A large scale simulation of excitation propagation in layer 2/3 of primary and secondary visual cortices of mice.

Analyzing network architecture and spatio-temporal dynamics of the visual cortical areas can facilitate understanding visual information processing in the brain. Recently, several physiological experiments utilizing the fast in-vivo imaging technique have demonstrated that the primary visual cortex (V1) and the secondary visual cortex (V2) in mice exhibit complex properties of the responses to visual and electrical stimuli. In order to provide a tool for quantitatively analyzing such a complex dynamics of the cortices at the level of neurons and circuits, here, we constructed a physiologically plausible large-scale network model of the layers 2/3 of V1 and V2, composed of 14,056 multi-compartment neuron models. The Message-Passing-Interface-based parallel simulations of our network model were able to reproduce, at least quantitatively, the neural responses experimentally observed in mouse V1 and V2 with the voltage-sensitive dye imaging.

Efficient delivery of immunostimulatory DNA to mouse and human immune cells through the construction of polypod-like structured DNA.

Investigation of mouse macrophage-like RAW264.7 cells showed that the immunostimulatory activity of CpG DNA is increased by formation of polypod-like structured DNA (polypodna), an assembly consisting of three or more oligodeoxynucleotides. To apply CpG polypodna to immunotherapy, its activity was examined in murine dendritic DC2.4 cells, splenic macrophages, and bone marrow-derived dendritic cells (BMDCs). In all cell types, increasing the pod number increased the cellular uptake of DNA and cytokine release. No significant release of cytokines was observed in macrophages lacking Toll-like receptor 9. Similar results were obtained after intradermal injection of polypodna. The polypodna preparations produced significantly higher amounts of interferon α in human peripheral blood mononuclear cells (PBMCs) compared with single-stranded DNA. The conditioned medium of hexapodna-treated human PBMCs effectively inhibited the activity of a hepatitis C virus subgenomic replicon reporter system. These results indicate that polypodna preparations are useful as an immunostimulator. FROM THE CLINICAL EDITOR: This study demonstrates the utility of polypoid-like structured DNA (polypodna) preparations as potent immunostimulators in a murine model.

5'-Phosphate oligodeoxynucleotides enhance the phosphodiester-CpG DNA-induced inflammatory response in macrophages.

Dying cells release genomic DNA into the surroundings where the DNA is first degraded to oligodeoxynucleotides, then to nucleotides, nucleosides and so on. Given that the unmethylated CpG dinucleotide (CpG motif), which is characteristic of bacterial DNA, is also contained in mammalian DNA and has been reported to be involved in the exacerbation of DNA-associated autoimmune diseases, we investigated whether nucleotides and nucleosides affect immune responses to phosphodiester (PO)-CpG DNA. Addition of non-CpG DNA to RAW264.7, murine macrophage-like cells, induced no significant TNF-α production irrespective of treatment with DNase I; however, DNase I-treated, but not untreated, non-CpG DNA increased the PO-CpG DNA-mediated TNF-α production. This increase was not observed with phosphorothioate-CpG DNA or ligands for TLR3, TLR4 or TLR7. Deoxynucleotides with a 5'-phosphate showed similar effects to those of DNase I-treated non-CpG DNA, but DNase II-treated DNA or deoxynucleosides did not. Subcutaneous injection of PO-CpG DNA into the mouse footpad induced little swelling of the paw; however, significant swelling was observed when DNase I-treated DNA was co-injected with PO-CpG DNA. These results imply that PO-CpG DNA-dependent inflammatory responses are increased by DNA molecules with a 5'-phosphate; such molecules could therefore be considered as exacerbating factors for CpG motif-related inflammation.