Reviews & Analysis

Approximately 5% of people that are hospitalized for any reason develop acute kidney failure, which, in some cases, progresses to a chronic condition resulting in fibrosis of the kidney and permanent changes in the organ's function. Two new studies suggest that cell cycle arrest of epithelial cells and epigenetic modifications have key roles in the switch to chronic disease (pages 535–543 and 544–550).

T lymphocytes engineered to produce T cell receptors specific for tumor antigens lead to an antitumor immune response. New findings draw attention to a potentially deadly problem with this strategy. The transgenic T cell receptors can shuffle components with native receptors to produce hybrid molecules with specificity against self antigens (pages 565–570).

Pain caused by chronic inflammation is a serious health problem. But the currently available analgesic drugs cause major side effects when taken long term. A new study points to a class of molecules, resolvins, which not only provide analgesia and are well tolerated but may also reduce inflammation (pages 592–597).

Many parasites vary their surface molecules to avoid the host's immune response, thereby perpetuating long-term infections. Disrupting this process in the intestinal parasite Giardia lamblia now provides a useful tool for vaccination (pages 551–557).

Activation of Toll-like receptors (TLRs) via a nuclear protein released from dying cells, high-mobility group box-1 (HMGB1) protein, leads to chronic epilepsy in rat models and in human epileptic tissue. Blocking this inflammatory pathway may constitute a new antiepileptic treatment strategy (pages 413–419).

The HIV drug raltegravir, which blocks viral integration into the genome, results in a transient increase in episomes, circularized HIV DNA. The findings suggest that persistent HIV replication occurs in people on antiretroviral therapy. Measuring episomes may also offer a new method to study viral persistence and latency and to gauge the effectiveness of antiviral regimens (pages 460–465).

Thalidomide, a drug reviled in the 1960s for its teratogenic effects, has been revived in recent years for cancer and leprosy therapy. A study now finds another use for this drug in vascular disease, providing further insights into the drug's mechanisms of action (pages 420–428).

Two reports in this issue identify a link between insulin action and the unfolded protein response—a pathway that helps the endoplasmic reticulum cope with cellular stress (pages 429–437 and 438–445). The results expand our understanding of the pathogenesis of insulin resistance and provide new targets for prevention and treatment of obesity.

Fewer than half of patients with multiple sclerosis respond to interferon-b, one of the most widely prescribed therapies. The discovery that different subtypes of T cells may be involved in disease development in each affected individual suggests that it may be possible to predict therapeutic success by determining a patient's cytokine profile (pages 406–412).

Galectins are carbohydrate-binding proteins with diverse activities, but there is no unifying picture of their primary physiological role. Galectins now emerge as autonomous bacteria-killing agents (pages 295–301), unexpected findings that may point to a principal role of these proteins in innate immunity.

Systemic inflammation results in a life-threatening drop in blood pressure. Targeting known players of blood pressure regulation has so far failed to improve outcomes for individuals with sepsis. But a study points to a regulatory pathway involving the amino acid metabolite kynurenine that may provide new avenues for therapies (pages 279–285).

Altered lipid metabolism underlies the production of excess mucus in a mouse model of cystic fibrosis (313–318). The findings point to the nuclear receptor peroxisome proliferator–activated receptor-γ (PPAR-γ) as a potential therapeutic target in this disease.

Serotonin produced in the gut reduces the formation of bone. This biology is now harnessed with an orally available inhibitor of gut serotonin synthesis (pages 308–312). The inhibitor promotes bone formation in rodents and points the way to the development of much-needed bone-building drugs.

The involuntary muscle spasms that occur as a result of neuromotor disorders and spinal cord injury can have dangerous consequences for affected individuals. New findings shed light on one mechanism contributing to spasticity: limited chloride transport in motoneurons (pages 302–307).

The extraordinary diversity of HIV is a major barrier in the path of developing a vaccine. One way forward may be mosaic antigens—biometrically designed genes that maximize overlap between sequences used in the vaccine and circulating HIV-1 strains worldwide (pages 319–323 and 324–328).

Microbes in the gut can influence distant events, affecting the function of neutrophils in the circulation of mice (pages 228–231). The findings should lead to new studies examining how intestinal microbes affect immunity.

The receptor for interleukin-7 is a susceptibility factor in multiple sclerosis, but its exact role in the disease has been unclear. New findings outline a function for interleukin-7 in the biology of T helper 17 cells, a subset of T cells recently identified as key players in autoimmune disorders (pages 191–197).

Inflammatory cells can promote tumor cell proliferation, but the range of mechanisms has not been fully explored. A proteinase produced by neutrophils is now shown to enter tumor cells and promote their proliferation (pages 219–223).