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Article: The Gut-Eye Axis: Lessons Learned from Murine Models.

Floyd, Jason L / Grant, Maria B

Ophthalmology and therapy

2020 Volume 9, Issue 3, Page(s) 499–513

Abstract: A healthy gut microbiota is essential in maintaining the human body in a homeostatic state by its functions in digestion and immune tolerance. Under states of aberrant microbial composition or function (dysbiosis), the gut microbiota induces systemic ... ...

Abstract	A healthy gut microbiota is essential in maintaining the human body in a homeostatic state by its functions in digestion and immune tolerance. Under states of aberrant microbial composition or function (dysbiosis), the gut microbiota induces systemic inflammation that can lead to the onset of many diseases. In this review, we describe some evidence, largely from rodent studies, that supports the possible role of a dysbiotic gut microbiota in the onset and exacerbation of ocular diseases, primarily diabetic retinopathy, age-related macular degeneration, choroidal neovascularization, and uveitis. Furthermore, we examine several potential therapeutic measures that show promise in restoring the gut microbiota to a eubiotic state, preventing the aforementioned disease pathologies.
Language	English
Publishing date	2020-07-02
Publishing country	England
Document type	Journal Article ; Review
ISSN	2193-8245
ISSN	2193-8245
DOI	10.1007/s40123-020-00278-2
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Article: Development and evaluation of two new droplet evaporation schemes for fire dynamics simulations

Floyd, Jason / Randall McDermott

Elsevier Ltd Fire safety journal. 2017 July, v. 91

2017

Abstract: The evaporation of sprinkler droplets is an important phenomenon in fire simulations both for heat removal from the gas and for heat removal from surfaces. In this paper, we address the problems of potential numerical instability and super-saturation ... ...

Abstract	The evaporation of sprinkler droplets is an important phenomenon in fire simulations both for heat removal from the gas and for heat removal from surfaces. In this paper, we address the problems of potential numerical instability and super-saturation that may occur in explicit time integration of the droplet equations. Two novel numerical approaches are developed and evaluated. The first is based on an analytical solution that relaxes the cell composition and temperature toward the equilibrium values. The second method is an implicit solution to the droplet equations. The two approaches are implemented in the Fire Dynamics Simulator (FDS) and verified and validated using both single droplet and practical sprinkler calculations. Ultimately, the implicit approach is deemed the most cost effective for practical fire simulations.
Keywords	cost effectiveness ; droplets ; equations ; evaporation ; heat ; temperature
Language	English
Dates of publication	2017-07
Size	p. 643-652.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	1483569-1
ISSN	0379-7112
ISSN	0379-7112
DOI	10.1016/j.firesaf.2017.04.036
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Article ; Online: Microbial Signatures in The Rodent Eyes With Retinal Dysfunction and Diabetic Retinopathy.

Prasad, Ram / Asare-Bediko, Bright / Harbour, Angela / Floyd, Jason L / Chakraborty, Dibyendu / Duan, Yaqian / Lamendella, Regina / Wright, Justin / Grant, Maria B

Investigative ophthalmology & visual science

2022 Volume 63, Issue 1, Page(s) 5

Abstract: Purpose: The gut microbiome has been linked to disease pathogenesis through their interaction in metabolic, endocrine, and immune functions. The goal of this study was to determine whether the gut and plasma microbiota could transfer microbes to the ... ...

Abstract	Purpose: The gut microbiome has been linked to disease pathogenesis through their interaction in metabolic, endocrine, and immune functions. The goal of this study was to determine whether the gut and plasma microbiota could transfer microbes to the retina in type 1 diabetic mice with retinopathy. Methods: We analyzed the fecal, plasma, whole globe, and retina microbiome in Akita mice and compared with age-matched wild-type (WT) mice using 16S rRNA sequencing and metatranscriptomic analysis. To eliminate the contribution of the ocular surface and plasma microbiome, mice were perfused with sterile saline solution, the whole globes were extracted, and the neural retina was removed under sterile conditions for retinal microbiome. Results: Our microbiome analysis revealed that Akita mice demonstrated a distinct pattern of microbes within each source: feces, plasma, whole globes, and retina. WT mice and Akita mice experienced transient bacteremia in the plasma and retina. Bacteria were identified in the retina of the Akita mice, specifically Corynebacterium, Pseudomonas, Lactobacillus, Staphylococcus, Enterococcus, and Bacillus. Significantly increased levels of peptidoglycan (0.036 ± 0.001 vs. 0.023 ± 0.002; P < 0.002) and TLR2 (3.47 ± 0.15 vs. 1.99 ± 0.07; P < 0.0001) were observed in the retina of Akita mice compared to WT. Increased IBA+ cells in the retina, reduced a- and b-waves on electroretinography, and increased acellular capillary formation demonstrated the presence of retinopathy in the Akita cohort compared to WT mice. Conclusions: Together, our findings suggest that transient bacteremia exists in the plasma and retina of both cohorts. The bacteria found in Akita mice are distinct from WT mice and may contribute to development of retinal inflammation and barrier dysfunction in retinopathy.
MeSH term(s)	Animals ; Bacteremia/microbiology ; Bacteria/genetics ; Bacteria/isolation & purification ; Diabetes Mellitus, Type 1/microbiology ; Diabetic Retinopathy/microbiology ; Disease Models, Animal ; Electroretinography ; Enzyme-Linked Immunosorbent Assay ; Eye/microbiology ; Feces/microbiology ; Gastrointestinal Microbiome/physiology ; Male ; Mice ; Mice, Inbred C57BL ; Microbiota/physiology ; RNA, Ribosomal, 16S/genetics ; Retina/microbiology
Chemical Substances	RNA, Ribosomal, 16S
Language	English
Publishing date	2022-01-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	391794-0
ISSN	1552-5783 ; 0146-0404
ISSN (online)	1552-5783
ISSN	0146-0404
DOI	10.1167/iovs.63.1.5
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Article: Sustained ACE2 Expression by Probiotic Improves Integrity of Intestinal Lymphatics and Retinopathy in Type 1 Diabetic Model.

Prasad, Ram / Adu-Agyeiwaah, Yvonne / Floyd, Jason L / Asare-Bediako, Bright / Li Calzi, Sergio / Chakraborty, Dibyendu / Harbour, Angela / Rohella, Aayush / Busik, Julia V / Li, Qiuhong / Grant, Maria B

Journal of clinical medicine

2023 Volume 12, Issue 5

Abstract: Intestinal lymphatic, known as lacteal, plays a critical role in maintaining intestinal homeostasis by regulating several key functions, including the absorption of dietary lipids, immune cell trafficking, and interstitial fluid balance in the gut. The ... ...

Abstract	Intestinal lymphatic, known as lacteal, plays a critical role in maintaining intestinal homeostasis by regulating several key functions, including the absorption of dietary lipids, immune cell trafficking, and interstitial fluid balance in the gut. The absorption of dietary lipids relies on lacteal integrity, mediated by button-like and zipper-like junctions. Although the intestinal lymphatic system is well studied in many diseases, including obesity, the contribution of lacteals to the gut-retinal axis in type 1 diabetes (T1D) has not been examined. Previously, we showed that diabetes induces a reduction in intestinal angiotensin-converting enzyme 2 (ACE2), leading to gut barrier disruption. However, when ACE2 levels are maintained, a preservation of gut barrier integrity occurs, resulting in less systemic inflammation and a reduction in endothelial cell permeability, ultimately retarding the development of diabetic complications, such as diabetic retinopathy. Here, we examined the impact of T1D on intestinal lymphatics and circulating lipids and tested the impact of intervention with ACE-2-expressing probiotics on key aspects of gut and retinal function.
Language	English
Publishing date	2023-02-23
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662592-1
ISSN	2077-0383
ISSN	2077-0383
DOI	10.3390/jcm12051771
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Article ; Online: Intravitreal Administration of AAV2-SIRT1 Reverses Diabetic Retinopathy in a Mouse Model of Type 2 Diabetes.

Adu-Agyeiwaah, Yvonne / Vieira, Cristiano P / Asare-Bediako, Bright / Li Calzi, Sergio / DuPont, Mariana / Floyd, Jason / Boye, Sanford / Chiodo, Vince / Busik, Julia V / Grant, Maria B

Translational vision science & technology

2023 Volume 12, Issue 4, Page(s) 20

Abstract: Purpose: The expression of silent information regulator (SIRT) 1 is reduced in diabetic retinopathy (DR). Previous studies showed that alterations in SIRT1 messenger RNA (mRNA) and protein expression are implicated in progressive inflammation and ... ...

Abstract	Purpose: The expression of silent information regulator (SIRT) 1 is reduced in diabetic retinopathy (DR). Previous studies showed that alterations in SIRT1 messenger RNA (mRNA) and protein expression are implicated in progressive inflammation and formation of retinal acellular capillaries. Treatment with the SIRT1 agonist, SRT1720, improved visual response by restoration of a- and b-wave responses on electroretinogram scotopic measurements in diabetic (db/db) mice. In this study, we investigated the effects of intravitreal SIRT1 delivery on diabetic retinal pathology. Methods: Nine-month-old db/db mice received one intravitreal injection of either AAV2-SIRT1 or AAV2-GFP control virus, and after 3 months, electroretinography and optomotor responses were measured. Their eyes were then removed and analyzed by immunohistochemistry and flow cytometry. Results: SIRT1 mRNA and protein levels were increased following AAV2-SIRT1 administration compared to control virus AAV2-GFP injected mice. IBA1+ and caspase 3 expression were decreased in retinas of db/db mice injected with AAV2-SIRT1, and reductions in scotopic a- and b-waves and high spatial frequency in optokinetic response were prevented. Retinal hypoxia inducible factor 1α (HIF-1α) protein levels were reduced in the AAV2-SIRT1-injected mice compared to control-injected mice. Using flow cytometry to assess changes in intracellular HIF-1α levels, endothelial cells (CD31+) from AAV-2 SIRT1 injected mice demonstrated reduced HIF-1α expression compared to db/db mice injected with the control virus. Conclusions: Intravitreal AAV2-SIRT1 delivery increased retina SIRT1 and transduced neural and endothelial cells, thus reversing functional damage and improving overall visual function. Translational relevance: AAV2-SIRT1 gene therapy represents a beneficial approach for the treatment of chronic retinal conditions such as DR.
MeSH term(s)	Mice ; Animals ; Diabetic Retinopathy/genetics ; Diabetic Retinopathy/therapy ; Sirtuin 1/genetics ; Diabetes Mellitus, Type 2/complications ; Diabetes Mellitus, Type 2/therapy ; Endothelial Cells/metabolism ; Disease Models, Animal ; RNA, Messenger
Chemical Substances	Sirtuin 1 (EC 3.5.1.-) ; RNA, Messenger ; Sirt1 protein, mouse (EC 3.5.1.-)
Language	English
Publishing date	2023-04-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2674602-5
ISSN	2164-2591 ; 2164-2591
ISSN (online)	2164-2591
ISSN	2164-2591
DOI	10.1167/tvst.12.4.20
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Article: Enforcing realizability in explicit multi-component species transport

McDermott, Randall J / Floyd, Jason E

Fire safety journal. 2015 Nov., v. 78

2015

Abstract: We propose a strategy to guarantee realizability of species mass fractions in explicit time integration of the partial differential equations governing fire dynamics, which is a multi-component transport problem (realizability requires all mass fractions ...

Abstract	We propose a strategy to guarantee realizability of species mass fractions in explicit time integration of the partial differential equations governing fire dynamics, which is a multi-component transport problem (realizability requires all mass fractions that are greater than or equal to zero and that the sum equals unity). For a mixture of n species, the conventional strategy is to solve for n−1 species mass fractions and to obtain the nth (or “background”) species mass fraction from one minus the sum of the others. The numerical difficulties inherent in the background species approach are discussed and the potential for realizability violations is illustrated. The new strategy solves all n species transport equations and obtains density from the sum of the species mass densities. To guarantee realizability the species mass densities must remain positive (semidefinite). A scalar boundedness correction is proposed that is based on a minimal diffusion operator. The overall scheme is implemented in a publicly available large-eddy simulation code called the Fire Dynamics Simulator. A set of test cases is presented to verify that the new strategy enforces realizability, does not generate spurious mass, and maintains second-order accuracy for transport.
Keywords	differential equation ; mass density ; simulation models
Language	English
Dates of publication	2015-11
Size	p. 180-187.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	1483569-1
ISSN	0379-7112
ISSN	0379-7112
DOI	10.1016/j.firesaf.2015.09.005
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Article ; Online: Hematopoietic Cells Influence Vascular Development in the Retina.

Asare-Bediako, Bright / Adu-Agyeiwaah, Yvonne / Abad, Antonio / Li Calzi, Sergio / Floyd, Jason L / Prasad, Ram / DuPont, Mariana / Asare-Bediako, Richmond / Bustelo, Xose R / Grant, Maria B

Cells

2022 Volume 11, Issue 20

Abstract: Hematopoietic cells play a crucial role in the adult retina in health and disease. Monocytes, macrophages, microglia and myeloid angiogenic cells (MACs) have all been implicated in retinal pathology. However, the role that hematopoietic cells play in ... ...

Abstract	Hematopoietic cells play a crucial role in the adult retina in health and disease. Monocytes, macrophages, microglia and myeloid angiogenic cells (MACs) have all been implicated in retinal pathology. However, the role that hematopoietic cells play in retinal development is understudied. The temporal changes in recruitment of hematopoietic cells into the developing retina and the phenotype of the recruited cells are not well understood. In this study, we used the hematopoietic cell-specific protein Vav1 to track and investigate hematopoietic cells in the developing retina. By flow cytometry and immunohistochemistry, we show that hematopoietic cells are present in the retina as early as P0, and include microglia, monocytes and MACs. Even before the formation of retinal blood vessels, hematopoietic cells localize to the inner retina where they eventually form networks that intimately associate with the developing vasculature. Loss of Vav1 lead to a reduction in the density of medium-sized vessels and an increased inflammatory response in retinal astrocytes. When pups were subjected to oxygen-induced retinopathy, hematopoietic cells maintained a close association with the vasculature and occasionally formed 'frameworks' for the generation of new vessels. Our study provides further evidence for the underappreciated role of hematopoietic cells in retinal vasculogenesis and the formation of a healthy retina.
MeSH term(s)	Animals ; Animals, Newborn ; Retina/metabolism ; Retinal Vessels/metabolism ; Oxygen/metabolism ; Microglia
Chemical Substances	Oxygen (S88TT14065)
Language	English
Publishing date	2022-10-13
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11203207
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Article ; Online: Plasma Microbiome in COVID-19 Subjects: An Indicator of Gut Barrier Defects and Dysbiosis.

Prasad, Ram / Patton, Michael John / Floyd, Jason Levi / Fortmann, Seth / DuPont, Mariana / Harbour, Angela / Wright, Justin / Lamendella, Regina / Stevens, Bruce R / Oudit, Gavin Y / Grant, Maria B

International journal of molecular sciences

2022 Volume 23, Issue 16

Abstract: The gut is a well-established route of infection and target for viral damage by SARS-CoV-2. This is supported by the clinical observation that about half of COVID-19 patients exhibit gastrointestinal (GI) complications. We aimed to investigate whether ... ...

Abstract	The gut is a well-established route of infection and target for viral damage by SARS-CoV-2. This is supported by the clinical observation that about half of COVID-19 patients exhibit gastrointestinal (GI) complications. We aimed to investigate whether the analysis of plasma could provide insight into gut barrier dysfunction in patients with COVID-19 infection. Plasma samples of COVID-19 patients (n = 146) and healthy individuals (n = 47) were collected during hospitalization and routine visits. Plasma microbiome was analyzed using 16S rRNA sequencing and gut permeability markers including fatty acid binding protein 2 (FABP2), peptidoglycan (PGN), and lipopolysaccharide (LPS) in both patient cohorts. Plasma samples of both cohorts contained predominately Proteobacteria, Firmicutes, Bacteroides, and Actinobacteria. COVID-19 subjects exhibit significant dysbiosis (p = 0.001) of the plasma microbiome with increased abundance of Actinobacteria spp. (p = 0.0332), decreased abundance of Bacteroides spp. (p = 0.0003), and an increased Firmicutes:Bacteroidetes ratio (p = 0.0003) compared to healthy subjects. The concentration of the plasma gut permeability marker FABP2 (p = 0.0013) and the gut microbial antigens PGN (p < 0.0001) and LPS (p = 0.0049) were significantly elevated in COVID-19 patients compared to healthy subjects. These findings support the notion that the intestine may represent a source for bacteremia and contribute to worsening COVID-19 outcomes. Therapies targeting the gut and prevention of gut barrier defects may represent a strategy to improve outcomes in COVID-19 patients.
MeSH term(s)	Actinobacteria/genetics ; Bacteria/genetics ; COVID-19 ; Dysbiosis/microbiology ; Feces/microbiology ; Firmicutes/genetics ; Gastrointestinal Microbiome/genetics ; Humans ; Lipopolysaccharides ; Microbiota ; Peptidoglycan ; RNA, Ribosomal, 16S/genetics ; SARS-CoV-2
Chemical Substances	Lipopolysaccharides ; Peptidoglycan ; RNA, Ribosomal, 16S
Language	English
Publishing date	2022-08-15
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23169141
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Article: Enforcing realizability in explicit multi-component species transport.

McDermott, Randall J / Floyd, Jason E

Fire safety journal

2015 Volume 78, Page(s) 180–187

Abstract	We propose a strategy to guarantee realizability of species mass fractions in explicit time integration of the partial differential equations governing fire dynamics, which is a multi-component transport problem (realizability requires all mass fractions are greater than or equal to zero and that the sum equals unity). For a mixture of
Language	English
Publishing date	2015-02-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1483569-1
ISSN	0379-7112
ISSN	0379-7112
DOI	10.1016/j.firesaf.2015.09.005
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Article ; Online: Circulating SARS-CoV-2+ megakaryocytes are associated with severe viral infection in COVID-19.

Blood advances

2023 Volume 7, Issue 15, Page(s) 4200–4214

Abstract: Several independent lines of evidence suggest that megakaryocytes are dysfunctional in severe COVID-19. Herein, we characterized peripheral circulating megakaryocytes in a large cohort of inpatients with COVID-19 and correlated the subpopulation ... ...

Abstract	Several independent lines of evidence suggest that megakaryocytes are dysfunctional in severe COVID-19. Herein, we characterized peripheral circulating megakaryocytes in a large cohort of inpatients with COVID-19 and correlated the subpopulation frequencies with clinical outcomes. Using peripheral blood, we show that megakaryocytes are increased in the systemic circulation in COVID-19, and we identify and validate S100A8/A9 as a defining marker of megakaryocyte dysfunction. We further reveal a subpopulation of S100A8/A9+ megakaryocytes that contain severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protein and RNA. Using flow cytometry of peripheral blood and in vitro studies on SARS-CoV-2-infected primary human megakaryocytes, we demonstrate that megakaryocytes can transfer viral antigens to emerging platelets. Mechanistically, we show that SARS-CoV-2-containing megakaryocytes are nuclear factor κB (NF-κB)-activated, via p65 and p52; express the NF-κB-mediated cytokines interleukin-6 (IL-6) and IL-1β; and display high surface expression of Toll-like receptor 2 (TLR2) and TLR4, canonical drivers of NF-κB. In a cohort of 218 inpatients with COVID-19, we correlate frequencies of megakaryocyte subpopulations with clinical outcomes and show that SARS-CoV-2-containing megakaryocytes are a strong risk factor for mortality and multiorgan injury, including respiratory failure, mechanical ventilation, acute kidney injury, thrombotic events, and intensive care unit admission. Furthermore, we show that SARS-CoV-2+ megakaryocytes are present in lung and brain autopsy tissues from deceased donors who had COVID-19. To our knowledge, this study offers the first evidence implicating SARS-CoV-2+ peripheral megakaryocytes in severe disease and suggests that circulating megakaryocytes warrant investigation in inflammatory disorders beyond COVID-19.
MeSH term(s)	Humans ; COVID-19 ; SARS-CoV-2 ; Megakaryocytes/metabolism ; NF-kappa B/metabolism ; Lung/metabolism
Chemical Substances	NF-kappa B
Language	English
Publishing date	2023-03-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2022009022
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