38 research outputs found
Identification and characterization of the E(var)3-5 gene in Drosophila melanogaster
The goals of my research project were to clone the E(var)3-5 gene and characterize the lethality of E(var)3-5 mutations. The E(var)3-5 gene was identified by dominant mutations that enhanced PEV of wm4, thus implicating the gene product in promoting a euchromatic chromatin structure (Dorn et al. 1993). These mutations were found to be recessive lethal as well and the lethal phenotype was used to map the E(var)3-5 gene (Dorn et al. 1993; this work). I characterized the lethality of E(var)3-5 mutations and found that lethality in E(var)3-5 hemizygotes is manifested at the pupal stage. I mapped the lethality to a region defined by Df(3R)Exel7310. I generated five FLP-FRT mediated deletions within the region defined by Df(3R)Exel7310 however, my complementation analysis revealed that E(var)3-5 mutants were not allelic to any of the genes in that region. However I identified a mutation in one of the genes, CG17360 in all E(var)3-5 mutants examined. The CG17360 mutants exhibit an unexpanded wing phenotype
The role of different microbiota in metastatic brain tumors
View full abstracthttps://openworks.mdanderson.org/leading-edge/1005/thumbnail.jp
Elucidating the Role of Microbiome in Low- and High-Grade Glioma
https://openworks.mdanderson.org/sumexp22/1117/thumbnail.jp
Liax Is a Surrogate Marker For Cell Envelope Stress and Daptomycin Non-Susceptibility in Enterococcus Faecium
Daptomycin (DAP) is often used as a first-line therapy to treat vancomycin-resistan
Contemporary Clinical and Molecular Epidemiology of Vancomycin-Resistant Enterococcal Bacteremia: A Prospective Multicenter Cohort Study (VENOUS I)
Background Vancomycin-resistant enterococci (VRE) are major therapeutic challenges. Prospective contemporary data characterizing the clinical and molecular epidemiology of VRE bloodstream infections (BSIs) are lacking. Methods The Vancomycin-Resistant Enterococcal BSI Outcomes Study (VENOUS I) is a prospective observational cohort of adult patients with enterococcal BSI in 11 US hospitals. We included patients with Enterococcus faecalis or Enterococcus faecium BSI with >= 1 follow-up blood culture(s) within 7 days and availability of isolate(s) for further characterization. The primary study outcome was in-hospital mortality. Secondary outcomes were mortality at days 4, 7, 10, 12, and 15 after index blood culture. A desirability of outcome ranking was constructed to assess the association of vancomycin resistance with outcomes. All index isolates were subjected to whole genome sequencing. Results Forty-two of 232 (18%) patients died in hospital and 39 (17%) exhibited microbiological failure (lack of clearance in the first 4 days). Neutropenia (hazard ratio [HR], 3.13), microbiological failure (HR, 2.4), VRE BSI (HR, 2.13), use of urinary catheter (HR, 1.85), and Pitt BSI score >= 2 (HR, 1.83) were significant predictors of in-hospital mortality. Microbiological failure was the strongest predictor of in-hospital mortality in patients with E faecium bacteremia (HR, 5.03). The impact of vancomycin resistance on mortality in our cohort changed throughout the course of hospitalization. Enterococcus faecalis sequence type 6 was a predominant multidrug-resistant lineage, whereas a heterogeneous genomic population of E faecium was identified. Conclusions Failure of early eradication of VRE from the bloodstream is a major factor associated with poor outcomes. Failure to eradicate enterococci from the bloodstream in the first 4 days after the index blood culture was the most consistent factor associated with increased risk of mortality. The association of vancomycin resistance with mortality changed throughout the course of the hospitalization
A Combination of Independent Transcriptional Regulators Shapes Bacterial Virulence Gene Expression during Infection
Transcriptional regulatory networks are fundamental to how microbes alter gene expression in response to environmental stimuli, thereby playing a critical role in bacterial pathogenesis. However, understanding how bacterial transcriptional regulatory networks function during host-pathogen interaction is limited. Recent studies in group A Streptococcus (GAS) suggested that the transcriptional regulator catabolite control protein A (CcpA) influences many of the same genes as the control of virulence (CovRS) two-component gene regulatory system. To provide new information about the CcpA and CovRS networks, we compared the CcpA and CovR transcriptomes in a serotype M1 GAS strain. The transcript levels of several of the same genes encoding virulence factors and proteins involved in basic metabolic processes were affected in both ΞccpA and ΞcovR isogenic mutant strains. Recombinant CcpA and CovR bound with high-affinity to the promoter regions of several co-regulated genes, including those encoding proteins involved in carbohydrate and amino acid metabolism. Compared to the wild-type parental strain, ΞccpA and ΞcovRΞccpA isogenic mutant strains were significantly less virulent in a mouse myositis model. Inactivation of CcpA and CovR alone and in combination led to significant alterations in the transcript levels of several key GAS virulence factor encoding genes during infection. Importantly, the transcript level alterations in the ΞccpA and ΞcovRΞccpA isogenic mutant strains observed during infection were distinct from those occurring during growth in laboratory medium. These data provide new knowledge regarding the molecular mechanisms by which pathogenic bacteria respond to environmental signals to regulate virulence factor production and basic metabolic processes during infection
Characterization of oral and gut microbiome temporal variability in hospitalized cancer patients
Identification and Whole Genome Sequencing of the First Case of Kosakonia radicincitans Causing a Human Bloodstream Infection
Streptococcus mitis Strains Causing Severe Clinical Disease in Cancer Patients
The genetically diverse viridans group streptococci (VGS) are increasingly recognized as the cause of a variety of human diseases. We used a recently developed multilocus sequence analysis scheme to define the species of 118 unique VGS strains causing bacteremia in patients with cancer; Streptococcus mitis (68 patients) and S. oralis (22 patients) were the most frequently identified strains. Compared with patients infected with nonβS. mitis strains, patients infected with S. mitis strains were more likely to have moderate or severe clinical disease (e.g., VGS shock syndrome). Combined with the sequence data, whole-genome analyses showed that S. mitis strains may more precisely be considered as >2 species. Furthermore, we found that multiple S. mitis strains induced disease in neutropenic mice in a dose-dependent fashion. Our data define the prominent clinical effect of the group of organisms currently classified as S. mitis and lay the groundwork for increased understanding of this understudied pathogen
Distinct single amino acid replacements in the control of virulence regulator protein differentially impact streptococcal pathogenesis.
Sequencing of invasive strains of group A streptococci (GAS) has revealed a diverse array of single nucleotide polymorphisms in the gene encoding the control of virulence regulator (CovR) protein. However, there is limited information regarding the molecular mechanisms by which CovR single amino acid replacements impact GAS pathogenesis. The crystal structure of the CovR C-terminal DNA-binding domain was determined to 1.50 Γ
resolution and revealed a three-stranded Ξ²-sheet followed by a winged helix-turn-helix DNA binding motif. Modeling of the CovR protein-DNA complex indicated that CovR single amino acid replacements observed in clinical GAS isolates could directly alter protein-DNA interaction and impact protein structure. Isoallelic GAS strains that varied by a single amino acid replacement in the CovR DNA binding domain had significantly different transcriptomes compared to wild-type and to each other. Similarly, distinct recombinant CovR variants had differential binding affinity for DNA from the promoter regions of several virulence factor-encoding genes. Finally, mice that were challenged with GAS CovR isoallelic strains had significantly different survival times, which correlated with the transcriptome and protein-DNA binding studies. Taken together, these data provide structural and functional insights into the critical and distinct effects of variation in the CovR protein on GAS pathogenesis