Research articles

There is an urgent need for quantitative magnetic resonance approaches for assessing brain development, as well as for studying the effects of drugs on neural tissue inflammation. Aviv Mezer and colleagues have developed a neuroimaging method for the quantification of local tissue volume and tissue-surface interaction, producing reliable quantitative measurements across a range of scanners. They apply their method to both the healthy brain and individuals with relapsing-remitting multiple sclerosis.

Alteration of the bone marrow microenvironment by activation of the parathyroid hormone receptor attenuates chronic myelogenous leukemia (CML) but enhances acute myeloid leukemia (AML) in mouse models, suggesting that the leukemia stem-cell niches in CML and AML are distinct.

Here, Honegger et al. study two HCV-infected women through two consecutive pregnancies and chronicle T cell escape mutations in viral proteins that revert during pregnancy and reappear postpartum. The findings highlight the dynamic between T cell–mediated pressure and viral fitness, with implications for vertical transmission of HCV.

The authors employ targeted next-generation sequencing to identify driving oncogenic alterations in patients with lung cancer with no known oncogenes. They discover two gene fusions involving NTRK1 that lead to constitutive activation of the kinase TRKA and can drive transformation. The fusions can be targeted with available kinase inhibitors and may represent therapeutic targets.

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by loss of the translational repressor protein FMRP. Now, Joel D. Richter and his colleagues report that knocking down the expression of the translational activator protein CPEB can restore normal levels of translation and rescue behavioral deficits in a mouse model of FXS.

The kinase Mst1, which acts in the Hippo pathway, controls cell proliferation, differentiation and apoptosis. Junichi Sadoshima and his colleagues show that Mst1 in cardiomyocytes phosphorylates the protein Beclin1 to coordinately suppress autophagy and promote apoptosis, thereby having deleterious effects on the heart.

Diabetic nephropathy is the most common cause of end-stage renal disease. Shu Wakino and colleagues now show that high-glucose conditions in the renal proximal tubules result in downregulation of Sirt1 expression there and in the glomeruli, resulting in epigentic upregulation of Claudin-1 in the glomeruli and thus proteinuria. They also show that genetic or chemical targeting of Sirt1 in the kidney is sufficient to improve kidney function in a mouse model of diabetic nephropathy.

Progress in T cell receptor (TCR) gene therapy has been hampered by the lack of a rapid and efficient screening system for antigen-specific TCRs. Here, Kobayashi et al. have developed a direct single-cell TCR cloning system for cloning antigen-specific TCRs from peripheral blood in 10 d. The approach is used to clone and analyze Epstein-Barr virus–specific TCRs from healthy donors with latent Epstein-Barr virus infection, as well as TCRs from peptide-vaccinated patients with hepatocellular carcinoma.

The lack of robust and high-throughput technologies to analyze the human TCR repertoire has been a bottleneck in the analysis of human T cell responses. Linnemann and colleagues have addressed this issue by using a TCR gene capture technology that, because of its quantitative nature, allows the rapid identification of TCRab pairs from bulk populations of cells without the need for single-cell cloning. Such an approach should be useful in obtaining defined antigen-reactive TCRs for therapeutic purposes.

Dysfunction of the potassium-chloride cotransporter KCC2 has been linked to many neurological diseases, including pain, anxiety and epilepsy. Now, Yves De Koninck and his colleagues report that they have developed a novel small-molecule compound that is orally bioavailable and can activate KCC2 and reduce chronic pain in rats.

Cellular stress results in the release of damage-associated molecular pattern (DAMP) molecules that promote inflammatory responses. Here Ping Wang and colleagues show that cold-inducible RNA-binding protein (CIRP) is a DAMP that is released into the circulation in response to hemorrhagic shock and sepsis. It promotes proinflammatory cytokine release by binding to the TLR4-MD2 complex. Blockade of CIRP reduces inflammation, organ injury and mortality in animal models of hemorrhage and sepsis, suggesting that CIRP may be targeted therapeutically in these conditions.

In a new study, Yingzi Yang and her colleagues show that a careful balance between Wnt and Hedgehog signaling is required to maintain proper differentiation of osteogenic precursor cells. Upon mutation of GNAS, this balance is disturbed and severe bone disease develops, including either heterotopic ossification or fibrous dysplasia.

This study identifies the concurrent activation of SHH and PI3K signaling by loss of PTEN as a frequent event in glioblastoma tumors that can be targeted with combination treatments using approved drugs to achieve antitumor responses in vivo. The results could potentially lead to the exploration of much needed new combination therapies for human brain tumors.

The authors provide preclinical testing of a CSFR-1 inhibitor in proneural glioma models. The compound targets macrophages in the tumor microenvironment rather than tumor cells themselves and is shown to portend considerable antitumor effects. Its activity relies on re-education of tumor-associated macrophages without affecting their survival, reverting their tumor-promoting phenotype. Moreover, gene signatures capturing the tumorigenic features of macrophages can predict survival in human patients with glioma, underscoring the potential relevance of this strategy as a glioma therapy.

In the process of autophagy, cellular constituents are degraded and recycled. Toren Finkel and his colleagues show that this process also regulates the secretion of a key blood-clotting protein by endothelial cells, such that transient inhibition of autophagy might be therapeutically useful for treating thrombotic disorders.

The correlates of protection against illness caused by natural influenza infection in seronegative individuals is important for the design of vaccines capable of conferring immunity against different influenza virus strains. Sridhar et al. now report their analysis of individuals infected by the 2009 H1N1 pandemic influenza virus and show that the presence of pre-existing CD8+ T cell responses to conserved influenza epitopes is associated with reduced severity of illness. The findings support the importance of developing universal influenza vaccines that are capable of inducing crossreactive T cell responses to mitigate influenza illness.

Rapamycin (also known as sirolimus) is a potent immunosuppressive drug that is often used after organ transplant to prevent rejection, but it also can cause kidney dysfunction. Fabiola Terzi and her colleagues now show this side effect of rapamycin is due to targeting of mTORC2 and suppression of AKT2 activity in podocytes. They also show that AKT2 normally acts to maintain podocyte viability and structure during chronic kidney disease.

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.

Patients with hemophilia lacking functional coagulation factor VIII (FVIII) are treated with replacement FVIII proteins. The development of neutralizing antibodies to the replacement FVIII, a major clinical problem, depends on the nature of the mutation in the gene encoding FVIII. The authors find that a prevalent inversion allele can unexpectedly produce FVIII protein, explaining why individuals with this allele do not frequently develop neutralizing antibodies.

After myocardial infarction, inflammatory cells are rapidly recruited to the heart and strongly affect the course of recovery. Ziad Mallat and his colleagues uncover a pathogenic role for B cells after myocardial infarction, showing that infarction triggers B cell secretion of the chemokine Ccl7, which mobilizes monocytes from the bone marrow, increases their recruitment to the heart and impairs heart function.