Research articles

A serious complication of blood transfusions is transfusion-related acute lung injury, which can be caused by antibodies in the donor blood that recognize and activate host neutrophils. Andreas Greinacher and his colleagues now determine the molecular identity of the antigen recognized by one of these antibodies, termed human neutrophil alloantigen-3a, as a variant of the choline transporter-like protein-2. This finding opens the door to systematic screening of blood donors and recipients.

Orexin, a neuropeptide best known for its role in arousal and its absence in people with narcolepsy, is also involved in the pathophysiology of panic anxiety disorder.

Sterol metabolism modulates immune responses through liver X receptor activation. Tumors harness this signaling pathway and can escape immunosurveillance by inhibiting dendritic cell migration to tumor-draining lymph nodes.

One of the major challenges of metastasis research is being able to track the fate of individual metastasizing cancer cells over time. Here, Kienast et al. describe an animal model in which multiphoton laser scanning microscopy is used to image the steps involved in the establishment of brain metastasis in vivo. The movement of systemically injected, red fluorescent protein–labeled tumor cells is monitored over several weeks, revealing potential targets for therapy.

The virus HTLV-1 is thought to pass between cells through synapses formed when infected lymphocytes make contact with other T cells. Isabelle Thoulouze and her colleagues uncover an alternative mechanism for the cell-to-cell transmission of this virus. They show that HTLV-1 virions bud at the plasma membrane and are held at the cell surface in structures reminiscent of bacterial biofilms. When infected lymphocytes make contacts with other cells, the adhesive viral assemblies are rapidly transferred to to the surface of the new lymphocyte, from which the virions mediate a new round of infection.

Kwakkenbos et al. describe an in vitro method to generate antibody-secreting B cell lines from human peripheral blood memory B cells by transducing them with retroviral vectors encoding Bcl-6 and Bcl-xL. The approach can be used to stably and simultaneously produce high levels of B cell receptor (BCR) on the cell surface and secreted immunoglobulins, useful for studying BCR signaling and producing antigen-specific antibodies.

The circadian clock controls many aspects of human physiology, and disturbances in circadian rhythms have been linked to cardiovascular disease. Masao Doi et al. now delineate a new pathway by which the circadian clock influences hormone production and blood pressure in mice—clock genes control expression of an aldosterone biosynthetic enzyme, such that increased activity of this enzyme in mice with a disrupted circadian clock may account for the increased aldosterone levels and salt-sensitive hypertension seen in these mice.

Premature infants can suffer from an anatomical defect in which the ductus arteriosus, a blood vessel that connects the pulmonary artery and the aorta during fetal development, fails to close at birth. Katrin Echtler et al. now show that platelets are needed for closure in mice and that reduced platelet function may be clinically relevant: in a retrospective study of preterm human infants, low platelet counts were associated with the presence of an unclosed ductus arteriosus.

Deficiency of the transcription factor HNF-1β results in kidney cyst formation. Marco Pontoglio and his colleagues now show that HNF-1β normally remains bound to condensed chromatin during mitosis to facilitate the rapid expression of key genes involved in cell quiescence post-mitosis. In the absence of HNF-1β, these genes fail to express, and the kidney epithelial cells continue to proliferate, resulting in cysts.

Mutations in NOD2—a bacterial sensor in dendritic cells—and mutations in genes related to autophagosome function have been linked to Crohn's disease. Alison Simmons and her colleagues link these susceptibility genes in a single functional pathway. They show that triggering of NOD2 induces autophagy, resulting in increased bacterial antigen presentation on the surface of the dendritic cell. They also show that this process goes awry in dendritic cells expressing the susceptibility variants from individuals with Crohn's disease.

Idiopathic pulmonary fibrosis, or lung scarring, is known, at least in part, to be driven by TGF-β signaling. Shuh Narumiya and colleagues now find that prostaglandin F_2α receptor also has a key role in this disease, independently of TGF-β signaling, and that its genetic deletion ameliorates disease progression in a mouse model.

Gökhan Hotamisligil and his colleagues report that reducing endoplasmic reticulum stress in macrophages by targeting the lipid chaperone aP2 ameliorates atherosclerosis in a mouse model, paving the way for a possible new clinical therapy.

Contrary to the widely held view that impaired γ-aminobutyric acid (GABA)-mediated neurotransmission underlies epileptic activity, extrasynaptic GABA-dependent thalamocortical inhibition caused by reduced GABA uptake is reported to be increased in diverse models of absence seizures.

Gallo and his colleagues report that commensal bacteria on the skin help to dampen inflammation caused by skin injury in mice. They show that, after wounding, necrotic cells release RNA that triggers TLR3 on keratinocytes, causing inflammatory cytokine release. Commensal bacteria in the skin suppress this inflammatory response through triggering TLR2 on the keratinocytes.

Excitotoxicity mediated by over activation of glutamate receptors results in neuronal loss after ischemia. Activation of sterol regulatory element–binding protein-1 is now shown to be crucial for glutamate-mediated excitotoxic neuronal death in a mouse model of stroke.

Adverse events stemming from the use of retroviral vectors in humans has prompted the search for methods predicting the fate and biological consequences of gene-modified cells after vector insertion. Methods of integration site analysis, such as linear amplification-mediated PCR (LAM-PCR), rely on use of restriction enzymes and identify only a fraction of all genomic integrants. This report describes a non–restriction enzyme–based LAM-PCR technique that provides comprehensive, unbiased integration site analysis.

By taking advantage of the direct interaction between heat shock protein 90 (Hsp90) and the transcriptional repressor Bcl-6, a purine-derived inhibitor of Hsp90 selectively kills diffuse large B cell lymphomas that depend on the expression of Bcl-6 for their survival.

In individuals with 5q– syndrome, deletion within chromosome 5q is associated with hematological abnormalities. Jillian Barlow et al. now create an animal model of the disease using chromosomal engineering to remove a corresponding region of the mouse genome. The resulting hematological abnormalities resemble those in the human disease, and the authors provide genetic evidence that p53 activation contributes to the disease process.

In a new report, Benjamin Alman and his colleagues find that the morphogenic pathway activated by Hedgehog signaling is a key mediator of osteoarthritis, a condition that is marked by irreversible degeneration of the joints and with no current treatment. They also found that blockade of Hedgehog signaling prevented osteoarthritis in a mouse model, suggesting this pathway as a possible target to treat this devastating disease.

In a mouse model of Huntington's disease, synaptic activation of NMDA receptors induces the formation of huntingtin-containing inclusions, rendering neurons more resistant to death in vivo and in vitro. In contrast, stimulation of extrasynaptic NMDA receptors increases neuronal vulnerability by preventing inclusion formation.