The 4 202 353 bp genome of the alkaliphilic bacterium Bacillus halodurans C-125 contains 4066 predicted protein coding sequences (CDSs), 2141 (52.7%) of which have functional assignments, 1182 (29%) of which are conserved CDSs with unknown function and 743 (18. 3%) of which have no match to any protein database. Among the total CDSs, 8.8% match sequences of proteins found only in Bacillus subtilis and 66.7% are widely conserved in comparison with the proteins of various organisms, including B.subtilis. The B. halodurans genome contains 112 transposase genes, indicating that transposases have played an important evolutionary role in horizontal gene transfer and also in internal genetic rearrangement in the genome. Strain C-125 lacks some of the necessary genes for competence, such as comS, srfA and rapC, supporting the fact that competence has not been demonstrated experimentally in C-125. There is no paralog of tupA, encoding teichuronopeptide, which contributes to alkaliphily, in the C-125 genome and an ortholog of tupA cannot be found in the B.subtilis genome. Out of 11 sigma factors which belong to the extracytoplasmic function family, 10 are unique to B. halodurans, suggesting that they may have a role in the special mechanism of adaptation to an alkaline environment.

DNA repair systems maintain the integrity of the genome; therefore, their activities are associated with mutation frequencies of cancer-related genes. Up to the present, a number of genes have been shown to be involved in DNA repair systems. 1 Some of the genes encode factors for base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), DNA doublestrand breaks repair (DSBR), or other repair pathways, while some others encode DNA polymerases that can bypass DNA damages. In addition, DNA damage response genes, which encode factors to transmit the signals of DNA damages to the cell cycle checkpoint machinery and to the monitoring systems controlling cellular apoptosis, can be regarded as a class of DNA repair genes. It has been considered that polymorphisms in DNA repair genes lead to interindividual differences in the capacities for repairing DNA damages; therefore, they could contribute to susceptibility to cancer. [2][3][4] Lung cancer is the leading cause of cancer-related deaths in the world, and genetic factors responsible for susceptibility to lung cancer have been searched for to establish novel and efficient ways of preventing the disease. Several epidemiologic studies have indicated that there are genetic factors to modify the risk of individuals to lung cancer. [5][6][7] Segregation analyses suggest that rare autosomal dominant genes may explain susceptibility to earlyonset lung cancer, but only a minority of lung cancer cases can be explained by the presence of such genes. 5-7 Therefore, more common genetic polymorphisms have been considered to affect the risk of lung cancer in the general population. Lung cancer patients were reported to have lower capacities to repair DNA damages than healthy individuals. 6,8 Therefore, it was indicated that polymorphisms of DNA repair genes are strong candidates for genetic factors responsible for lung cancer susceptibility. In fact, single nucleotide polymorphisms (SNPs) in several DNA repair genes were examined for associations with lung cancer risk, and a few SNPs, TP53-Arg72Pro, OGG1-Ser326Cys, XRCC1-Arg399Gln and XPD-Asp312Asn, showed associations. 3 Therefore, the significance of genetic polymorphisms in DNA repair genes in lung cancer risk is being revealed. However, to make their contribution on lung cancer risks clearer, polymorphisms in various classes of DNA repair genes should be more extensively examined for associations with the risk. For this reason, in this study, 36 DNA repair genes involved in diverse intracellular processes that maintain genome integrity (Table I) were searched for nonsynonymous (associated with amino acid changes) SNPs, and 50 SNPs detected were subjected to a case-control study to examine their associations with risks for lung cancer. Lung cancer subjects analyzed in this case-control study consisted of adenocarcinoma (ADC) and squamous cell carcinoma (SQC) cases. ADC and SQC are the first and second major histologic subtypes of lung cancer, respectively, and epidemiologic studies have indicated that ca...

The potential threat of smallpox bioterrorism has made urgent the development of lower-virulence vaccinia virus vaccines. An attenuated LC16m8 (m8) vaccine was developed in 1975 from the Lister strain used in the World Health Organization smallpox eradication program but was not used against endemic smallpox. Today, no vaccines can be tested with variola virus for efficacy in humans, and the mechanisms of immune protection against the major intracellular mature virion (IMV) and minor extracellular enveloped virion (EEV) populations of poxviruses are poorly understood. Here, we determined the full-genome sequences of the m8, parental LC16mO (mO), and grandparental Lister (LO) strains and analyzed their evolutionary relationships. Sequence data and PCR analysis indicated that m8 was a progeny of LO and that m8 preserved almost all of the open reading frames of vaccinia virus except for the disrupted EEV envelope gene B5R. In accordance with this genomic background, m8 induced 100% protection against a highly pathogenic vaccinia WR virus in mice by a single vaccination, despite the lack of anti-B5R and anti-EEV antibodies. The immunogenicity and priming efficacy with the m8 vaccine consisting mainly of IMV were as high as those with the intact-EEV parental mO and grandparental LO vaccines. Thus, mice vaccinated with 10 7 PFU of m8 produced low levels of anti-B5R antibodies after WR challenge, probably because of quick clearance of B5R-expressing WR EEV by strong immunity induced by the vaccination. These results suggest that priming with m8 IMV provides efficient protection despite undetectable levels of immunity against EEV.

Significance The nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) is a pattern recognition receptor that forms an inflammasome. The cryo-electron microscopy structure of the dodecameric form of full-length NLRP3 bound to the clinically relevant NLRP3-specific inhibitor MCC950 has established the structural basis for the oligomerization-mediated regulation of NLRP3 inflammasome activation and the mechanism of action of the NLRP3 specific inhibitor. The inactive NLRP3 oligomer represents the NLRP3 resting state, capable of binding to membranes and is likely disrupted for its activation. Visualization of the inhibitor binding mode will enable optimization of the activity of NLRP3 inflammasome inhibitor drugs.

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