Research articles

By immunizing mice with a small synthetic metal-baring complex mimicking the active site of matrix metalloproteinases (MMPs), the authors have generated antibodies that bind and inhibit activated MMP2 and MMP9 in a manner analogous to the mechanism of action of tissue inhibitors of metalloproteinases. Targeting the active conformation of these MMPs is therapeutically effective in mouse models of inflammatory bowel disease.

Ali Ertürk and colleagues present a novel tetrahydrofuran-based histological tissue clearing procedure that renders fixed and unsectioned adult CNS tissue (spinal cord and brainstem) transparent and, as such, fully amenable to a range of different optical imaging techniques. This three-dimensional imaging method can be used for studying axon regeneration and glial reactions.

Sepsis is associated with a hyperinduction of proinflammatory cytokines. ATF3, a transcription factor, is induced in macrophages under conditions of endotoxic shock and downregulates expression of cytokines, including interleukin-6 (IL-6). Although ATF3 may thereby mitigate the severity of sepsis, Hoetzenecker et al. now show that endotoxin-induced ATF3 increases the susceptibility of mice to secondary pathogenic infections due to suppression of IL-6. Their findings suggest that temporal modulation of ATF3 may be important for the successful resolution of sepsis and the ensuing sepsis-associated immunosuppression.

Huntington's disease is a neurodegenerative disease caused by the accumulation of mutant HTT protein. Now, two groups led by Dimitri Krainc and Wenzhen Duan report that mutant HTT binds and inactivates the deacetylase enzyme SIRT1 and that SIRT1 overexpression is protective in Huntington's disease mouse models.

Salmonella infection is a common complication in people with malaria. Here the authors show that induction of heme oxygenase-1, a mechanism of tolerance to malaria, impairs resistance to Salmonella infection by limiting production of bactericidal reactive oxygen species.

Huntington's disease is a neurodegenerative disease caused by the accumulation of mutant htt protein. Now, two groups led by Dimitri Krainc and Wenzhen Duan report that mutant htt binds and inactivates the deacetylase enzyme SIRT1 and that SIRT1 overexpression is protective in Huntington's disease mouse models.

Congenital disorder of glycosylation-Ia in humans is a multisystemic disease marked by severe neurological deficits and results from deficient glycoprotein processing during development. Christian Körner and his colleagues now show that orally supplying mannose to pregnant dams in a mouse model of the disease is sufficient to ameliorate disease symptoms and early lethality, suggesting a possible therapy to treat this devastating condition.

A major issue in the clinic is excessive, or hypertrophic, scarring of the skin after injury. Geoffrey Gurtner and his colleagues have now shown that mechanical forces during such injury upregulates focal adhesion kinase (FAK), which in turn leads to the release of a cytokine that promotes inflammation and fibrosis. They also show that genetic deletion of FAK or its pharmacological inhibition results in minimal scarring in a mouse model.

The authors identify a set of microRNAs regulated by EGFR and MET that are involved in the oncogenic signaling exerted by these receptors and also modulate the response of tumors to targeted EGFR inhibition. These results shed light on the known contribution of MET to therapy resistance and suggest that MET-regulated microRNAs can be key mediators of its effects and potential markers of clinical utility.

The authors find a reciprocal negative regulation loop between TCTP and P53. TCTP modulates P53 by competing with NUMB for MDM2 binding and increasing MDM2-mediated degradation of P53. This is reciprocated by p53's direct transcriptional repression of TCTP. Some human breast tumors have increased amounts of TCTP, which only in some cases correlateswith decreased P53 activity, and elevated TCTP is associated with poor prognosis and may influence P53-regulated stemness of tumor cells.

New methods for analyzing ligand-receptor binding under physiologic conditions in cell-based assays and living animals are much needed for the testing and validation of candidate therapeutic agents targeting ligand-receptor binding. Here, Kathryn Luker and her colleagues developed a molecular imaging assay for ligand-receptor binding based on Gaussia luciferase complementation, focusing on chemokine CXCL12 and its chemokine receptors CXCR4 and CXCR7, although the assay could be applied more broadly to any receptor with a protein ligand.

This report uncovers a role for the mRNA binding factor CPEB4 in cancer. CEPB4 is upregulated in human pancreatic adenocarcinomas and glioblastomas, where it supports tumor growth by providing translational activation of normally silent mRNAs, including tPA, an important contributor to malignancy. The findings illustrate that altered post-transcriptional regulation of gene expression may be an important contributing factor to cancer.

The cytokine PDGF has multiple effects on the vasculature and influences tumor growth and progression. Yuan Xue et al. uncover a new role for PDGF as a regulator of hematopoiesis and provide a unifying mechanism by which PDGF induction of the cytokine erythropoietin in stromal cells underlies PDGF's effects on both hematopoiesis and the tumor vasculature.

Steven Artandi and his colleagues have found that dedifferentiation and proliferation of kidney podocytes as a result of TERT or Wnt signaling leads to a collapsing glomerulopathy phenotype in mice, similar to that seen in HIV-associated nephropathy (HIVAN) in humans, and that inhibiting these pathways corrected disease progression. They also found that TERT expression and Wnt activity is elevated in a mouse model of HIVAN and in human HIVAN renal samples, suggesting possible targets to treat this disease.

Graft-versus-host disease (GVHD) can be a life-threatening complication of bone marrow transplantation (BMT). Understanding the mechanisms causing GVHD is important to developing treatments or preventive therapies. In this issue, Koyama et al. report the surprising finding that recipient nonhematopoietic antigen-presenting cells, rather than dendritic cells, are the crucial factor in inducing CD4⁺ T cell–dependent GVHD and death in mice.

Wound healing involves a transient regeneration of tissue, but, if this process continues unabated, pathology occurs in the form of fibrosis, which can prevent normal organ function and even death. Derek Mann and his colleagues have found that serotonin-responsive profibrogenic hepatic stellate cells inhibit the growth of neighboring liver cells during the termination phase of liver injury. They also found that inhibiting serotonin signaling during established disease improved liver fibrosis in various mouse models of liver injury.

Timothy syndrome is a neurodevelopmental disease that includes autism-like features. Using iPS-derived neurons from individuals with Timothy syndrome, Ricardo Dolmetsch and his colleagues identify changes in cortical neuron fate and neurotransmitter expression that may begin to explain the neural mechanisms that underlie this disorder.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects motor neurons. Now, Valentin Gribkoff and his colleagues show some preliminary evidence that the drug dexpramipexole may have clinical activity in a small placebo-controlled trial in patients with ALS.

This report identifies oncogenic fusions in individuals with breast cancer involving the genes encoding NOTCH and MAST, recurring in approximately 5–7% of studied cases. The fusions show growth-promoting properties that suggest that they may represent targetable events in a subset of people with breast cancer.

Bone marrow-derived mesenchymal stem cells (BMMSCs) have so far failed to live up to their potential as a treatment for the repair of large bone defects. Songtao Shi and his colleagues now show that this may be due to their apoptosis mediated by resident T cells in the wound as a result of excess IFN-γ and TNF-α signaling. They show that reducing the levels of these cytokines, including through the local administration of aspirin, markedly increases the survival of implanted BMMSCs and improves bone wound healing in a mouse model.