Role of E6 in Maintaining the Basal Cell Reservoir during Productive Papillomavirus Infection.

Papillomaviruses exclusively infect stratified epithelial tissues and cause chronic infections. To achieve this, infected cells must remain in the epithelial basal layer alongside their uninfected neighbors for years or even decades. To examine how papillomaviruses achieve this, we used the in vivo MmuPV1 (Mus musculus papillomavirus 1) model of lesion formation and persistence. During early lesion formation, an increased cell density in the basal layer, as well as a delay in the infected cells' commitment to differentiation, was apparent in cells expressing MmuPV1 E6/E7 RNA. Using cell culture models, keratinocytes exogenously expressing MmuPV1 E6, but not E7, recapitulated this delay in differentiation postconfluence and also grew to a significantly higher density. Cell competition assays further showed that MmuPV1 E6 expression led to a preferential persistence of the cell in the first layer, with control cells accumulating almost exclusively in the second layer. Interestingly, the disruption of MmuPV1 E6 binding to MAML1 protein abrogated these phenotypes. This suggests that the interaction between MAML1 and E6 is necessary for the lower (basal)-layer persistence of MmuPV1 E6-expressing cells. Our results indicate a role for E6 in lesion establishment by facilitating the persistence of infected cells in the epithelial basal layer, a mechanism that is most likely shared by other papillomavirus types. Interruption of this interaction is predicted to impede persistent papillomavirus infection and consequently provides a novel treatment target. IMPORTANCE Persistent infection with high-risk HPV types can lead to development of HPV-associated cancers, and persistent low-risk HPV infection causes problematic diseases, such as recurrent respiratory papillomatosis. The management and treatment of these conditions pose a considerable economic burden. Maintaining a reservoir of infected cells in the basal layer of the epithelium is critical for the persistence of infection in the host, and our studies using the mouse papillomavirus model suggest that E6 gene expression leads to the preferential persistence of epithelial cells in the lower layers during stratification. The E6 interaction with MAML1, a component of the Notch pathway, is required for this phenotype and is linked to E6 effects on cell density and differentiation. These observations are likely to reflect a common E6 role that is preserved among papillomaviruses and provide us with a novel therapeutic target for the treatment of recalcitrant lesions

Requirement of Interaction between Mast Cells and Skin Dendritic Cells to Establish Contact Hypersensitivity

The role of mast cells (MCs) in contact hypersensitivity (CHS) remains controversial. This is due in part to the use of the MC-deficient Kit W/Wv mouse model, since Kit W/Wv mice congenitally lack other types of cells as a result of a point mutation in c-kit. A recent study indicated that the intronic enhancer (IE) for Il4 gene transcription is essential for MCs but not in other cell types. The aim of this study is to re-evaluate the roles of MCs in CHS using mice in which MCs can be conditionally and specifically depleted. Transgenic Mas-TRECK mice in which MCs are depleted conditionally were newly generated using cell-type specific gene regulation by IE. Using this mouse, CHS and FITC-induced cutaneous DC migration were analyzed. Chemotaxis assay and cytoplasmic Ca2+ imaging were performed by co-culture of bone marrow-derived MCs (BMMCs) and bone marrow-derived dendritic cells (BMDCs). In Mas-TRECK mice, CHS was attenuated when MCs were depleted during the sensitization phase. In addition, both maturation and migration of skin DCs were abrogated by MC depletion. Consistently, BMMCs enhanced maturation and chemotaxis of BMDC in ICAM-1 and TNF-α dependent manners Furthermore, stimulated BMDCs increased intracellular Ca2+ of MC upon direct interaction and up-regulated membrane-bound TNF-α on BMMCs. These results suggest that MCs enhance DC functions by interacting with DCs in the skin to establish the sensitization phase of CHS

2-Chloro-7-methyl-12-phenyldibenzo[b,g][1,8]naphthyridin-11(6H)-one

In the title compound, C23H15ClN2O, the fused ring system is planar: the deviation of all the non-H atoms from the plane through all four fused rings is less than 0.31 Å. The plane of the phenyl ring is inclined at 71.78 (5)° to the mean plane of the 1,8-naphthrydine ring system. The crystal structure is devoid of any classical hydrogen bonds but π–π inter­actions are present

Autoimmune Responses in the Rheumatoid Synovium

Rene Toes and Tom Huizinga discuss a new study indicating that lymphoneogenesis in the inflamed synovial tissue of patients with rheumatoid arthritis is fostering potentially pathogenic immune responses

Rotor design of a novel self-start type permanent magnet synchronous motor

Recently, permanent magnet type synchronous motor has been used widely for industry application. In the paper, we propose a novel self-start type permanent magnet synchronous motor with squirrel-cage and analyze the basic characteristics of the motor. We try to increase the efficiency by the rotor design with the finite element analysis.15th International Conference on Electrical Machines and Systems, ICEMS 2012; Sapporo; Japan; 21 October 2012 ～ 24 October 201