In Vivo Targeting Of Inflammation-Associated Myeloid-Related Protein 8/14 Via Gadolinium Immunonanoparticles

Moving queries over mobile objects are an important type of query in moving object database systems. In recent years, there have been quite a few works in this area. Due to the high frequency in location updates and the expensive cost of continuous query processing, server computation capacity and wireless communication bandwidth are the two limiting factors for large-scale deployment of moving object database systems. Many techniques have been proposed to address the server bottleneck including one using distributed servers. To address both scalability factors, distributed query processing techniques have been considered. These schemes enable moving objects to participate in query processing to substantially reduce the demand on server computation, and wireless communications associated with location updates. Most of these techniques, however, assume an open-space environment. Since Euclidean distance is different from network distance, techniques designed specifically for an open space cannot be easily adapted for a spatial network. In this paper, we present a distributed framework which can answer moving query over moving objects in a spatial network. To illustrate the effectiveness of the proposed framework, we study two representative moving queries, namely, moving range queries and moving k-nearest-neighbor queries. Detailed algorithms and communication mechanisms are presented. The simulation studies indicate that the proposed technique can significantly reduce server workload and wireless communication cost. © Springer Science+Business Media, LLC 2011

Visceral adipose inflammation in obesity is associated with critical alterations in tregulatory cell numbers.

The development of insulin resistance (IR) in mouse models of obesity and type 2 diabetes mellitus (DM) is characterized by progressive accumulation of inflammatory macrophages and subpopulations of T cells in the visceral adipose. Regulatory T cells (Tregs) may play a critical role in modulating tissue inflammation via their interactions with both adaptive and innate immune mechanisms. We hypothesized that an imbalance in Tregs is a critical determinant of adipose inflammation and investigated the role of Tregs in IR/obesity through coordinated studies in mice and humans.Foxp3-green fluorescent protein (GFP) "knock-in" mice were randomized to a high-fat diet intervention for a duration of 12 weeks to induce DIO/IR. Morbidly obese humans without overt type 2 DM (n = 13) and lean controls (n = 7) were recruited prospectively for assessment of visceral adipose inflammation. DIO resulted in increased CD3(+)CD4(+), and CD3(+)CD8(+) cells in visceral adipose with a striking decrease in visceral adipose Tregs. Treg numbers in visceral adipose inversely correlated with CD11b(+)CD11c(+) adipose tissue macrophages (ATMs). Splenic Treg numbers were increased with up-regulation of homing receptors CXCR3 and CCR7 and marker of activation CD44. In-vitro differentiation assays showed an inhibition of Treg differentiation in response to conditioned media from inflammatory macrophages. Human visceral adipose in morbid obesity was characterized by an increase in CD11c(+) ATMs and a decrease in foxp3 expression.Our experiments indicate that obesity in mice and humans results in adipose Treg depletion. These changes appear to occur via reduced local differentiation rather than impaired homing. Our findings implicate a role for Tregs as determinants of adipose inflammation

Visceral Adipose MicroRNA 223 Is Upregulated in Human and Murine Obesity and Modulates the Inflammatory Phenotype of Macrophages

<div><p>Obesity in humans and mice is typified by an activated macrophage phenotype in the visceral adipose tissue (VAT) leading to increased macrophage-mediated inflammation. microRNAs (miRNAs) play an important role in regulating inflammatory pathways in macrophages, and in this study we compared miRNA expression in the VAT of insulin resistant morbidly obese humans to a non-obese cohort with normal glucose tolerance. miR-223-3p was found to be significantly upregulated in the whole omental tissue RNA of 12 human subjects, as were 8 additional miRNAs. We then confirmed that miR-223 upregulation was specific to the stromal vascular cells of human VAT, and found that miR-223 levels were unchanged in adipocytes and circulating monocytes of the non-obese and obese. miR-223 ablation increased basal / unstimulated TLR4 and STAT3 expression and LPS-stimulated TLR4, STAT3, and NOS2 expression in primary macrophages. Conversely, miR-223 mimics decreased TLR4 expression in primary macrophage, at the same time it negatively regulated FBXW7 expression, a well described suppressor of Toll-like receptor 4 (TLR4) signaling. We concluded that the abundance of miR-223 in macrophages significantly modulates macrophage phenotype / activation state and response to stimuli via effects on the TLR4/FBXW7 axis.</p></div

Effects of a Novel Pharmacologic Inhibitor of Myeloperoxidase in a Mouse Atherosclerosis Model

<div><p>Inflammation and oxidative stress play fundamental roles in the pathogenesis of atherosclerosis. Myeloperoxidase has been extensively implicated as a key mediator of inflammatory and redox-dependent processes in atherosclerosis. However, the effect of synthetic myeloperoxidase inhibitors on atherosclerosis has been insufficiently studied. In this study, ApoE^−/− mice were randomized to low- and high-dose INV-315 groups for 16 weeks on high-fat diet. INV-315 resulted in reduced plaque burden and improved endothelial function in response to acetylcholine. These effects occurred without adverse events or changes in body weight or blood pressure. INV-315 treatment resulted in a decrease in iNOS gene expression, superoxide production and nitrotyrosine content in the aorta. Circulating IL-6 and inflammatory CD11b⁺/Ly6G^low/7/4^hi monocytes were significantly decreased in response to INV-315 treatment. Acute pretreatment with INV-315 blocked TNFα-mediated leukocyte adhesion in cremasteric venules and inhibited myeloperoxidase activity. Cholesterol efflux was significantly increased by high-dose INV-315 via ex-vivo reverse cholesterol transport assays. Our results suggest that myeloperoxidase inhibition may exert anti-atherosclerotic effects via inhibition of oxidative stress and enhancement of cholesterol efflux. These findings demonstrate a role for pharmacologic modulation of myeloperoxidase in atherosclerosis.</p> </div

miR-223 mimic reduces TLR4 expression in macrophages stimulated with LPS.

<p>(A) WT BMM have about 21,000-fold greater expression of miR-223 by TaqMan probe-based qPCR compared to miR223KO BMMs. (B) miR223KO BMMs electroporated with miR-223 mimic at 500nM have approximately 290,000-fold higher expression than miR223KO BMMs electroporated in the presence of 500nM of mimic control oligo. (C) qPCR of total cDNA (RNA used in B) shows that the miR-223 mimic (“mimic”) significantly decreases mTLR4 and mFBXW7 (pan-detecting primer) in the presence of LPS, compared to BMM not receiving miR-223 mimic (“Ctrl,” control oligo) relative to beta-2 microglobulin (B2M).</p

Cohort 1—Patient Characteristics—MicroRNA Arrays.

<p>Cohort 1—Patient Characteristics—MicroRNA Arrays.</p

Pathway analysis of miR-223 gene targets using IPA^® software by Ingenuity Systems (Qiagen).

<p>KEGG Canonical pathways are labeled (CP). All targets are depicted by the official gene symbol and function of protein product can be found in legend. Genes symbols are: ADIPOQ, Adiponectin; PIK3C2A, phosphoinositide-3-kinase (PI3K), class 2, alpha polypeptide; IRS1, insulin receptor substrate 1; INSR, insulin receptor; PDPK1, 3-phosphoinositide dependent protein kinase-1; RPS6KB1, ribosomal protein S6 kinase, 70kDa, polypeptide 1; PRKACB, protein kinase A, cAMP-dependent, catalytic, beta.</p