Research articles

Polymorphisms in a primate-specific isoform of K⁺ channel KCNH2 are associated with schizophrenia. This isoform induces a rapidly deactivating K⁺ current and high-frequency neuronal firing pattern. The disease-associated alleles predict lower intelligence quotient scores, lower speed of cognitive processing and altered memory. This channel isoform represents a potential new drug target for psychotherapypages 488–490.

The development of a long-term intestinal culture system has, until recently, eluded researchers. Here the authors describe a method allowing long-term culture of both small intestine and colon that incorporates an air-liquid interface coupled with a three-dimensional matrix scaffold. The cultures show epithelial cell proliferation and multilineage differentiation to the major cell types and accurately recapitulate the Wnt- and Notch-dependent intestinal stem cell niche.

Interleukin-7 (IL-7) promotes immune responses and has been touted as a potential tool for improving immune targeting of tumors. Here Pellegrini et al. investigate the mechanisms by which IL-7 increases antitumor responses and the treatment strategies necessary to optimize its effects.

T cells must enter the brain to induce the autoimmune disease multiple sclerosis. Lydia Sorokin and her colleagues identify a mechanism by which T cells migrate across the endothelial basement membrane, a key step to their passage from the blood into the brain.

Vanneste and her colleagues describe an array-based approach for scoring genome-wide DNA copy number variations and loss of heterozygosity in single cells. They show that chromosome instability patterns, reminiscent of those seen in human cancers, are also common in cleavage-stage in vitro–fertilized embryos. Such findings during early human embryogenesis could provide a basis for the low fecundity and high miscarriage rate in humanspages 490–491..

Hypoxia-triggered neovascularization occurs in many types of disease. Endothelial cells must be able to cope with hypoxic stress, which in other cell types can induce a DNA repair response and inhibit replication. Matina Economopoulou et al. now show that hypoxia induces the generation of a hallmark of the DNA repair response, phosphorylated histone H2AX, in proliferating endothelial cells and that H2AX function is required for neovascularization under hypoxic or ischemic conditions in vivopages 491–493..

In this study, Galbán and his colleagues describe a voxel-wise approach for the quantification of tumor microvasculature properties from perfusion magnetic resonance imaging data. When compared to the standard method of using region of interest analysis of changes in relative cerebral blood flow and volume, the parametric response map approach was found to be more predictive of treatment outcomes and overall survival in individuals with high-grade glioma.

Here Fan et al. describe a protein analysis platform for the sensitive, nanoscale diagnosis and investigation of clinical specimens, including monitoring the response to targeted therapeutics. The nanofluidic proteomic immunoassay can be used to quantify total and phosphorylated forms of oncoproteins in small tumor samples and has been validated in vivo in mouse tumors and in clinical specimens from blood, surgical biopsies and fine-needle aspirates.

Primary prostate cancer is genomically highly heterogeneous and is thought to derive from multiple independent clones of cancer cells. Using high-resolution genomic analyses, Bova et al. now show that, in contrast to primary tumors, metastases are monoclonal, originating from a single cancer cell. These findings call into question current views of the origins of primary prostate cancer and suggest that the genomic profile of prostate cancer metastases should inform therapeutic decisions.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome that is often difficult to treat. Hiroshi Watanabe and coworkers now show that flecainide, an approved drug known to inhibit sodium channels, is able to target the underlying cause of CPVT by inhibiting calcium release through the ryanodine receptor. Flecainide prevented arrhythmia in a mouse model of CPVT and was also effective when tested in two individuals with CPVT.

Granulocyte colony-stimulating factor (G-CSF) is used to accelerate neutrophil engraftment in bone marrow transplant (BMT) recipients to reduce bacterial infections but may also enhance the risk of graft-versus-host disease (GVHD). Morris et al. now show that total body irradiation increases the expression of the G-CSF receptor on recipient dendritic cells, resulting in the activation of donor natural killer T cells and enhanced GVHD when G-CSF is administered shortly after BMT (pages 363–364).

Kurt Redlich and his colleagues show that estrogen deficiency results in increased numbers of preosteoclast progenitor cells in the bones of mice. But they also find that lack of CCR2 in these future bone-resorbing cells prevents their maturation and thus protects the mice from osteoporosis, suggesting a future target for therapy in humans.

House dust mite allergen (HDM) is a potent trigger of airway inflammation. Dendritic cells (DCs) and lung epithelial cells both express the pathogen receptor TLR4, which senses lipopolysaccharide contaminating the allergen. Bart Lambrecht and his colleagues show that TLR4 on the epithelial cells, not the DCs, is the primary sensor of HDM. TLR4 on these lung structural cells is required for recruitment of DCs and the induction of allergic inflammation in response to HDM (pages 366–367).

Inhibitors of α_vβ₃ and α_vβ₅ integrins have previously been shown to inhibit tumor angiogenesis and growth and have entered human clinical trials. Andrew Reynolds and his coworkers now show that low (nanomolar) concentrations of these inhibitors can unexpectedly promote VEGF-dependent tumor angiogenesis and growth in vivo. Such effects could compromise the anticancer efficacy of these agents in humans.

Signaling between endothelial and blood cell types controls inflammatory and thrombotic responses. Andrés Hidalgo and his coworkers now uncover a signaling mechanism by which the endothelium, acting on adherent leukocytes, promotes the capture of platelets or red blood cells by those leukocytes, contributing to pathology in mouse models of two very different types of disease—transfusion-related acute lung injury and sickle cell disease(pages 364–366).

The leukocyte enzyme myeloperoxidase (MPO) is key to normal host defense mechanisms. Dysregulated MPO, however, is linked to acute and chronic inflammatory conditions, such as atherosclerosis and cancer. The authors describe a luminol-based bioluminescence imaging system that provides an optical readout of physiological levels of MPO activity in vivo. The system is demonstrated in animal models of acute dermatitis, focal arthritis and spontaneous large granular lymphocytic tumors.

One way to reduce obesity is to alter fat absorption from the diet. Here Robert Farese, Jr. and his colleagues identify MGAT2 as a potential therapeutic target for doing so. The enzyme is mostly expressed in the gut of humans and mice, and its genetic deletion in mice results in slower kinetics of fat absorption—more of the fat is burned and less is stored, offering protection from diet-induced obesity.

The neurotoxic Aβ peptide is produced after traumatic brain injury. Mark P. Burns and his colleagues show that inhibiting the enzymes involved in Aβ production can block the neuron death and neurological dysfunction that occurs after traumatic brain injury.

Viral-mediated gene therapy presents many challenges in the clinic, including the potential for physiological effects that overshoot the intended goals. In a new report by Matthew During and his colleagues, the authors devise a scheme by which packaging of a microRNA into the virus, expressed under the control of a physiological response induced by the viral transgene, allows coordinated dampening of the transgene expression when the therapeutic response achieves a certain threshold.

New factors in wound healing are sorely needed. Here Youngsook Son and colleagues identify substance P, a small neuropeptide, as one such factor that seems to work by mobilizing stromal-like cells to the site of wounding, accelerating the healing process (pages 367–369).