bluuebunny/crossref_metadata_2025_split huggingface dataset:
288-OR: Role of Endoplasmic Reticulum (ER) Calcium in ß-Cell Senescence and Type 1 Diabetes Pathophysiology
Authors: WEAVER STACI A. , KONO TATSUYOSHI , SYED FAROOQ , BONE ROBERT N. , EVANS-MOLINA CARMELLA 
Published: June 2021

Type 1 diabetes (T1D) results from immune-mediated destruction of pancreatic β cells. Recent data suggest that activation of senescence and acquisition of a senescence-associated secretory phenotype (SASP) by β cells may contribute to T1D pathogenesis; however, the molecular mechanisms responsible for this phenotype are not well understood. Our previous work has linked loss of β cell ER Ca2+ with diabetes pathophysiology and demonstrated accelerated onset of hyperglycemia in non-obese diabetic (NOD) mice with haploinsufficiency of the SERCA2 pump (NOD-S2+/-). Therefore, we hypothesized that loss of ER Ca2+ via reduced SERCA2 activity may drive β cell senescence, SASP, mitochondrial dysfunction and T1D development. To test this hypothesis, SERCA2 KO INS-1 β cells (S2KO) and islets from NOD-S2+/- mice were assessed for senescence associated β-galactosidase staining (SA-β-gal), mRNA expression of senescence markers cdkn1a and cdkn2a, mitochondrial membrane potential and function (TMRM, Seahorse) as well as mitochondrial DNA copy number. S2KO β cells displayed increased SA-β-gal staining as well as increased mitochondrial coupling efficiency and baseline mitochondrial copy number compared to WT β cells, suggesting a senescence phenotype, and altered mitochondrial function. Pancreatic islets isolated from NOD-S2+/- mice show increased mRNA expression of the senescence marker cdkn2a at 12wks compared to age matched control mice (p&lt;0.05), whereas cdkn1a remained unchanged across all timepoints tested. Our results suggest that loss of SERCA2 and reduced ER Ca2+ alters β cell mitochondrial function and is associated with features of senescence. Future studies will test whether SERCA2 activation and/or senolytic/senomorphic drugs are able to prevent or delay diabetes onset in NOD-S2+/- mice. This study has the potential to inform new paradigms of T1D prevention and therapy with the overall goal of improving β cell health during autoimmunity.

Disclosure
S. A. Weaver: None. T. Kono: None. F. Syed: None. R. N. Bone: None. C. Evans-molina: Advisory Panel; Self; Provention Bio, Inc., Consultant; Self; Dompe, Other Relationship; Self; Bristol-Myers Squibb Company, Nimbus Pharmaceuticals, Pfizer Inc.

Funding
Indiana Clinical and Translational Sciences Institute (UL1TR002529)
30-OR: Identification of LRG1 as an Insulin Sensitizing Adipokine
Authors: CHOI CHAN HEE J. , BARR WILL , KOENEN MASCHA , LIN ZERAN , SZWED SARAH , COHEN PAUL 
Published: June 2021

Adipocytes play a central role in obesity, type 2 diabetes, and metabolic disease. White adipocytes store excess energy, and brown adipocytes dissipate chemical energy into heat. In addition to these bioenergetics functions, adipocytes also have important endocrine properties. Bioinformatic analyses suggest that adipocytes may secrete over 1,000 unique polypeptides, the vast majority of which remain uncharacterized. We employed bio-orthogonal non-canonical amino acid tagging (BONCAT) along with mass spectrometry to comprehensively characterize the secreted proteome of murine subcutaneous and visceral white adipocytes and interscapular brown adipocytes. We identified more than 700 unique proteins, with approximately 300 showing fat cell type specific enrichment. We here describe a novel role for leucine-rich alpha-2 glycoprotein 1 (LRG1), a secreted protein expressed across all types of adipose tissues. Plasma LRG1 levels were increased in aged and diet-induced obese (DIO) mice. Longitudinal overexpression of LRG1, using an adeno-associated virus (AAV) with tropism for adipose tissue, led to significantly improved glucose and insulin tolerance in DIO mice, despite equivalent body weights. AAV-mediated overexpression of LRG1 in the db/db model of type 2 diabetes resulted in accelerated weight gain due to increased white fat mass, but improved insulin tolerance and a delayed diabetic phenotype. LRG1 overexpressing mice had markedly reduced macrophage accumulation in white adipose tissues, and LRG1 significantly reduced pro-inflammatory gene expression. Taken together, these data suggest LRG1 acts as an insulin sensitizer by promoting healthier lipid storage with reduced inflammation.

Disclosure
C. J. Choi: None. W. Barr: None. M. Koenen: None. Z. Lin: None. S. Szwed: None. P. Cohen: None.

Funding
American Diabetes Association/Pathway to Stop Diabetes (1-17-ACE-17 to P.C.)
306-OR: Changes in Adipose-Derived Circulating MicroRNA Levels and Improvements in Visceral and Ectopic Fat Depots and Insulin Sensitivity: The CENTRAL Trial
Authors: HEIANZA YORIKO , KROHN KNUT K. , WANG MENGYING , MEIR ANAT YASKOLKA , XUE QIAOCHU , ZIESCHE STEFANIE , CEGLAREK UTA , BLÜHER MATTHIAS , KELLER MARIA , KOVACS PETER , SHAI IRIS , QI LU 
Published: June 2021

MicroRNAs (miRNAs) are small non-coding RNAs, and adipose tissue is a major source of circulating miRNAs that may regulate body fat distribution. We investigated whether changes in circulating adipose-derived miRNAs (miR-99a-5p, miR-99b-5p, and miR-100-5p) were related to improvements in visceral and ectopic fat depots in abdominal obese adults who participated in the CENTRAL diet-and-lifestyle intervention trial. We further tested whether changes in these miRNAs were related to improved glucose metabolism and insulin sensitivity after the intervention. Plasma levels of miRNAs were measured both at baseline (n=227) and 18 months (n=157) after the intervention; changes in miRNAs from baseline to 18 months were calculated. Magnetic resonance imaging (MRI) was performed to assess visceral adipose tissue (VAT), intrahepatic fat %, and pancreatic fat %. At baseline, higher levels of miR-99a-5p and miR-100-5p were associated with greater intrahepatic fat (p &lt;0.0001 for both). The study participants showed considerable differences in circulating miRNA changes in response to the diet/physical activity intervention, and greater decreases in miR-99a-5p were associated with greater improvements in VAT (p=0.0027) and intrahepatic fat (p=0.015) at 18 months. Similarly, the reduction of miR-100-5p was related to 18-month improvements in VAT (p=0.0025) and intrahepatic fat (p=0.0023). Further, decreases in miR-99b-5p (p=0.038) and miR-100-5p (p=0.033) levels were associated with improved pancreatic fat at 18 months. Participants with more decreases in miR-99b-5p had reduced pancreatic fat and were also characterized as having lower glucose levels and higher HOMA of β-cell function at the end of the intervention. Our findings underscore the importance of changes in specific adipose-derived circulating miRNAs in improving diabetogenic fat depots and insulin sensitivity during the intervention for abdominal obese patients.

Disclosure
Y. Heianza: None. P. Kovacs: None. I. Shai: None. L. Qi: None. K. K. Krohn: None. M. Wang: None. A. Yaskolka meir: None. Q. Xue: None. S. Ziesche: None. U. Ceglarek: Research Support; Self; Roche Diagnostics Germany. M. Blüher: Consultant; Self; Amgen Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk, Sanofi-Aventis Deutschland GmbH, Speaker’s Bureau; Self; Daiichi Sankyo, Novartis AG. M. Keller: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (DK091718, DK100383, DK115679)
319-OR: Effects of Empagliflozin on Markers of Liver Steatosis and Fibrosis and Their Relation to Cardiorenal Outcomes in the EMPA-REG OUTCOME Trial
Authors: KAHL SABINE , OFSTAD ANNE PERNILLE , ZINMAN BERNARD , WANNER CHRISTOPH , SCHUELER ELKE , INZUCCHI SILVIO E. , RODEN MICHAEL 
Published: June 2021

Treatment with empagliflozin (EMPA) improves cardiorenal outcomes, but also reduces liver fat content in individuals with both type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD). Thus, we evaluated the effects of EMPA vs. placebo (PLAC) on NAFLD-related steatosis and fibrosis risks and the relation of fibrosis risk to cardiorenal outcomes in individuals with T2D in the randomized controlled trial EMPA-REG OUTCOME. The trial enrolled 7020 people with T2D and cardiovascular disease for treatment with 10 or 25 mg daily EMPA or PLAC. Post-hoc, we derived the Dallas Steatosis Index (DSI) and NAFLD fibrosis score (NFS) to assess the risks of steatosis and fibrosis from baseline to week 164 of treatment, respectively. Changes from baseline in DSI and NFS were examined by mixed model repeated measures analysis, and effects on cardiovascular and all-cause death, hospitalization for heart failure and nephropathy by Cox regression across fibrosis risk categories. At baseline, 72% of participants had high risk of steatosis (DSI probability of &gt;50%; mean, 0.74±0.00 and 23% had high risk of advanced fibrosis (NFS &gt;0.675; mean, 1.26±0.01. Overall DSI (logit) decreased with EMPA compared to PLAC at all timepoints (p&lt;0.001; placebo-corrected change -0.13±0.03 at 164 weeks) and also in the subgroup at high steatosis risk. Despite comparable overall NFS over time in EMPA and PLAC groups, NFS was lower in the EMPA-treated advanced fibrosis subgroup at weeks 12, 28 and 108 (placebo-corrected changes -0.08±0.03, -0.11±0.03 and -0.11±0.04, all timepoints p&lt;0.01 vs. PLAC). Of note, effects of EMPA on cardiorenal and mortality outcomes were consistent across high and low fibrosis risk groups.
In conclusion, EMPA may attenuate NAFLD-related steatosis as well as fibrosis progression specifically in individuals at risk of advanced fibrosis, and improves cardiorenal outcomes as well as all-cause mortality independent of fibrosis risk category.

Disclosure
S. Kahl: None. A. Ofstad: Employee; Self; Boehringer Ingelheim International GmbH. B. Zinman: Advisory Panel; Self; Abbott Diabetes, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk, Sanofi. C. Wanner: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, Speaker’s Bureau; Self; Eli Lilly and Company. E. Schueler: None. S. E. Inzucchi: Consultant; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Esperion, Merck & Co., Inc., Novo Nordisk. M. Roden: Advisory Panel; Self; Allergan plc, Bristol-Myers Squibb Company, Novo Nordisk A/S, Research Support; Self; Boehringer Ingelheim International GmbH, Danone Nutricia, Sanofi-Aventis Deutschland GmbH.
323-OR: SGLT2 Inhibition Promotes Myocardial Ketone Utilization in the Normal and Failing Heart
Authors: GOEDEKE LEIGH , LEE JI EUN , MA YINA , HU XIAOYUE , ZHANG JIASHENG , DONG JIANYING , GALSGAARD KATRINE D. , GUERRERA NICOLE , HAEDERSDAL SOFIE , ZHANG XIAN-MAN , PERRY RACHEL J. , CLINE GARY , YOUNG LAWRENCE H. , SHULMAN GERALD I. 
Published: June 2021

Recent clinical outcome studies demonstrate that SGLT2 inhibitors (i) significantly reduce major adverse cardiovascular events and heart failure in patients with and without type 2 diabetes; however, the mechanisms by which SGLT2i exert their cardiovascular benefits remain unclear. Here, we aimed to elucidate the acute effects of SGLT2i (dapagliflozin, dapa) on cardiac mitochondrial substrate oxidation. Using LC-MS/MS methodology combined with an infusion of [13C6]glucose and [13C4]βOHB, we assessed the ratio of cardiac mitochondrial pyruvate (VPDH) and βOHB (VβOHB) oxidation rates to rates of mitochondrial citrate synthase flux (VCS) in awake male Sprague Dawley (SD) rats. Metabolic studies were performed 4-6 h after oral dapa (1.5 mg/kg) or vehicle treatment in control rats and after induction of heart failure induced by permanent ligation of the left anterior descending coronary artery. Acute dapa treatment led to marked glycosuria with a 15% reduction in fasting plasma glucose concentrations and 50% increase in whole-body βOHB turnover and plasma βOHB concentrations (all P&lt;0.05 vs. VEH). Dapa caused a 40-60% decrease in myocardial [14C]deoxyglucose uptake and pyruvate oxidation (VPDH/VCS) and a 60% increase in myocardial ketone oxidation (VβOHB/VCS) (all P&lt;0.05 vs. VEH). Similar effects were observed in heart failure rats. Dapa treatment caused a 15% decrease in fasting plasma glucose concentrations, 50% increase in plasma βOHB levels and 60% increase in left ventricular VβOHB/VCS (all P&lt;0.05 vs. VEH).
Conclusion: Collectively, these studies demonstrate that dapa shifts both the normal and failing heart to increased mitochondrial ketone oxidation, which may be mediated by increased hepatic ketogenesis and βOHB availability.

Disclosure
L. Goedeke: None. X. Zhang: None. R. J. Perry: None. G. Cline: None. L. H. Young: None. G. I. Shulman: Consultant; Self; 89bio, Inc., BridgeBio, Ionis Pharmaceuticals, Maze Therapeutics, Novo Nordisk, Other Relationship; Self; AstraZeneca, Esperion Therapeutics, Inc, Generian Pharmaceuticals, Inc., Gilead Sciences, Inc., iMetabolic Biopharma Corporation, Janssen Research & Development, LLC, Merck & Co., Inc., The Liver Company. J. Lee: None. Y. Ma: None. X. Hu: None. J. Zhang: n/a. J. Dong: None. K. D. Galsgaard: None. N. Guerrera: None. S. Haedersdal: None.

Funding
National Institutes of Health (R01DK113984, R01DK045735, K99HL150234); AstraZeneca
335-OR: Lipid-Induced Insulin Resistance in the Renal Cortex Is Associated with Plasma Membrane Sn-1,2-diacylglycerol Accumulation and PKCe Translocation
Authors: HUBBARD BRANDON T. , GASPAR RAFAEL C. , ZHANG DONGYAN , KAHN MARIO , NASIRI ALI , ZHANG XIAN-MAN , CLINE GARY , SHULMAN GERALD I. 
Published: June 2021

While there is substantial evidence that the kidney is insulin responsive, it is unclear whether the organ becomes insulin resistant. Here, we investigate whether the kidney is susceptible to lipid-induced insulin resistance and, if so, whether insulin resistance may be mediated by increases in plasma membrane sn-1,2-diacylglycerol (DAG) content and activation of Protein Kinase Cε (PKCε). We studied 14 week old C57BL/6J mice fed either regular chow (RC) or a high fat diet (HFD) for three weeks. Infusion of [13C6]glucose under hyperinsulinemic-euglycemic clamp (HEC) conditions revealed HFD fed mice to have an ~40% reduction (P&lt;0.01) in renal cortical mitochondrial pyruvate dehydrogenase flux relative to citrate synthase flux (VPDH/VCS) compared to RC mice. Next, we infused RC mice with a lipid emulsion (Intralipid® 20%) (RC+IL) during HEC. Despite matched plasma NEFAs at the clamp conclusion, renal cortical VPDH/VCS was significantly higher in RC+IL mice than in HFD mice (P&lt;0.02). These findings suggest that reductions in insulin-stimulated mitochondrial VPDH/VCS observed in HFD mice are intrinsic to the kidney and cannot be attributed to alterations in fatty acid flux to the kidney. Consistent with our mitochondrial flux data, we found that feeding a HFD induced a defect in insulin signaling at the level of the insulin receptor (INSR) as evidenced by ~50% reductions in both insulin-stimulated INSRY1162 (P&lt;0.05) and AKTS473 phosphorylation (P&lt;0.001). HFD-induced reductions in insulin signaling were associated with an ~2-fold increase (P&lt;0.01) in plasma membrane sn-1,2-DAG content, which was associated with an ~4-fold increase (P&lt;0.05) in PKCε translocation.
Conclusion: HFD feeding induces insulin resistance in the renal cortex at the level of INSRY1162 phosphorylation. This defect in INSR signaling is associated with reduced insulin-stimulated pyruvate oxidation and may be mediated by a sn-1,2-DAG-PKCε-INSR mechanism.

Disclosure
B. T. Hubbard: None. R. C. Gaspar: None. D. Zhang: None. M. Kahn: None. A. Nasiri: Employee; Spouse/Partner; Medtronic. X. Zhang: None. G. Cline: None. G. I. Shulman: Consultant; Self; 89bio, Inc., BridgeBio, Ionis Pharmaceuticals, Maze Therapeutics, Novo Nordisk, Other Relationship; Self; AstraZeneca, Esperion Therapeutics, Inc, Generian Pharmaceuticals, Inc., Gilead Sciences, Inc., iMetabolic Biopharma Corporation, Janssen Research & Development, LLC, Merck & Co., Inc., The Liver Company.
336-OR: Mandarin Fish Ranavirus Viral Insulin/IGF-Like Peptide Inhibits Human IGF-1 Receptor
Authors: CHRUDINOVA MARTINA , GELFANOV VASILY , ZAKOVA LENKA , CUTONE JULIANNE , POWIS AMAYA , SEVGI KAAN , JIRACEK JIRI , DIMARCHI RICHARD , ALTINDIS EMRAH 
Published: June 2021

Our recent studies published in PNAS and Molecular Metabolism showed for the very first time that viruses possess genes encoding viral insulin/IGF-1 like peptides (VILPs). These two studies provided several important insights on VILPs: 1. Identified VILPs in six different Iridoviridae viruses 2. Showed that chemically synthesized single chain (sc, IGF-1 like) and double chain (dc, insulin-like) VILPs can bind to human insulin and IGF-1 receptors and stimulate downstream signaling. 3. Demonstrated that VILPs can increase glucose uptake in vitro and in vivo. 4. Identified the unique tissue-specific effects of VILPs. 5. Found sequences of these viruses in the human gut and plasma virome.
In the present study, we focused on a novel, Mandarin Fish Ranavirus (MFRV) VILP and characterized both sc and dc forms for the first time. MFRV scVILP binds to human IGF1R with an affinity 100x higher than insulin, making it a VILP with the highest affinity to this receptor so far discovered. MFRV scVILP also activates IGF1R phosphorylation and post-receptor signaling. Interestingly, although MFRV scVILP is a weak agonist of IGF1R, it inhibits IGF-1 signaling at higher concentrations. When we treat cells with both IGF-1 and MFRV VILP, MFRV scVILP inhibits IGF-1 (10nM) stimulated IGF1R phosphorylation and activation of PI3K and MAPK pathways at high concentrations (&gt; 250 nM). Surprisingly, the dc version of MFRV VILP neither bind nor stimulate IGF1R. This suggests that the C-chain of MFRV VILP is essential for both binding to IGF1R and the IGF-1 inhibitory effects.
Taken together, our results revealed that MFRV scVILP is a novel antagonist/inhibitor of IGF-1R. IGF1R signaling is overly activated in breast, prostate and colorectal cancers. Despite tremendous efforts to develop an effective inhibitor of IGF1R, these attempts failed. MFRV VILP has the potential to contribute development of new therapeutics in cancer therapy and to help us better understand ligand-receptor interactions and mechanisms of IGF1R inhibition.

Disclosure
M. Chrudinova: None. V. Gelfanov: Employee; Self; Novo Nordisk, Employee; Spouse/Partner; Eli Lilly and Company. L. Zakova: None. J. Cutone: None. A. Powis: None. K. Sevgi: None. J. Jiracek: None. R. Dimarchi: Employee; Self; Novo Nordisk. E. Altindis: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (K01DK117967)
337-OR: Intensive Insulin Treatment in a Patient with Type A Insulin Resistance Syndrome Associated with a Novel Heterozygous Mutation of Trp1120Gly in the Insulin Receptor Gene
Authors: YANG YU , HUANG ZHIMIN , WEI GUOHONG , LI YUELI , DENG WANPING , LI YANBING 
Published: June 2021

Background: Type A insulin resistance syndrome is a rare congenital severe insulin resistance syndrome resulting from mutations in the insulin receptor (IR) gene. We herein report a case treated with continuous subcutaneous insulin infusion (CSII) followed by insulin glargine and pioglitazone.
Clinical Case: A 16 year-old girl with BMI of 19.1 kg/m2, complained of primary amenorrhea and elevated glucose for 2 years. She was diagnosed with precocious puberty at the age of 7, and treated with letrozole and triptorelin successively for 6.5 years. Hyperinsulinemia was noted but not ameliorated with metformin treatment. All the treatment was suspended for 2 years before referring to our department. Plasma glucose during OGTT showed fasting glucose was 8.4 mmol/L, and 2-hour post-load was 23.5 mmol/L. HbA1c was 10.8%. Markedly increased fasting (245μU/mL) and post-load serum insulin (628μU/mL) were observed. Next generation sequencing revealed a novel heterozygous missense mutation of Trp1120Gly in the IR gene. The patient received CSII with 0.8U/kg as the starting daily total, and titrated the dosage according to SMBG, followed by insulin glargine and pioglitazone treatment. Her glucose was well controlled, insulin glargine was down to 8U/d at the end of 3 months. Her HbA1c dropped to 7.9%, along with fasting plasma glucose (4.6mmol/L) and serum insulin (95.44μU/mL), while 2-hour postprandial glucose and insulin were still high. Her menarche occurred after one cycle of ethinylestradiol and cyproterone combo tablets.
Conclusion: Improvement of glucose control with intensive insulin treatment was observed in a patient with type A insulin resistance syndrome. However, amelioration of insulin resistance was limited. No standard treatment was recommended for this rare syndrome. Thus, large-scale long-term studies assembled worldwide to optimize treatment strategy are needed.

Disclosure
Y. Yang: None. Z. Huang: None. G. Wei: None. Y. Li: None. W. Deng: None. Y. Li: None.

Funding
National Natural Science Foundation of China (82070918)
341-P: Effect of Pitolisant on Glucagon in Human Islets and People with Type 1 Diabetes
Authors: DEHN CLAYTON A. , FEIN MELANIE , HU JACK , YESILDAG BURCAK , MAXWELL ROBERT , HARP JOYCE B. 
Published: June 2021

In 3D human islet microtissues from nondiabetic donors, pitolisant, a histamine 3 receptor antagonist, increased glucagon secretion &gt;3-fold compared to vehicle control. However, the effect of pitolisant on glucagon was diminished in islets treated with cytokines, insulin, and low glucose to mimic T1D hypoglycemia. The purpose of this study was to determine if pitolisant can restore impaired glucagon secretion response to hypoglycemia in people with T1D. The study was a double-blind randomized placebo-controlled study of five adults (3 on pitolisant and 2 on placebo), 4 men, with long-duration T1D. Patients were domiciled overnight, at baseline and after 7 days of once daily oral pitolisant (36 mg) or matching placebo. Blood glucose levels were kept at 100-120 mg/dL overnight with regular insulin infusion and an insulin tolerance test (ITT) was conducted the following morning. Glucagon was measured by the Mercodia ELISA and glucose by a YSI Glucose Analyzer. Glucose was also assessed using a blinded Dexcom G6 CGM during the trial. Safety tolerability was assessed by standard methods. Mean change (95% CI) from baseline in peak glucagon (pg/ml) was 7.5 (-2.07-17.02) for the pitolisant group and 13.1 (2.08-24.09) for the placebo group. One patient on pitolisant and no patients on placebo returned to blood glucose &gt;/=70 mg/dL during the 180-minute ITT. The pitolisant group required significantly less rescue D50 on-drug vs. at baseline (5 vs. 19 grams, p=0.05), while there was no difference in the placebo group (36 vs. 25 grams). In general, patients on pitolisant had numerically higher mean glucose on CGM during the on-drug period. There were no severe hypoglycemic events and no deaths. Pitolisant was well tolerated. We conclude that pitolisant does not increase glucagon secretion during hypoglycemia in people with T1D but may mitigate hypoglycemia by a glucagon-independent mechanism. The T1D islet microtissue model better predicts the clinical effects of pitolisant on glucagon secretion compared to healthy islets.

Disclosure
C. A. Dehn: None. M. Fein: None. J. Hu: None. B. Yesildag: None. R. Maxwell: Other Relationship; Self; Ferox Therapeutics LLC. J. B. Harp: Other Relationship; Self; Ferox Therapeutics.

Funding
Ferox Therapeutics; The Leona M. and Harry B. Helmsley Charitable Trust