The Gonococcal Genetic Island and Type IV Secretion in the Pathogenic Neisseria

Eighty percent of Neisseria gonorrhoeae strains and some Neisseria meningitidis strains encode a 57-kb gonococcal genetic island (GGI). The GGI was horizontally acquired and is inserted in the chromosome at the replication terminus. The GGI is flanked by direct repeats, and site-specific recombination at these sites results in excision of the GGI and may be responsible for its original acquisition. Although the role of the GGI in N. meningitidis is unclear, the GGI in N. gonorrhoeae encodes a type IV secretion system (T4SS). T4SS are versatile multi-protein complexes and include both conjugation systems as well as effector systems that translocate either proteins or DNA–protein complexes. In N. gonorrhoeae, the T4SS secretes single-stranded chromosomal DNA into the extracellular milieu in a contact-independent manner. Importantly, the DNA secreted through the T4SS is effective in natural transformation and therefore contributes to the spread of genetic information through Neisseria populations. Mutagenesis experiments have identified genes for DNA secretion including those encoding putative structural components of the apparatus, peptidoglycanases which may act in assembly, and relaxosome components for processing the DNA and delivering it to the apparatus. The T4SS may also play a role in infection by N. gonorrhoeae. During intracellular infection, N. gonorrhoeae requires the Ton complex for iron acquisition and survival. However, N. gonorrhoeae strains that do not express the Ton complex can survive intracellularly if they express structural components of the T4SS. These data provide evidence that the T4SS is expressed during intracellular infection and suggest that the T4SS may provide an advantage for intracellular survival. Here we review our current understanding of how the GGI and type IV secretion affect natural transformation and pathogenesis in N. gonorrhoeae and N. meningitidis

Management of Elbow Dislocations in the National Football League.

Background: Although much literature exists regarding the treatment and management of elbow dislocations in the general population, little information is available regarding management in the athletic population. Furthermore, no literature is available regarding the postinjury treatment and timing of return to play in the contact or professional athlete. Purpose: To review the clinical course of elbow dislocations in professional football players and determine the timing of return to full participation. Study Design: Case series; Level of evidence, 4. Methods: All National Football League (NFL) athletes with elbow dislocations from 2000 through 2011 who returned to play during the season were identified from the NFL Injury Surveillance System (NFL ISS). Roster position, player activity, use of external bracing, and clinical course were reviewed. Mean number of days lost until full return to play was determined for players with elbow dislocations who returned in the same season. Results: From 2000 to 2011, a total of 62 elbow dislocations out of 35,324 injuries were recorded (0.17%); 40 (64.5%) dislocations occurred in defensive players, 12 (19.4%) were in offensive players; and 10 (16.1%) were during special teams play. Over half of the injuries (33/62, 53.2%) were sustained while tackling, and 4 (6.5%) patients required surgery. A total of 47 (75.8%) players who sustained this injury were able to return in the same season. For this group, the mean number of days lost in players treated conservatively (45/47) was 25.1 days (median, 23.0 days; range, 0.0-118 days), while that for players treated operatively (2/47) was 46.5 days (median, 46.5 days; range, 29-64 days). Mean return to play based on player position was 25.8 days for defensive players (n = 28; median, 21.5 days; range, 3.0-118 days), 24.1 days for offensive players (n = 11; median, 19 days; range, 2.0-59 days), and 25.6 days for special teams players (n = 8; median, 25.5 days; range, 0-44 days). Conclusion: Elbow dislocations comprise less than a half of a percent of all injuries sustained in the NFL. Most injuries occur during the act of tackling, with the majority of injured athletes playing a defensive position. Players treated nonoperatively missed a mean of 25.1 days, whereas those managed operatively missed a mean of 46.5 days

Substrate Electric Dipole Moment Exerts a Ph-Dependent Effect On Electron Transfer in Escherichia Coli Photolyase

Transient absorption spectroscopy is used to demonstrate that the electric dipole moment of the substrate cyclobutane thymine dimer affects the charge recombination reaction between fully reduced flavin adenine dinucleotide (FADH-) and the neutral radical tryptophan 306 (Trp306•) in Escherichia coli DNA photolyase. At pH 7.4, the charge recombination is slowed by a factor of 1.75 in the presence of substrate, but not at pH 5.4. Photolyase does bind substrate at pH 5.4, and it seems that this pH effect originates from the conversion of FADH- to FADH2 at lower pH. The free-energy changes calculated from the electric field parameters and from the change in electron transfer rate are in good agreement and support the idea that the substrate electric dipole is responsible for the observed change in electron transfer rate. It is expected that the substrate electric field will also modify the physiologically important from excited 1FADH- to the substrate in the DNA repair reaction

Resonance Raman and UV-Vis Spectroscopic Characterization of FADH• in the Complex of Photolyase with UV-Damaged DNA

Escherichia coli photolyase uses blue light to repair cyclobutane pyrimidine dimers which are formed upon irradiation of DNA with ultraviolet (UV) light. E. coli photolyase is a flavoenzyme which contains a flavin adenine dinucleotide (FAD) in its active site and a 5,10-methenyltetrahydrofolate (MTHF) as a light-harvesting pigment. In the isolated enzyme, the FAD cofactor is present as a stable neutral radical semiquinone (FADH•). In this paper, we investigate the interaction between photolyase and UV-damage DNA by using resonance Raman and UV-vis spectroscopy. Substrate binding results in intensity changes and frequency shifts of the FADH• vibrations and also induces electrochromic shifts of the FADH• electronic transitions because of the substrate electric dipole moment. The intensity changes in the resonance Raman spectra can be largely explained by changes in the Raman excitation profiles because of the electrochromic shift. The size of the electrochromic shift suggests that the substrate binding geometry is similar to that of oxidized FAD in reconstituted photolyase. The frequency changes are partially a manifestation of the vibrational Stark effect induced by the substrate electric dipole moment but also because of small perturbations of the hydrogen-bonding environment of FADH• upon substrate binding. Furthermore, differences in the resonance Raman spectra of MTHF-containing photolyase and of an MTHF-less mutant suggests that MTHF may play a structural role in stabilizing the active site of photolyase while comparison to other flavoproteins indicates that the FAD cofactor has a strong hydrogen-bonding protein environment. Finally, we show that the electrochromic shift can be used as a direct method to measure photolyase-substrate binding kinetics

Planning and Conducting a Pharmacogenetics Association Study

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/169261/1/cpt2270.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/169261/2/cpt2270_am.pd

Control of the Type 3 Secretion System in Vibrio harveyi by Quorum Sensing through Repression of ExsA ▿ ‡

The type 3 secretion system (T3SS) genes of Vibrio harveyi are activated at low cell density and repressed at high cell density by quorum sensing (QS). Repression requires LuxR, the master transcriptional regulator of QS-controlled genes. Here, we determine the mechanism underlying the LuxR repression of the T3SS system. Using a fluorescence-based cell sorting approach, we isolated V. harveyi mutants that are unable to express T3SS genes at low cell density and identified two mutations in the V. harveyi exsBA operon. While LuxR directly represses the expression of exsBA, complementation and epistasis analyses reveal that it is the repression of exsA expression, but not exsB expression, that is responsible for the QS-mediated repression of T3SS genes at high cell density. The present work further defines the genes in the V. harveyi QS regulon and elucidates a mechanism demonstrating how multiple regulators can be linked in series to direct the expression of QS target genes specifically at low or high cell density

Intravenous versus Partial Oral Antibiotic Therapy in the Treatment of Uncomplicated Bloodstream Infection Due to <i>Streptococcus</i> Species

This retrospective cohort study examines effectiveness of partial oral antibiotic regimens in uncomplicated bloodstream infections (BSIs) due to Streptococcus species compared to standard intravenous therapy. Adult patients with uncomplicated streptococcal BSIs from April 2016 to June 2020 in seven hospitals in South Carolina, USA, were evaluated. Multivariate Cox proportional hazards regression was used to examine the time to treatment failure within 90 days of a BSI after adjustment for the propensity to receive partial oral therapy. Multivariate linear regression was used to examine the hospital length of stay (HLOS). Among the 222 patients included, 99 received standard intravenous antibiotics and 123 received partial oral therapy. Of the standard intravenous therapy group, 46/99 (46.5%) required outpatient parenteral antibiotic therapy (OPAT). There was no difference in the risk of treatment failure between partial oral and standard intravenous therapy (hazards ratio 0.53, 95% CI 0.18, 1.60; p = 0.25). Partial oral therapy was independently associated with a shorter HLOS after adjustments for the propensity to receive partial oral therapy and other potential confounders (−2.23 days, 95% CI −3.53, −0.94; p < 0.001). Transitioning patients to oral antibiotics may be a reasonable strategy in the management of uncomplicated streptococcal BSIs. Partial oral therapy does not seem to have a higher risk of treatment failure and may spare patients from prolonged hospitalizations and OPAT complications