There has been some debate about the disease-invoking potential of Staphylococcus aureus strains and whether invasive disease is associated with particularly virulent genotypes, or “superbugs.” A study in this issue of the JCI describes the genotyping of a large collection of nonclinical, commensal S. aureus strains from healthy individuals in a Dutch population. Extensive study of their genetic relatedness by amplified restriction fragment typing and comparison with strains that are associated with different types of infections revealed that the S. aureus population is clonal and that some strains have enhanced virulence. This is discussed in the context of growing interest in the mechanisms of bacterial colonization, antibiotic resistance, and novel vaccines.
Timothy J. Foster
The kidney adjusts net acid excretion to match production with exquisite precision, despite little or no change in the plasma bicarbonate concentration. The acid-sensing pathway that signals the kidney to increase acid secretion involves activation of the proto-oncogene c-Src. A new study in this issue shows that proline-rich tyrosine kinase 2 (Pyk2) is responsible for acid-induced activation of c-Src and is essential for acid sensing in renal epithelial cells. The findings implicate a broader role for Pyk2 in acid-base homeostasis in bone and other tissues beyond the kidney.
Stephen L. Gluck
Innate immunity critically depends on signaling by Toll-like receptors (TLRs) that rely heavily on an intracellular adapter protein called myeloid differentiation factor 88 (MyD88). Adaptive immune defenses are generally thought to be orchestrated by innate immune responses and so should require intact TLR-MyD88 signaling pathways. But a surprising new study in MyD88-null mice infected with Mycobacterium tuberculosis challenges this view and instead suggests that MyD88 may not be absolutely required for a normal adaptive immune response.
Terence M. Doherty, Moshe Arditi
Cardiovascular disease is the leading cause of morbidity and mortality in Western countries. Previous studies have highlighted the beneficial effects of PPARγ activators on cardiovascular disease; however, the role of other PPAR family members in atherosclerosis is less clear. A report in this issue of the JCI expands our understanding of PPARs in vascular biology and highlights the potential use of multiple PPAR agonists to limit lipid accumulation in macrophages.
Antonio Castrillo, Peter Tontonoz
Several studies have demonstrated the existence of pluripotent bone marrow–derived stem cells capable of homing to injured cardiac and skeletal muscle; however, there has been little evidence demonstrating the induction of tissue-specific endogenous genes in donor stem cells following engraftment. A new study in this issue reports an intriguing finding that raises additional concerns relating to stem cell plasticity and stem cell therapy in an already heated and controversial field. The study demonstrates that wild-type bone marrow–derived side population stem cells are indeed readily incorporated into both skeletal and cardiac muscle when transplanted into mice that lack δ-sarcoglycan — a model of cardiomyopathy and muscular dystrophy. However, these cells fail to express sarcoglycan and thus to repair the tissue, which suggests that this stem cell population has limited potential for cardiac and skeletal muscle regeneration.
Giulio Cossu
Mitral valve prolapse (MVP), an abnormal displacement into the left atrium of a thickened and redundant mitral valve during systole, is a relatively frequent abnormality in humans and may be associated with serious complications. A recent study implicates fibrillin-1, a component of extracellular matrix microfibrils, in the pathogenesis of a murine model of MVP. This investigation represents an initial step toward understanding the mechanisms involved in human MVP disease and the development of potential treatments.
Arthur E. Weyman, Marielle Scherrer-Crosbie
Studies in genetically engineered mice have shown the importance of cross-talk between organs in the regulation of energy metabolism. In this issue, a careful metabolic characterization of mice with genetic deficiency of the GLUT4 glucose transporter in adipocytes and muscle is reported. These mice compensate for decreased peripheral glucose disposal by increasing hepatic glucose uptake and lipid synthesis as well as by increasing lipid utilization in peripheral tissues. These findings are relevant to humans with type 2 diabetes, in whom a key feature is diminished peripheral glucose disposal.
Perry E. Bickel
Polycystin-1, the protein encoded by the principal gene involved in autosomal dominant polycystic kidney disease, has been implicated in extracellular sensing as well as in cell-cell and cell-matrix interactions. However, the precise mechanisms involved in polycystin-1 signaling are not well defined. A report in this issue of the JCI demonstrates that the C-terminal tail of polycystin-1 is cleaved from the membrane through regulated intramembrane proteolysis (RIP) and that this domain translocates to the nucleus, where it activates the AP-1 transcription pathway. This translocation appears to be modulated by polycystin-2, with which polycystin-1 is thought to interact. These findings provide what we believe to be the first evidence that polycystin-1 can signal directly to the nucleus and that polycystin-1–polycystin-2 interactions do not require colocalization of these proteins in the same membrane compartment.
Lisa M. Guay-Woodford
Autosomal dominant disorders of the skin may present in a pattern following the lines of embryologic development of the ectoderm. In these cases, the surrounding skin is normal, and molecular studies have shown that the causative mutation is confined to the affected ectodermal tissue (type 1 mosaicism). Rarely, an individual shows skin lesions that follow the pattern of type 1 mosaicism, but the rest of the skin shows a milder form of the disorder (type 2 mosaicism). A new study provides the molecular basis for type 2 mosaicism .
Amy S. Paller
SCID, a syndrome characterized by the absence of T cells and adaptive immunity, can result from mutations in multiple genes that encode components of the immune system. Three such components are cytokine receptor chains or signaling molecules, five are needed for antigen receptor development, one is adenosine deaminase — a purine salvage pathway enzyme, and the last is a phosphatase, CD45. In this issue of the JCI, a report describes how complete deficiency of the CD3ε chain of the T cell antigen receptor/CD3 complex causes human SCID.
Rebecca H. Buckley
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