Research articles

Temporal lobe epilepsy (TLE) is linked to neuron death in the hippocampus. Now David Henshall and colleagues show that miR-134 is upregulated in humans with TLE and in an experimental epilepsy model in mice. Decreasing miR-134 before induction of epilepsy in mice reduces neuron death and the generation of spontaneous seizures.

Several microRNAs have been identified that affect lymphocyte effector function and contribute to autoimmune inflammatory disease. Here Youcun Qian and his colleagues find that interleukin-17 (IL-17) suppresses miR-23b expression in nonimmune cells present in inflammatory lesions from individuals with rheumatoid arthritis, systemic lupus erythematosus or multiple sclerosis and in the respective mouse models. MiR-23b targets several signaling molecules downstream of IL-17, TNF-α and IL-1β signaling, thereby suppressing proinflammatory cytokine expression and inhibitng autoimmune pathogenesis in vivo.

Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by aggregation of the androgen receptor (AR) protein. Here Gen Sobue and colleagues show that upregulation of miR-196a can reduce expression of AR mRNA and ameliorate disease symptoms in mouse models of SBMA.

Endometriosis afflicts ~15% of women of reproductive age, causing pelvic pain, and is often associated with infertility. In a new study, Bert O'Malley and his colleagues now show that in response to TNF-α signaling, a unique isoform of SRC-1, an estrogen receptor coactivator, is elevated in endometriotic tissue, preventing the normal apoptosis of these cells. These results could explain the proliferation of these cells, while also further suggesting the antibody to TNF-α etanercept as a therapy for this condition.

Nadia Dominici and her colleagues have developed a multidirectional robotic neurorehabilitation system that is capable of operating as a propulsive or postural neuroprosthesis and overcomes some of the limitations of existing systems. The robotic interface allows for the independent assessment and restoration of motor function in rats with mild to severe neuromotor disorders and is validated in various models of spinal cord injury and stroke.

Kaposi's sarcoma–associated herpesvirus (KSHV) can infect endothelial cells, leading to the development of Kaposi's sarcoma in some individuals. The mechanisms underlying cell entry by KSHV are not fully elucidated. ahn et al. now report that ephrin receptor tyrosine kinase A2 (EphA2) acts as a cellular receptor for KSHV and show that blocking EphA2 inhibits infection of endothelial cells.

Exosomes can transfer proteins and nucleic acids from one cell to another, altering the phenotype of the recipient cell. In the case of cancer, tumor-derived exosomes have been shown to promote tumor cell proliferation. Now, in a mouse model of melanoma, Peinado et al. report that exosomes derived from highly metastatic tumor cells can influence bone marrow cells, resulting in increased recruitment of provasculogenic bone marrow progenitors to sites of metastasis, increased primary tumor growth and metastatic spread.

For years, manufacturers have used one of only two chemicals to inactivate viruses for vaccine production: formaldehyde or β-propiolactone, and formaldehyde can damage key antigenic epitopes, leading to reduced immunogenicity or exacerbated disease. Ian Amanna and his colleagues have now found a third, the oxidizing agent hydrogen peroxide (H₂O₂), which they show can be more effective than the conventional approaches. Utility of the H₂O₂-based approach is demonstrated in three model systems.

Tony Lam and his colleagues show that the middle intestine senses glucose and has a role in a gut-brain-liver axis to regulate hepatic glucose production. They also show that an experimental form of bariatric surgery quickly ameliorates hyperglycemia in two rat models of type 1 diabetes, and the intestinal sensing of glucose they have identified probably contributes to this metabolic effect.

Entamoeba histolytica causes human amebiasis. Although antibiotic therapy for this infection exists, there are limited treatment options for this potentially fatal invasive disease. Anjan Debnath and colleagues now report their identification of auranofin, an approved treatment for rheumatoid arthritis, as a candidate new drug for combating E. histolytica infection.

The crosstalk between the transcriptional activity of β-catenin and FOXO3a reveals unexpected pro-metastatic cooperative effects of these pathways through concurrent modulation of cell adhesion and motility programs. In tumors with high FOXO3a and β-catenin activity, the proapoptotic effect of FOXO3a is subverted and the pro-proliferative effect of β-catenin is also dampened, but pro-metastatic pathways are activated. These findings suggest that caution should be exerted when using targeted inhibitors that activate FOXO3a in tumors with high β-catenin activity, as coactivation of both pathways also correlates with more aggressive disease in humans.

Brain cells that die after stroke release intracellular proteins into their environment. Akihiko Yoshimura and his colleagues demonstrate that peroxiredoxin proteins released from dying cells induce inflammatory cytokine expression and drive brain damage after stroke.

Glucose and its metabolic derivatives are increased the plasma of patients with diabetes. Peter Nawroth and colleagues demonstrate that one such metabolite, methylglyoxal, is increased in patients with painful diabetic neuropathy, and find that it acts by modifying the excitability characteristics of a sodium channel protein.

Hepatic glucose production is elevated in obesity and type 2 diabetes, contributing to the hyperglycemia that occurs in these conditions. In a new study, Liangyou Rui and colleagues show that NF-κB–inducing kinase (NIK) is abnormally activated in states of obesity, resulting in elevated hepatic glucose production. When they inhibit NIK activity in the liver, hyperglycemia is lowered, suggesting NIK as a potential therapeutic target in the management of type 2 diabetes.

High concentrations of some types of plasma lipoproteins, such as low-density lipoprotein, promote atherosclerosis and a wide range of vascular-related diseases. These pathogenic lipoproteins have in common the protein component apolipoprotein B. Through study of the effects of modulating lipoprotein levels in experiments involving zebrafish, mice and cultured human endothelial cells, Inbal Avraham-Davidi et al. uncover a potentially deleterious role of apolipoprotein B–containing lipoproteins as direct inhibitors of the angiogenic behavior of vascular endothelial cells.

It is believed that lipid accumulation in the liver, or fatty liver disease, contributes to insulin resistance in this organ and, thus, poorly controlled gluconeogenesis and hyperglycemia during type 2 diabetes. Mitch Lazar and colleagues now show that deletion of the chromatin modifier Hdac3 in mice results in increased fatty liver disease but improved hepatic insulin sensitivity because metabolic flux in the liver is increased toward lipid synthesis and storage and away from gluconeogenesis.

Cigarette smoking raises the risk for cardiovascular disease, including the risk for abdominal aortic aneurysm. Shuangxi Wang et al. now show that nicotine itself is a causal factor in promoting abdominal aortic aneurysms in mice and delineate a pathogenic mechanism by which nicotine exposure leads to activation of the enzyme AMP-kinase in vascular smooth muscle cells and increased expression of the metallopeptidase MMP2.

T cell receptor (TCR)-based immunotherapeutic approaches have so far had limited success because of a lack of specific immune recognition and activation by the TCR. Here Nathaniel Liddy and his colleagues describe the generation, optimization and characterization of a new set of reagents—immune-mobilizing monoclonal TCRs against cancer (or ImmTACs)—designed to overcome some of these limitations. The ImmTACs were used to redirect and activate T cells to lyse tumor cells both in vitro and in vivo, even those expressing very low epitope numbers on the cell surface.

Retinoids and their precursors are known to regulate adipose tissue maturation. Jorge Plutzky and his colleagues now show that an increased endogenous level of retinaldehyde in white adipose tissue, generated by genetic deletion of Raldh1, promotes its 'beiging' in a retinoic acid receptor–dependent manner. They also showed that genetic knockdown of Raldh1 and conversion of white to brown fat leads to weight loss and heightened glucose tolerance in obese mice in a therapeutic manner.

Interleukin-25 (IL-25) is released from lung epithelial cells in response to allergen challenge and promotes type 2 immune responses and allergic airway inflammation. Nicholas Lukacs and his colleagues now report that IL-25 acts on a myeloid population in the lung. These cells represent a major source of IL-4 and IL-13, promote allergic lung inflammation and are steroid resistant. The frequency of IL-4– and IL-13–producing myeloid cells is increased in individuals with asthma, suggesting these cells may have a crucial role in the development of asthma.