Oxidative stress fuels Trypanosoma cruzi infection in mice
Trypanosoma cruzi is a parasitic flagellate protozoa that causes Chagas disease. Dr. Claudia Paiva and colleagues at the Universidade Federal of Rio de Janeiro in Brazil report on how oxidative damage produced by immune cells contributes to the parasite burden. Using a mouse model of T. cruzi infection, they report that induction of a protein called NRF2 and heme-oxygenase-1 (HO-1) mounted antioxidant defenses during infection that enhanced infection. Further, several antioxidants reduced parasite burden in immune cells, while pro-oxidants promoted parasite populations. In a related commentary, Dr. Norma Andrews notes that this report sheds light on an unresolved issue in the field and suggests that oxidative stress may facilitate parasite access to iron. The Paiva team work indicates that oxidative stress contributes to parasite persistence in host tissues and open a new avenue for the development of anti-T. cruzi drugs.
TITLE: Oxidative stress fuels Trypanosoma cruzi infection in mice
ACCOMPANYING COMMENTARY TITLE: Oxidative stress and intracellular infections: more iron to the fire
Keeping the beat: regulating the cardiac conduction system
Heart rate is controlled by the cardiac conduction system, which produces electrical impulses the heart and stimulates muscle contractions that pump blood. Defects in the cardiac conduction system result in the serious and often fatal cardiac conduction system disease. While current treatment options are limited, an improved understanding of the molecular basis of cardiac conduction could improve the development of new therapies. Dr. Ivan Moskowitz and colleages at the University of Chicago tested a hypothesis that TBX5, a critical developmental transcription factor, regulates transcriptional networks required for mature cardiac conduction. They found that mice lacking TBX5 from the mature ventricular conduction system had severe defects in cardiac conduction including loss of fast conduction, arrhythmias, and sudden death. They went on to show that TBX5 binds to regulatory elements in important cardiac genes, including a sodium channel encoded by Scn5a. Their results provide important understanding the molecular pathology of cardiac conduction system disease.
TITLE: A Tbx5-Scn5a Molecular Network Modulates Function of the Adult Murine Cardiac Conduction System
ACCOMPANYING ARTICLE TITLE: Genetic variation in T-box binding element functionally affects SCN5A/SCN10A enhancer
Neutralizing antibody improves hyperparathyroidism but increases mortality
Chronic kidney disease-mineral and bone disorder is associated with hyperparathyroidism and elevations in serum levels of the phosphaturic hormone FGF23 To better understand the role of FGF23 in the development of chronic kidney disease-mineral and bone disorder, Dr. Victoria Shalhoub and colleagues at Amgen Inc. developed a specific antibody to neutralize FGF23 in a rat model of the disease. Neutralization of FGF23 reduced hyperparathyroidism, including decreased parathyroid hormone, increased vitamin D, increased serum calcium, and normalized bone-formation rate. However, they also observed dose-dependent increases in serum phosphate and aortic calcification associated with increased risk of mortality treated rats. Thus, mineral disturbances caused by neutralization of FGF23 limited the efficacy of FGF23 antibody therapy and likely contributed to the increased mortality observed in the rat model.
TITLE: FGF23 neutralization improves chronic kidney disease-associated hyperparathyroidism yet increases mortality
ACCOMPANYING COMMENTARY TITLE: Fibroblast growth factor 23: friend or foe in uremia?
Biochemical cause of neuromuscular disorder revealed
Congenital myasthenic syndromes are neuromuscular disorders that can be caused by defects in acetylcholine receptor (AChR) function. By studying point mutations in patients with myasthenic syndromes, Dr. Xin-Ming Shen and colleagues at the Mayo Clinic in Rochester, MN uncovered unsuspected functional significance of specific amino acids in AChR. Their results indicate that an identified amino acid in the AChRα subunit is contributes to the response of the AChR to the neurotransmitter acetylcholine and that mutation of this residue underlies the neuromuscular defects observed.
TITLE: Key role of myasthenic syndrome mutant residue in loop-C of AChR α-subunit in initial coupling of binding to gating
ACCOMPANYING COMMENTARY TITLE: Pharmacogenomics: mapping monogenic mutations to direct therapy
Journal of Clinical Investigation