Reviews & Analysis

Lipid accumulation leads to atherosclerosis partly by eliciting lethal levels of cellular stress in macrophages. A signaling pathway that drives such lipid-induced toxicity is now identified. The findings reveal a chaperoning function that might provide the clue needed to rescue this pathogenic effect (pages 1383–1391).

The deposition of excess scar tissue that occurs in lung fibrosis is known to be mediated by transforming growth factor-β (TGF-β). Prostaglandin F_2α and the F prostanoid (FP) receptor are now identified as mediators that act independently of TGF-β (pages 1426–1430).

A molecular pathway known for regulating cholesterol and lipid metabolism is now implicated in stroke (pages 1399–1406). The pathway is bumped up by N-methyl-D-aspartate glutamate receptors (NMDARs), which are hyperactivated in stroke and other conditions.

Excessive stimulation of glutamate receptors results in excitotoxicity and has a role in a variety of neurodegenerative disorders, including Huntington's disease. By blocking pathological extrasynaptic activity but preserving normal synaptic function, the N-methyl-D-aspartic acid (NMDA) receptor antagonist memantine—at the proper dosage—emerges as a potential treatment for such neurological disorders (pages 1407–1413).

Transcription factors known for handling the body's response to lipids promote clearance of apoptotic cells by macrophages, according to new research (pages 1266–1272). When this process goes awry, autoimmunity can result.

High blood sugar can lead to diabetic retinopathy and subsequent blindness. Glucose is now found to quench a growth factor that keeps pericytes alive. Without these key support cells, the retinal vasculature degenerates (pages 1298–1306).

Injection of activated protein C (APC) is the last resort to rescue a patient with severe sepsis. Research into how APC works reveals that the drug inactivates histones (pages 1318–1321), which are toxic during severe sepsis.

The blood-brain barrier constitutes a major obstacle to effective treatment of diseases affecting the central nervous system. A new strategy to target specifically the endothelium of diseased brain may allow the development of more effective gene-based therapies (pages 1215–1218).

The number of copies of the gene encoding a ligand for an HIV co-receptor have been found to influence the susceptibility to HIV infection and AIDS progression. New studies dispute this conclusion. The studies are contested by the authors of the original findings, and highlight the inherent difficulties in accurately measuring gene copy numbers (pages 1110–1112, 1112–1115, 1115–1117 and 1117–1120).

Imatinib (trade name Gleevec) preserves fertility in female mice treated with the common chemotherapeutic agent cisplatin. Imatinib seems to block an apoptotic pathway activated by cisplatin in ovarian germ cells (pages 1179–1185). The findings could lead to new ways to protect germ cells from the damaging effects of cancer treatment.

Mouse experiments show how mutation of a gene involved in human epilepsy causes hyperexcitability of the neuronal network (pages 1208–1214). The mutations interfere with the maturation of excitatory synapses during postnatal development.

Identification of an endogenous inhibitor of lymphatic vessel formation provides a glimpse at how lymphatic vessel growth is restrained (pages 1023–1030). The findings might be exploited to lower transplant rejection rates.

The primary cilium can keep cancer at bay, or it can instigate tumor development, according to studies in mice (pages 1055–1061 and 1062–1065). The outcome depends on the nature of the initiating event, which involves signaling through the Hedgehog pathway.

Obesity accelerates the aging of adipose tissue, a process only now beginning to come to light at the molecular level. Experiments in mice suggest that obesity increases the formation of reactive oxygen species in fat cells, shortens telomeres—and ultimately results in activation of the p53 tumor suppressor, inflammation and the promotion of insulin resistance (pages 1082–1087).

Mammary epithelial cell development is thought to progress from undifferentiated stem cells into at least two differentiated cell types. A new study has now characterized some of these distinct developmental stages and links them to tumor subtypes previously defined by gene expression profiling (pages 907–913).

Inflammation in neural tissue has long been suspected to have a role in stroke. A new study in mouse models of focal cerebral ischemia suggest that a stereotyped sequence of T cell infiltration and activation may underlie the progression of brain injury that can last up to days after stroke onset (pages 946–950).

Obesity generates a proinflammatory environment in adipose tissue, but the factors that initiate this inflammatory cascade have been unclear. Three studies now show that alterations in the composition of adipose tissue T cells occur early in obesity and shape the relationship between immunity and metabolism (pages 914–920, 921–929 and 930–939).

Two studies suggest that low levels of antibodies, when present continuously, effectively limit or prevent HIV infection (pages 951–954 and 901–906). The findings provide hope for the development of a vaccine.