Ranganath Muniyappa

State University of New York, New York, New York, United States

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Publications (64)

  • [Show abstract] [Hide abstract] ABSTRACT: Epidemiological studies show a dose-dependent relationship between green tea consumption and reduced risk for type 2 diabetes and cardiovascular disease. Bioactive compounds in green tea including the polyphenol epigallocatechin 3-gallate (EGCG) have insulin-mimetic actions on glucose metabolism and vascular function in isolated cell culture studies. The aim of this study is to explore acute vascular and metabolic actions of EGCG in skeletal muscle of Sprague–Dawley rats. Direct vascular and metabolic actions of EGCG were investigated using surgically isolated constant-flow perfused rat hindlimbs. EGCG infused at 0.1, 1, 10 and 100 μM in 15 min step-wise increments caused dose-dependent vasodilation in 5-hydroxytryptamine pre-constricted hindlimbs. This response was not impaired by the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin or the AMP-kinase inhibitor Compound C. The nitric oxide synthase (NOS) inhibitor NG-Nitro-L-Arginine Methyl Ester (L-NAME) completely blocked EGCG-mediated vasodilation at 0.1–10 μM, but not at 100 μM. EGCG at 10 μM did not alter muscle glucose uptake nor did it augment insulin-stimulated muscle glucose uptake. The acute metabolic and vascular actions of 10 μM EGCG in vivo were investigated in anesthetized rats during a hyperinsulinemic-euglycemic clamp (10 mU/min/kg insulin). EGCG and insulin both stimulated comparable increases in muscle microvascular blood flow without an additive effect. EGCG-mediated microvascular action occurred without altering whole body or muscle glucose uptake. We concluded that EGCG has direct NOS-dependent vasodilator actions in skeletal muscle that do not acutely alter muscle glucose uptake or enhance the vascular and metabolic actions of insulin in healthy rats.
    Article · Oct 2016 · The Journal of nutritional biochemistry
  • Andrea Kassai · Ranganath Muniyappa · Amy E. Levenson · [...] · Rebecca J. Brown
    [Show abstract] [Hide abstract] ABSTRACT: Context: Apolipoprotein CIII (apoCIII), an inhibitor of lipoprotein lipase, plays an important role in triglyceride metabolism. However, the role of apoCIII in hypertriglyceridemia in lipodystrophy and the effects of leptin replacement on apoCIII levels are unknown. Objective: To test the hypotheses that apoCIII is elevated in hypertriglyceridemic patients with lipodystrophy and that leptin replacement in these patients lowers circulating apoCIII. Design, Setting, Study Participants, Intervention, and Outcome Measures: Using a post-hoc cross-sectional case-control design, we compared serum apoCIII levels from patients with lipodystrophy not associated with HIV (n=60) and age-, gender-, race-, and ethnicity-matched controls (n=54) participating in ongoing studies at the National Institutes of Health. In a prospective, open-label, ongoing study, we studied the effects of 6-12 months of leptin replacement on apoCIII in lipodystrophy patients as an exploratory outcome. Results: ApoCIII was higher in lipodystrophy patients (geometric mean [25th, 75th percentile]) (23.9 mg/dL [14.6, 40.3]) compared to controls (14.9 mg/dL [12.3, 17.7]) (p< 0.0001). ApoCIII and triglyceride levels were positively correlated in patients with lipodystrophy (R=0.72, p< 0.0001) and healthy controls (R=0.6, p< 0.0001). Leptin replacement (6-12) months did not significantly alter apoCIII [before leptin: 23.4 mg/dL (14.5, 40.1), after leptin: 21.4 mg/dL (16.7, 28.3); p=0.34]. Conclusions: Leptin replacement in lipodystrophy did not alter plasma apoCIII levels. Elevated apoCIII may play a role in the hypertriglyceridemia of lipodystrophy independent of leptin deficiency and replacement.
    Article · Feb 2016 · Journal of Clinical Endocrinology & Metabolism
  • [Show abstract] [Hide abstract] ABSTRACT: Leptin treatment has beneficial effects on plasma lipids in patients with lipodystrophy, but the underlying mechanism is unknown. Proprotein convertase subtilisin/kexin type 9 (PCSK9) decreases LDL clearance, promotes hypercholesterolemia, and has recently emerged as a novel therapeutic target. To determine the effect of leptin on PCSK9, we treated male and female ob/ob mice with leptin for four days via subcutaneous osmotic pumps (∼24 μg/day). Leptin reduced body weight and food intake in all mice, but the effects of leptin on plasma PCSK9 and lipids differed markedly between the sexes. In male mice, leptin suppressed PCSK9, but had no effect on plasma triglycerides or cholesterol. In female mice, leptin suppressed plasma triglycerides and cholesterol, but had no effect on plasma PCSK9. In parallel, we treated female lipodystrophic patients (8 females, ages 5-23 years) with subcutaneous metreleptin injections (∼4.4 mg/day) for four to six months. In this case, leptin reduced plasma PCSK9 by 26% (298 ± 109 vs 221 ± 102 ng/mL; n=8; p=0.008), and the change in PCSK9 was correlated with a decrease in LDL cholesterol (r(2)=0.564, p=0.03). In summary, in leptin-deficient ob/ob mice, the effects of leptin on PCSK9 and plasma lipids appeared to be independent of one another and strongly modified by sex. On the other hand, in lipodystrophic females, leptin treatment reduced plasma PCSK9 in parallel with LDL cholesterol.
    Article · Jan 2016 · Endocrinology
  • Brent S Abel · Ranganath Muniyappa · Pamela Stratton · [...] · Rebecca J Brown
    [Show abstract] [Hide abstract] ABSTRACT: Leptin replacement in patients with leptin gene mutations improves hypogonadotropic hypogonadism. The effects of leptin replacement on LH secretion in patients with lipodystrophy are unknown. We examined nocturnal LH secretory dynamics on and off exogenous leptin therapy using a 2 period, non-randomized study that included leptin-naïve and -treated subjects with lipodystrophy. In period 1 (5 days) the leptin-treated group (n = 4) continued leptin; leptin was withdrawn for the next 14 days (period 2). Leptin-naïve subjects (n = 8) were studied without leptin in period 1, and with leptin replacement in period 2. LH secretory dynamics were assessed [23:00-7:00, q10 min sampling, analyzed by multiparameter deconvolution algorithm] at the end of each period. Mean (on vs. off: 5.0 ± 3.1 U/l vs. 3.2 ± 1.3, p = 0.04) and integrated LH concentrations (2,403 ± 1,495 U × L(-a) × min(-a) vs. 1,534 ± 642, p = 0.04) were higher on leptin therapy. Leptin treatment increased burst mass (9.7± 15.4 U/l vs. 7.0 ± 11.2, p = 0.03) and tended to non-significantly increase LH burst frequency (0.77 ± 0.26 h(-a) vs. 0.67 ± 0.24, p = 0.08). Consequently, leptin therapy increased pulsatile production rate (64 ± 101 U × L(-a) × 8 h(-a) vs. 57 ± 73, p = 0.01). On leptin, testosterone (507 ± 286 ng/dl vs. 360 ± 174, p = 0.09) and estradiol levels (74 ± 36 pg/ml vs. 29 ± 24, p = 0.01) were higher, in males and females, respectively. Leptin increases spontaneous nocturnal LH secretion in patients with lipodystrophy. This is consistent with rodent and in vitro studies showing a direct stimulatory effect (hypothalamic, pituitary or both) of leptin on LH secretion. These novel findings may explicate some of the salutary effects of leptin therapy on the hypothalamic-pituitary-gonadal axis in lipodystrophy. © 2015 S. Karger AG, Basel.
    Article · Aug 2015 · Neuroendocrinology
  • Ranganath Muniyappa · Radwa Noureldin · Ronald Ouwerkerk · [...] · Ahmed M Gharib
    [Show abstract] [Hide abstract] ABSTRACT: Myocardial steatosis, an independent predictor of diastolic dysfunction is frequently present in type 2 diabetes mellitus. High FFA flux, hyperglycemia, and hyperinsulinemia, may play a role in myocardial steatosis. There are no prior studies examining the relationship between insulin sensitivity (anti-lipolytic and glucose disposal actions of insulin) and cardiac steatosis. Using a cross-sectional study design of individuals with and without metabolic syndrome (MetSyn), we examined the relationships between cardiac steatosis and the sensitivity of the anti-lipolytic and glucose disposal actions of insulin. Pericardial fat volume (PF), intramyocardial and hepatic fat content (MF and HF), visceral and subcutaneous fat content (VF and SF) were assessed by MRI in 77 subjects (49 without MetSyn and 28 with MetSyn). In a subset of the larger cohort (n=52), peripheral insulin sensitivity index (SI) and adipocyte insulin sensitivity (Adipo-SI) was determined from Insulin Modified Frequently sampled intravenous glucose tolerance test (IM-FSIVGTT). Quantitative Insulin Sensitivity Check Index (QUICKI) was used as a surrogate for hepatic insulin sensitivity. Individuals with the MetSyn had significantly higher BMI, total body fat, MF, PF, HF and VF content. HF and VF, but not MF were negatively correlated with QUICKI, Adipo-SI, and SI. Stepwise regression revealed that waist circumference and serum TG levels independently predicted MF and PF, respectively. Adipo-SI and serum TG levels independently predict HF. Myocardial steatosis is unrelated to hepatic, adipocyte, or peripheral insulin sensitivity. Although frequently observed in insulin-resistant subjects, further studies are necessary to identify and delineate pathogenic mechanisms that differentially affect cardiac and hepatic steatosis.
    Article · May 2015 · The Journal of Clinical Endocrinology and Metabolism
  • Kong Y Chen · Ranganath Muniyappa · Brent S Abel · [...] · Monica C Skarulis
    [Show abstract] [Hide abstract] ABSTRACT: Context: Activation of MC4R with the synthetic agonist RM-493 decreases body weight and increases energy expenditure (EE) in non-human primates. The effects of MC4R agonists on EE in humans have not been examined to date. Objective:, Design, and Setting: In a randomized, double-blind, placebo-controlled, crossover study, we examined the effects of the MC4R agonist, RM-493, on resting EE (REE) in obese subjects in an inpatient setting. Study Participants and Methods: Twelve healthy adults (6 M, 6 F) with BMI 35.7 ± 2.9 kg/m(2) (mean, SD) received RM-493 (1 mg/24 h) or placebo by continuous subcutaneous infusion over 72 hours, followed immediately by crossover to the alternate treatment. All subjects received a weight-maintenance diet (50% carbohydrate, 30% fat, 20% protein) and performed 30 minutes of standardized exercise daily. Continuous EE was measured on the third treatment day in a room calorimeter and REE in the fasting state was defined as the mean of two 30-minute resting periods. Results: RM-493 increased REE vs. placebo by 6.4% (95% CI: 0.68 to 13.02 %), on average by 111 kcal/24h (95% CI: 15 to 207 kcal, p=0.03). Total daily EE trended higher while the thermic effect of a test meal and exercise EE did not differ significantly. The 23-h non-exercise respiratory quotient was lower during RM-493 treatment (0.833 ± 0.021 vs. 0.848 ± 0.022, p=0.02). No adverse effect on heart rate or blood pressure was observed. Conclusions: Short-term administration of the MC4R agonist, RM-493 increases REE and shifts substrate oxidation to fat in obese individuals.
    Article · Feb 2015 · Journal of Clinical Endocrinology & Metabolism
  • Ranganath Muniyappa · Pothur R Srinivas
    Article · Nov 2014 · Diabetes
  • Article · May 2014 · Therapeutic drug monitoring
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    Ranganath Muniyappa · James R Sowers
    Full-text available · Article · Apr 2014 · Diabetes
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    Ranganath Muniyappa · Rebecca J Brown · Andrea Mari · [...] · Phillip Gorden
    [Show abstract] [Hide abstract] ABSTRACT: OBJECTIVE Leptin administration is known to directly modulate pancreatic β-cell function in leptin-deficient rodent models. However, human studies examining the effects of leptin administration on β-cell function are lacking. In this study, we examined the effects (16-20 weeks) of leptin replacement on β-cell function in patients with lipodystrophy.RESEARCH DESIGN AND METHODS In a prospective, open-label, currently ongoing study we studied the effects of leptin replacement on β-cell function in 13 patients with congenital or acquired lipodystrophy. Insulin secretory rate (ISR) was calculated by C-peptide deconvolution from plasma glucose and C-peptide levels measured during oral glucose tolerance tests (OGTTs) performed at baseline and after 16-20 weeks of leptin replacement. β-Cell glucose sensitivity and rate sensitivity were assessed by mathematical modeling of OGTT.RESULTSThere was a significant decrease in triglycerides, free fatty acids, and glycosylated hemoglobin levels (A1C) after leptin therapy. Patients with lipodystrophy have high fasting and glucose-stimulated ISR. However, leptin therapy had no significant effect on fasting ISR, total insulin secretion during OGTT, β-cell glucose sensitivity, rate sensitivity, or insulin clearance.CONCLUSIONS In contrast to the suppressive effects of leptin on β-cell function in rodents, 16-20-week treatment with leptin in lipodystrophy patients did not significantly affect insulin secretion or β-cell function in leptin-deficient individuals with lipodystrophy.
    Full-text available · Article · Feb 2014 · Diabetes care
  • Ranganath Muniyappa · Mary A Warren · Xiongce Zhao · [...] · Monica C Skarulis
    [Show abstract] [Hide abstract] ABSTRACT: Context:Disruption of the Gsαmaternal allele leads to severe obesity and insulin resistance in mice and early-onset obesity in patients with pseudohypoparathyroidism (PHP) type 1a. However, insulin resistance and glucose metabolism have not been systematically characterized in patients with PHP1a.Objective, Design, and Setting:In a cross-sectional, case-control study, we examined insulin sensitivity, β-cell function, energy expenditure, and sympathetic nervous system activity (SNA) in adults with PHP1a.Study Participants:PHP1a patients (n=8) and healthy control subjects (n=24) matched for age (41 ± 7 vs. 41 ± 7 yr [mean ± SD]), gender, and percent body fat.Methods:Insulin sensitivity (SI), acute insulin response to glucose, and disposition index (DI) were assessed during an FSIVGTT. Oral glucose insulin sensitivity (OGIS) was measured during a mixed meal. Energy expenditure was measured using whole room indirect calorimetry. Body composition was assessed via dual-energy x-ray absorptiometry and SNA by measuring 24-hr urinary catecholamine concentrations.Results:Results: PHP1a patients were less insulin-sensitive than their matched controls based upon SI and OGIS. Non-diabetic PHP1a patients tended to have a lower SI (p = 0.09) and reduced OGIS (p = 0.03). DI, a composite measure of β-cell function also tended to be lower in patients (p=0.07). Total caloric intake, resting energy expenditure (REE), total EE, meal-induced thermogenesis, and 24-hr urinary catecholamine concentrations were not significantly different between the groups.Conclusions:Adults with PHP-1a have reduced insulin sensitivity compared with their matched controls that may contribute to the pathogenesis of glucose intolerance and diabetes in these patients.
    Article · Sep 2013 · The Journal of Clinical Endocrinology and Metabolism
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    Ranganath Muniyappa · Sara Sable · Ronald Ouwerkerk · [...] · Monica C Skarulis
    [Show abstract] [Hide abstract] ABSTRACT: OBJECTIVE We examined if chronic cannabis smoking is associated with hepatic steatosis, insulin resistance, reduced β-cell function, or dyslipidemia in healthy individuals.RESEARCH DESIGN AND METHODS In a cross-sectional, case-control study, we studied cannabis smokers (n = 30; women, 12; men, 18; 27 ± 8 years) and control subjects (n = 30) matched for age, sex, ethnicity, and BMI (27 ± 6). Abdominal fat depots and intrahepatic fat content were quantified by magnetic resonance imaging and proton magnetic resonance spectroscopy, respectively. Insulin-sensitivity indices and various aspects of β-cell function were derived from oral glucose tolerance tests (OGTT).RESULTSSelf-reported cannabis use was: 9.5 (2-38) years; joints/day: 6 (3-30) [median (range)]. Carbohydrate intake and percent calories from carbohydrates, but not total energy intake, were significantly higher in cannabis smokers. There were no group differences in percent total body fat, or hepatic fat, but cannabis smokers had a higher percent abdominal visceral fat (18 ± 9 vs. 12 ± 5%; P = 0.004). Cannabis smokers had lower plasma HDL cholesterol (49 ± 14 vs. 55 ± 13 mg/dL; P = 0.02), but fasting levels of glucose, insulin, total cholesterol, LDL cholesterol, triglycerides, or free fatty acids (FFA) were not different. Adipocyte insulin resistance index and percent FFA suppression during an OGTT was lower (P < 0.05) in cannabis smokers. However, oral glucose insulin sensitivity index, measures of β-cell function, or incretin concentrations did not differ between the groups.CONCLUSIONS Chronic cannabis smoking was associated with visceral adiposity and adipose tissue insulin resistance but not with hepatic steatosis, insulin insensitivity, impaired pancreatic β-cell function, or glucose intolerance.
    Full-text available · Article · Mar 2013 · Diabetes care
  • Ranganath Muniyappa · James R Sowers
    [Show abstract] [Hide abstract] ABSTRACT: Insulin resistance is frequently associated with endothelial dysfunction and has been proposed to play a major role in cardiovascular diseases. Insulin exerts pro- and anti-atherogenic actions on the vasculature. The balance between nitric oxide (NO)-dependent vasodilator actions and endothelin-1- dependent vasoconstrictor actions of insulin is regulated by phosphatidylinositol 3-kinase-dependent (PI3K) - and mitogen-activated protein kinase (MAPK)-dependent signaling in vascular endothelium, respectively. During insulin-resistant conditions, pathway-specific impairment in PI3K-dependent signaling may cause imbalance between production of NO and secretion of endothelin-1 and lead to endothelial dysfunction. Insulin sensitizers that target pathway-selective impairment in insulin signaling are known to improve endothelial dysfunction. In this review, we discuss the cellular mechanisms in the endothelium underlying vascular actions of insulin, the role of insulin resistance in mediating endothelial dysfunction, and the effect of insulin sensitizers in restoring the balance in pro- and anti-atherogenic actions of insulin.
    Article · Jan 2013 · Reviews in Endocrine and Metabolic Disorders
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    Ranganath Muniyappa · James R Sowers
    Full-text available · Article · Sep 2012 · Diabetes
  • Ranganath Muniyappa · Sahzene Yavuz
    [Show abstract] [Hide abstract] ABSTRACT: Metabolic actions of insulin to promote glucose disposal are augmented by nitric oxide (NO)-dependent increases in microvascular blood flow to skeletal muscle. The balance between NO-dependent vasodilator actions and endothelin-1-dependent vasoconstrictor actions of insulin is regulated by phosphatidylinositol 3-kinase-dependent (PI3K) - and mitogen-activated protein kinase (MAPK)-dependent signaling in vascular endothelium, respectively. Angiotensin II acting on AT(2) receptor increases capillary blood flow to increase insulin-mediated glucose disposal. In contrast, AT(1) receptor activation leads to reduced NO bioavailability, impaired insulin signaling, vasoconstriction, and insulin resistance. Insulin-resistant states are characterized by dysregulated local renin-angiotensin-aldosterone system (RAAS). Under insulin-resistant conditions, pathway-specific impairment in PI3K-dependent signaling may cause imbalance between production of NO and secretion of endothelin-1, leading to decreased blood flow, which worsens insulin resistance. Similarly, excess AT(1) receptor activity in the microvasculature may selectively impair vasodilation while simultaneously potentiating the vasoconstrictor actions of insulin. Therapeutic interventions that target pathway-selective impairment in insulin signaling and the imbalance in AT(1) and AT(2) receptor signaling in microvascular endothelium may simultaneously ameliorate endothelial dysfunction and insulin resistance. In the present review, we discuss molecular mechanisms in the endothelium underlying microvascular and metabolic actions of insulin and Angiotensin II, the mechanistic basis for microvascular endothelial dysfunction and insulin resistance in RAAS dysregulated clinical states, and the rationale for therapeutic strategies that restore the balance in vasodilator and constrictor actions of insulin and Angiotensin II in the microvasculature.
    Article · Jun 2012 · Molecular and Cellular Endocrinology
  • Philomena Pullikotil · Hui Chen · Ranganath Muniyappa · [...] · Michael J Quon
    [Show abstract] [Hide abstract] ABSTRACT: Epigallocatechin gallate (EGCG), the major polyphenol in green tea, acutely stimulates production of nitric oxide (NO) from vascular endothelium to reduce hypertension and improve endothelial dysfunction in spontaneously hypertensive rats. Herein, we explored additional mechanisms whereby EGCG may mediate beneficial cardiovascular actions. When compared with vehicle-treated controls, EGCG treatment (2.5 μM, 8 h) of human aortic endothelial cells (HAEC) caused a ~three-fold increase in heme oxygenase-1 (HO-1) mRNA and protein with comparable increases in HO-1 activity. This was unaffected by pretreatment of cells with wortmannin, LY294002, PD98059 or L-NAME (PI 3-kinase, MEK and NO synthase inhibitors, respectively). Pretreatment of HAEC with SB203580 (p38 MAPK inhibitor) or siRNA knockdown of p38 MAPK completely blocked EGCG-stimulated induction of HO-1. EGCG treatment also inhibited tumor-necrosis-factor-α-stimulated expression of vascular cell adhesion molecule (VCAM)-1 and decreased adhesion of monocytes to HAEC. siRNA knockdown of HO-1, p38 MAPK or Nrf-2 blocked these inhibitory actions of EGCG. In HAEC transiently transfected with a human HO-1 promoter luciferase reporter (or an isolated Nrf-2 responsive region), luciferase activity increased in response to EGCG. This was inhibitable by SB203580 pretreatment. EGCG-stimulated expression of HO-1 and Nrf-2 was blocked by siRNA knockdown of Nrf-2 or p38 MAPK. Finally, liver from mice chronically treated with EGCG had increased HO-1 and decreased VCAM-1 expression. Thus, in vascular endothelium, EGCG requires p38 MAPK to increase expression of Nrf-2 that drives expression of HO-1, resulting in increased HO-1 activity. Increased HO-1 expression may underlie anti-inflammatory actions of EGCG in vascular endothelium that may help mediate beneficial cardiovascular actions of green tea.
    Article · Nov 2011 · The Journal of nutritional biochemistry
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    Ranganath Muniyappa · Vandana Sachdev · Stanislav Sidenko · [...] · Anne E Sumner
    [Show abstract] [Hide abstract] ABSTRACT: Insulin resistance is associated with endothelial dysfunction. Because African-American women are more insulin-resistant than white women, it is assumed that African-American women have impaired endothelial function. However, racial differences in postprandial endothelial function have not been examined. In this study, we test the hypothesis that African-American women have impaired postprandial endothelial function compared with white women. Postprandial endothelial function following a breakfast (20% protein, 40% fat, and 40% carbohydrate) was evaluated in 36 (18 African-American women, 18 white women) age- and body mass index (BMI)-matched (age: 37 ± 11 yr; BMI: 30 ± 6 kg/m(2)) women. Endothelial function, defined by percent change in brachial artery flow-mediated dilation (FMD), was measured at 0, 2, 4, and 6 h following a meal. There were no significant differences between the groups in baseline FMD, total body fat, abdominal visceral fat, and fasting levels of glucose, insulin, total cholesterol, low-density lipoprotein cholesterol, or serum estradiol. Although African-American women were less insulin-sensitive [insulin sensitivity index (mean ± SD): 3.6 ± 1.5 vs. 5.2 ± 2.6, P = 0.02], both fasting triglyceride (TG: 56 ± 37 vs. 97 ± 49 mg/dl, P = 0.007) and incremental TG area under the curve (AUC(0-6hr): 279 ± 190 vs. 492 ± 255 mg·dl(-1)·min(-1)·10(-2), P = 0.008) were lower in African-American than white women. Breakfast was associated with a significant increase in FMD in whites and African-Americans, and there was no significant difference in postprandial FMD between the groups (P > 0.1 for group × time interactions). Despite being insulin-resistant, postprandial endothelial function in African-American women was comparable to white women. These results imply that insulin sensitivity may not be an important determinant of racial differences in endothelial function.
    Full-text available · Article · Nov 2011 · AJP Endocrinology and Metabolism
  • Amy R DuFlo · Ranganath Muniyappa · Gail Hall · [...] · Monica C Skarulis
    Chapter · Jun 2011
  • Ho-Won Lee · Ranganath Muniyappa · Giovanni Cizza · [...] · Marc R Blackman
    Chapter · Jun 2011
  • Ho-Won Lee · Ranganath Muniyappa · S Mitchell Harman · Marc R Blackman
    Chapter · Jun 2011