Reviews & Analysis

Changes in gut microbial composition have been linked to inflammatory bowel disease, obesity and allergies in humans. A new study shows that pattern recognition of commensal bacteria by B cells reduces allergic inflammation in mice, adding to the mounting evidence for the 'hygiene hypothesis' (pages 538–546).

Cancer genome sequencing projects focus exclusively on the discovery of somatic changes. A new study shows that germline alterations in the proapoptotic protein BIM can have a crucial role in how a tumor responds to treatment (pages 521–528).

A recent study provides new insights into the central control of energy balance and obesity, showing that feeding behavior in mice can be modulated by local dendritic translation of a key protein in neuronal plasticity brain-derived neurotrophic factor (pages 564–571).

Vitamin E is commonly taken as a dietary supplement because it has been shown to have cardioprotective effects. However, its effects on bone metabolism are unknown. A new study in mice shows that α-tocopherol, the main isoform of vitamin E, stimulates bone osteoclast fusion independently of its antioxidant activity, resulting in increased bone resorption (pages 589–594).

Combination-based antiretroviral therapy has been very successful in preventing disease progression in HIV-infected individuals. However, a rational method for predicting the effect of a particular drug combination on clinical outcome is needed. A new study takes us closer to this goal by computationally predicting the inhibitory effects of combinations of three antiretroviral drugs (pages 446–451).

Kinase inhibitors are now standard treatment for patients with lung cancer whose tumors harbor specific mutant kinases. Four recent studies, including three in this issue (pages 375–384), have identified new fusion proteins involving another receptor tyrosine kinase that may potentially be responsive to existing targeted therapies.

Researchers have isolated a rare population of germline stem cells from adult mouse and human ovaries that are capable of forming oocytes. The ability to harvest such cells from human ovaries could change the options available for fertility preservation and the treatment of infertility (pages 413–421).

The kinase AKT has been regarded as an obligate intermediate in the insulin signaling pathway that suppresses glucose production by inhibiting the transcription factor forkhead box O1 (FoxO1) after meals. A new study shows that, without AKT-FoxO1 signaling, insulin still contributes to postprandial responses, revealing an AKT-independent pathway for insulin action that might be exploited to treat metabolic disease (pages 388–395).

This review highlights the importance of immunometabolism to obesity and metabolic diseases such as diabetes. The authors describe recent advances in dissecting the cellular and signaling networks that link the immune and metabolic systems together, and how these insights could be translated to develop new therapeutic strategies to combat metabolic disease.

New strategies for selectively stimulating bone formation without promoting bone resorption are required, as all currently approved agents for osteoporosis act on both of these aspects of the bone remodeling process. A recent study describes an approach that specifically delivers therapeutic siRNAs to bone-forming surfaces without affecting bone resorption (pages 307–314).

Some individuals with colorectal cancer benefit from therapies targeting the epidermal growth factor receptor (EGFR). However, resistance to EGFR blockade inevitably occurs. The characterization of a new mechanism of resistance to the EGFR-specific antibody cetuximab provides clues into how therapeutic strategies might be designed to overcome this specific resistance mechanism (pages 221–223).

Why do some influenza infections cause fatal disease and others barely a sniffle? Although viral virulence can vary, the immunological history of the host is also important. A new study in humans suggests that CD4⁺ T lymphocytes activated during previous infections can limit disease severity in the absence of specific antibodies (pages 274–280).

A new study shows that mice lacking tau develop parkinsonism because of intracellular iron accumulation that results in degeneration of dopamine neurons. Tau deficiency seems to impair ferroportin iron export by retention of the amyloid precursor protein, a neuronal ferroxidase partner, inside the endoplasmic reticulum (pages 291–295).

Noise-induced hearing loss is caused primarily by damage to auditory hair cells; however, humans are unable to regenerate damaged hair cells, necessitating the development of new therapeutic strategies to protect auditory hair cells. A new study suggests that the use of phosphodiesterase 5 (PDE5) inhibitors may provide a protective therapeutic route for hearing loss (pages 252–259).

A newly identified role for SMAD specific E3 ubiquitin protein ligase 2 (Smurf2) in the regulation of histone ubiquitination uncovers a broad tumor suppressor activity that helps to maintain genomic stability in mice. A recent study suggests a new mechanism underlying the role of ubiquitination in cancer (pages 227–234).

The search for compounds to treat neurodegenerative disorders is especially pressing given the rapidly growing elderly human population and has led to the consideration of sirtuin proteins as potential therapeutic candidates. Two studies now report that modulating the expression of the sirtuin Sirt1 has therapeutic benefit in Huntington's disease mouse models and identify putative downstream targets of Sirt1 involved in improved disease outcomes (pages 159–165 and 153–158).

The beneficial cytoprotective effects of heme oxygenase-1 (HO-1) in malaria infection are counterpoised by higher susceptibility to nontyphoidal Salmonella (NTS) bacteremia. A new study in mice co-infected with malaria and Salmonella provides a mechanism for the long-recognized association between malaria and NTS infection in African children.

A new study in mice shows that platelet-derived growth factor-B (PDGF-B) boosts tumor growth by exerting a double function after induction of erythropoietin (EPO) expression from stromal components—a proangiogeneic response in the endothelium and hematopoietic stimulation (pages 100–110).

Collapsing glomerulopathy, the classic kidney lesion in HIV-associated nephropathy, is characterized by the closure of glomerular capillary loops and epithelial cell proliferation. A new study shows that upregulation of TERT, the reverse transcriptase component of telomerase, in podocytes, the key filtration cells in the kidney, plays a major part in the development of this condition by activating Wnt signaling (pages 111–119).