we did not find any positive role of AP-1 during DMBA/TPA papilloma induction. Elk1, as a member of ETS oncogene family, is an identified target of MAPK which has been reported to play a key role in cell proliferation. We found reduced Elk1 expression in JWAD2/D2 mouse skin tissues as well as in cultured JWAD2/D2 MEFs, suggesting that Elk1 may be involved in TPA induced cell proliferation. The other two MAP kinase pathways have observed to counteract malignant transformation under the stress response. Consistent with those findings, we observed that, JWA Is Required for Induction of Skin Papillomas unlike the B-Raf/MEK/ERK proteins, TPA treatment increased phosphorylations of neither p38 nor JNK in both skin tissue and keratinocytes. In this study, the reduced skin tumor formation observed in the JWAD2/D2 mice might be also partially contributed by the similar mechanisms of premature ageing like phenotype, however, the exact Chebulinic acid web molecular evidences need to be further provided. To exclude the contribution of non cell autonomous effects in skin tumor phenotypes observed in the full knockout mice, future studies should include the conditional deletion of this gene from the skin. In summary, we demonstrate for the first time that JWA deficiency enhances DNA damage in epidermal cells induced by DMBA, however, suppresses TPA-induced MEK-ERK activation, cell proliferation, ” and formation of skin papillomas. These data has potential clinical implications for targeting JWA in chemoprevention and therapy of skin tumors. or total amounts of JNK and p38 were detected by Western blotting. Each experiment was performed in triplicate. Supporting Information treated with DMBA/TPA. PCNA expression in the skin of 
JWA/ and JWAD2/D2 mice treated with DMBA/TPA was analyzed at mRNA level by real-time PCR and protein level by Western blotting. P,0.05. Typical PCNA immunostaining in skin from JWA/ and JWAD2/D2 mice. Arrows indicate PCNA-positive cells. The numbers of PCNA positive epidermal cells were counted ” from at least 100 cells in five separate fields for each section. P,0.05. Data were presented as means 6 s.d. from three independent experiments. in JWA/ and JWAD2/D2 mouse skin and keratinocytes. Skin lysates were prepared in tissue protein extraction buffer from JWA/ and JWAD2/D2 mouse skin treated with DMBA/ TPA at the end point of experiment. Total protein from paired samples was run on SDS-PAGE and probed with antibodies for phosphorylated or total amounts of JNK and p38. JWA/ and JWAD2/D2 keratinocytes were treated with 100 ng/ml TPA for the time period indicated, and phosphorylated Acknowledgments The authors thank Dr. Yihong Zhong in Department of Pathology, the Safety Assessment and Research Center for Drugs, Jiangsu Province, Nanjing Medical University for the assistance of immunohitochemistry analysis. Malaria infects 200 to 300 million people globally and kills approximately 900,000 every year. Current anti-malaria drugs, such as quinine and artemisinin derivatives can effectively clear malaria parasites in blood, however a significant numbers of severe malaria patients including CM patients die or develop severe sequelae regardless of treatment. It is not clear which factors exacerbate mortality among this subset of CM patients, therefore important questions remain to be answered concerning the mechanism of malaria pathogenesis and development of effective therapies. Existing anti-malaria therapy focus on clearance of parasites from blood. This
