Letters in 2013

Macrophages are abundant in atherosclerotic plaques and are a pivotal cell type in plaque formation and progression. But how do they get there? Filip Swirski and his colleagues show that, contrary to most previous work that has emphasized the importance of monocyte recruitment from the blood, most macrophages in established lesions are generated by local macrophage proliferation, which depends on the SR-A scavenger receptor.

Blood brain integrity is compromised in autoimmune disorders of the central nervous system (CNS0. Here Stefan Bittner et al. report that expression of TWIK-related potassium channel-1 (TREK1) is decreased in individuals with multiple sclerosis and mice with autoimmune disease. The severity of EAE is increased in mice deficient in TREK1. Activation of TREK1 using riluzole or a diet enriched in linseed oil attenuates disease severity and reduces leukocyte infiltration into the CNS, suggesting that TREK1 may be targeted to reduce the migration of immune cells into the CNS.

Tuberculosis kills more than a million people annually, and new treatments are necessary to counter the spread of drug-resistant forms of Mycobacterium tuberculosis. In this issue, Kevin Pethe and his colleagues report their identification of a new antibercular drug, called Q203, that targets the mycobacterial cytochrome bc₁ complex and that showed efficacy in vitro and in vivo.

Liver receptor homolog-1 is an orphan nuclear receptor. Murphy and colleagues now show that this protein is crucial for different phases of pregnancy, including implantation and maintenance of the developing fetus, in mice, as well as for the proper function of human endometrial cells in culture.

CD8⁺ T cell responses have been associated with control of HIV replication, but the role of CD4⁺ T cells in protecting against this virus is unclear. In an analysis of HLA class II–restricted CD4⁺ T cell responses in HIV-infected individuals, Hendrik Streeck and his colleagues now report that certain HLA-DRB1 variants are associated with low viremia and can present a wide breadth of peptides, suggesting that CD4⁺ T cell responses in infected individuals may help control HIV.

Depression is a debilitating condition for which new treatments are sorely needed. Now, Erich Gulbins and his colleagues report that reducing ceramide levels in the brain has antidepressant effects in mouse models of the disease.

Mayumi Ito and her colleagues show that during skin wounding in mice, melanocyte stem cells in the hair follicle are induced by melanocortin 1 receptor (Mc1r) signaling to migrate towards the epidermis and differentiate into mature pigment-producing cells. This mechanism allows for protection of the healing skin from ultraviolet light–induced damage.

Nitric oxide donors protect from myocardial ischemia-reperfusion injury, but the underlying mechanisms have been unclear. Edward T Chouchani et al. uncover the molecular target of such donors, a cysteine residue in a subunit of complex I of the mitochondrial respiratory chain, and suggest that this cysteine residue has a general role in regulating complex I activity and modulating ischemia-reperfusion injury.

Glucagon has traditionally been thought to act exclusively on the liver to promote endogenous glucose production in that organ. Tony Lam and his colleagues now show that it also acts on the hypothalamus to inhibit glucose production through a neural relay to the liver and that under high fat–fed conditions in rats this pathway is inhibited. This resistance may further explain the hyperglycemia that exists during obesity and diabetes.

Abnormalities in how pulmonary veins connect to the heart underlie a type of congenital heart disease. Jonathan Epstein and his colleagues show that this condition, termed anomalous pulmonary venous connections, can be caused by mutation of the gene encoding the guidance protein semaphorin 3d and show how this protein acts in the embryo to pattern the developing pulmonary veins.

Astrocytic dysfunction is a common feature in the brains of depressed subjects. Now, Xin-Hong Zhu and colleagues show that astrocytic release of ATP is reduced in the brains of stressed mice and that restoring brain ATP levels can rapidly reverse depressed behaviors in mice.

Identifying tumor-associated T cell epitopes can be laborious. Robbins et al. now report that they used whole-exome sequence data to identify mutated peptides from tumor antigens that are recognized by tumor-infiltrating T cells from patients with melanoma who experienced therapy-associated tumor regressions. The method will contribute to the identification of new tumor-specific epitopes that may further the development of effective T cell therapies for the treatment of patients with melanoma as well as a variety of additional malignancies.

Brown fat is a thermogenically active organ that burns energy instead of storing it and has been the focus of intense research recently in the hopes of harnessing this activity to combat obesity. Sven Enerbäck and his colleagues now show that human neonates possess a classical form of this type of fat, suggesting hope that its expansion in adults may indeed be an avenue of therapy to treat obesity.

Brown adipose tissue (BAT) burns, rather than stores, energy and has thus been explored as a way to combat obesity. Aaron Cypess and his colleagues isolate neck fat from adult humans and show that BAT exists in this region, define its anatomical localization in the neck relative to white adipose tissue and demonstrate that it is functional.

The MAPK cascade scaffolding protein IQGAP1, although dispensable for normal epithelial homeostasis, is required for RAS- and RAF-driven tumorigenesis in mouse tumor models. Accordingly, peptide-specific disruption of the interaction between IQGAP1 and ERK1/2 can bypass acquired resistance of vemurafenib-treated BRAF-mutant melanomas and extend the life span of tumor-bearing mice.

Analysis of gene-expression profiles led to the identification of three molecularly distinct subtypes of colon cancer. One of these subtypes is new, and its identification is of clinical interest because it tends to have a particularly unfavorable prognosis and is refractory to existing targeted therapies.

Gene-expression profiles from over 1,000 colorectal tumors define six subtypes with specific phenotypical features, responses to therapy and clinical progression.

It has been thought that a switch by the muscle from oxidative phosphorylation to glycolysis is associated with the development of insulin resistance. Jiandie Lin and colleagues now show that transgenic mice that undergo this switch, due to modest overexpression of Baf60c, are actually more glucose tolerant and insulin sensitive compared to wild-type mice when both are placed on a high-fat diet, suggesting the switch is actually an adaptive process.

Gerhard Krönke and his colleagues show that PPARβ/δ regulates Wnt signaling in osteoblasts, which in turn determines the proper ratio of OPG to RANKL and thus bone homeostasis. They go on to show that pharmacological activation of this receptor normalizes bone density in a mouse model of osteoporosis.

Fragile X syndrome is a type of mental retardation caused by mutations in the Fmr1 gene. Now Andres Ozaita and colleagues show that blocking cannabinoid signaling can restore learning in these mice, suggesting a potential therapeutic approach to this disease.