Novel AlkB Dioxygenases—Alternative Models for In Silico and In Vivo Studies

Background: ALKBH proteins, the homologs of Escherichia coli AlkB dioxygenase, constitute a direct, single-protein repair system, protecting cellular DNA and RNA against the cytotoxic and mutagenic activity of alkylating agents, chemicals significantly contributing to tumor formation and used in cancer therapy. In silico analysis and in vivo studies have shown the existence of AlkB homologs in almost all organisms. Nine AlkB homologs (ALKBH1–8 and FTO) have been identified in humans. High ALKBH levels have been found to encourage tumor development, questioning the use of alkylating agents in chemotherapy. The aim of this work was to assign biological significance to multiple AlkB homologs by characterizing their activity in the repair of nucleic acids in prokaryotes and their subcellular localization in eukaryotes. Methodology and Findings: Bioinformatic analysis of protein sequence databases identified 1943 AlkB sequences with eight new AlkB subfamilies. Since Cyanobacteria and Arabidopsis thaliana contain multiple AlkB homologs, they were selected as model organisms for in vivo research. Using E. coli alkB2 mutant and plasmids expressing cyanobacterial AlkBs, we studied the repair of methyl methanesulfonate (MMS) and chloroacetaldehyde (CAA) induced lesions in ssDNA, ssRNA, and genomic DNA. On the basis of GFP fusions, we investigated the subcellular localization of ALKBHs in A. thaliana and established its mostly nucleo-cytoplasmic distribution. Some of the ALKBH proteins were found to change their localization upon MMS treatment. Conclusions: Our in vivo studies showed highly specific activity of cyanobacterial AlkB proteins towards lesions and nucleic acid type. Subcellular localization and translocation of ALKBHs in A. thaliana indicates a possible role for these proteins in the repair of alkyl lesions. We hypothesize that the multiplicity of ALKBHs is due to their involvement in the metabolism of nucleo-protein complexes; we find their repair by ALKBH proteins to be economical and effective alternative to degradation and de novo synthesis

Hand, Foot, and Mouth Disease in China: Critical Community Size and Spatial Vaccination Strategies

Hand Foot and Mouth Disease (HFMD) constitutes a considerable burden for health care systems across China. Yet this burden displays important geographic heterogeneity that directly affects the local persistence and the dynamics of the disease, and thus the ability to control it through vaccination campaigns. Here, we use detailed geographic surveillance data and epidemic models to estimate the critical community size (CCS) of HFMD associated enterovirus serotypes CV-A16 and EV-A71 and we explore what spatial vaccination strategies may best reduce the burden of HFMD. We found CCS ranging from 336,979 (±225,866) to 722,372 (±150,562) with the lowest estimates associated with EV-A71 in the southern region of China where multiple transmission seasons have previously been identified. Our results suggest the existence of a regional immigration-recolonization dynamic driven by urban centers. If EV-A71 vaccines doses are limited, these would be optimally deployed in highly populated urban centers and in high-prevalence areas. If HFMD vaccines are included in China’s National Immunization Program in order to achieve high coverage rates (>85%), routine vaccination of newborns largely outperforms strategies in which the equivalent number of doses is equally divided between routine vaccination of newborns and pulse vaccination of the community at large

Observation of the suppressed ADS modes B →[πKππ]DKand B →[πKππ]Dπ

An analysis of B → DK and B → Dπ decays is presented where the D meson is reconstructed in the four-body nal state Kπππ. Using LHCb data corresponding to an integrated luminosity of 1.0fb1, rst observations are made of the suppressed ADS modes B →[πKππ]D K and B → [πKππ]Dπ with a signicance of 5.1σ and greater than 10σ, respectively. Measurements of CP asymmetries and CP-conserving ratios of partial widths from this family of decays are also performed. The magnitude of the ratio between the suppressed and favoured B → DK amplitudes is determined to be r = 0.097 ±0.011. © 2013 CERN. Published by Elsevier B.V

Observation of the suppressed ADS modes B →[πKππ]DKand B →[πKππ]Dπ

An analysis of B → DK and B → Dπ decays is presented where the D meson is reconstructed in the four-body nal state Kπππ. Using LHCb data corresponding to an integrated luminosity of 1.0fb1, rst observations are made of the suppressed ADS modes B →[πKππ]D K and B → [πKππ]Dπ with a signicance of 5.1σ and greater than 10σ, respectively. Measurements of CP asymmetries and CP-conserving ratios of partial widths from this family of decays are also performed. The magnitude of the ratio between the suppressed and favoured B → DK amplitudes is determined to be r = 0.097 ±0.011. © 2013 CERN. Published by Elsevier B.V