MICHAEL STEPHEN GLICKMAN

..A remaining challenge in both fields is identifying drugs that eliminate drug-tolerant "persister" cells (infectious disease) or tumor-initiating/stem cells (cancer) to prevent late relapse and shorten treatment duration...

..These results expand our knowledge of the biosynthesis of the Mtb cell envelope and will allow further elucidation of the relationship between Mtb pathogenesis and the fine structure of mycolic acids...

..Although still a young field, bacterial NHEJ promises to teach us a great deal about the nexus of DNA repair and bacterial pathogenesis...

..Our results demonstrate that pathogen-specific Th1 cells can provide protection against inhaled M. tuberculosis, but only after the first week of infection...

..We conclude that the mechanisms of mycobacterial NHEJ are many and the outcomes depend on the initial structures of the DSBs and the available ensemble of end-processing and end-sealing components, which are not limited to Ku and LigD...

..These findings demonstrate that prokaryotic NHEJ is specifically required for DSB repair in late stationary phase and can mediate mutagenic repair of homing endonuclease-generated chromosomal DSBs...

..The physical and functional interactions of bacterial Ku and UvrD1 highlight the potential for cross-talk between components of nonhomologous end joining and nucleotide excision repair pathways...

..tuberculosis-induced inflammation and virulence. In addition, cyclopropane stereochemistries on mycolic acids interact directly with host cells to both positively and negatively influence host innate immune activation...

..We surmise that the signature error-prone quality of bacterial NHEJ in vivo arises from a dynamic balance between the end-remodeling and end-sealing steps...

..tuberculosis...

..Another ATP-dependent DNA ligase (LigC) provides a backup mechanism for LigD-independent error-prone repair of blunt-end DSBs. We speculate that NHEJ allows mycobacteria to evade genotoxic host defense...

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..avium. In combination with the forthcoming M. avium genome sequence, these tools will allow the distinct physiologic and pathogenic properties of M. avium to be dissected in molecular detail...

..These structures provide a foundation for rational-drug design, which may lead to the development of new inhibitors effective against persistent bacteria...

..Isolation and characterization of such mutants will likely yield important insights into the role of the mycobacterial cell envelope in the pathogenesis of Tuberculosis and the interaction of the tubercle bacillus with host cells. ..

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..This knowledge may validate this new antibiotic target in Mtb and lead to new vaccine strategies. ..

..Finally, we will define the molecular basis for site one cleavage of anti-sigma factors by genetically ablating candidate site one proteases and testing anti-sigma factor cleavage in these mutant strains. . ..

..The experiments in this application are designed to validate this enzyme family as a target for antibiotic development and to understand their role in causing disease. ..

..The experiments in this application are designed to validate this enzyme family as a target for antibiotic development and to understand their role in causing disease. ..

..tuberculosis, cause of the disease Tuberculosis. These studies will advance our understanding of how mycobacteria resist elimination by the host and may lead to novel drug strategies for infections caused by mycobacteria. ..

..This knowledge may validate this new antibiotic target in Mtb and lead to new vaccine strategies. ..