Research articles

Animals use their muscles to shiver to generate heat when exposed to the cold. But this is a short-term adaptation. Long term, it is believed the body relies on the brown adipose tissue (BAT) to generate heat in a nonshivering fashion. New work from Muthu Periasamy and colleagues challenge this BAT-centric view by showing that the muscle is also a key site of nonshivering thermogenesis.

Obesity is often associated with mitochondrial dysfunction. What is not clear, however, is whether this is a cause or a consequence of the condition and its detrimental effects on metabolic health. Phil Scherer and colleagues now show that by manipulating a key protein involved in mitochondrial function specifically in adipocytes the mitochondria is crucial in maintaining proper lipid levels and whole-body insulin sensitivity.

Recurrent infections with respiratory syncytial virus (RSV) early in life increase susceptibility to asthma. Nandini Krishnamoorthy et al. show that RSV infection of young mice impairs maternally transferred tolerance to allergens. Regulatory T (T_reg) cells in infected mice have impaired suppressor function and adopt a T_H2-like phenotype.

Live attenuated SIV vaccines protect nonhuman primates from infection with pathogenic wild-type SIV, but the crucial mechanisms have not been clear. In this issue, Louis Picker and colleagues show that protection by live attenuated vaccines against intravenous SIV challenge in rhesus macaques is associated with SIV-specific T cell response in the lymph nodes, and not the blood, and persistent SIV replication in lymph node follicular T helper cells.

Derek Mann and his colleagues have found that experimental induction of liver fibrosis in male rats results in an epigenetic modification of the chromatin in their sperm such that their offspring have a more mild wound-healing response to hepatic fibrogenic insults. The mechanism responsible for this phenomenon is not clear, but it seems to involve a yet unidentified soluble factor released by myofibroblasts that act on either the germ cells or mature sperm.

Ciliopathies are caused by alterations in the development and function of cilia. Now Jeffrey Martens and his colleagues demonstrate anatomic and functional rescue of cilia development in mature, differentiated neurons by adenovirus-mediated restoration of expression of the wild-type protein intraflagellar transport protein 88 (Ift88) and show restoration of olfactory function in a mouse model of ciliopathy. A loss-of-function mutation in IFT88 is also identified in individuals with ciliopathies.

Highly active antiretroviral therapy is crucial to controlling the progression of HIV infection. Therapy failure is often—but not always—attributed to resistance mutations in the HIV-1–encoded protein targets. Here Rosenbloom et al. use mathematical modeling to explain the distinct patterns of resistance found with different classes of antiretroviral drugs and predict specific single-pill combination therapies that might prevent resistance even in the setting of poor patient adherence.

The mineralocorticoid receptor, targeted by drugs commonly used to treat hypertension, is generally thought to contribute to hypertension by altering kidney function. Using mice lacking the mineralocorticoid receptor specifically in smooth muscle cells, Iris Jaffe and her colleagues show that it also controls many aspects of vascular aging, including blood vessel tone, and that these vascular effects contribute to the mineralocorticoid receptor's prohypertensive actions.

Complement components activate and recruit immune cells, promoting host defense and inflammatory disease. Jörg Köhl and his colleagues demonstrate that IgG1 immune complexes inhibit C5a-mediated inflammatory responses and disease. The inhibitory effect of IgG1 immune complexes requires galactosylation of the antibody, binding to the inhibitory IgG receptor FcγRIIB and the association of FcγRIIB with the C-type lectin–like receptor dectin-1.

Bacteria can be trapped by neutrophil extracellular traps (NETs) in vitro, but their relevance in vivo is uncertain, in part because NETs are thought to be released by dying neutrophils, thereby eliminating the other antimicrobial functions of these cells. Paul Kubes and his colleagues report in this issue that NET release need not kill neutrophils and that NETosis can by dynamically imaged in vivo.

Epha4 is a receptor involved in axonal repulsion. Wim Robberecht and his colleagues report that genetic or pharmacological inhibition of Epha4 is protective in rodent and zebrafish models of amyotrophic lateral sclerosis. In humans, expression of Epha4 inversely correlates with disease onset and survival, and in two patients, mutations in Epha4 are associated with longer survival, suggesting Epha4 may be targeted therapeutically to prevent axonal degeneration.

Using the semiconductor synthesis technology of maskless photolithography on microprocessor-grade silicon wafers, Jordan Price and colleagues synthesized microarrays containing every possible overlapping peptide in a linear sequence covering the N terminus of human histone H2B, including post-translational modifications. They demonstrated use of the 'on silico' peptide microarrays for the high-resolution mapping (at the single amino acid level) of epitopes targeted by commercially available H2B-specific antibodies and also by autoantibodies in samples from individuals with systemic lupus erythematosus.

Keisuke Ito et al. uncover a new pathway regulating hematopoietic stem cell maintenance and function. In this pathway, the promyelocytic leukemia protein (PML) regulates the activity of the PPAR-δ nuclear hormone receptor and, thereby, fatty acid oxidation, such that PPAR-δ activators have the potential of improving stem cell function. Intriguingly, this pathway controls the cell fate of dividing stem cells.

Ronald Duman and colleagues report that synapse number is reduced in subjects with major depressive disorder. This is associated with decreased expression of synapse-related genes and increased expression of the transcriptional repressor, GATA1. Expression of GATA1 in prefrontal cortex neurons decreases the expression of synapse-related genes, reduces dendrite branching and produces depressive behavior in a rat model of depression.

Infiltration of various immune cell types into the fat tissue and liver has been implicated in obesity-induced insulin resistance. Jerry Olefsky and his colleagues now show that neutrophils are one of the earliest immune cells to arrive in these tissues, that they release the protease neutrophil elastase and that this enzyme degrades IRS-1, a key member of the insulin signaling pathway. These results show that neutrophils contribute to insulin resistance and how they may do so.

Responses to anticancer therapy are hampered by several factors, and Peter S. Nelson and colleagues here identify a protective effect of the tumor microenvironment. After cytotoxic chemotherapy, inflammatory NF-κB signaling activates the secretion of WNT16B, which acts on epithelial cells, promoting their survival and fostering tumor growth in vivo. This pathway is also active in human tumors treated with chemotherapy and illustrates the potential caveats of cyclical therapy and the need to overcome environmental protection to successfully eliminate tumors.

T cell immunoglobulin and mucin domain–containing 3 (Tim-3) is an inhibitory receptor that is expressed on exhausted T cells and suppresses T helper type 1 (T_H1) responses. Vijay Kuchroo and his colleagues show that human leukocyte antigen B (HLA-B)-associated transcript 3 (Bat3) binds intracellularly to Tim-3 and represses its function. Bat3 knockdown suppresses the development of experimental autoimmune encephalomyelitis and induces an exhaustion-like phenotype in T cells.

A slight mechanical pressure applied to healthy skin results in blood vessel dilation, preserving blood flow. Defects in this vasodilatory response lead to an increased risk of pressure ulcers. Fromy et al. identify the neuronal mechanosensor that mediates this response in both rodents and humans: the ion channel Asic3.

In this issue, Walter et al. report the results of two clinical trials of a new therapeutic vaccine, IMA901, for the treatment of renal cell carcinoma (RCC). IMA901 consists of ten tumor-associated peptides identified as naturally presented T cell epitopes in RCC, and the authors show longer overall survival in subjects with immune responses to multiple vaccine peptides and identify serum and cellular biomarkers that may help predict overall survival in future studies of the vaccine.

Organ fibrosis often leads to end-stage organ failure, but the origin of key profibrotic cell types is still unclear. Lucie Peduto and her colleagues have used genetic lineage tracing and pharmacological ablation techniques to show that ADAM12⁺ perivascular cells are a key source of profibrotic cells in acute skin and muscle injury in the mouse. They also show that knockdown of ADAM12 expression is beneficial, suggesting a possible therapeutic target for the treatment of fibrosis.