Research articles

Kelly et al. offer a method for controlling the tropism of replicating viruses. Viral replication in a specific target tissue is inhibited by incorporation of tissue-specific microRNA targets within the viral genome. Using an oncolytic picornavirus that causes myositis in tumor-bearing mice, they show the virus is unable to replicate in muscle but still retains oncolytic activity, with implications for the clinical use of oncolytic viruses and vaccine development.

Niemann-Pick type C1 is a lysosomal storage disease caused by mutations in the NPC1 gene. The authors show that NPC1 regulates calcium levels in the lysosome, and calcium dysregulation could be the proximal event in inducing the accumulation of lipids that characterizes the disease.

Although major histocompatibility complex (MHC) class II alleles and CD4⁺ T cells have been implicated in multiple sclerosis, Friese et al. provide here the first direct evidence incriminating MHC class I genes and CD8⁺ T cells in the pathogenesis of this autoimmune disorder (pages 1150–1151).

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.

Bjorn Olsen and his coworkers shed light on the molecular mechanisms underpinning the proangiogenic properties of endothelial cells in hemangiomas, tracing these properties to decreased activity of a signaling pathway involving NFAT transcription factor regulation of VEGFR1 receptor expression. They also identify germline mutations in genes encoding elements of this signaling pathway in a subset of individuals with hemangioma and suggest that interventions in this pathway could have therapeutic effects (pages 1147–1148).

There is a pressing need for better methods to analyze specific proteins in a high-throughput manner. Current approaches involve studying only a few markers at a time. Here Kattah and his colleagues describe a new technology for multiplexed protein detection called high-throughput immunophenotyping using transcription (HIT). Use of this multianalyte, antibody-based protein array platform is demonstrated for profiling cytokines in serum, intracellular signaling molecules and cell surface markers.

Pauci-immune crescentic glomerulonephritis—an inflammatory disease of the kidneys— may be triggered by bacterial infection. Kain et al. show that almost all individuals with this disease have auto-antibodies to the membrane protein LAMP-2. These antibodies cross-react with the bacterial adhesion FimH, and immunization with FimH causes disease in rats.

The mechanisms that control blood vessel formation are incompletely understood. Sylvain Chemtob and his colleagues now find that blood vessel formation in mouse and rat retinas is controlled by succinate generated during hypoxic and ischemic conditions. Succinate acting through its receptor, GPR91, on retinal ganglion neurons, triggers secretion of canonical proangiogenic factors and the formation of new blood vessels to reinstate adequate tissue supply. This work also identifies GPR91 as a potential therapeutic target for the treatment of ischemic retinopathies.

Banaszynski et al. combine genetic manipulation with small-molecule regulation to produce rapid, reversible and tunable regulation of protein expression in vivo. The approach builds on earlier work showing that fusion of a destabilizing domain to a gene of interest confers instability to the expressed protein. Degradation of the protein is then prevented by subsequent addition of the cell-permeable stabilizing ligand, Shield-1, which binds specifically to the destabilizing domains. Three in vivo applications of the technology in mice are described.

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.

Although increased levels of lipoprotein-associated phospholipase A2 (Lp-PLA2) have been associated with cardiac disease, whether this enzyme has a causal role in the development of atherosclerosis has not been clear. Wilensky et al. now show in a pig model of atherosclerosis that a selective Lp-PLA2 inhibitor reduces progression to complex atherosclerotic lesion formation, an effect that is associated with decreased infiltration of inflammatory cells into the lesions. These results support the use of Lp-PLA2 inhibitors for the treatment of atherosclerotic cardiovascular disease.

Mitochondrial dysfunction has been described in Alzheimer's disease, but how it is induced has remained unclear. Shi Du Yan and her colleagues find that a neurotoxic amyloid protein associated with the disease binds a mitochondrial protein called cyclophilin D and causes neuron death. The authors show that Alzheimer's disease model mice that lack cyclophilin D show improvements in learning and memory.

Unlike HIV-infected humans or SIV-infected rhesus macaques, natural monkey hosts for SIV do not show immune activation or progress to AIDS, even though they have high viral loads after infection. Differences in the innate immune response in these monkeys may provide a clue as to why they remain healthy.

De-Xue Fu et al. present a novel approach to radiotherapy of herpesvirus-associated tumors by first inducing the expression of viral thymidine kinase by pretreatment with bortezomib and then by administering a radiopharmaceutical that targets the viral enzyme. The authors show that this approach is effective in lymphoid and epithelial malignancies in several xenograft mouse models of human tumors.

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).

Traykova-Brauch et al. have developed a new approach to modeling renal diseases such as polycystic kidney disease, renal fibrosis and renal cancer in transgenic mice. In contrast to currently available tools, Pax8-rtTA–transgenic mice have high levels of transgene expression in a highly kidney-specific, uniform and tetracycline–dependent manner. The usefulness of the Pax8–rtTA system, which is both inducible and reversible, has been shown in three different settings.

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.

Currently, there are few options for treating chronic kidney disease. The immunosuppressant cyclosporine A is effective, but the mechanism has been unclear. In this new report, the authors now show that the benefit of cyclosporine A is not through an effect on the immune system but rather through stabilizing the cytoskeleton, and thus the integrity, of a key cell type needed for proper kidney function.