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Children born to mothers with lupus have a higher rate of learning disorders. Now, in mouse studies, Betty Diamond and her colleagues show that neurotoxic antibodies found in mothers with lupus are transferred to the brains of their offspring. This leads to abnormalities in cortical formation during development and in cognitive function when the pups become adults.
Inhibitors of PI3 kinase are in development for the treatment of cancer. But whether these compounds will work as single agents remains to be seen. Engelman et al. now show that a PI3K-mTOR inhibitor is effective in a mouse model of lung cancer induced by a mutant PIK3CA but has no effect on Kras-induced tumors. Combining the PI3K-mTOR inhibitor with a MEK inhibitor induced regression of mouse Kras tumors, suggesting that such combinations may be beneficial in human tumors (pages 1315–1316).
Ectopic ossification often involves the transformation of soft tissue into bone. In this new study, Paul Yu et al. show that inflammation is a key step in disease progression and that a small molecule inhibitor of the disease gene’s protein product is therapeutic, thus offering a potential treatment for this devastating condition.
Inhibition of mineralcorticoid receptor activity is known to improve the outcome of chronic kidney disease. In this new report, Toshiro Fujita and his colleagues show that Rac1 strongly potentiates mineralcorticoid receptor signaling by enhancing its nuclear localization and that Rac1 inhibition is ameliorative in two rodent models of renal disease.
When viruses infect cells, they trigger changes such as exposure of phosphatidylserine on the cell surface. Thorpe et al. have shown that this 'inside-out' phosphatidylserine can be targeted by an antibody, and this approach can clear virus infection in mice.
The authors examine how brain inflammation affects the development of epilepsy. They show that genetic or antibody-mediated blockade of leukocyte-vascular interactions reduces epileptogenesis in mice (pages 1309–1310).
Drug hypersensitivity reactions can result in life-threatening epidermal necrosis caused by cytotoxic T lymphocytes and natural killer cells. Chung et al. show that an unusual form of granulysin secreted from these cells is largely responsible for the cell death (pages 1311–1313).
Two microRNAs, miR-15a and miR-16, localize to a chromosome region that is frequently deleted in cancer. Bonci et al. now show that these microRNAs have tumor suppressive effects in prostate cancer cells and regulate the expression of crucial oncogenic targets.
Some Aβ peptides contain pyroglutamate modifications that affect the aggregation properties of these peptides. The authors find that the enzyme glutaminyl cyclase is responsible for this pyroglutamate modification. When they inhibit the enzyme in Alzheimer's model mice, fewer plaques form in the brain, and some measures of learning and memory are improved.
Malaria parasites lacking an enzyme from the purine salvage pathway show attenuated replication in red blood cells and are cleared from mice. The findings suggest a strategy for the development of blood-stage malaria vaccine strains (pages 912–913).
Brain-type creatine kinase (Ckb) has an unexpected role in bone biology. Decreasing its activity suppresses the bone-resorbing activity of osteoclasts, and mice lacking Ckb are protected from osteoporosis-inducing treatments. These findings identify Ckb as a new molecular against bone loss.
Yousefi et al. reveal a new function of eosinophils and suggest they have an antibacterial role in the gut. The cells fire spurts of mitochondrial DNA and granule proteins in response to infection, entrapping and killing the extracellular bacteria (pages 910–911).
Chaperone-mediated autophagy (CMA), a mechanism for the lysosomal degradation of proteins, declines in aging cells. Using transgenic mice in which such a decline does not occur in the liver, the authors found that preserving CMA leads to reduced accumulation of damaged proteins and improved organ function in aged mice (pages 909–910).
Promising results using cell therapy in animal models of muscular dystrophy have recently been reported. However, a limitation of this previous work is that therapeutic effects have been shown only in young animals, whereas many patients who could benefit from such therapy are at advanced stages of disease. As dystrophic muscle ages, it becomes sclerotic and is infiltrated by fat, presenting an obstacle to cell delivery. This paper reports that this obstacle can be overcome by pretreatment of the muscle with tendon fibroblasts that have been genetically modified to express an angiogenic factor and a metalloprotease.
Direct proof that women with pre-eclampsia develop autoantibodies to the AT1 receptor, which explains the hypertension and other symptoms of the disease, is now provided. Additionally, blocking these autoantibodies or treating with losartin, a drug that targets the AT1 receptor, in a new mouse model of this condition helps ameliorate disease outcome (pages 810–812).
Acidification of the phagosome is a key mechanism thought to be used by macrophages against Mycobacterium tuberculosis. The authors identify a previously undescribed gene that confers acid resistance to the bacterium and is essential for virulence (pages 809–810).
Statins and aminobisphosphonates inhibit post-translational modifications and membrane accumulation of progerin, the protein that causes Hutchinson-Gilford progeria syndrome, pointing to a potential combination therapy for this disease.
People with the metabolic syndrome often develop gallstones. Why these two disorders are linked has not been not clear, but now Kahn and his colleagues have shown that lack of insulin signaling in the liver leads to dysregulation of genes that control the transport and synthesis of bile acids, thus altering the proper profile of bile salts and resulting in the formation of gallstones.
Tuberous sclerosis is a neurological disorder associated with seizures and cognitive dysfunction. Alcino Silva and his colleagues find that rapamycin, an inhibitor of the mTOR signaling pathway, can ameliorate cognitive deficits in a mouse model of the disease.