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Hindsight

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Insulin resistance in the vasculature
Kieren J. Mather, … , Helmut O. Steinberg, Alain D. Baron
Kieren J. Mather, … , Helmut O. Steinberg, Alain D. Baron
Published March 1, 2013
Citation Information: J Clin Invest. 2013;123(3):1003-1004. https://doi.org/10.1172/JCI67166.
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Insulin resistance in the vasculature

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Abstract

Insulin resistance is typically defined as a reduced ability of insulin to induce glucose uptake by target tissues such as fat and skeletal muscle cells. It accompanies several disease states, including obesity, type 2 diabetes, hepatitis C, and polycystic ovary syndrome, and is a primary feature of metabolic syndrome. Outside of its effects on blood glucose levels, insulin resistance is also associated with a 2- to 3-fold increased risk of cardiovascular mortality. In 1996, Alain Baron, Helmut Steinberg, and colleagues demonstrated that insulin resistance is associated with endothelial dysfunction. This seminal observation led to significant advances in our understanding of insulin’s action in health and disease.

Authors

Kieren J. Mather, Helmut O. Steinberg, Alain D. Baron

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Linking endothelial dysfunction with endothelial cell activation
James K. Liao
James K. Liao
Published February 1, 2013
Citation Information: J Clin Invest. 2013;123(2):540-541. https://doi.org/10.1172/JCI66843.
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Linking endothelial dysfunction with endothelial cell activation

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Abstract

The thin layer of cells that lines the interior of blood vessels, known as the endothelium, plays a complex role in vascular biology. The endothelium mediates blood vessel tone, hemostasis, neutrophil recruitment, hormone trafficking, and fluid filtration. Endothelial dysfunction, as defined by a lack of NO, has been linked to a variety of disease states, including atherosclerosis, diabetes mellitus, coronary artery disease, hypertension, and hypercholesterolemia. Indeed, restoration of endothelial function is one of the earliest recognizable benefits of statin therapy. In 1995, James Liao and colleagues published a study in the JCI demonstrating that NO is a vascular protective factor that limits endothelial activation and prevents leukocyte adhesion to the vessel wall.

Authors

James K. Liao

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From an ACE polymorphism to genome-wide searches for eQTL
Florent Soubrier
Florent Soubrier
Published January 2, 2013
Citation Information: J Clin Invest. 2013;123(1):111-112. https://doi.org/10.1172/JCI66618.
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From an ACE polymorphism to genome-wide searches for eQTL

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Abstract

Angiotensin I–converting enzyme (ACE, or DCP1) is a zinc metallopeptidase that converts angiotensin I into the vasoactive and aldosterone-stimulating peptide angiotensin II and cleaves bradykinin into inactive peptides. Plasma ACE measurement is widely used for the diagnosis of sarcoidosis. While enzyme concentrations are highly stable in an individual, there is a high level of interindividual variability. In 1990, we identified an insertion/deletion polymorphism in ACE that functions as a quantitative trait locus (QTL), accounting for half of the interindividual variability. Since then, technological advances have allowed for the elucidation of expression QTLs (eQTL). Such studies are allowing researchers to determine how underlying genetic predisposition contributes to human disease.

Authors

Florent Soubrier

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Better tools for assessing osteoporosis
B. Lawrence Riggs, … , Sundeep Khosla, L. Joseph Melton III
B. Lawrence Riggs, … , Sundeep Khosla, L. Joseph Melton III
Published December 3, 2012
Citation Information: J Clin Invest. 2012;122(12):4323-4324. https://doi.org/10.1172/JCI66746.
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Better tools for assessing osteoporosis

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Abstract

Some 30 years ago, we applied the newly described method of dual photon absorptiometry (DPA) to demonstrate that osteoporotic women with vertebral fractures had lost substantially more bone from the vertebrae than controls. This opened a whole new field of research into the determinants of bone loss and fractures in the axial skeleton and set the stage for subsequent development of dual-energy x-ray absorptiometry (DXA) and quantitative computed tomography (QCT), which are now the standard methods for assessing osteoporosis severity and treatment efficacy.

Authors

B. Lawrence Riggs, Sundeep Khosla, L. Joseph Melton III

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Autoantibodies, autoimmune disease, and the birth of immune diagnostics
Eng M. Tan
Eng M. Tan
Published November 1, 2012
Citation Information: J Clin Invest. 2012;122(11):3835-3836. https://doi.org/10.1172/JCI66510.
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Autoantibodies, autoimmune disease, and the birth of immune diagnostics

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Abstract

The appearance of autoantibody to DNA followed sequentially by the disappearance of anti-DNA and appearance of DNA antigen in a patient with systemic lupus erythematosus demonstrated that autoantibodies participate in immune complex–mediated pathogenesis. Continuing studies showed that autoantibodies are also useful biomarkers in clinical diagnosis and important reagents for elucidating the structure and function of intracellular proteins in cell biology. Recently, autoantibodies to tumor-associated antigens have been identified in cancer, and these findings have expanded the field of cancer immunodiagnostics.

Authors

Eng M. Tan

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TLRs and IFNs: critical pieces of the autoimmunity puzzle
Argyrios N. Theofilopoulos
Argyrios N. Theofilopoulos
Published October 1, 2012
Citation Information: J Clin Invest. 2012;122(10):3464-3466. https://doi.org/10.1172/JCI63835.
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TLRs and IFNs: critical pieces of the autoimmunity puzzle

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Abstract

Discoveries revealing the molecular basis of innate immune responses, particularly the identification of Toll-like receptors (TLRs) as the major recognition sensors for microbial and even self-molecules, have provided new insights into the pathogenesis of both systemic and organ-specific autoimmune diseases. These insights will permit the development of novel treatment modalities for these disorders.

Authors

Argyrios N. Theofilopoulos

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Complement, oxidants, and endothelial injury: how a bedside observation opened a door to vascular biology
Gregory M. Vercellotti, … , Charles F. Moldow, Harry S. Jacob
Gregory M. Vercellotti, … , Charles F. Moldow, Harry S. Jacob
Published September 4, 2012
Citation Information: J Clin Invest. 2012;122(9):3044-3045. https://doi.org/10.1172/JCI64953.
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Complement, oxidants, and endothelial injury: how a bedside observation opened a door to vascular biology

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Abstract

A single encounter with a dialysis patient led to the study of complement and neutrophil aggregation, which in turn spawned our work and the remarkable development of the field of vascular biology. As our understanding of these cellular interactions and the signaling pathways involved in these processes has expanded, so has our appreciation for the broad impact of this work on an array of human diseases.

Authors

Gregory M. Vercellotti, Charles F. Moldow, Harry S. Jacob

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Liver function from Y to Z
Irwin M. Arias
Irwin M. Arias
Published August 1, 2012
Citation Information: J Clin Invest. 2012;122(8):2763-2764. https://doi.org/10.1172/JCI64587.
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Liver function from Y to Z

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Abstract

In the 1960s, my lab was interested in understanding how bilirubin and other organic anions are transferred from the plasma through the liver cell and into the bile. We performed gel filtration of liver supernatants and identified two protein fractions, designated Y and Z, which bound organic anions including bilirubin, and thus we proposed that they were involved in hepatic uptake of organic anions from plasma. Subsequently, the Y and Z proteins responsible for this binding activity were purified, cloned, and sequenced. Y was identified as a member of the glutathione S-transferase (GST) protein family and Z found to be a member of the fatty acid–binding protein (FABP) family. These proteins have since been shown to have additional surprising roles, but understanding of their full role in physiology and disease has not yet been achieved.

Authors

Irwin M. Arias

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Malonyl-CoA: the regulator of fatty acid synthesis and oxidation
Daniel W. Foster
Daniel W. Foster
Published June 1, 2012
Citation Information: J Clin Invest. 2012;122(6):1958-1959. https://doi.org/10.1172/JCI63967.
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Malonyl-CoA: the regulator of fatty acid synthesis and oxidation

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Abstract

In the catabolic state with no food intake, the liver generates ketones by breaking down fatty acids. During the nocturnal fast or longer starvation periods, this protects the brain, which cannot oxidize fatty acids. In 1977, we published a study in the JCI noting the surprising realization that malonyl-CoA, the substrate of fatty acid synthesis, was also an inhibitor of fatty acid oxidation. Subsequent experiments have borne out this finding and furthered our understanding of molecular metabolism.

Authors

Daniel W. Foster

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Degranulation deconstructed
Robert L. Baehner, Morris J. Karnovsky
Robert L. Baehner, Morris J. Karnovsky
Published May 1, 2012
Citation Information: J Clin Invest. 2012;122(5):1596-1597. https://doi.org/10.1172/JCI62990.
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Degranulation deconstructed

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Abstract

Pediatricians first described the clinical features of chronic granulomatous disease (CGD) in 1959. Almost a decade later, in a collaborative effort that crossed disciplines, we participated in the discoveries that defined the cellular deficiencies of CGD, specifically finding that improper degranulation of leukocytes did not explain their failure to fight pathogens, rather that the fundamental defect was due to problems in the unique NADPH oxidase system of phagocytizing leukocytes. In the years that followed, the subunit components and structure of NADPH oxidase and their translocation during leukocyte phagocytosis to form the active enzyme were well described, leading to the identification of the component genes, the mapping of their chromosomal locations, and their subsequent cloning. This remarkable progress has led to effective therapies, including bone marrow transplants and gene therapy, that would have been unimaginable when we began.

Authors

Robert L. Baehner, Morris J. Karnovsky

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