Scholars@Duke
Sudarshan Rajagopal

Sudarshan Rajagopal

Associate Professor of Medicine
Medicine, Cardiology
sudarshan.rajagopal@duke.edu
Box 102147, DUMC, Durham, NC 27710
Duke University Medical Center, Box 3126, Durham, NC 27710

Selected Publications

G Protein-Coupled Receptors: A Century of Research and Discovery.

Journal Article Circ Res · June 21, 2024 GPCRs (G protein-coupled receptors), also known as 7 transmembrane domain receptors, are the largest receptor family in the human genome, with ≈800 members. GPCRs regulate nearly every aspect of human physiology and disease, thus serving as important drug ... Full text Link to item Cite

GPCR kinases differentially modulate biased signaling downstream of CXCR3 depending on their subcellular localization.

Journal Article Sci Signal · February 13, 2024 Some G protein-coupled receptors (GPCRs) demonstrate biased signaling such that ligands of the same receptor exclusively or preferentially activate certain downstream signaling pathways over others. This phenomenon may result from ligand-specific receptor ... Full text Link to item Cite

How carvedilol does not activate β2-adrenoceptors.

Journal Article Nat Commun · November 30, 2023 Full text Link to item Cite

Location bias: A "Hidden Variable" in GPCR pharmacology.

Journal Article Bioessays · November 2023 G protein-coupled receptors (GPCRs) are the largest family of transmembrane receptors and primarily signal through two main effector proteins: G proteins and β-arrestins. Many agonists of GPCRs promote "biased" responses, in which different cellular signal ... Full text Link to item Cite

Inhaled Epoprostenol Compared With Nitric Oxide for Right Ventricular Support After Major Cardiac Surgery.

Journal Article Circulation · October 24, 2023 BACKGROUND: Right ventricular failure (RVF) is a leading driver of morbidity and death after major cardiac surgery for advanced heart failure, including orthotopic heart transplantation and left ventricular assist device implantation. Inhaled pulmonary-sel ... Full text Open Access Link to item Cite

Quantitative assessment of ligand bias from bias plots: The bias coefficient "kappa".

Journal Article Biochim Biophys Acta Gen Subj · October 2023 The current methods for quantifying ligand bias involve the construction of bias plots and the calculations of bias coefficients that can be compared using statistical methods. However, widely used bias coefficients can diverge in their abilities to identi ... Full text Link to item Cite

Location Biased G Protein-Coupled Receptor Signaling Modulates Distinct Spatial Conformations of β-arrestins

Conference The Journal of Pharmacology and Experimental Therapeutics · June 2023 Full text Cite

Single-Cell Analysis Reveals Distinct Immune and Smooth Muscle Cell Populations that Contribute to Chronic Thromboembolic Pulmonary Hypertension.

Journal Article Am J Respir Crit Care Med · May 15, 2023 Rationale: Chronic thromboembolic pulmonary hypertension (CTEPH) is a sequela of acute pulmonary embolism (PE) in which the PE remodels into a chronic scar in the pulmonary arteries. This results in vascular obstruction, pulmonary microvasculopathy, and pu ... Full text Link to item Cite

Sildenafil and Kidney Function in Heart Failure with Preserved Ejection Fraction.

Journal Article Kidney360 · May 1, 2023 KEY POINTS: Sildenafil induced an acute effect on eGFR without change in the overall eGFR slope after 24 weeks in a heart failure with preserved ejection fraction (HFpEF) cohort. N-terminal pro–brain natriuretic peptide levels and baseline diuretic use wer ... Full text Link to item Cite

Evaluation and Management of Pulmonary Hypertension in Noncardiac Surgery: A Scientific Statement From the American Heart Association.

Journal Article Circulation · April 25, 2023 Pulmonary hypertension, defined as an elevation in blood pressure in the pulmonary arteries, is associated with an increased risk of death. The prevalence of pulmonary hypertension is increasing, with an aging population, a rising prevalence of heart and l ... Full text Open Access Link to item Cite

Imaging the right atrium in pulmonary hypertension: A systematic review and meta-analysis.

Journal Article J Heart Lung Transplant · April 2023 BACKGROUND: Right atrial (RA) imaging has emerged as a promising tool for the evaluation of patients with pulmonary hypertension (PH), albeit without systematic validation. METHODS: PubMed, Web of Science and the Cochrane library were searched for studies ... Full text Link to item Cite

Phosphorylation barcodes direct biased chemokine signaling at CXCR3.

Journal Article Cell chemical biology · April 2023 G protein-coupled receptor (GPCR)-biased agonism, selective activation of certain signaling pathways relative to others, is thought to be directed by differential GPCR phosphorylation "barcodes." At chemokine receptors, endogenous chemokines can act as "bi ... Full text Cite

Phosphorylation barcodes direct biased chemokine signaling at CXCR3.

Journal Article bioRxiv · March 14, 2023 G protein-coupled receptor (GPCR) biased agonism, the activation of some signaling pathways over others, is thought to largely be due to differential receptor phosphorylation, or "phosphorylation barcodes." At chemokine receptors, ligands act as "biased ag ... Full text Link to item Cite

Inhaled Treprostinil Dosage in Pulmonary Hypertension Associated With Interstitial Lung Disease and Its Effects on Clinical Outcomes.

Journal Article Chest · February 2023 BACKGROUND: Pulmonary hypertension (PH) complicates the course of many patients with fibrotic interstitial lung disease (ILD). Inhaled treprostinil (iTre) has been shown to improve functional ability and to delay clinical worsening in patients with PH resu ... Full text Link to item Cite

Location bias contributes to functionally selective responses of biased CXCR3 agonists.

Journal Article Nat Commun · October 4, 2022 Some G protein-coupled receptor (GPCR) ligands act as "biased agonists" that preferentially activate specific signaling transducers over others. Although GPCRs are primarily found at the plasma membrane, GPCRs can traffic to and signal from many subcellula ... Full text Link to item Cite

Endothelial β-arrestins regulate mechanotransduction by the type II bone morphogenetic protein receptor in primary cilia.

Journal Article Pulm Circ · October 2022 Modulation of endothelial cell behavior and phenotype by hemodynamic forces involves many signaling components, including cell surface receptors, intracellular signaling intermediaries, transcription factors, and epigenetic elements. Many of the signaling ... Full text Link to item Cite

Community guidelines for GPCR ligand bias: IUPHAR review 32.

Journal Article Br J Pharmacol · July 2022 GPCRs modulate a plethora of physiological processes and mediate the effects of one-third of FDA-approved drugs. Depending on which ligand activates a receptor, it can engage different intracellular transducers. This 'biased signalling' paradigm requires t ... Full text Link to item Cite

Hemodynamics of the right ventricle and the pulmonary circulation

Journal Article Applications in Engineering Science · June 1, 2022 Most cardiac diseases affect the left ventricle (LV), with its treatment being the focus of the majority of cardiovascular medical therapies and mechanical support. Many diseases also affect the right ventricle (RV) and pulmonary circulation, either direct ... Full text Cite

Location Bias Contributes to Functionally Selective Responses of Biased CXCR3 Agonists to Regulate Inflammation.

Journal Article FASEB J · May 2022 G Protein-Coupled Receptors (GPCRs) represent the largest and most diverse family of cell receptors in the human genome and are targeted by ~35% of all FDA-approved drugs. GPCR signaling is mediated by various effectors, including G proteins, β-arrestins, ... Full text Link to item Cite

Phosphorylation barcode ensembles encoded by biased CXCR3 agonists direct non-redundant chemokine signaling.

Journal Article FASEB J · May 2022 Chemokine receptors, a group of G protein-coupled receptors (GPCRs), interact with transducers such as G proteins, β-arrestins, and GPCR kinases (GRKs). In the chemokine system, many chemokine agonists act as "biased agonists" that preferentially activate ... Full text Link to item Cite

GPCR systems pharmacology: a different perspective on the development of biased therapeutics.

Journal Article Am J Physiol Cell Physiol · May 1, 2022 G protein-coupled receptors (GPCRs) are the largest family of transmembrane receptors and are the target of approximately one-third of all Food and Drug Administration (FDA)-approved pharmaceutical drugs. GPCRs interact with many transducers, such as heter ... Full text Link to item Cite

Determining the Requirements for Gαi:β-arrestin Complex Formation at G Protein-Coupled Receptors

Journal Article FASEB journal : official publication of the Federation of American Societies for Experimental Biology · May 1, 2022 G protein-coupled receptors (GPCRs) comprise the largest class of transmembrane receptors and are targeted by nearly a third of prescription drugs. Canonical GPCR signaling involves pathways mediated by G proteins and β-arrestins (βarrs). While these have ... Full text Cite

Regulation of Endothelial Cell function by Integration of Gαi and β-arrestin signaling at Atypical Chemokine Receptor 3

Journal Article FASEB journal : official publication of the Federation of American Societies for Experimental Biology · May 1, 2022 Atypical Chemokine receptor 3 (ACKR3), also known as C-X-C chemokine receptor type 7 (CXCR7), is a G protein-coupled receptor (GPCR) implicated in several physiological processes including leukocyte trafficking, cancer, and angiogenesis. Commonly co-expres ... Full text Cite

Location Bias of G Protein-Coupled Receptor Kinases Promotes Biased Signaling at CXCR3

Journal Article FASEB journal : official publication of the Federation of American Societies for Experimental Biology · May 1, 2022 G protein-coupled receptors (GPCRs) are the largest family of cell-surface receptors and are known to canonically signal through two main effector proteins: G proteins and β-arrestins. Biased agonism at GPCRs refers to the functional selectivity of a ligan ... Full text Cite

Distinct Spatial Conformations and Trafficking Patterns of β-arrestin Isoforms in AT1R Signaling

Journal Article FASEB journal : official publication of the Federation of American Societies for Experimental Biology · May 1, 2022 Excessive activation of the AT1R by the hormone Angiotensin II (AngII) is implicated in the pathogenesis of hypertension by promoting vascular smooth muscle cell migration, hypertrophy, and cardiac remodeling. A limitation of current drug development to ta ... Full text Cite

Noninvasive diagnosis of pulmonary hypertension with hyperpolarised 129Xe magnetic resonance imaging and spectroscopy.

Conference ERJ Open Res · April 2022 BACKGROUND: The diagnosis of pulmonary hypertension (PH) remains challenging. Pre- and post-capillary PH have different signatures on noninvasive 129Xe gas-exchange magnetic resonance imaging (MRI) and dynamic MR spectroscopy (MRS). We tested the accuracy ... Full text Link to item Cite

Novel Approaches to Imaging the Pulmonary Vasculature and Right Heart.

Journal Article Circulation research · April 2022 There is an increased appreciation for the importance of the right heart and pulmonary circulation in several disease states across the spectrum of pulmonary hypertension and left heart failure. However, assessment of the structure and function of the righ ... Full text Cite

Biased agonists of the chemokine receptor CXCR3 differentially signal through Gαi:β-arrestin complexes.

Journal Article Sci Signal · March 22, 2022 G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors and signal through the proximal effectors, G proteins and β-arrestins, to influence nearly every biological process. The G protein and β-arrestin signaling pathways have l ... Full text Open Access Link to item Cite

The Pathobiology of Pulmonary Arterial Hypertension.

Journal Article Cardiol Clin · February 2022 Pulmonary arterial hypertension is characterized by obliteration and obstruction of the pulmonary arterioles that in turn results in high right ventricular afterload and right heart failure. The pathobiology of pulmonary arterial hypertension is complex, w ... Full text Link to item Cite

Noninvasive Risk Score to Screen for Pulmonary Hypertension With Elevated Pulmonary Vascular Resistance in Diseases of Chronic Volume Overload.

Journal Article Am J Cardiol · November 15, 2021 Volume overload promotes pulmonary hypertension (PH) through pulmonary venous hypertension. However, PH with elevated pulmonary vascular resistance (hereafter PH-PVR) may develop in patients with diseases of volume overload, such as heart failure or chroni ... Full text Link to item Cite

Inhaled treprostinil and forced vital capacity in patients with interstitial lung disease and associated pulmonary hypertension: a post-hoc analysis of the INCREASE study.

Journal Article Lancet Respir Med · November 2021 BACKGROUND: INCREASE was a randomised, placebo-controlled, phase 3 trial that evaluated inhaled treprostinil in patients with interstitial lung disease (ILD) and associated pulmonary hypertension. Treprostinil improved exercise capacity from baseline to we ... Full text Link to item Cite

β-Arrestin-Mediated Angiotensin II Type 1 Receptor Activation Promotes Pulmonary Vascular Remodeling in Pulmonary Hypertension.

Journal Article JACC Basic Transl Sci · November 2021 Pulmonary arterial hypertension (PAH) is a disease of abnormal pulmonary vascular remodeling whose medical therapies are thought to primarily act as vasodilators but also may have effects on pulmonary vascular remodeling. The angiotensin II type 1 receptor ... Full text Link to item Cite

Chronic Thromboembolic Pulmonary Hypertension: the Bench.

Journal Article Curr Cardiol Rep · August 19, 2021 PURPOSE OF REVIEW: Chronic thromboembolic pulmonary hypertension (CTEPH) is an uncommon complication of acute pulmonary embolism (PE), in which the red, platelet-rich thrombus does not resolve but forms into an organized yellow, fibrotic scar-like obstruct ... Full text Link to item Cite

Chronic Thromboembolic Pulmonary Hypertension: the Bedside.

Journal Article Curr Cardiol Rep · August 19, 2021 PURPOSE OF REVIEW: Chronic thromboembolic pulmonary hypertension (CTEPH), included in group 4 PH, is an uncommon complication of acute pulmonary embolism (PE), in which emboli in the pulmonary vasculature do not resolve but rather form into an organized sc ... Full text Link to item Cite

A multiscale model of vascular function in chronic thromboembolic pulmonary hypertension.

Journal Article Am J Physiol Heart Circ Physiol · August 1, 2021 Chronic thromboembolic pulmonary hypertension (CTEPH) is caused by recurrent or unresolved pulmonary thromboemboli, leading to perfusion defects and increased arterial wave reflections. CTEPH treatment aims to reduce pulmonary arterial pressure and reestab ... Full text Link to item Cite

G protein- and β-arrestin Signaling Profiles of Endothelin Derivatives at the Type A Endothelin Receptor.

Journal Article Kidney360 · July 29, 2021 BACKGROUND: Endothelin-1 (ET-1) is a potent vasoconstrictor in the cardiovascular system, an effect mediated through the type A endothelin receptor (ETAR), a G protein-coupled receptor (GPCR). Antagonists of the ETAR have shown promising results in randomi ... Full text Link to item Cite

NEDD9 Is a Novel and Modifiable Mediator of Platelet-Endothelial Adhesion in the Pulmonary Circulation.

Journal Article Am J Respir Crit Care Med · June 15, 2021 Rationale: Data on the molecular mechanisms that regulate platelet-pulmonary endothelial adhesion under conditions of hypoxia are lacking, but may have important therapeutic implications. Objectives: To identify a hypoxia-sensitive, modifiable mediator of ... Full text Link to item Cite

The right atrium, more than a storehouse.

Journal Article Int J Cardiol · May 15, 2021 Full text Link to item Cite

Using hyperpolarized 129Xe gas-exchange MRI to model the regional airspace, membrane, and capillary contributions to diffusing capacity.

Journal Article J Appl Physiol (1985) · May 1, 2021 Hyperpolarized 129Xe MRI has emerged as a novel means to evaluate pulmonary function via 3D mapping of ventilation, interstitial barrier uptake, and RBC transfer. However, the physiological interpretation of these measurements has yet to be firmly establis ... Full text Link to item Cite

Noncanonical scaffolding of Gαi and β-arrestin by G protein-coupled receptors.

Journal Article Science · March 12, 2021 Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) are common drug targets and canonically couple to specific Gα protein subtypes and β-arrestin adaptor proteins. G protein-mediated signaling and β-arrestin-mediated sig ... Full text Link to item Cite

Biased agonism at chemokine receptors.

Journal Article Cell Signal · February 2021 In the human chemokine system, interactions between the approximately 50 known endogenous chemokine ligands and 20 known chemokine receptors (CKRs) regulate a wide range of cellular functions and biological processes including immune cell activation and ho ... Full text Open Access Link to item Cite

The role of chemokines and chemokine receptors in pulmonary arterial hypertension.

Journal Article Br J Pharmacol · January 2021 Pulmonary arterial hypertension (PAH) is characterized by progressive pulmonary artery remodelling leading to increased right ventricular pressure overload, which results in right heart failure and premature death. Inflammation plays a central role in the ... Full text Open Access Link to item Cite

Mass Spectrometry-Based Proteomics for Analysis of Hydrophilic Phosphopeptides.

Journal Article Methods Mol Biol · 2021 Protein phosphorylation is a critical posttranslational modification (PTM), with cell signaling networks being tightly regulated by protein phosphorylation. Despite recent technological advances in reversed-phase liquid chromatography (RPLC)-mass spectrome ... Full text Link to item Cite

β-arrestin-mediated Angiotensin II type 1 Receptor Activation Promotes Pulmonary Vascular Remodeling in Pulmonary Hypertension

Journal Article · 2021 Objectives The goal of this study was to test whether a β-arrestin-biased agonist of the angiotensin II (AngII) type 1 receptor (AT 1 R), which acts as a vasodilator while not blocking cellular proliferation, would have positive effects compared t ... Full text Cite

IL-27 Derived From Macrophages Facilitates IL-15 Production and T Cell Maintenance Following Allergic Hypersensitivity Responses.

Journal Article Front Immunol · 2021 Crosstalk between T cells, dendritic cells, and macrophages in temporal leukocyte clusters within barrier tissues provides a new concept for T cell activation in the skin. Activated T cells from these leukocyte clusters play critical roles in the efferent ... Full text Link to item Cite

Beta-Arrestins and Receptor Signaling in the Vascular Endothelium.

Journal Article Biomolecules · December 23, 2020 The vascular endothelium is the innermost layer of blood vessels and is a key regulator of vascular tone. Endothelial function is controlled by receptor signaling through G protein-coupled receptors, receptor tyrosine kinases and receptor serine-threonine ... Full text Open Access Link to item Cite

Echocardiography to Screen for Pulmonary Hypertension in CKD.

Journal Article Kidney Int Rep · December 2020 INTRODUCTION: Pulmonary hypertension (PH) is a common yet incompletely understood complication of chronic kidney disease (CKD). Although transthoracic echocardiogram is commonly used to noninvasively estimate PH, it has not been validated in a CKD populati ... Full text Open Access Link to item Cite

Pulmonary Hypertension Subtypes and Mortality in CKD.

Journal Article Am J Kidney Dis · May 2020 RATIONALE & OBJECTIVE: Pulmonary hypertension (PH) contributes to cardiovascular disease and mortality in patients with chronic kidney disease (CKD), but the pathophysiology is mostly unknown. This study sought to estimate the prevalence and consequences o ... Full text Open Access Link to item Cite

Quantitative 129Xe MRI detects early impairment of gas-exchange in a rat model of pulmonary hypertension.

Journal Article Sci Rep · April 30, 2020 Hyperpolarized 129Xe magnetic resonance imaging (MRI) is capable of regional mapping of pulmonary gas-exchange and has found application in a wide range of pulmonary disorders in humans and animal model analogs. This study is the first application of 129Xe ... Full text Link to item Cite

Experience in Transitioning From Parenteral Prostacyclins to Selexipag in Pulmonary Arterial Hypertension.

Journal Article J Cardiovasc Pharmacol · April 2020 Parenteral prostacyclin therapies remain first-line therapy for patients with pulmonary arterial hypertension (PAH) with class IV symptoms. In selected patients who have been clinically stabilized, switching to selexipag, a chemically distinct prostacyclin ... Full text Open Access Link to item Cite

Biased Agonism at CXCR3 Drives Differential Phosphoproteomic and Transcriptomic Profiles and Cellular Outputs

Conference The FASEB Journal · April 2020 ObjectiveTo demonstrate that the endogenous agonists of the chemokine receptor CXCR3 differentially impact the phosphoproteome and transcriptome to drive distinct cellular outputs. Full text Cite

Biased agonists of the chemokine receptor CXCR3 differentially drive formation of Gαi and β‐arrestin complexes

Conference The FASEB Journal · April 2020 G‐protein‐coupled receptors (GPCRs) are the most common cell surface receptor class and influence nearly every biological process within a cell. Approximately 30% of all FDA‐approved medications target GPCRs. Following recept ... Full text Cite

ACKR3 Regulates Endothelial Cell Function with Non‐canonical Integration of Gαi and β‐arrestin

Conference The FASEB Journal · April 2020 Atypical Chemokine receptor 3 (ACKR3), also known as C‐X‐C chemokine receptor type 7 (CXCR7), is a G protein‐coupled receptor (GPCR) implicated in several physiological processes including leukocyte trafficking, cancer, and ... Full text Cite

Nonclassical Monocytes Sense Hypoxia, Regulate Pulmonary Vascular Remodeling, and Promote Pulmonary Hypertension.

Journal Article J Immunol · March 15, 2020 An increasing body of evidence suggests that bone marrow-derived myeloid cells play a critical role in the pathophysiology of pulmonary hypertension (PH). However, the true requirement for myeloid cells in PH development has not been demonstrated, and a sp ... Full text Link to item Cite

Identification of potent pyrazole based APELIN receptor (APJ) agonists.

Journal Article Bioorg Med Chem · February 15, 2020 The apelinergic system comprises the apelin receptor and its cognate apelin and elabela peptide ligands of various lengths. This system has become an increasingly attractive target for pulmonary and cardiometabolic diseases. Small molecule regulators of th ... Full text Open Access Link to item Cite

Biased agonists of the chemokine receptor CXCR3 differentially drive formation of Gαi:β-arrestin complexes

Journal Article · 2020 G-protein-coupled receptors (GPCRs), the largest family of cell surface receptors, signal through the proximal effectors G proteins and β-arrestins to influence nearly every biological process. Classically, the G protein and β-arrestin signaling pathways h ... Full text Cite

EXTRA VOLUME: PULMONARY HYPERTENSION CAUSED BY EXTRA-CARDIAC AND INTRA-CARDIAC SHUNTING

Conference JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY · 2020 Cite

Monitoring Pulmonary Arterial Hypertension Using an Implantable Hemodynamic Sensor.

Journal Article Chest · December 2019 BACKGROUND: Pulmonary arterial hypertension (PAH) is a chronic disease that ultimately progresses to right-sided heart failure (HF) and death. Close monitoring of pulmonary artery pressure (PAP) and right ventricular (RV) function allows clinicians to appr ... Full text Open Access Link to item Cite

Diverse cardiopulmonary diseases are associated with distinct xenon magnetic resonance imaging signatures.

Journal Article Eur Respir J · December 2019 BACKGROUND: As an increasing number of patients exhibit concomitant cardiac and pulmonary disease, limitations of standard diagnostic criteria are more frequently encountered. Here, we apply noninvasive 129Xe magnetic resonance imaging (MRI) and spectrosco ... Full text Open Access Link to item Cite

Echocardiographic Assessment of Right Ventricular Function and Response to Therapy in Pulmonary Arterial Hypertension.

Journal Article Am J Cardiol · October 15, 2019 Echocardiography is a key tool in the management of patients with pulmonary arterial hypertension (PAH), but many potential parameters could be used to assess response to therapy. In this retrospective study of 48 patients with severe PAH at baseline, we e ... Full text Link to item Cite

Tandem Mass Tag Labeling Facilitates Reversed-Phase Liquid Chromatography-Mass Spectrometry Analysis of Hydrophilic Phosphopeptides.

Journal Article Anal Chem · September 17, 2019 Protein phosphorylation is a critical post-translational modification (PTM). Despite recent technological advances in reversed-phase liquid chromatography (RPLC)-mass spectrometry (MS)-based proteomics, comprehensive phosphoproteomic coverage in complex bi ... Full text Open Access Link to item Cite

Vascular Endothelial Growth Factor Receptor 3 Regulates Endothelial Function Through β-Arrestin 1.

Journal Article Circulation · March 26, 2019 BACKGROUND: Receptor signaling is central to vascular endothelial function and is dysregulated in vascular diseases such as atherosclerosis and pulmonary arterial hypertension (PAH). Signaling pathways involved in endothelial function include vascular endo ... Full text Link to item Cite

Clinical Features and Outcomes of Patients with Sarcoidosis-associated Pulmonary Hypertension.

Journal Article Sci Rep · March 11, 2019 The presence of pulmonary hypertension (PH) significantly worsens outcomes in patients with advanced sarcoidosis, but its optimal management is unknown. We aimed to characterize a large sarcoidosis-associated pulmonary hypertension (SAPH) cohort to better ... Full text Open Access Link to item Cite

Pathogen-encoded evasion of CXCL10 and T cell responses

Journal Article · February 22, 2019 Abstract Clearance of intracellular pathogens, such as Leishmania (L.) major , depends on a well-regulated adaptive T cell response. Here we describe a pathogen-encoded mechanism to alter T cell recruitment by suppressing CXCL10, a chemokine that recruits ... Full text Open Access Cite

How do chemokines navigate neutrophils to the target site: Dissecting the structural mechanisms and signaling pathways.

Journal Article Cell Signal · February 2019 Chemokines play crucial roles in combating microbial infection and initiating tissue repair by recruiting neutrophils in a timely and coordinated manner. In humans, no less than seven chemokines (CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, and CXCL8) and two ... Full text Open Access Link to item Cite

A protocol for quantifying cardiogenic oscillations in dynamic 129 Xe gas exchange spectroscopy: The effects of idiopathic pulmonary fibrosis.

Journal Article NMR Biomed · January 2019 The spectral parameters of hyperpolarized 129 Xe exchanging between airspaces, interstitial barrier, and red blood cells (RBCs) are sensitive to pulmonary pathophysiology. This study sought to evaluate whether the dynamics of 129 Xe spectroscopy provide ad ... Full text Link to item Cite

Pathogen Evasion of Chemokine Response Through Suppression of CXCL10.

Journal Article Front Cell Infect Microbiol · 2019 UNLABELLED: Clearance of intracellular pathogens, such as Leishmania (L.) major, depends on an immune response with well-regulated cytokine signaling. Here we describe a pathogen-mediated mechanism of evading CXCL10, a chemokine with diverse antimicrobial ... Full text Link to item Cite

MEF2 and the Right Ventricle: From Development to Disease.

Journal Article Front Cardiovasc Med · 2019 Pulmonary arterial hypertension is a progressive and ultimately life-limiting disease in which survival is closely linked to right ventricular function. The right ventricle remains relatively understudied, as it is known to have key developmental and struc ... Full text Open Access Link to item Cite

Arrestin-mediated signaling at GPCRs

Chapter · January 1, 2019 The arrestins are multifunctional adapter proteins that regulate G protein-coupled receptor (GPCR) signaling. There are four isoforms of arrestin: arrestins 1 and 4 are expressed exclusively in the visual system and are primarily associated with the visual ... Full text Cite

Surgical pulmonary embolectomy and catheter-based therapies for acute pulmonary embolism: A contemporary systematic review.

Journal Article J Thorac Cardiovasc Surg · December 2018 OBJECTIVES: Mortality in acute pulmonary embolism (PE) is believed to be principally due to the subgroup of PEs that are massive. Systemic thrombolysis is the therapeutic mainstay for acute massive PE, despite evidence suggesting limited survival benefits. ... Full text Link to item Cite

Hyperpolarized 129 Xe gas transfer MRI: the transition from 1.5T to 3T.

Journal Article Magn Reson Med · December 2018 PURPOSE: Hyperpolarized 129 Xe MRI depicting 3D ventilation, interstitial barrier uptake, and transfer to red blood cells (RBCs) has emerged as a powerful new means of detecting pulmonary disease. However, given the challenging susceptibility environment o ... Full text Link to item Cite

Biased agonists of the chemokine receptor CXCR3 differentially control chemotaxis and inflammation.

Journal Article Sci Signal · November 6, 2018 The chemokine receptor CXCR3 plays a central role in inflammation by mediating effector/memory T cell migration in various diseases; however, drugs targeting CXCR3 and other chemokine receptors are largely ineffective in treating inflammation. Chemokines, ... Full text Link to item Cite

Clinical Utility and Prognostic Value of Right Atrial Function in Pulmonary Hypertension.

Journal Article Circ Cardiovasc Imaging · November 2018 Background Although right atrial (RA) enlargement is an established marker for adverse outcomes, the prognostic importance of RA dysfunction independent of RA size in pulmonary arterial hypertension is not known. Methods and Results Study subjects with pul ... Full text Link to item Cite

Manifold roles of β-arrestins in GPCR signaling elucidated with siRNA and CRISPR/Cas9.

Journal Article Sci Signal · September 25, 2018 G protein-coupled receptors (GPCRs) use diverse mechanisms to regulate the mitogen-activated protein kinases ERK1/2. β-Arrestins (βArr1/2) are ubiquitous inhibitors of G protein signaling, promoting GPCR desensitization and internalization and serving as s ... Full text Link to item Cite

Clinical and Echocardiographic Predictors of Outcomes in Patients With Pulmonary Hypertension.

Journal Article Am J Cardiol · September 1, 2018 In pulmonary hypertension (PH), measurement of various echocardiographic parameters that assess right heart function is recommended by current clinical guidelines. Limited data exists on the combined value of clinical and echocardiographic parameters in pr ... Full text Link to item Cite

Right Ventricular Longitudinal Strain Reproducibility Using Vendor-Dependent and Vendor-Independent Software.

Journal Article J Am Soc Echocardiogr · June 2018 BACKGROUND: Right ventricular peak systolic longitudinal strain (RVLS) has emerged as an approach for quantifying right ventricular function in diseases such as pulmonary hypertension and congenital heart disease. A major limitation in applying RVLS is tha ... Full text Link to item Cite

Biased signalling: from simple switches to allosteric microprocessors.

Journal Article Nat Rev Drug Discov · April 2018 G protein-coupled receptors (GPCRs) are the largest class of receptors in the human genome and some of the most common drug targets. It is now well established that GPCRs can signal through multiple transducers, including heterotrimeric G proteins, GPCR ki ... Full text Link to item Cite

GPCR desensitization: Acute and prolonged phases.

Journal Article Cell Signal · January 2018 G protein-coupled receptors (GPCRs) transduce a wide array of extracellular signals and regulate virtually every aspect of physiology. While GPCR signaling is essential, overstimulation can be deleterious, resulting in cellular toxicity or uncontrolled cel ... Full text Link to item Cite

Chemokine Signaling in Allergic Contact Dermatitis: Toward Targeted Therapies.

Journal Article Dermatitis · 2018 Allergic contact dermatitis (ACD) is a common skin disease that results in significant cost and morbidity. Despite its high prevalence, therapeutic options are limited. Allergic contact dermatitis is regulated primarily by T cells within the adaptive immun ... Full text Link to item Cite

A Study on the Assessment of Haller Cells in Panoramic Radiograph.

Journal Article Niger Med J · 2018 CONTEXT: Haller cells are extensions of ethmoid cells which can be seen in several imaging modalities. Literature search has shown that idiopathic orofacial pain is associated with the presence of Haller cells. Hence, a simple cost-effective imaging modali ... Full text Link to item Cite

The Role of G Protein-Coupled Receptors in the Right Ventricle in Pulmonary Hypertension.

Journal Article Front Cardiovasc Med · 2018 Pressure overload of the right ventricle (RV) in pulmonary arterial hypertension (PAH) leads to RV remodeling and failure, an important determinant of outcome in patients with PAH. Several G protein-coupled receptors (GPCRs) are differentially regulated in ... Full text Link to item Cite

Improving on the diagnostic characteristics of echocardiography for pulmonary hypertension.

Journal Article Int J Cardiovasc Imaging · September 2017 This retrospective study evaluated the diagnostic characteristics of a combination of echocardiographic parameters for pulmonary hypertension (PH). Right ventricular systolic pressure (RVSP) estimation by echocardiography (echo) is used to screen for PH. H ... Full text Link to item Cite

C-X-C Motif Chemokine Receptor 3 Splice Variants Differentially Activate Beta-Arrestins to Regulate Downstream Signaling Pathways.

Journal Article Mol Pharmacol · August 2017 Biased agonism, the ability of different ligands for the same receptor to selectively activate some signaling pathways while blocking others, is now an established paradigm for G protein-coupled receptor signaling. One group of receptors in which endogenou ... Full text Link to item Cite

Quantitative analysis of hyperpolarized 129 Xe gas transfer MRI.

Journal Article Med Phys · June 2017 PURPOSE: Hyperpolarized 129 Xe magnetic resonance imaging (MRI) using Dixon-based decomposition enables single-breath imaging of 129 Xe in the airspaces, interstitial barrier tissues, and red blood cells (RBCs). However, methods to quantitatively visualize ... Full text Link to item Cite

Systematic errors in detecting biased agonism: Analysis of current methods and development of a new model-free approach.

Journal Article Sci Rep · March 14, 2017 Discovering biased agonists requires a method that can reliably distinguish the bias in signalling due to unbalanced activation of diverse transduction proteins from that of differential amplification inherent to the system being studied, which invariably ... Full text Link to item Cite

Plasma acylcarnitines are associated with pulmonary hypertension.

Journal Article Pulm Circ · March 2017 Quantifying metabolic derangements in pulmonary hypertension (PH) by plasma metabolomics could identify biomarkers useful for diagnosis and treatment. The objective of this paper is to test the hypotheses that circulating metabolites are differentially exp ... Full text Link to item Cite

Echocardiography in the Risk Assessment of Acute Pulmonary Embolism.

Journal Article Semin Respir Crit Care Med · February 2017 Acute pulmonary embolism (PE) is a major cause of morbidity and mortality and is classified as massive (high risk), submassive (intermediate risk), or nonmassive (low risk) based on the hemodynamic status and clinical characteristics of the patient. At thi ... Full text Link to item Cite

Novel approach to classifying patients with pulmonary arterial hypertension using cluster analysis.

Journal Article Pulm Circ · 2017 Pulmonary arterial hypertension (PAH) patients have distinct disease courses and responses to treatment, but current diagnostic and treatment schemes provide limited insight. We aimed to see if cluster analysis could distinguish clinical phenotypes in PAH. ... Full text Link to item Cite

A Practical Guide to Approaching Biased Agonism at G Protein Coupled Receptors.

Journal Article Front Neurosci · 2017 Biased agonism, the ability of a receptor to differentially activate downstream signaling pathways depending on binding of a "biased" agonist compared to a "balanced" agonist, is a well-established paradigm for G protein-coupled receptor (GPCR) signaling. ... Full text Link to item Cite

Clinical and echocardiographic predictors of mortality in acute pulmonary embolism.

Journal Article Cardiovasc Ultrasound · October 28, 2016 PURPOSE: The aim of this study was to evaluate the utility of adding quantitative assessments of cardiac function from echocardiography to clinical factors in predicting the outcome of patients with acute pulmonary embolism (PE). METHODS: Patients with a d ... Full text Open Access Link to item Cite

Clinical and echocardiographic predictors of mortality in acute pulmonary embolism

Journal Article Cardiovascular ultrasound · October 28, 2016 PURPOSE: The aim of this study was to evaluate the utility of adding quantitative assessments of cardiac function from echocardiography to clinical factors in predicting the outcome of patients with acute pulmonary embolism (PE). METHODS: Patients with a d ... Cite

The β-Arrestins: Multifunctional Regulators of G Protein-coupled Receptors.

Journal Article J Biol Chem · April 22, 2016 The β-arrestins (βarrs) are versatile, multifunctional adapter proteins that are best known for their ability to desensitize G protein-coupled receptors (GPCRs), but also regulate a diverse array of cellular functions. To signal in such a complex fashion, ... Full text Link to item Cite

Hemodynamic Characterization of Rodent Models of Pulmonary Arterial Hypertension.

Journal Article J Vis Exp · April 11, 2016 Pulmonary arterial hypertension (PAH) is a rare disease of the pulmonary vasculature characterized by endothelial cell apoptosis, smooth muscle proliferation and obliteration of pulmonary arterioles. This in turn results in right ventricular (RV) failure, ... Full text Link to item Cite

Safety and Tolerability of High-dose Inhaled Treprostinil in Pulmonary Hypertension.

Journal Article J Cardiovasc Pharmacol · April 2016 Pulmonary arterial hypertension (PAH) has emerging therapeutic options including prostacyclin analogs. Inhaled therapy offers advantages compared with alternative routes of administration. We aimed to determine the safety and tolerability of inhaled trepro ... Full text Link to item Cite

Abnormalities in hyperpolarized (129)Xe magnetic resonance imaging and spectroscopy in two patients with pulmonary vascular disease.

Journal Article Pulm Circ · March 2016 The diagnosis of pulmonary vascular disease (PVD) is usually based on hemodynamic and/or clinical criteria. Noninvasive imaging of the heart and proximal vasculature can also provide useful information. An alternate approach to such criteria in the diagnos ... Full text Link to item Cite

Toward Theranostic Biomarkers In Pulmonary Hypertension

Conference AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE · January 1, 2016 Link to item Cite

Use of outcome measures in pulmonary hypertension clinical trials.

Journal Article Am Heart J · September 2015 OBJECTIVES: To evaluate the use of surrogate measures in pulmonary hypertension (PH) clinical trials and how it relates to clinical practice. BACKGROUND: Studies of pulmonary arterial hypertension (PAH) employ a variety of surrogate measures in addition to ... Full text Link to item Cite

The influence of angle of insonation and target depth on speckle-tracking strain.

Journal Article J Am Soc Echocardiogr · May 2015 BACKGROUND: Speckle-tracking strain is almost universally cited as being independent of angle of insonation, but there are minimal confirmatory studies, and this claim may not be consistent with the known limitations of ultrasound axial and lateral spatial ... Full text Link to item Cite

Predictors Of 30-Day Survival In Acute Pulmonary Embolism

Conference AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE · January 1, 2015 Link to item Cite

What is biased efficacy? Defining the relationship between intrinsic efficacy and free energy coupling.

Journal Article Trends Pharmacol Sci · December 2014 A G protein-coupled receptor (GPCR) is only biologically active when associated with a transduction protein, but it can also switch function by interacting with different types of transduction proteins. Biased agonism arises when the ligand induces the rec ... Full text Link to item Cite

Comprehensive assessment of right ventricular function in patients with pulmonary hypertension with global longitudinal peak systolic strain derived from multiple right ventricular views.

Journal Article J Am Soc Echocardiogr · June 2014 BACKGROUND: Right ventricular (RV) function is a strong predictor of mortality in pulmonary hypertension (PH), but two-dimensional (2D) echocardiography-derived assessments of RV function that could aid in risk assessment and management of patients with PH ... Full text Link to item Cite

Right ventricular mechanics using a novel comprehensive three-view echocardiographic strain analysis in a normal population.

Journal Article J Am Soc Echocardiogr · April 2014 BACKGROUND: Although quantitative right ventricular (RV) strain analysis may be useful in congenital and acquired heart disease populations with RV failure, a comprehensive, standardized approach is lacking. An 18-segment RV strain analysis obtained from t ... Full text Link to item Cite

Monitoring protein conformational changes and dynamics using stable-isotope labeling and mass spectrometry.

Journal Article Nat Protoc · 2014 An understanding of the mechanism accompanying functional conformational changes associated with protein activation has important implications for drug design. Here we describe a powerful method, conformational changes and dynamics using stable-isotope lab ... Full text Link to item Cite

Biased agonism as a mechanism for differential signaling by chemokine receptors.

Journal Article J Biol Chem · December 6, 2013 Chemokines display considerable promiscuity with multiple ligands and receptors shared in common, a phenomenon that is thought to underlie their biochemical "redundancy." Their receptors are part of a larger seven-transmembrane receptor superfamily, common ... Full text Link to item Cite

Quantifying ligand bias at seven-transmembrane receptors.

Journal Article Mol Pharmacol · September 2011 Seven transmembrane receptors (7TMRs), commonly referred to as G protein-coupled receptors, form a large part of the "druggable" genome. 7TMRs can signal through parallel pathways simultaneously, such as through heterotrimeric G proteins from different fam ... Full text Link to item Cite

Multiple ligand-specific conformations of the β2-adrenergic receptor.

Journal Article Nat Chem Biol · August 21, 2011 Seven-transmembrane receptors (7TMRs), also called G protein-coupled receptors (GPCRs), represent the largest class of drug targets, and they can signal through several distinct mechanisms including those mediated by G proteins and the multifunctional adap ... Full text Link to item Cite

A stress response pathway regulates DNA damage through β2-adrenoreceptors and β-arrestin-1.

Journal Article Nature · August 21, 2011 The human mind and body respond to stress, a state of perceived threat to homeostasis, by activating the sympathetic nervous system and secreting the catecholamines adrenaline and noradrenaline in the 'fight-or-flight' response. The stress response is gene ... Full text Link to item Cite

Distinct phosphorylation sites on the β(2)-adrenergic receptor establish a barcode that encodes differential functions of β-arrestin.

Journal Article Sci Signal · August 9, 2011 Phosphorylation of G protein-coupled receptors (GPCRs, which are also known as seven-transmembrane spanning receptors) by GPCR kinases (GRKs) plays essential roles in the regulation of receptor function by promoting interactions of the receptors with β-arr ... Full text Link to item Cite

Therapeutic potential of β-arrestin- and G protein-biased agonists.

Journal Article Trends Mol Med · March 2011 Members of the seven-transmembrane receptor (7TMR), or G protein-coupled receptor (GPCR), superfamily represent some of the most successful targets of modern drug therapy, with proven efficacy in the treatment of a broad range of human conditions and disea ... Full text Link to item Cite

Global phosphorylation analysis of beta-arrestin-mediated signaling downstream of a seven transmembrane receptor (7TMR).

Journal Article Proc Natl Acad Sci U S A · August 24, 2010 beta-Arrestin-mediated signaling downstream of seven transmembrane receptors (7TMRs) is a relatively new paradigm for signaling by these receptors. We examined changes in protein phosphorylation occurring when HEK293 cells expressing the angiotensin II typ ... Full text Link to item Cite

Teaching old receptors new tricks: biasing seven-transmembrane receptors.

Journal Article Nat Rev Drug Discov · May 2010 Seven-transmembrane receptors (7TMRs; also known as G protein-coupled receptors) are the largest class of receptors in the human genome and are common targets for therapeutics. Originally identified as mediators of 7TMR desensitization, beta-arrestins (arr ... Full text Link to item Cite

Beta-arrestin- but not G protein-mediated signaling by the "decoy" receptor CXCR7.

Journal Article Proc Natl Acad Sci U S A · January 12, 2010 Ubiquitously expressed seven-transmembrane receptors (7TMRs) classically signal through heterotrimeric G proteins and are commonly referred to as G protein-coupled receptors. It is now recognized that 7TMRs also signal through beta-arrestins, which act as ... Full text Link to item Cite

Total chemical synthesis and biophysical characterization of the minimal isoform of the KChIP2 potassium channel regulatory subunit.

Journal Article Protein Sci · September 2007 The potassium channel accessory subunit KChIP2 associates with Kv4.2 channels in the cardiac myocyte and is involved in the regulation of the transient outward current (I(to)) during the early phase of repolarization of the action potential. As a first ste ... Full text Link to item Cite

A rare cause for recurrent cystitis.

Journal Article Postgrad Med J · June 2006 Answers on p e12 ... Full text Link to item Cite

How do signaling photoreceptors respond to light?

Conference Acta Crystallographica Section A Foundations of Crystallography · August 23, 2005 Full text Cite

Visualizing reaction pathways in photoactive yellow protein from nanoseconds to seconds.

Journal Article Proc Natl Acad Sci U S A · May 17, 2005 Determining 3D intermediate structures during the biological action of proteins in real time under ambient conditions is essential for understanding how proteins function. Here we use time-resolved Laue crystallography to extract short-lived intermediate s ... Full text Link to item Cite

A structural pathway for signaling in the E46Q mutant of photoactive yellow protein.

Journal Article Structure · January 2005 In the bacterial photoreceptor photoactive yellow protein (PYP), absorption of blue light by its chromophore leads to a conformational change in the protein associated with differential signaling activity, as it executes a reversible photocycle. Time-resol ... Full text Link to item Cite

Analytical trapping: extraction of time-independent structures from time-dependent crystallographic data.

Journal Article J Struct Biol · September 2004 All chemical and biological reactions involve atomic motion, embodied in dynamic structural changes. Identifying these changes is the goal of time-resolved crystallography. The "raw" output of a time-resolved macromolecular crystallography experiment is th ... Full text Link to item Cite

Protein kinetics: relaxations on atomic length scales

Conference Acta Crystallographica Section A Foundations of Crystallography · August 26, 2004 Full text Cite

Chromophore conformation and the evolution of tertiary structural changes in photoactive yellow protein.

Journal Article Structure · June 2004 We use time-resolved crystallography to observe the structural progression of a bacterial blue light photoreceptor throughout its photocycle. Data were collected from 10 ns to 100 ms after photoactivation of the E46Q mutant of photoactive yellow protein. R ... Full text Link to item Cite

Analysis of experimental time-resolved crystallographic data by singular value decomposition.

Journal Article Acta Crystallogr D Biol Crystallogr · May 2004 Singular value decomposition (SVD) separates time-dependent crystallographic data into time-independent and time-dependent components. Procedures for the effective application of SVD to time-resolved macromolecular crystallographic data have yet to be expl ... Full text Link to item Cite

Protein kinetics: structures of intermediates and reaction mechanism from time-resolved x-ray data.

Journal Article Proc Natl Acad Sci U S A · April 6, 2004 We determine the number of authentic reaction intermediates in the later stages of the photocycle of photoactive yellow protein at room temperature, their atomic structures, and a consistent set of chemical kinetic mechanisms, by analysis of a set of time- ... Full text Link to item Cite

Purification and initial characterization of a putative blue light-regulated phosphodiesterase from Escherichia coli.

Journal Article Photochem Photobiol · 2004 The Escherichia coli protein YcgF contains a photosensory flavin adenine dinucleotide (FAD)-binding BLUF domain covalently linked to an EAL domain, which is predicted to have cyclic-di-guanosine monophosphate (GMP) phosphodiesterase activity. We have clone ... Full text Link to item Cite

Purification and initial characterization of a putative blue light-regulated phosphodiesterase from Escherichia coli

Journal Article Photochemistry and Photobiology · January 1, 2004 The Escherichia coli protein YcgF contains a photosensory flavin adenine dinucleotide (FAD)-binding BLUF domain covalently linked to an EAL domain, which is predicted to have cyclic-di-guanosine monophosphate (GMP) phosphodiesterase activity. We have clone ... Full text Cite

Application of singular value decomposition to the analysis of time-resolved macromolecular x-ray data.

Journal Article Biophys J · March 2003 Singular value decomposition (SVD) is a technique commonly used in the analysis of spectroscopic data that both acts as a noise filter and reduces the dimensionality of subsequent least-squares fits. To establish the applicability of SVD to crystallographi ... Full text Link to item Cite

Crystal structure of a photoactive yellow protein from a sensor histidine kinase: conformational variability and signal transduction.

Journal Article Proc Natl Acad Sci U S A · February 18, 2003 Photoactive yellow protein (E-PYP) is a blue light photoreceptor, implicated in a negative phototactic response in Ectothiorhodospira halophila, that also serves as a model for the Per-Arnt-Sim superfamily of signaling molecules. Because no biological sign ... Full text Link to item Cite

The LOV domain family: photoresponsive signaling modules coupled to diverse output domains.

Journal Article Biochemistry · January 14, 2003 For single-cell and multicellular systems to survive, they must accurately sense and respond to their cellular and extracellular environment. Light is a nearly ubiquitous environmental factor, and many species have evolved the capability to respond to this ... Full text Link to item Cite

Application of singular value decomposition to time-resolved X-ray data; simulations and experiments

Conference Acta Crystallographica Section A Foundations of Crystallography · August 6, 2002 Full text Cite

Time-resolved macromolecular crystallography: molecular movies?

Conference Acta Crystallographica Section A Foundations of Crystallography · August 6, 2002 Full text Cite