Reviews & Analysis

Thyroid hormones increase the energy metabolism of the body in a process called 'thyroid thermogenesis'. Its molecular mechanism, however, has been elusive. Recent findings in rats suggest that it is localized to brown adipose tissue—our one truly thermogenic organ—and is mediated via the brain (pages 1001–1008).

Thick, adherent mucus in the airway causes respiratory failure—the leading cause of death in cystic fibrosis. A new study now shows how the formation of neutrophil extracellular traps (NETs) in the airway, in an attempt to kill colonizing bacteria, results in chronic cell carnage that thickens the sputum, worsening lung function in individuals with cystic fibrosis (pages 1018–1023).

A drug that discourages alcohol ingestion has shown promise as a treatment for cocaine addiction. New findings in rats suggest a potential mechanism—the drug decreases amounts of dopamine in the brain (pages 1024–1028). Blocking enzymes that regulate dopamine abundance may be a new way to treat cocaine addiction and prevent relapse in humans.

Vaccines can prevent infections by several pathogens. Success, however, has been limited for other chronic diseases, reflecting a constraint for effectively manipulating the human immune system. The results from four studies describe a novel dendritic cell (DC) subset in humans that may be crucial for the design of vaccines against cancer and other chronic diseases.

Elevated amounts of glutamate, which acts as a neurotransmitter but is also a neurotoxin, are a hallmark of the autoimmune neurological disease multiple sclerosis and may contribute to its pathology. The discovery that a receptor for glutamate can inhibit the development of autoimmunity and protect from neuroinflammation in a mouse model of multiple sclerosis suggests that glutamate may also have a protective role and that its receptor may represent a therapeutic target (pages 897–902).

Cancers can compromise the capacity of the host immune system to recognize tumor antigens. Recent findings now show that increased accumulation of lipids in dendritic cells in tumors can impair presentation of tumor antigens—which is crucial for activation of the immune system—providing a conceptual framework that may help increase the efficacy of therapeutic vaccines (pages 880–886).

Blood coagulation protects from microbial infections. A recent study now shows that neutrophils fine tune the procoagulant response to invading pathogens (pages 887–896). Neutrophils degrade an inhibitor of coagulation, locally 'trapping' bacteria in small blood vessels. But they also increase blood clots in large vessels in the absence of infection, which may be relevant for the treatment of thrombosis.

The angiogenic switch, which leads to the activation of endothelial cell proliferation and the growth of new blood vessels, is a crucial step in tumorigenesis. A study now shows that this process is linked to a microRNA in endothelial cells (909–914). Blocking microRNAs may offer new avenues for antiangiogenesis therapy to treat cancer.

Findings in mice and people suggest that glycosphingolipids have a role in the formation of large fluid-filled cysts in polycystic kidney disease. An inhibitor of glycosphingolipid synthesis may provide a potential therapy for this disorder, which often progresses to kidney failure (pages 788–792).

Chromosomal translocations can promote cancers by eliciting the expression of fusion genes with oncogenic activity. The identification of translocations affecting RAF genes in prostate and gastric cancers and melanoma provides compelling evidence for the key role of RAF signaling in a subset of these cancers and suggests possible new avenues for personalized cancer therapy (pages 793–798).

Ephrin-B2 is required for the formation of blood and lymphatic vessels, but the mechanism has been enigmatic. Two independent studies show that ephrin-B2 controls the internalization and signaling of two types of vascular endothelial growth factor (VEGF) receptors—thereby regulating VEGF-induced angiogenesis in normal and pathological conditions.

The stress response protein Rtp801 mediates damage to the lung in response to smoke. This finding might lead to new ways to treat chronic obstructive pulmonary disease and emphysema (pages 767–773).

Pregnancy increases the demand for insulin by various tissues in the body, a condition that can lead to gestational diabetes. To shield against this condition, insulin-producing beta cells proliferate in a process now shown to involve the local production of serotonin in response to lactogenic hormones (pages 804–808).

Basophils have recently been identified as antigen-presenting cells that are required for optimal antibody responses. New findings now show that activation of these cells can amplify autoimmune responses in systemic lupus erythematosus (SLE) (pages 701–707).

Activation of Toll-like receptor (TLR) signaling by microbes in the intestine promotes tumor growth in genetically susceptible mice. Inactivation of extracellular signal–regulated kinase (ERK), a molecule downstream of TLR signaling, may offer a route to preventing colorectal cancer (pages 665–670).

Cytokines have a fundamental role in orchestrating innate immune responses to bacterial infections. Interleukin-33 (IL-33) is now shown to protect from sepsis by promoting neutrophil influx into the focus of infection (pages 708–712).

There is no cure for osteoarthritis—the most common disease of the joints. By piecing together the molecular events that drive the progression of this debilitating disease, recent studies published in Nature Medicine put hypoxia-inducible factor-2α (HIF-2α) in the driver's seat, opening up new avenues for early detection and treatment (pages 678–686 and 687–693).

Mammalian genomes harbor regulatory elements from ancient retroviral infections. These retroviral remnants are normally silenced by DNA methylation—but this can change. Reactivation of one such element triggers the expression of a nearby oncogene during the development of Hodgkin's lymphoma (571–579).