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In two separate studies, Amato Giaccia and Calvin Kuo and colleagues show that targeting of hypoxia-inducible factor-2α to increase its expression results in elevation of a key downstream effector of insulin signaling and thus improved insulin sensitivity in a mouse model of type 2 diabetes.
The Middle East respiratory syndrome coronavirus (MERS-CoV) has killed ∼50% of individuals known to be infected, making understanding its mechanisms of transmission and pathogenesis and identifying candidate treatments a high priority. Heinz Feldmann, Vincent J. Munster and Michael G. Katze and their colleagues now report that treating MERS-CoV-infected rhesus macaques with interferon-α2b and ribavirin reduced virus replication and infection severity, suggesting the potential use of this combination for the clinical treatment of infected humans.
Thorek et al. describe an activatable imaging agent based on a radioactive decay signal through the Cerenkov luminescence effect, which is light produced by β-particle–emitting radionuclides, such as clinically available PET tracers. The approach offers a means of simultaneously investigating multiple disease-relevant biological activities in vivo—the radioluminescent readout providing a quantitative measure of enzymatic activation with reduced background.
Sensitization to the fungus Aspergillus fumigatus is associated with allergic airway disease and asthma. Now Dale Umetsu and colleagues report that invariant natural killer T (iNKT) cells directly recognize the glycosphingolipid asperamide B derived from A. fumigatus. Asperamide B stains and activates mouse and human iNKT cells and induces airway hyper-reactivity in mice, suggesting that fungi can be directly detected by iNKT cells.
Qiong Wang and colleagues introduce the AdipoChaser mouse, an in vivo tool to track the formation and turnover of adipocytes. They use this inducible mature adipocyte lineage-tracing system to monitor adipogenesis and follow the formation of white and beige adipocytes under different conditions: high-fat diet, cold exposure and β-adrenergic stimulation. The system produced some interesting findings on in vivo adipogenesis, including that beige adipocytes differentiate de novo from specialized precursors rather than by transdifferentiation of mature white adipocytes.
Thioredoxin-interacting protein (TXNIP) regulates the redox potential of cells and has previously been found to be upregulated in diabetic states. In a new study, Anath Shalev and colleagues show that TXNIP upregulates the expression of miR-204, which in turn downregulates the expression of MAFA, a key transcription factor regulating insulin expression. These results could further explain the progression of diabetes.
Hans Wehrl et al. use a multimodal approach to demonstrate the feasibility of measuring functional brain responses in activated and resting states with PET and MRI simultaneously. Using this method, which allows brain function studies to be conducted on multiple time and metabolic scales, they could tease apart the complex relationships between neural activity, blood flow and oxygenation that form the basis of the blood oxygen level–dependent (BOLD) effect.
α-secretase–mediated processing of cellular prion protein and amyloid precursor protein is decreased in prion and Alzheimer's diseases. Mathéa Pietri et al. now show that activity of a kinase, PDK1, is increased in the brain following prion infection and with amyloid pathology. This results in internalization of TACE and impairs TACE-mediated α-secretase activity. Inhibition of PDK1 is beneficial in mouse models of prion infection and Alzheimer's disease, suggesting PDK1 may be targeted to attenuate disease progression.
The immunosuppressive activity of T regulatory (Treg) cells has been shown to impair antitumor responses, but depleting these cells has not proved highly promising in the clinic. Wayne Hancock and his colleagues now report that targeting the histone acetyltransferase p300 in Treg cells is an alternate approach to modulating the function of Treg cells and show that inhibiting p300 impairs tumor growth without promoting autoimmunity.
George Kunos and his colleagues show in a rat model that endocannabinoid activation of the Nlrp3 inflammasome in macrophages results in death of pancreatic beta cells, and thus development of type 2 diabetes mellitus. These results suggest that preventing this process might be a therapeutic option for diabetes in the clinic.
Fibroblast growth factor 21 (FGF21) is a cytokine synthesized and released by the liver, muscle and fat and acts both locally and systemically to regulate whole-body metabolism. David Mangelsdorf and his colleagues now show in two separate studies that FGF21 also acts on the region of the brain that regulates circadian rhythm, the suprachiasmatic nucleus, to further regulate whole-body metabolism as well as reproductive function.
Fibroblast growth factor 21 (FGF21) is a cytokine synthesized and released by the liver, muscle and fat and acts both locally and systemically to regulate whole-body metabolism. David Mangelsdorf and his colleagues now show in two separate studies that FGF21 also acts on the region of the brain that regulates circadian rhythm, the suprachiasmatic nucleus, to further regulate whole-body metabolism as well as reproductive function.
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.
Mutations in mitochondrial DNA that inhibit the normal function of this organelle can result in disease if a sufficient percentage of mitochondria in the body's cells harbor such alterations. Using transcription activator–like effector nuclease (TALEN) technology, Carlos Moraes and his colleagues show that mutant mitochondria can be selectively targeted and eliminated, allowing for a sufficient percentage increase of normal mitochondria and thus restoration of normal respiration in a cell-based model.
The efficacy of anti-angiogenic therapy for cancer could be improved if tumor resistance mechanisms were better understood. In this report, Napoleone Ferrara and his colleagues uncover a tumor resistance mechanism to VEGF-neutralizing antibodies triggered by IL-17, the hallmark cytokine of TH17 cells.
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.
Eosinophilic esophagitis (EoE) is characterized by esophageal eosinophilia, but the underlying mechanisms promoting eosinophil accumulation remain unclear. David Artis and his colleagues describe a new mouse model of EoE-like disease. The development of EoE-like disease is dependent on thymic stromal lymphopoietin (TSLP) and basophils, whereas inhibition of TSLP or depletion of basophils attenuates established disease. Moreover, individuals with EoE have increased TSLP expression and basophils in the esophagus, suggesting that the TSLP-basophil axis can be targeted in patients with EoE.
Huntington's disease is a neurodegenerative disorder associated with glutamate receptor dysfunction. Now Isabel Pérez-Otaño and colleagues report that the HTT protein that aggregates in the brains of individuals with the disease disrupts the ability of the adaptor protein PACSIN1 to keep the glutamate receptor subunit GluN3A away from the surface of neurons.
