NLRP3 Inflammasome Mediates Immune-Stromal Interactions in Vasculitis

Rationale: NLRP3 (NLR family pyrin domain containing 3) activation and IL-1β (interleukin-1β) production are implicated in Kawasaki disease (KD) pathogenesis; however, a detailed and complete characterization of the molecular networks and cellular subsets involved in the development of cardiovascular lesions is still lacking. Objective: Here, in a murine model of KD vasculitis, we used single-cell RNA sequencing and spatial transcriptomics to determine the cellular landscape of inflamed vascular tissues. Methods and Results: We observe infiltrations of innate and adaptive immune cells in murine KD cardiovascular lesions, associated with increased expression of Nlrp3 and Il1b . Monocytes, macrophages, and dendritic cells were the main sources of IL-1β, whereas fibroblasts and vascular smooth muscle cells (VSMCs) expressed high levels of IL-1 receptor. VSMCs type 1 surrounding the inflamed coronary artery undergo a phenotype switch to become VSMCs type 2, which are characterized by gene expression changes associated with decreased contraction and enhanced migration and proliferation. Genetic inhibition of IL-1β signaling on VSMCs efficiently attenuated the VSMCs type 2 phenotypic switch and the development of cardiovascular lesions during murine KD vasculitis. In addition, pharmacological inhibition of NLRP3 prevented the development of cardiovascular inflammation. Conclusions: Our studies unravel the cellular diversity involved in IL-1β production and signaling in murine KD cardiovascular lesions and provide the rationale for therapeutic strategies targeting NLRP3 to inhibit cardiovascular lesions associated with KD.

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Characterization of damage and biotic factors associated with the decline of Eucalyptus wandoo in southwest Western Australia

Canadian Journal of Forest Research ◽

10.1139/x05-162 ◽

2005 ◽

Vol 35 (11) ◽

pp. 2589-2602 ◽

Cited By ~ 16

Author(s):

Ryan J Hooper ◽

K Sivasithamparam

Keyword(s):

Western Australia ◽

Partial Harvest ◽

Foliage Density ◽

Density Ratios ◽

The Relationship ◽

Mixed Age ◽

Eucalyptus Wandoo

Crown decline of wandoo, Eucalyptus wandoo, in southwest Western Australia has escalated over the last 10 years, so very few unaffected stands remain. To assess the canopy-damage characteristics of trees in decline a destructive, partial-harvest method was used to sample branches in natural mixed-age stands. Necrosis of common cankers was closely associated with type-1 borer damage, characterized by "longitudinal" gallery structure on declining trees only. Cankers were found to be consistently more severe on declining trees, with decay regions affecting a greater proportion of sapwood tissue. Several infestations causing type-1 borer damage that varied in age were found on declining branches, providing evidence of cyclical damage events. Type-2 borer damage characterized by "ring-barking" gallery structure caused extensive damage in canopies, but was not always associated with decline. Interactions between foliage density and canker score showed that 17.8% and 63.1% of the variability in foliage-density ratios was accounted for in declining intermediate-health and unhealthy classes, respectively. The relationship was negligible for the healthy class (9.9%), providing strong evidence that cankers are causing foliage loss in declining canopies. Evidence suggests that an interaction between type-1 borer infestations and decay-causing fungi is responsible for the decline in E. wandoo wandoo canopies.

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Adaptive immune cells shape obesity-associated type 2 diabetes mellitus and less prominent comorbidities

Nature Reviews Endocrinology ◽

10.1038/s41574-021-00575-1 ◽

2021 ◽

Author(s):

Sara SantaCruz-Calvo ◽

Leena Bharath ◽

Gabriella Pugh ◽

Lucia SantaCruz-Calvo ◽

Raji Rajesh Lenin ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Immune Cells ◽

Adaptive Immune ◽

Adaptive Immune Cells

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The Blue Copper-Containing Nitrite Reductase fromAlcaligenes xylosoxidans: Cloning of the nirAGene and Characterization of the Recombinant Enzyme

Journal of Bacteriology ◽

10.1128/jb.181.8.2323-2329.1999 ◽

1999 ◽

Vol 181 (8) ◽

pp. 2323-2329 ◽

Cited By ~ 25

Author(s):

Miguel Prudêncio ◽

Robert R. Eady ◽

Gary Sawers

Keyword(s):

Amino Acid ◽

Nitrite Reductase ◽

Recombinant Enzyme ◽

Leader Peptide ◽

Resonance Spectroscopy ◽

Gene Encoding ◽

Blue Copper

ABSTRACT The nirA gene encoding the blue dissimilatory nitrite reductase from Alcaligenes xylosoxidans has been cloned and sequenced. To our knowledge, this is the first report of the characterization of a gene encoding a blue copper-containing nitrite reductase. The deduced amino acid sequence exhibits a high degree of similarity to other copper-containing nitrite reductases from various bacterial sources. The full-length protein included a 24-amino-acid leader peptide. The nirA gene was overexpressed inEscherichia coli and was shown to be exported to the periplasm. Purification was achieved in a single step, and analysis of the recombinant Nir enzyme revealed that cleavage of the signal peptide occurred at a position identical to that for the native enzyme isolated from A. xylosoxidans. The recombinant Nir isolated directly was blue and trimeric and, on the basis of electron paramagnetic resonance spectroscopy and metal analysis, possessed only type 1 copper centers. This type 2-depleted enzyme preparation also had a low nitrite reductase enzyme activity. Incubation of the periplasmic fraction with copper sulfate prior to purification resulted in the isolation of an enzyme with a full complement of type 1 and type 2 copper centers and a high specific activity. The kinetic properties of the recombinant enzyme were indistinguishable from those of the native nitrite reductase isolated from A. xylosoxidans. This rapid isolation procedure will greatly facilitate genetic and biochemical characterization of both wild-type and mutant derivatives of this protein.

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Genetic Risk Scores for Diabetes Diagnosis and Precision Medicine

Endocrine Reviews ◽

10.1210/er.2019-00088 ◽

2019 ◽

Vol 40 (6) ◽

pp. 1500-1520 ◽

Cited By ~ 34

Author(s):

Miriam S Udler ◽

Mark I McCarthy ◽

Jose C Florez ◽

Anubha Mahajan

Keyword(s):

Risk Scores ◽

Diabetes Diagnosis ◽

Physiological Mechanisms ◽

Risk Variants ◽

Polygenic Scores ◽

Disease Predisposition ◽

Dna Sequence Variants

Abstract During the last decade, there have been substantial advances in the identification and characterization of DNA sequence variants associated with individual predisposition to type 1 and type 2 diabetes. As well as providing insights into the molecular, cellular, and physiological mechanisms involved in disease pathogenesis, these risk variants, when combined into a polygenic score, capture information on individual patterns of disease predisposition that have the potential to influence clinical management. In this review, we describe the various opportunities that polygenic scores provide: to predict diabetes risk, to support differential diagnosis, and to understand phenotypic and clinical heterogeneity. We also describe the challenges that will need to be overcome if this potential is to be fully realized.

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The TUDID Study – Background and Design of a Prospective Cohort

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/a-1221-9618 ◽

2020 ◽

Author(s):

Benjamin Assad Jaghutriz ◽

Robert Wagner ◽

Stephanie Kullmann ◽

Louise Fritsche ◽

Sabine S. Eckstein ◽

...

Keyword(s):

Diabetes Mellitus ◽

Laboratory Tests ◽

Diabetes Complications ◽

Treatment Options ◽

University Hospital ◽

Tailored Treatment ◽

The Individual

AbstractPrevalence of both type 1 and type 2 diabetes mellitus is growing worldwide and one major cause for morbidity and mortality. However, not every patient develops diabetes-related complications, but causes for the individual susceptibility are still not fully understood. As a platform to address this, we initiated the TUDID (TUebingen DIabetes Database) study, a prospective, monocentric, observational study that includes adults with diabetes mellitus who are treated in the inpatient clinic of a University Hospital in southern Germany. Besides a thorough clinical examination and extensive laboratory tests (with integrated biobanking), major study focuses are the kidneys, the eyes, the vasculature as well as cognition and mood where standardized investigations for early stages for diabetes complications are performed. Analyses of the data generated by this precise characterization of diabetes-related complications will contribute to our understanding of the development and course of such complications, and thus facilitate the implementation of tailored treatment options that can reduce the risk and severity of diabetes-related complications.

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A Combinatorial Approach for Small and Strong Formulations of Disjunctive Constraints

Mathematics of Operations Research ◽

10.1287/moor.2018.0946 ◽

2019 ◽

Vol 44 (3) ◽

pp. 793-820 ◽

Cited By ~ 2

Author(s):

Joey Huchette ◽

Juan Pablo Vielma

Keyword(s):

Piecewise Linear ◽

Expressive Power ◽

Complete Characterization ◽

Linear Functions ◽

Mixed Integer ◽

Ordered Sets ◽

Special Ordered Sets ◽

Disjunctive Constraints

A framework is presented for constructing strong mixed-integer programming formulations for logical disjunctive constraints. This approach is a generalization of the logarithmically sized formulations of Vielma and Nemhauser for special ordered sets of type 2 (SOS2) constraints, and a complete characterization of its expressive power is offered. The framework is applied to a variety of disjunctive constraints, producing novel small and strong formulations for outer approximations of multilinear terms, generalizations of special ordered sets, piecewise linear functions over a variety of domains, and obstacle avoidance constraints.

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Characterization of cDNAs encoding isoforms of hamster 3 beta-hydroxysteroid dehydrogenase/delta 5-->4 isomerase

Journal of Molecular Endocrinology ◽

10.1677/jme.0.0200099 ◽

1998 ◽

Vol 20 (1) ◽

pp. 99-110 ◽

Cited By ~ 9

Author(s):

FM Rogerson ◽

J Courtemanche ◽

A Fleury ◽

JG LeHoux ◽

JI Mason ◽

...

Keyword(s):

Hydroxysteroid Dehydrogenase ◽

Cdna Libraries ◽

Sexually Dimorphic ◽

High Affinity ◽

Liver And Kidney ◽

Low Levels ◽

Type 3

Western blot analyses of various hamster tissues reveal high levels of expression of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) in adrenal and liver, and moderate levels of expression in kidney. The expression in liver is sexually dimorphic; very high levels of protein are observed in adult male liver but very low levels are seen in the female liver. Three distinct cDNAs encoding isoforms of 3 beta-HSD were isolated from hamster cDNA libraries. The type 1 isoform is a high-affinity dehydrogenase/isomerase expressed in adrenal and male kidney. The type 2 isoform is also a high-affinity dehydrogenase/isomerase expressed in kidney and male liver. The type 3 enzyme is a 3-ketosteroid reductase expressed predominantly in kidney. Sequencing of the clones showed that all three are structurally very similar, although types 1 and 2 share the greatest degree of similarity. Immunohistochemical staining for 3 beta-HSD in the adrenal was found throughout the adrenal cortex. In the kidney staining was confined to tubules, and in the liver, heavy staining was found in hepatocytes. The cloning of cDNAs for 3 beta-HSD from the liver and kidney should help in elucidating the function of this enzyme in these tissues.

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The Innate Immune Responses of Colonic Epithelial Cells to Trichuris muris Are Similar in Mouse Strains That Develop a Type 1 or Type 2 Adaptive Immune Response

Infection and Immunity ◽

10.1128/iai.01609-05 ◽

2006 ◽

Vol 74 (11) ◽

pp. 6280-6286 ◽

Cited By ~ 20

Author(s):

Matthew L. deSchoolmeester ◽

Harinder Manku ◽

Kathryn J. Else

Keyword(s):

Immune Response ◽

Epithelial Cells ◽

Immune Responses ◽

Adaptive Immune Response ◽

Subsequent Development ◽

Trichuris Muris ◽

Adaptive Immune ◽

Ifn Γ

ABSTRACT Trichuris muris resides in intimate contact with its host, burrowing within cecal epithelial cells. However, whether the enterocyte itself responds innately to T. muris is unknown. This study investigated for the first time whether colonic intestinal epithelial cells (IEC) produce cytokines or chemokines following T. muris infection and whether divergence of the innate response could explain differentially polarized adaptive immune responses in resistant and susceptible mice. Increased expression of mRNA for the proinflammatory cytokines gamma interferon (IFN-γ) and tumor necrosis factor and the chemokine CCL2 (MCP-1) were seen after infection of susceptible and resistant strains, with the only difference in expression being a delayed increase in CCL2 in BALB/c IEC. These increases were ablated in MyD88−/− mice, and NF-κB p65 was phosphorylated in response to T. muris excretory/secretory products in the epithelial cell line CMT-93, suggesting involvement of the MyD88-NF-κB signaling pathway in IEC cytokine expression. These data reveal that IEC respond innately to T. muris. However, the minor differences identified between resistant and susceptible mice are unlikely to underlie the subsequent development of a susceptible type 1 (IFN-γ-dominated) or resistant type 2 (interleukin-4 [IL-4]/IL-13-dominated) adaptive immune response.

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