Research articles

For myelodysplastic syndromes caused by deletion of chromosome 5q, Daniel Starczynowski et al. provide evidence that decreased expression of two miRNAs in this region—miR-145 and miR-146a—contributes to abnormal megakaryocyte differentiation and platelet production and progression of the disease to either bone marrow failure or leukemia. The authors also provide a mechanistic explanation for these effects by which loss of these two miRNAs leads to derepression of innate immune signaling.

Rheumatoid arthritis usually begins in one joint but spreads to other joints as the disease progresses. Elena Neumann and her colleagues show that rheumatoid arthritis synovial fibroblasts (RASFs) may be key mediators of this process. They show, using a SCID mouse model, that human RASFs can migrate long distances through the bloodstream from diseased cartilage to unaffected cartilage, where they can mount a new attack.

Vascular defects resulting from pericyte cell death are thought to be a major underlying cause of diabetic retinopathy. Pedro Geraldes et al. investigate the signaling mechanisms by which hyperglycemia leads to pericyte death and delineate a pathway by which PKC-δ activation decreases antiapoptotic PDGF receptor signaling (pages 1248–1249).

David Hassel et al. show that mutations affecting the protein nexilin underlie an unusual type of dilated cardiomyopathy characterized by disrupted Z-disk structures in cardiac muscle. Functional studies in zebrafish revealed that nexilin has an essential role in maintaining Z-disk stability and suggested that the disease-causing nexilin mutations found in humans encode proteins that act in a dominant-negative fashion.

Viral gene expression can be regulated by chromatin methylation and demethylation. Thomas Kristie and his colleagues have identified a histone demethylase that is required to remove repressive methylation from the immediate early promoters of two α-herpesviruses. Monoamine oxidase inhibitors, which block this demethylase, prevented lytic replication and reactivation from latency.

Extracellular histones released in response to inflammatory challenge contribute to organ failure and death during sepsis. Histone-specific antibodies and activated protein C had beneficial effects in animal models of sepsis, pointing to extracellular histones as therapeutics targets for sepsis and other inflammatory conditions (pages 1245–1246).

Notch signaling is known to modulate the phenotype of vascular smooth muscle cells. Xiaodong Li et al. now provide evidence for the importance of signaling through the NOTCH3 receptor and its downstream target HES-5 in pulmonary arterial smooth muscle cells for the development of pulmonary arterial hypertension, and they demonstrate the therapeutic potential of targeting this signaling pathway in a mouse model of pulmonary hypertension.

Soman Abraham and his colleagues report a new mechanism of immune suppression used by Salmonella. The bacteria traffic to lymph nodes, where Salmonella lipopolysaccharide triggers the downmodulation of certain chemokines, disrupting the cellular organization of the lymph node and impairing adaptive immunity.

Hepatic insulin resistance is often associated with mitochondrial dysfunction, leading to defects in cellular activity. Morris White and his colleagues have now found that continued activity of the transcription factor Foxo1, which is normally inhibited by insulin signaling, is at the crux of this dysfunction, and, when it is genetically deleted, proper mitochondrial function in two models of insulin resistance is restored.

Macrophages coordinate the disposal of apoptotic cells. Ajay Chawla and his colleagues show that PPAR-δ, a sensor of fatty acids, is involved in this process. Ingestion of apoptotic cells by macrophages prompts the upregulation of PPAR-δ, which then responds by enhancing the expression of opsonins. Lack of PPAR-δ reduces apoptotic cell clearance and predisposes to autoimmunity (pages 1246–1248).

Nonhuman primates are key preclinical models for infectious disease, vaccine development and transplantation research, but their use has been hampered by the complexity and diversity of their major histocompatibility complex (MHC) class I genotypes. Wiseman and his colleagues provide a cost-effective solution to this problem using a next-generation pyrosequencing approach to high-resolution MHC genotyping in various nonhuman primates, identifying both known and new MHC class I alleles.

Despite progress in the biosensor field, a platform that allows the sensitive detection of disease-specific proteins in a diverse range of clinical samples such as saliva, serum and urine has proved elusive. Here, Richard Gaster and his colleagues introduce a magnetic nanosensing protein detection platform that offers quantitative multiplex protein detection at attomolar concentrations over a large linear dynamic range and in a range of biological fluids.

In an effort to develop safer therapeutic agents and to limit unintended side effects, Sabah Oney and her colleagues have designed a set of antidote molecules for a series of aptamers exhibiting anticoagulant activities. These so-called universal antidotes are shown to sequester circulating aptamers and reverse their activity, irrespective of the primary sequence and folded structure of the aptamer.

Chemotherapy often leads to premature death of oocytes, and thus infertility, in young individuals with cancer. Here, Stefania Gonfloni and her colleagues show that chemotherapy-induced activation of the kinase c-Abl is responsible for this oocyte failure and that, in vivo, the c-Abl inhibitor imatinib prevents this effect (pages 1124–1125).

Unlike other types of blood components, refrigeration of platelets leads to their rapid clearance from the circulation after transfusion. Platelets must therefore be stored at room temperature, a serious limitation to their use for transfusions. Viktoria Rumjantseva et al. now dissect two platelet clearance pathways by which exposed carbohydrate residues on platelets are recognized by receptors on liver macrophages and hepatocytes, which differentially control the clearance of short-term– and long-term–refrigerated platelets.

Torsten Roepke et al. show that the potassium channel subunit KCNE2—which previously has been most recognized for its role in controlling electrical activity in the heart—is important for normal thyroid function. KCNE2, together with its partner KCNQ1, is expressed in both mouse and human thyroid epithelial cells, and Kcne2 deficiency in mice leads to a constellation of defects resulting from decreased thyroid hormone biosynthesis. These results suggest new genetic links between thyroid and heart function.

Insulin action in the brain is known to inhibit food intake. Now Leona Plum and her colleagues show that in hypothalamic neurons insulin inhibits FoxO1-mediated transcriptional repression of Cpe, a gene that encodes a carboxypeptidase that is required for proper processing of key anorexigenic neuropeptides. The team also found that this pathway is disturbed in states of diet-induced obesity, suggesting that obesity-induced insulin resistance may affect obesity even further.

Dying tumor cells release ATP, which activates the NLRP3 inflammasome in dendritic cells, enabling the secretion of interleukin-1β and the subsequent priming of tumor-specific interferon-γ-producing T lymphocytes.

Optical frequency domain imaging (OFDI) is a wide-field, three-dimensional intravital imaging technique that provides information on the entire tumor vasculature and surrounding tissue microenvironment, allowing visualization of angiogenesis and lymphangiogenesis during tumor growth and with therapy. Here, Vakoc et al. show that, in contrast to multiphoton microscopy, OFDI can image at greater tissue depths with a wider field of view and without the need for exogenous contrast agents.