While Asian Americans and Pacific Islanders (AAPIs) are growing faster than any other racial group in the United States, they are all but invisible in higher education, and generally ignored in the ...research literature, and thus greatly misrepresented and misunderstood.
This book presents disaggregated data to unmask important academic achievement and other disparities within the population, and offers new insights that promote more authentic understandings of the realities masked by the designation of AAPI. In offering new perspectives, conceptual frameworks, and empirical research by seasoned and emerging scholars, this book both makes a significant contribution to the emerging knowledge base on AAPIs, and identifies new directions for future scholarship on this population.
Its overarching purpose is to provide policymakers, practitioners, and researchers in higher education with the information they need to serve an increasingly important segment of their student populations.
The inflammatory nature of atherosclerosis is well established but the agent(s) that incite inflammation in the artery wall remain largely unknown. Germ-free animals are susceptible to ...atherosclerosis, suggesting that endogenous substances initiate the inflammation. Mature atherosclerotic lesions contain macroscopic deposits of cholesterol crystals in the necrotic core, but their appearance late in atherogenesis had been thought to disqualify them as primary inflammatory stimuli. However, using a new microscopic technique, we revealed that minute cholesterol crystals are present in early diet-induced atherosclerotic lesions and that their appearance in mice coincides with the first appearance of inflammatory cells. Other crystalline substances can induce inflammation by stimulating the caspase-1-activating NLRP3 (NALP3 or cryopyrin) inflammasome, which results in cleavage and secretion of interleukin (IL)-1 family cytokines. Here we show that cholesterol crystals activate the NLRP3 inflammasome in phagocytes in vitro in a process that involves phagolysosomal damage. Similarly, when injected intraperitoneally, cholesterol crystals induce acute inflammation, which is impaired in mice deficient in components of the NLRP3 inflammasome, cathepsin B, cathepsin L or IL-1 molecules. Moreover, when mice deficient in low-density lipoprotein receptor (LDLR) were bone-marrow transplanted with NLRP3-deficient, ASC (also known as PYCARD)-deficient or IL-1 / -deficient bone marrow and fed on a high-cholesterol diet, they had markedly decreased early atherosclerosis and inflammasome-dependent IL-18 levels. Minimally modified LDL can lead to cholesterol crystallization concomitant with NLRP3 inflammasome priming and activation in macrophages. Although there is the possibility that oxidized LDL activates the NLRP3 inflammasome in vivo, our results demonstrate that crystalline cholesterol acts as an endogenous danger signal and its deposition in arteries or elsewhere is an early cause rather than a late consequence of inflammation. These findings provide new insights into the pathogenesis of atherosclerosis and indicate new potential molecular targets for the therapy of this disease.
OBJECTIVE—CSL112 (apolipoprotein A-I apoA-I; human) is a novel formulation of apoA-I in development for reduction of early recurrent cardiovascular events after acute myocardial infarction. ...Cholesterol efflux capacity (CEC) is a marker of high-density lipoprotein (HDL) function that is strongly correlated with incident cardiovascular disease. Impaired CEC has been observed in patients with coronary heart disease. Here, we determined whether infused apoA-I improves CEC when administered to patients with stable atherosclerotic disease versus healthy volunteers.
APPROACH AND RESULTS—Measurements of apoA-I, HDL unesterified cholesterol, HDL esterified cholesterol, pre–β1-HDL, and CEC were determined in samples from patients with stable atherosclerotic disease before and after intravenous administration of CSL112. These measures were compared with 2 prior studies in healthy volunteers for differences in CEC at baseline and after CSL112 infusion. Patients with stable atherosclerotic disease exhibited significantly lower ATP-binding cassette transporter 1–mediated CEC at baseline (P<0.0001) despite slightly higher apoA-I levels when compared with healthy individuals (2 phase 1 studies pooled; P≤0.05), suggesting impaired HDL function. However, no differences were observed in apoA-I pharmacokinetics or in pre–β1-HDL (P=0.5) or CEC (P=0.1) after infusion of CSL112. Similar elevation in CEC was observed in patients with low or high baseline HDL function (based on tertiles of apoA-I–normalized CEC; P=0.1242). These observations were extended and confirmed using cholesterol esterification as an additional measure.
CONCLUSIONS—CSL112 shows comparable, strong, and immediate effects on CEC despite underlying cardiovascular disease. CSL112 is, therefore, a promising novel therapy for lowering the burden of atherosclerosis and reducing the risk of recurrent cardiovascular events.
OBJECTIVE—The ability of high-density lipoprotein (HDL) to remove cholesterol from atherosclerotic plaque is thought to underlie its inverse correlation with cardiovascular risk. Our objective was to ...produce and characterize a human apolipoprotein AI (apoA-I) product optimized to treat clinical atherosclerotic disease.
APPROACH AND RESULTS—A new formulation of full length, plasma-derived human apoA-I termed CSL112 was designed to maximize the cholesterol efflux from cells and exhibit favorable pharmacological properties. CSL112 is a disc-shaped particle that strongly elevates cholesterol esterification and shows good pharmacokinetics in rabbits. Infusion of CSL112 into rabbits caused a strong and immediate increase in the ATP binding cassette transporter A1 (ABCA1)-dependent efflux capacity of plasma, an increase in plasma unesterified cholesterol and rapid subsequent cholesterol esterification. In the presence of human plasma, CSL112 was significantly more potent than native HDL at enhancing cholesterol efflux from macrophages, and the efflux elevation was predominantly via the ABCA1 transporter. Consistent with this observation, addition of CSL112 to plasma led to generation of high levels of HDL-VS, a favorable substrate for ABCA1. The lipid profile of plasma did not affect these behaviors. In studies with whole human blood, CSL112 reduced expression of intercellular adhesion molecule 1 and cytokine secretion, and as with cholesterol efflux, these activities were substantially greater than those of native HDL assayed in parallel.
CONCLUSIONS—CSL112 has favorable pharmacological properties and strongly elevates the ability of plasma to withdraw cholesterol from cells. Preferential elevation of ABCA1-dependent efflux may target atherosclerotic plaque for cholesterol removal and this property makes CSL112 a promising candidate therapy for acute coronary syndrome.
OBJECTIVE—The ability of apolipoprotein A-I (apoA-I) to transport cholesterol from atherosclerotic plaque is thought to underlie its inverse correlation with cardiovascular risk. To gauge the ...potential of infused apoA-I to transport cholesterol, we quantified cholesterol transport markers in human subjects infused with a novel formulation of apoA-I (CSL112).
APPROACH AND RESULTS—CSL112 was infused into human subjects in single (57 subjects) and multiple (36 subjects) ascending dose trials. Pharmacokinetic and biomarker assessments were conducted before and after infusions. CSL112 caused an immediate, up to 3-fold elevation of apoA-I and subsequent movement of tissue cholesterol into plasma. Cholesterol appeared first as unesterified cholesterol in the high-density lipoprotein (HDL) fraction and was promptly esterified by lecithin cholesterol acyltransferase. HDL cholesterol increased up to 81±16.5%. Underlying this movement of cholesterol was an immediate and strong rise in the ability of plasma to promote cholesterol efflux from cells ex vivo. CSL112 had its greatest impact on the fraction of efflux mediated by ATP-binding cassette transporter A1 (ABCA1), a cholesterol transporter induced in cholesterol-loaded tissues such as plaque. ABCA1-dependent efflux capacity increased ≤630±421% and total efflux capacity by ≤192±40%. In keeping with this finding, we observed a profound rise in very small HDL, also known as preβ1-HDL, the preferred substrate for ABCA1. Very small HDL increased ≤3596±941%. Elevations in apoA-I, cholesterol efflux, and very small HDL were dose-proportional over a wide range. No significant changes in atherogenic lipids were observed at any dose.
CONCLUSIONS—Infusion of CSL112 elevates the ability of plasma to withdraw cholesterol from cells. Preferential elevation of ABCA1-dependent efflux may target atherosclerotic plaque for cholesterol removal, making CSL112 a promising candidate therapy for acute coronary syndrome.
Scavenger receptors constitute a large family of proteins that are structurally diverse and participate in a wide range of biological functions. These receptors are expressed predominantly by myeloid ...cells and recognize a diverse variety of ligands including endogenous and modified host-derived molecules and microbial pathogens. There are currently eight classes of scavenger receptors, many of which have multiple names, leading to inconsistencies and confusion in the literature. To address this problem, a workshop was organized by the United States National Institute of Allergy and Infectious Diseases, National Institutes of Health, to help develop a clear definition of scavenger receptors and a standardized nomenclature based on that definition. Fifteen experts in the scavenger receptor field attended the workshop and, after extensive discussion, reached a consensus regarding the definition of scavenger receptors and a proposed scavenger receptor nomenclature. Scavenger receptors were defined as cell surface receptors that typically bind multiple ligands and promote the removal of nonself or altered-self targets. They often function by mechanisms that include endocytosis, phagocytosis, adhesion, and signaling that ultimately lead to the elimination of degraded or harmful substances. Based on this definition, nomenclature and classification of these receptors into 10 classes were proposed. This classification was discussed at three national meetings and input from participants at these meetings was requested. The following manuscript is a consensus statement that combines the recommendations of the initial workshop and incorporates the input received from the participants at the three national meetings.
The increasing neoliberalization of institutions of higher education poses several challenges for racially minoritized faculty who advocate equity. Unfortunately, explorations of how neoliberalism ...shapes the realities of these faculty are sparse. This study analyzes some of the ways in which neoliberal systems and the resistance of racially minoritized faculty advocating equity conceptualize their own success in the academy. In-depth, face-to-face, individual interviews were conducted with 12 racially minoritized faculty members advocating equity at predominantly white institutions (PWIs) in the Rocky Mountain region. Findings reveal that these faculty conceptualize success as meeting neoliberal expectations defined by quantifiable metrics of productivity, fulfilling commitments to having a positive impact, and cultivating agency to express voice for positive change. Findings also illuminate how participants found themselves in precarious situations where they feel an overwhelming pressure to balance the neoliberal demands of the academy and their desire to make a broader and more meaningful impact. Implications for research and practice outline how stakeholders within institutions of higher education can support racially minoritized faculty members' success in the academy.
Heavy exercise or oxygen deficit often links with higher levels of arterial lactate and lower levels of plasma free fatty acids (FFA). Treatment with lactate reduces circulating levels of FFA
in vivo ...and lipolysis in adipose tissues
in vitro. However, the underlying mechanism has remained unclear. Here we employ pharmacological and genetic approaches to show that GPR81, an orphan G-protein-coupled receptor with relatively restricted expression in the adipose tissues, functions as a receptor for lactate and can mediate an anti-lipolytic effect of lactate. GPR81 may thus function as a sensor of lactate that can modulate the FFA pool under exercise or conditions of oxygen deficit.
Atherosclerosis is an inflammatory disease linked to elevated blood cholesterol concentrations. Despite ongoing advances in the prevention and treatment of atherosclerosis, cardiovascular disease ...remains the leading cause of death worldwide. Continuous retention of apolipoprotein B-containing lipoproteins in the subendothelial space causes a local overabundance of free cholesterol. Because cholesterol accumulation and deposition of cholesterol crystals (CCs) trigger a complex inflammatory response, we tested the efficacy of the cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin (CD), a compound that increases cholesterol solubility in preventing and reversing atherosclerosis. We showed that CD treatment of murine atherosclerosis reduced atherosclerotic plaque size and CC load and promoted plaque regression even with a continued cholesterol-rich diet. Mechanistically, CD increased oxysterol production in both macrophages and human atherosclerotic plaques and promoted liver X receptor (LXR)-mediated transcriptional reprogramming to improve cholesterol efflux and exert anti-inflammatory effects. In vivo, this CD-mediated LXR agonism was required for the antiatherosclerotic and anti-inflammatory effects of CD as well as for augmented reverse cholesterol transport. Because CD treatment in humans is safe and CD beneficially affects key mechanisms of atherogenesis, it may therefore be used clinically to prevent or treat human atherosclerosis.
Hepatic steatosis is a hallmark of non-alcoholic fatty liver disease (NAFLD), a common comorbidity in type 2 diabetes mellitus (T2DM). The pathogenesis of NAFLD is complex and involves the crosstalk ...between the liver and the white adipose tissue (WAT). Vascular endothelial growth factor B (VEGF-B) has been shown to control tissue lipid accumulation by regulating the transport properties of the vasculature. The role of VEGF-B signaling and the contribution to hepatic steatosis and NAFLD in T2DM is currently not understood.
C57BL/6 J mice treated with a neutralizing antibody against VEGF-B, or mice with adipocyte-specific overexpression or under-expression of VEGF-B (AdipoqCre+/VEGF-BTG/+ mice and AdipoqCre+/Vegfbfl/+mice) were subjected to a 6-month high-fat diet (HFD), or chow-diet, whereafter NAFLD development was assessed. VEGF-B expression was analysed in WAT biopsies from patients with obesity and NAFLD in a pre-existing clinical cohort (n = 24 patients with NAFLD and n = 24 without NAFLD) and correlated to clinicopathological features.
Pharmacological inhibition of VEGF-B signaling in diabetic mice reduced hepatic steatosis and NAFLD by blocking WAT lipolysis. Mechanistically we show, by using HFD-fed AdipoqCre+/VEGF-BTG/+ mice and HFD-fed AdipoqCre+/Vegfbfl/+mice, that inhibition of VEGF-B signaling targets lipolysis in adipocytes. Reducing VEGF-B signaling ameliorated NAFLD by decreasing WAT inflammation, resolving WAT insulin resistance, and lowering the activity of the hormone sensitive lipase. Analyses of human WAT biopsies from individuals with NAFLD provided evidence supporting the contribution of VEGF-B signaling to NAFLD development. VEGF-B expression levels in adipocytes from two WAT depots correlated with development of dysfunctional WAT and NAFLD in humans.
Taken together, our data from mouse models and humans suggest that VEGF-B antagonism may represent an approach to combat NAFLD by targeting hepatic steatosis through suppression of lipolysis.
Non-alcoholic fatty liver disease (NAFLD) is a common comorbidity in type 2 diabetes mellitus (T2DM) and has a global prevalence of between 25-29%. There are currently no approved drugs for NAFLD, and given the scale of the ongoing diabetes epidemics, there is an urgent need to identify new treatment options. Our work suggests that VEGF-B antagonism may represent an approach to combat NAFLD by targeting hepatic steatosis through suppression of lipolysis. The neutralizing anti-VEGF-B antibody, which was used in this study, has already entered clinical trials for patients with diabetes. Therefore, we believe that our results are of great general interest to a broad audience, including patients and patient organizations, the medical community, academia, the life science industry and the public.
Display omitted
•Inhibition of VEGF-B signaling reduced hepatic steatosis and NAFLD in diabetic mice.•VEGF-B-regulated lipolysis in the white adipose tissue contributed to NAFLD.•The beneficial effect was due to re-sensitizing adipocytes to insulin signaling.•VEGF-B signaling was upregulated in clinical WAT biopsies from individuals with NAFLD.•VEGF-B antagonism may be a therapeutic strategy for the treatment of NAFLD.
PDF
