News & Views in 2013

Excitatory neurotransmission through NMDA receptors (NMDARs) has a pivotal role in healthy brain function, and its dysfunction has long been implicated in the pathogenesis of neurodegenerative disorders, including Huntington's disease. A new study uncovers a molecular link between mutant huntingtin and aberrant trafficking of an unconventional NDMAR subunit (GluN3A). Targeting this disease mechanism in a Huntington's disease mouse model had multiple therapeutic benefits (pages 1030–1038).

A new study provides an example of the delicate balance between stem cell migration, differentiation and maintenance in the context of skin wounding. In mice, wounding or ultraviolet irradiation induces melanocyte stem cells in the hair follicle to leave their niche before cell division and migrate up the follicle to differentiate into functional melanocytes, thus providing a protective pigmented barrier (pages 924–929).

Metabolic alterations, such as those caused by mutations in the enzyme isocitrate dehydrogenase (IDH), define a clinically distinct subset of primary brain cancers. Expression of BCAT1 is now reported as a new metabolic change defining brain cancers without IDH mutations (pages 901–908).

Malaria remains the most deadly human parasitic disease. A new study finds that malaria parasites signal to mast cells to promote disease through the expansion of specialist dendritic cells and the subsequent activation of pathogenic CD8⁺ T cells (pages 730–738).

Anticancer cytotoxic drugs also kill normal progenitors found in rapidly regenerating tissues, resulting in prolonged hematopoietic insufficiency. Chemotherapy-induced toxicity of the nerves that regulate bone marrow niches required for regeneration of hematopoietic stem cells (HSCs) is involved in this insufficiency, which suggests that co-administration of neuroprotective agents may protect HSCs from the toxic effects of drugs such as cisplatin and vincristine (pages 695–703).

New insights into the actions of the hormone glucagon are provided by a recent study in rodents, which shows that glucagon can suppress hepatic glucose production by acting through the mediobasal hypothalamic region of the brain. This central regulatory mechanism is impaired in rats fed a high-fat diet, suggesting that hypothalamic glucagon resistance may be relevant to the hyperglycemia observed in obesity, diabetes or both (pages 766–772).

During resuscitation after cardiac arrest, a burst of reactive oxygen species (ROS) generated in mitochondria triggers a lethal cascade of events. Nitric oxide is known to be protective, but the mechanism is unknown. A new study shows that a mitochondria-targeted nitric oxide donor S-nitrosates the ND3 subunit of mitochondrial complex I, limiting its ability to generate ROS and protecting the heart against injury (pages 753–759).

Liver steatosis is a characteristic feature of hepatitis C virus (HCV) infection, and the virus itself is known to alter the lipid metabolism of infected hepatocytes. A recent study shows that HCV co-opts the antiviral innate immune response to stimulate the production of hepatic fat droplets, which it can then use to complete its own life cycle and spread (pages 722–729).

Blockage of transforming growth factor-β (TGF-β) signaling in subchondral bone after acute injury in rodents prevents aberrant bone remodeling and cartilage degeneration, suggesting that TGF-β signaling in bone may initiate osteoarthritis in some cases (pages 704–712).

Although it is now accepted that adult humans possess active brown adipose tissue, it has been questioned whether this is genuine classical brown adipose tissue. Two new studies provide evidence that humans, both as babies and adults, do have classical brown tissue and also indicate that there is heterogeneity in the composition of brown fat depots in humans, as in mice (pages 631–634 and 635–639).

The RAS-RAF-MEK-ERK signaling kinase pathway has been the focus of intense cancer drug development efforts because of its central role in tumor cell proliferation and survival. Although inhibitors of RAF and MEK provide therapeutic validation, tumor resistance challenges their effectiveness. Targeting scaffolding proteins such as IQGAP1 may be a new approach (pages 626–630).

It has long been unknown how activation of resident macrophages in the brain, or microglia, is regulated during the inflammatory pathogenesis of multiple sclerosis. Work in a mouse model of human multiple sclerosis identifies the E3 ubiquitin ligase Peli1 as a new crucial regulator of microglia activation (pages 595–602).

L-Carnitine is a common food supplement and naturally occurs in red meat. This nutrient is metabolized into trimethyl metabolites by the gut microbiota and is associated with an elevated risk for cardiovascular disease. A recent study provides new insights into this link by exploring how the gut microbiota generates proatherogenic metabolites from L-carnitine and how the microbiota is altered in response to an omnivorous diet (pages 576–585).

A study now links platelet generation and cholesterol metabolism, providing new understanding of the mechanisms involved in thrombocytosis and atherogenesis. The authors show that the cholesterol transporter ABCG4 is highly expressed in bone marrow megakaryocyte progenitors, and in its absence, these cells have defective cholesterol efflux and increased proliferation, leading to increased megakaryocyte production, thrombocytosis and accelerated atherogenesis in atherosclerosis-prone mice (pages 586–594).

A new study establishes a link between glucagon-like peptide-1 (GLP-1) release from the gut and the cardiac hormone atrial natriuretic peptide, which lowers blood pressure. As GLP-1 receptor agonists are used to control glycemia in patients with type 2 diabetes, this new gut-heart axis suggests a role of these agents in overall cardiovascular homeostasis (pages 567–575).

Although cancer vaccines can induce tumor-specific cytotoxic CD8⁺ T cells, tumors treated by vaccination often fail to regress. A study in mice provides a potential explanation for this phenomenon by showing that a peptide vaccine in a water-oil adjuvant leads to the trapping of tumor-specific CD8⁺ T cells at the vaccination site, instead of promoting an effective T cell response at the tumor site (pages 465–472).

Trisomy 21 triggers multiple potential routes to intellectual disability in Down's syndrome. A new study suggests that aberrant endosomal function may contribute to the neuronal deficits behind learning and memory impairments in affected individuals (pages 473–480).

Two new studies suggest a crucial role for macrophages in boosting the number of red blood cells produced in vivo during stress, with translational implications for disease states such as β-thalassemia and polycythemia vera (pages 429–436 and 437–445).

Many HIV-infected people show impaired humoral immune responses, but it is unclear why. A new view into this conundrum may be provided with the recent discovery of altered interactions between follicular helper T (T_FH) cells and germinal center B cells from HIV-infected individuals. This leads to inadequate T_FH cell help for germinal center B cells and decreased B cell antibody responses (pages 494–499).

Adenovirus type 5 (Ad5) has been intensively studied as a viral vector for gene therapy, and understanding host–Ad5 interactions will be key to the safe and effective use of this vector. A recent study in mice provides new insights in this area by showing that Ad5 enlists a host coagulation factor to overcome complement-mediated blockade and infect the liver (pages 452–457).