leaf shape variation and indicate that leaf shape traits are genetically complex, likely determined by numerous small-effect variations in gene expression. Genes associated with shape variation were peripheral within the population-wide co-expression network, were not highly connected within the leaf development co-expression network, and exhibited signatures of relaxed selection. As such, our results are consistent with the omnigenic model.
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http://dx.doi.org/10.1002/ece3.6691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663049PMC
November 2020

Exploring the Role of Contactins across Psychological, Psychiatric and Cardiometabolic Traits within UK Biobank.

Genes (Basel) 2020 11 10;11(11). Epub 2020 Nov 10.

Institute of Health and Wellbeing, University of Glasgow, Glasgow G12 8RZ, UK.

Individuals with severe mental illness have an increased risk of cardiometabolic diseases compared to the general population. Shared risk factors and medication effects explain part of this excess risk; however, there is growing evidence to suggest that shared biology (including genetic variation) is likely to contribute to comorbidity between mental and physical illness. Contactins are a family of genes involved in development of the nervous system and implicated, though genome-wide association studies, in a wide range of psychological, psychiatric and cardiometabolic conditions. Contactins are plausible candidates for shared pathology between mental and physical health. We used data from UK Biobank to systematically assess how genetic variation in contactin genes was associated with a wide range of psychological, psychiatric and cardiometabolic conditions. We also investigated whether associations for cardiometabolic and psychological traits represented the same or distinct signals and how the genetic variation might influence the measured traits. We identified: A novel genetic association between variation in and current smoking; two independent signals in for BMI; and demonstrated that associations between and neuroticism were distinct from those between and blood pressure/HbA1c. There was no evidence that the contactin genes contributed to shared aetiology between physical and mental illness.
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http://dx.doi.org/10.3390/genes11111326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697406PMC
November 2020

Robust neutralizing antibodies to SARS-CoV-2 infection persist for months.

Science 2020 12 28;370(6521):1227-1230. Epub 2020 Oct 28.

Clinical Microbiology Laboratory, Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic with millions infected and more than 1 million fatalities. Questions regarding the robustness, functionality, and longevity of the antibody response to the virus remain unanswered. Here, on the basis of a dataset of 30,082 individuals screened at Mount Sinai Health System in New York City, we report that the vast majority of infected individuals with mild-to-moderate COVID-19 experience robust immunoglobulin G antibody responses against the viral spike protein. We also show that titers are relatively stable for at least a period of about 5 months and that anti-spike binding titers significantly correlate with neutralization of authentic SARS-CoV-2. Our data suggest that more than 90% of seroconverters make detectable neutralizing antibody responses. These titers remain relatively stable for several months after infection.
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http://dx.doi.org/10.1126/science.abd7728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810037PMC
December 2020

Exotropic bilateral internuclear ophthalmoplegia following a superior cerebellar artery aneurysm clipping.

Can J Ophthalmol 2021 Jun 17;56(3):211-212. Epub 2020 Oct 17.

Baylor College of Medicine, Houston, TX; Department of Ophthalmology, Blanton Eye Institute, Houston Methodist Hospital, Houston, TX; Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX; Departments of Ophthalmology, Neurology, and Neurosurgery, Weill Cornell Medicine, New York, NY; Department of Ophthalmology, University of Texas Medical Branch, Galveston, TX; University of Texas MD Anderson Cancer Center, Houston, TX; Texas A and M College of Medicine, Bryan, TX; Department of Ophthalmology, The University of Iowa Hospitals and Clinics, Iowa City, IA. Electronic address:

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http://dx.doi.org/10.1016/j.jcjo.2020.09.019DOI Listing
June 2021

Quality improvement in neurology: Headache Quality Measurement Set.

Neurology 2020 11 23;95(19):866-873. Epub 2020 Sep 23.

From the Department of Neurology (M.S.R.), Weill Cornell Medicine, New York, NY; NeuroDevelopmental Science Center (M.C.V.), Akron Children's Hospital, OH; University of Alabama at Birmingham (M.B.), Indian Springs, AL; Emory University (C.C.), School of Nursing, Healthcare, Atlanta, GA; Mayo Clinic (I.V.), Rochester, MN; University of Virginia Health System (J.S.H.), Charlottesville, VA; Baylor Scott & White (D.R.), Temple, TX; Department of Anesthesiology (N.M.S.), University of California San Diego Center for Pain Medicine, La Jolla, CA; Sutter Imaging (D.S.), Sacramento, CA; Albert Einstein College of Medicine and Yeshiva University (E.S.), Bronx, NY; Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania (C.S.), Philadelphia, PA; American Academy of Neurology (E.R.), Minneapolis, MN; and University of Rochester (R.V.), NY.

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http://dx.doi.org/10.1212/WNL.0000000000010634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713732PMC
November 2020

Durable infrared optical coatings based on pulsed DC-sputtering of hydrogenated amorphous carbon (a-C:H).

Appl Opt 2020 Mar;59(9):2731-2738

Optical properties of low-temperature pulsed DC-sputter deposited ($ {\le} {70° {\rm C}}$≤70°C) hydrogenated carbon are presented. Increasing hydrogen incorporation into the sputter deposited carbon significantly decreases infrared optical absorption due to a decrease in deep absorptive states associated with dangling bonds. Hydrogen flow is optimized (hydrogen flow 3 sccm), achieving the best compromise between increased infrared transmittance and hardness for durable coating performance. Optical, environmental, and durability performance of pulsed DC-sputtered carbon incorporated in multilayer (a-C:H/Ge) infrared antireflective coatings indicates suitability as a durable infrared optical coating for commonly used infrared substrates, including temperature sensitive chalcogenide glass.
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http://dx.doi.org/10.1364/AO.378266DOI Listing
March 2020

The PRT6 N-degron pathway restricts VERNALIZATION 2 to endogenous hypoxic niches to modulate plant development.

New Phytol 2021 01 16;229(1):126-139. Epub 2020 Mar 16.

School of Biosciences, University of Birmingham, Edgbaston, B15 2TT, UK.

VERNALIZATION2 (VRN2), an angiosperm-specific subunit of the polycomb repressive complex 2 (PRC2), is an oxygen (O )-regulated target of the PCO branch of the PRT6 N-degron pathway of ubiquitin-mediated proteolysis. How this post-translational regulation coordinates VRN2 activity remains to be fully established. Here we use Arabidopsis thaliana ecotypes, mutants and transgenic lines to determine how control of VRN2 stability contributes to its functions during plant development. VRN2 localizes to endogenous hypoxic regions in aerial and root tissues. In the shoot apex, VRN2 differentially modulates flowering time dependent on photoperiod, whilst its presence in lateral root primordia and the root apical meristem negatively regulates root system architecture. Ectopic accumulation of VRN2 does not enhance its effects on flowering, but does potentiate its repressive effects on root growth. In late-flowering vernalization-dependent ecotypes, VRN2 is only active outside meristems when its proteolysis is inhibited in response to cold exposure, as its function requires concomitant cold-triggered increases in other PRC2 subunits and cofactors. We conclude that the O -sensitive N-degron of VRN2 has a dual function, confining VRN2 to meristems and primordia, where it has specific developmental roles, whilst also permitting broad accumulation outside of meristems in response to environmental cues, leading to other functions.
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http://dx.doi.org/10.1111/nph.16477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754370PMC
January 2021

Carotid Intima-Media Thickness: Novel Loci, Sex-Specific Effects, and Genetic Correlations With Obesity and Glucometabolic Traits in UK Biobank.

Arterioscler Thromb Vasc Biol 2020 02 5;40(2):446-461. Epub 2019 Dec 5.

From the Institute of Health and Wellbeing (R.J.S., J.W., B.C., A.F., N.G., K.J.A.J., L.M.L., R.P., J.P., R.J.S., R.T., D.M.L., D.J.S.), University of Glasgow, United Kingdom.

Objective: Atherosclerosis is the underlying cause of most cardiovascular disease, but mechanisms underlying atherosclerosis are incompletely understood. Ultrasound measurement of the carotid intima-media thickness (cIMT) can be used to measure vascular remodeling, which is indicative of atherosclerosis. Genome-wide association studies have identified many genetic loci associated with cIMT, but heterogeneity of measurements collected by many small cohorts have been a major limitation in these efforts. Here, we conducted genome-wide association analyses in UKB (UK Biobank; N=22 179), the largest single study with consistent cIMT measurements. Approach and Results: We used BOLT-LMM software to run linear regression of cIMT in UKB, adjusted for age, sex, and genotyping chip. In white British participants, we identified 5 novel loci associated with cIMT and replicated most previously reported loci. In the first sex-specific analyses of cIMT, we identified a locus on chromosome 5, associated with cIMT in women only and highlight as a good candidate gene at this locus. Genetic correlations with body mass index and glucometabolic traits were also observed. Two loci influenced risk of ischemic heart disease.

Conclusions: These findings replicate previously reported associations, highlight novel biology, and provide new directions for investigating the sex differences observed in cardiovascular disease presentation and progression.
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http://dx.doi.org/10.1161/ATVBAHA.119.313226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6975521PMC
February 2020

Novel genome-wide associations for anhedonia, genetic correlation with psychiatric disorders, and polygenic association with brain structure.

Transl Psychiatry 2019 12 4;9(1):327. Epub 2019 Dec 4.

Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK.

Anhedonia is a core symptom of several psychiatric disorders but its biological underpinnings are poorly understood. We performed a genome-wide association study of state anhedonia in 375,275 UK Biobank participants and assessed for genetic correlation between anhedonia and neuropsychiatric conditions (major depressive disorder, schizophrenia, bipolar disorder, obsessive compulsive disorder and Parkinson's Disease). We then used a polygenic risk score approach to test for association between genetic loading for anhedonia and both brain structure and brain function. This included: magnetic resonance imaging (MRI) assessments of total grey matter volume, white matter volume, cerebrospinal fluid volume, and 15 cortical/subcortical regions of interest; diffusion tensor imaging (DTI) measures of white matter tract integrity; and functional MRI activity during an emotion processing task. We identified 11 novel loci associated at genome-wide significance with anhedonia, with a SNP heritability estimate (hSNP) of 5.6%. Strong positive genetic correlations were found between anhedonia and major depressive disorder, schizophrenia and bipolar disorder; but not with obsessive compulsive disorder or Parkinson's Disease. Polygenic risk for anhedonia was associated with poorer brain white matter integrity, smaller total grey matter volume, and smaller volumes of brain regions linked to reward and pleasure processing, including orbito-frontal cortex. In summary, the identification of novel anhedonia-associated loci substantially expands our current understanding of the biological basis of state anhedonia and genetic correlations with several psychiatric disorders confirm the utility of this phenotype as a transdiagnostic marker of vulnerability to mental illness. We also provide the first evidence that genetic risk for state anhedonia influences brain structure, including in regions associated with reward and pleasure processing.
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http://dx.doi.org/10.1038/s41398-019-0635-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892870PMC
December 2019

Identification of novel common variants associated with chronic pain using conditional false discovery rate analysis with major depressive disorder and assessment of pleiotropic effects of LRFN5.

Transl Psychiatry 2019 11 20;9(1):310. Epub 2019 Nov 20.

School of Life Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow, Scotland, UK.

Chronic pain is a complex trait that is moderately heritable and genetically, as well as phenotypically, correlated with major depressive disorder (MDD). Use of the conditional false discovery rate (cFDR) approach, which leverages pleiotropy identified from existing GWAS outputs, has been successful in discovering novel associated variants in related phenotypes. Here, genome-wide association study outputs for both von Korff chronic pain grade and for MDD were used to identify variants meeting a cFDR threshold for each outcome phenotype separately, as well as a conjunctional cFDR (ccFDR) threshold for both phenotypes together. Using a moderately conservative threshold, we identified a total of 11 novel single nucleotide polymorphisms (SNPs), six of which were associated with chronic pain grade and nine of which were associated with MDD. Four SNPs on chromosome 14 were associated with both chronic pain grade and MDD. SNPs associated only with chronic pain grade were located within SLC16A7 on chromosome 12. SNPs associated only with MDD were located either in a gene-dense region on chromosome 1 harbouring LINC01360, LRRIQ3, FPGT and FPGT-TNNI3K, or within/close to LRFN5 on chromosome 14. The SNPs associated with both outcomes were also located within LRFN5. Several of the SNPs on chromosomes 1 and 14 were identified as being associated with expression levels of nearby genes in the brain and central nervous system. Overall, using the cFDR approach, we identified several novel genetic loci associated with chronic pain and we describe likely pleiotropic effects of a recently identified MDD locus on chronic pain.
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http://dx.doi.org/10.1038/s41398-019-0613-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868167PMC
November 2019

The impact of sequencing depth on the inferred taxonomic composition and AMR gene content of metagenomic samples.

Environ Microbiome 2019 Oct 24;14(1). Epub 2019 Oct 24.

Nuffield Department of Medicine, University of Oxford, Oxford, UK.

Background: Shotgun metagenomics is increasingly used to characterise microbial communities, particularly for the investigation of antimicrobial resistance (AMR) in different animal and environmental contexts. There are many different approaches for inferring the taxonomic composition and AMR gene content of complex community samples from shotgun metagenomic data, but there has been little work establishing the optimum sequencing depth, data processing and analysis methods for these samples. In this study we used shotgun metagenomics and sequencing of cultured isolates from the same samples to address these issues. We sampled three potential environmental AMR gene reservoirs (pig caeca, river sediment, effluent) and sequenced samples with shotgun metagenomics at high depth (~ 200 million reads per sample). Alongside this, we cultured single-colony isolates of Enterobacteriaceae from the same samples and used hybrid sequencing (short- and long-reads) to create high-quality assemblies for comparison to the metagenomic data. To automate data processing, we developed an open-source software pipeline, 'ResPipe'.

Results: Taxonomic profiling was much more stable to sequencing depth than AMR gene content. 1 million reads per sample was sufficient to achieve < 1% dissimilarity to the full taxonomic composition. However, at least 80 million reads per sample were required to recover the full richness of different AMR gene families present in the sample, and additional allelic diversity of AMR genes was still being discovered in effluent at 200 million reads per sample. Normalising the number of reads mapping to AMR genes using gene length and an exogenous spike of Thermus thermophilus DNA substantially changed the estimated gene abundance distributions. While the majority of genomic content from cultured isolates from effluent was recoverable using shotgun metagenomics, this was not the case for pig caeca or river sediment.

Conclusions: Sequencing depth and profiling method can critically affect the profiling of polymicrobial animal and environmental samples with shotgun metagenomics. Both sequencing of cultured isolates and shotgun metagenomics can recover substantial diversity that is not identified using the other methods. Particular consideration is required when inferring AMR gene content or presence by mapping metagenomic reads to a database. ResPipe, the open-source software pipeline we have developed, is freely available ( https://gitlab.com/hsgweon/ResPipe ).
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http://dx.doi.org/10.1186/s40793-019-0347-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204541PMC
October 2019

Characterization and assessment of the potential toxicity/pathogenicity of fibrous glaucophane.

Environ Res 2019 11 4;178:108723. Epub 2019 Sep 4.

Department of Chemical and Geological Sciences, University of Modena and Reggio Emilia, Via Campi 103, Modena, 41125, Italy.

In California, the metamorphic blueschist occurrences within the Franciscan Complex are commonly composed of glaucophane, which can be found with a fibrous habit. Fibrous glaucophane's potential toxicity/pathogenicity has never been determined and it has not been considered by the International Agency for Research on Cancer (IARC) as a potential carcinogen to date. Notwithstanding, outcrops hosting fibrous glaucophane are being excavated today in California for building/construction purposes (see for example the Calaveras Dam Replacement Project - CDRP). Dust generated by these excavation activities may expose workforces and the general population to this potential natural hazard. In this work, the potential toxicity/pathogenicity of fibrous glaucophane has been determined using the fibre potential toxicity index (FPTI). This model has been applied to a representative glaucophane-rich sample collected at San Anselmo, Marin County (CA, USA), characterized using a suite of experimental techniques to determine morphometric, crystal-chemical parameters, surface reactivity, biodurability and related parameters. With respect to the asbestos minerals, the FPTI of fibrous glaucophane is remarkably higher than that of chrysotile, and comparable to that of tremolite, thus supporting the application of the precautionary approach when excavating fibrous glaucophane-rich blueschist rocks. Because fibrous glaucophane can be considered a potential health hazard, just like amphibole asbestos, it should be taken into consideration in the standard procedures for the identification and assessment of minerals fibres in soil and air samples.
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http://dx.doi.org/10.1016/j.envres.2019.108723DOI Listing
November 2019

Genetic hallmarks of recurrent/metastatic adenoid cystic carcinoma.

J Clin Invest 2019 10;129(10):4276-4289

Head and Neck Service, Department of Surgery, and.

BACKGROUNDAdenoid cystic carcinoma (ACC) is a rare malignancy arising in salivary glands and other sites, characterized by high rates of relapse and distant spread. Recurrent/metastatic (R/M) ACCs are generally incurable, due to a lack of active systemic therapies. To improve outcomes, deeper understanding of genetic alterations and vulnerabilities in R/M tumors is needed.METHODSAn integrated genomic analysis of 1,045 ACCs (177 primary, 868 R/M) was performed to identify alterations associated with advanced and metastatic tumors. Intratumoral genetic heterogeneity, germline mutations, and therapeutic actionability were assessed.RESULTSCompared with primary tumors, R/M tumors were enriched for alterations in key Notch (NOTCH1, 26.3% vs. 8.5%; NOTCH2, 4.6% vs. 2.3%; NOTCH3, 5.7% vs. 2.3%; NOTCH4, 3.6% vs. 0.6%) and chromatin-remodeling (KDM6A, 15.2% vs. 3.4%; KMT2C/MLL3, 14.3% vs. 4.0%; ARID1B, 14.1% vs. 4.0%) genes. TERT promoter mutations (13.1% of R/M cases) were mutually exclusive with both NOTCH1 mutations (q = 3.3 × 10-4) and MYB/MYBL1 fusions (q = 5.6 × 10-3), suggesting discrete, alternative mechanisms of tumorigenesis. This network of alterations defined 4 distinct ACC subgroups: MYB+NOTCH1+, MYB+/other, MYBWTNOTCH1+, and MYBWTTERT+. Despite low mutational load, we identified numerous samples with marked intratumoral genetic heterogeneity, including branching evolution across multiregion sequencing.CONCLUSIONThese observations collectively redefine the molecular underpinnings of ACC progression and identify further targets for precision therapies.FUNDINGAdenoid Cystic Carcinoma Research Foundation, Pershing Square Sohn Cancer Research grant, the PaineWebber Chair, Stand Up 2 Cancer, NIH R01 CA205426, the STARR Cancer Consortium, NCI R35 CA232097, the Frederick Adler Chair, Cycle for Survival, the Jayme Flowers Fund, The Sebastian Nativo Fund, NIH K08 DE024774 and R01 DE027738, and MSKCC through NIH/NCI Cancer Center Support Grant (P30 CA008748).
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http://dx.doi.org/10.1172/JCI128227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763222PMC
October 2019

Comparison of long-read sequencing technologies in the hybrid assembly of complex bacterial genomes.

Microb Genom 2019 09 30;5(9). Epub 2019 Aug 30.

Nuffield Department of Medicine, University of Oxford, Oxford, UK.

Illumina sequencing allows rapid, cheap and accurate whole genome bacterial analyses, but short reads (<300 bp) do not usually enable complete genome assembly. Long-read sequencing greatly assists with resolving complex bacterial genomes, particularly when combined with short-read Illumina data (hybrid assembly). However, it is not clear how different long-read sequencing methods affect hybrid assembly accuracy. Relative automation of the assembly process is also crucial to facilitating high-throughput complete bacterial genome reconstruction, avoiding multiple bespoke filtering and data manipulation steps. In this study, we compared hybrid assemblies for 20 bacterial isolates, including two reference strains, using Illumina sequencing and long reads from either Oxford Nanopore Technologies (ONT) or SMRT Pacific Biosciences (PacBio) sequencing platforms. We chose isolates from the family , as these frequently have highly plastic, repetitive genetic structures, and complete genome reconstruction for these species is relevant for a precise understanding of the epidemiology of antimicrobial resistance. We assembled genomes using the hybrid assembler Unicycler and compared different read processing strategies, as well as comparing to long-read-only assembly with Flye followed by short-read polishing with Pilon. Hybrid assembly with either PacBio or ONT reads facilitated high-quality genome reconstruction, and was superior to the long-read assembly and polishing approach evaluated with respect to accuracy and completeness. Combining ONT and Illumina reads fully resolved most genomes without additional manual steps, and at a lower consumables cost per isolate in our setting. Automated hybrid assembly is a powerful tool for complete and accurate bacterial genome assembly.
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http://dx.doi.org/10.1099/mgen.0.000294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6807382PMC
September 2019

Forty years of reform and opening up: China's progress toward a sustainable path.

Sci Adv 2019 Aug 7;5(8):eaau9413. Epub 2019 Aug 7.

Ma Yinchu School of Economics, Tianjin University, 92 Weijin Road, Tianjin 300072, China.

After 40 years of reform and "opening up," China has made remarkable economic progress. Such economic prosperity, however, has been coupled with environmental degradation. We analyze diverse long-term data to determine whether China is experiencing a decoupling of economic growth and environmental impacts, and where China stands with respect to the Sustainable Development Goals (SDGs) in terms of reducing regional division, urban-rural gap, social inequality, and land-based impacts on oceans. The results highlight that China's desire to achieve "ecological civilization" has resulted in a decoupling trend for major pollutants since 2015, while strong coupling remains with CO emissions. Progress has been made in health care provision, poverty reduction, and gender equity in education, while income disparity continues between regions and with rural-urban populations. There is a considerable way to go toward achieving delivery of the SDGs; however, China's progress toward economic prosperity and concomitant sustainability provides important insights for other countries.
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http://dx.doi.org/10.1126/sciadv.aau9413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685713PMC
August 2019

Extending the Stalk Enhances Immunogenicity of the Influenza Virus Neuraminidase.

J Virol 2019 09 28;93(18). Epub 2019 Aug 28.

Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA

Influenza viruses express two surface glycoproteins, the hemagglutinin (HA) and the neuraminidase (NA). Anti-NA antibodies protect from lethal influenza virus challenge in the mouse model and correlate inversely with virus shedding and symptoms in humans. Consequently, the NA is a promising target for influenza virus vaccine design. Current seasonal vaccines, however, poorly induce anti-NA antibodies, partly because of the immunodominance of the HA over the NA when the two glycoproteins are closely associated. To address this issue, here we investigated whether extending the stalk domain of the NA could render it more immunogenic on virus particles. Two recombinant influenza viruses based on the H1N1 strain A/Puerto Rico/8/1934 (PR8) were rescued with NA stalk domains extended by 15 or 30 amino acids. Formalin-inactivated viruses expressing wild-type NA or the stalk-extended NA variants were used to vaccinate mice. The virus with the 30-amino-acid stalk extension induced significantly higher anti-NA IgG responses (characterized by increased antibody-dependent cellular cytotoxicity [ADCC] activity) than the wild-type PR8 virus, while anti-HA IgG levels were unaffected. Similarly, extending the stalk domain of the NA of a recent H3N2 virus enhanced the induction of anti-NA IgGs in mice. On the basis of these results, we hypothesize that the subdominance of the NA can be modulated if the protein is modified such that its height surpasses that of the HA on the viral membrane. Extending the stalk domain of NA may help to enhance its immunogenicity in influenza virus vaccines without compromising antibody responses to HA. The efficacy of influenza virus vaccines could be improved by enhancing the immunogenicity of the NA protein. One of the reasons for its poor immunogenicity is the immunodominance of the HA over the NA in many seasonal influenza virus vaccines. Here we demonstrate that, in the mouse model, extending the stalk domain of the NA protein can enhance its immunogenicity on virus particles and overcome the immunodominance of the HA without affecting antibody responses to the HA. The antibody repertoire is broadened by the extended NA and includes additional ADCC-active antibodies. Our findings may assist in the efforts toward more effective influenza virus vaccines.
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http://dx.doi.org/10.1128/JVI.00840-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714795PMC
September 2019
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