Role of arginase 2 in systemic metabolic activity and adipose tissue fatty acid metabolism in diet-induced obese mice

Visceral adipose tissue (VAT) inflammation and metabolic dysregulation are key components of obesity-induced metabolic disease. Upregulated arginase, a ureahydrolase enzyme with two isoforms (A1-cytosolic and A2-mitochondrial), is implicated in pathologies associated with obesity and diabetes. This study examined A2 involvement in obesity-associated metabolic and vascular disorders. WT and globally deleted A2(−/−) or A1(+/−) mice were fed either a high fat/high sucrose (HFHS) diet or normal diet (ND) for 16 weeks. Increases in body and VAT weight of HFHS-fed WT mice were abrogated in A2−/−, but not A1+/−, mice. Additionally, A2−/− HFHS-fed mice exhibited higher energy expenditure, lower blood glucose, and insulin levels compared to WT HFHS mice. VAT and adipocytes from WT HFHS fed mice showed greater A2 expression and adipocyte size and reduced expression of PGC-1α, PPAR-γ, and adiponectin. A2 deletion blunted these effects, increased levels of active AMPK-α, and upregulated genes involved in fatty acid metabolism. A2 deletion prevented HFHS-induced VAT collagen deposition and inflammation, which are involved in adipocyte metabolic dysfunction. Endothelium-dependent vasorelaxation, impaired by HFHS diet, was significantly preserved in A2−/− mice, but more prominently maintained in A1+/− mice. In summary, A2 is critically involved in HFHS-induced VAT inflammation and metabolic dysfunction

COMPUTER SIMULATION OF OVERTOPPING OF LEVEES

There have been many cases of earth embankment failures, for example, Hurricane Katrina in 2005, where breaching occurred and devastated the surrounding population. Levee failures are preventable by a better understanding of the ways in which these embankments are designed and fail. The objective of this research is to protect levees against future failures. This paper studies various overtopping quantities and durations to represent the same level of levee erosion hazard. This study is based on experimental results of steady flows on the land side of a levee. The effect of water flow has been investigated and a comparison has been done between rills formations and erosion time for various water flows. Results showed that the pictures of digital simulations and real photographs which have been taken during tests in the laboratory are in a good concordance. Ha habido muchos casos de fallos de terraplén, por ejemplo, el huracán Katrina en 2005, en el cual se produjo una ruptura, devastando la población de los alrededores. Las fallas de diques se pueden prevenir, y es un objetivo de esta investigación alcanzar una mejor comprensión de las maneras en que estos diques se diseñan y fallan, a fin de poder protegerlos contra futuros fallos. Este documento desarrolla y recomienda equivalencias preliminares de combinaciones acumulativas de varias cantidades de desbordamiento y las duraciones asociadas que representan el mismo nivel de riesgo de erosión del dique. Las metodologías se basan en los resultados experimentales de flujos constantes en el lado seco de un dique. El efecto del flujo de agua se ha estudiado específicamente en esta investigación, y se ha hecho una comparación entre las formaciones de surcos y el tiempo de erosión para distintos flujos de agua

Simulating Levee Erosion with Physical Modeling Validation

This paper studies rill and gully initiation and propagation on levees, dams, and general earth embankments. It specifically studies where these erosion features occur, and how long a particular embankment can sustain overtopping before breaching and catastrophic failure. This contrasts to previous levee erosion analysis, which has primarily concerned the final effects of erosion, such as soil loss, depth of scour and breach width. This paper describes the construction of scaled-down physical models of levees composed of different homogeneous sands, as well as sand-clay mixtures, and their laboratory testing. A 3-D laser range scanner captured the surface features of the physical model, before and after erosion. The resulting data is utilized in developing digital simulations of the rill erosion process. Those simulations combine 3-D Navier-Stokes fluid simulations and a segmented height field data structure to produce an accurate portrayal of the erosive processes, which will be validated by physical modeling

Measuring terrain distances through extracted channel networks

This paper initiates a forensic analysis of the causes of levee failures by analyzing and extracting information from a sequence of elevation data. This is a crucial step in bettering the design and construction of levees and dams. (Fully diagnosing failures usually requires knowledge beyond the geometry of the levee, such as weather conditions and material properties). We use results from computer simulations of levee overtopping for training data. The simulations use smoothed particle hydrodynamics coupled with a well-known erodibility model. Using the sequential nature of our data, we extract important channel networks that form as the soil is scoured away. We present a series of metrics to measure the distance between channel networks to assist in determining the critical threshold value used to extract important channels from the flow network. Methods for determining this ideal threshold have gone mainly unexplored, and so we present a comparison of various threshold values and how closely they identify matching channel networks on sequential terrains. These threshold values allow us to identify important properties of the terrain that form its fingerprint, a way of characterizing the geometry of the terrain. Our method for fingerprinting terrain is an important step toward the diagnosis of levee failure from digital elevation data

Quantitative analysis of simulated erosion for different soils

Levee overtopping can lead to failure and cause catastrophic damage, as was the case during Hurricane Katrina. We present a computer simulation of erosion to study the development of the rills and gullies that form along an earthen embankment during overtopping. We have coupled 3D Smoothed Particle Hydrodynamics with an erodibility model to produce our simulation. Through comparison between simulations and between simulation and analogous laboratory experiments, we provide quantitative and qualitative results, evaluating the accuracy of our simulation

Should Attendance Be Required in Lecture Classrooms in Dental Education? Two Viewpoints

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153624/1/jddj0022033720168012tb06236x.pd

Allogeneic Hematopoietic Cell Transplantation Improves Outcome in Myelodysplastic Syndrome Across High-Risk Genetic Subgroups:Genetic Analysis of the Blood and Marrow Transplant Clinical Trials Network 1102 Study

PURPOSE:Allogeneic hematopoietic cell transplantation (HCT) in patients with myelodysplastic syndrome (MDS) improves overall survival (OS). We evaluated the impact of MDS genetics on the benefit of HCT in a biological assignment (donor v no donor) study.METHODS:We performed targeted sequencing in 309 patients age 50-75 years with International Prognostic Scoring System (IPSS) intermediate-2 or high-risk MDS, enrolled in the Blood and Marrow Transplant Clinical Trials Network 1102 study and assessed the association of gene mutations with OS. Patients with TP53 mutations were classified as TP53multihit if two alleles were altered (via point mutation, deletion, or copy-neutral loss of heterozygosity).RESULTS:The distribution of gene mutations was similar in the donor and no donor arms, with TP53 (28% v 29%; P =.89), ASXL1 (23% v 29%; P =.37), and SRSF2 (16% v 16%; P =.99) being most common. OS in patients with a TP53 mutation was worse compared with patients without TP53 mutation (21% ± 5% [SE] v 52% ± 4% at 3 years; P &lt;.001). Among those with a TP53 mutation, OS was similar between TP53single versus TP53multihit (22% ± 8% v 20% ± 6% at 3 years; P =.31). Considering HCT as a time-dependent covariate, patients with a TP53 mutation who underwent HCT had improved OS compared with non-HCT treatment (OS at 3 years: 23% ± 7% v 11% ± 7%; P =.04), associated with a hazard ratio of 3.89; 95% CI, 1.87 to 8.12; P &lt;.001 after adjustment for covariates. OS among patients with molecular IPSS (IPSS-M) very high risk without a TP53 mutation was significantly improved if they had a donor (68% ± 10% v 0% ± 12% at 3 years; P =.001).CONCLUSION:HCT improved OS compared with non-HCT treatment in patients with TP53 mutations irrespective of TP53 allelic status. Patients with IPSS-M very high risk without a TP53 mutation had favorable outcomes when a donor was available.</p

Metabolic reprogramming through mitochondrial biogenesis drives adenosine anti-inflammatory effects: new mechanism controlling gingival fibroblast hyper-inflammatory state

IntroductionFibroblasts are the dominant stromal cells in the gingival lamina propria with a well-established relevance in regulation of inflammation, and in innate immunity. This is exemplified by their hypersecretion of CXCL8, enhancing leukocyte infiltration in chronic and sustained inflammatory conditions. We have previously shown adenosine to be a key metabolic nucleoside that regulates stromal inflammation, but the underlying mechanisms linking adenosine to the metabolic status of fibroblasts and to the resultant inflammatory response are unclear. This study examined, by seahorse real-time cell metabolic analysis, the bioenergetics of the stromal fibroblast response to extracellular adenosine and IL-1β, focusing on CXCL8 secretion by primary human gingival fibroblasts (HGF).MethodsMarkers of the glycolytic pathway and mitochondrial biogenesis were tracked through immunoblot. Further, the influence of adenosine on mitochondrial accumulation was measured by uptake of MitoTracker Red fluorescent probe and assessment of the role of FCCP (a mitochondrial uncoupler) in CXCL8 secretion and mitochondrial accumulation. ResultsOur results show that the anti-inflammatory response of HGF to extracellular adenosine, typified by reduced CXCL8 secretion, is mediated by mitochondrial oxidative phosphorylation, reflected in higher oxygen consumption rate (OCR). In the presence of IL-1β, adenosine-treated cells induced higher ATP production, basal respiration and proton leak compared to IL-1β without adenosine. Surprisingly, adenosine had no additional effect on the IL-1β-induced higher glycolysis rate demonstrated by the extracellular acidification rate (ECAR). In addition, the higher OCR in adenosine-stimulated cells was not due to the mitochondrial fuel dependency or capacity, but due to an increase in mitochondrial biogenesis and accumulation in the cells with concomitant decrease in mitophagy-required p-PINK1 marker. We detected the accumulation of functional mitochondria with increased activation of the AMPK/SIRT1/PGC-1α pathway. The adenosine-induced uptake of MitoTracker was abrogated by PGC-1α inhibition with SR-12898. In addition, the adenosine effects on reduced CXCL8 were ablated by treatment with FCCP, a potent uncoupler of mitochondrial oxidative phosphorylation.ConclusionOur findings reveal a key role for mitochondrial bioenergetics in regulation of CXCL8-mediated inflammation by HGF through the adenosine/AMPK/SIRT1/PGC-1α axis. Therapeutically targeting this pathway in gingival fibroblasts might be a promising future strategy to modulate stromal-mediated sustained hyper-inflammatory responses