Biology subjects

Hamilton, C.

Publications and source records attributed to Hamilton, C..

3 recordsLinked to original sources

bioRxiv2019

Staphylococcus aureus uses the bacilliredoxin (BrxAB)/bacillithiol disulfide reductase (YpdA) redox pathway to defend against oxidative stress under infections

Staphylococcus aureus is a major human pathogen and has to cope with reactive oxygen and chlorine species (ROS, RCS) during infections. The low molecular weight thiol bacillithiol (BSH) is an important defense mechanism of S. aureus for detoxification of ROS and HOCl stress to maintain the reduced state of the cytoplasm. Under HOCl stress, BSH forms mixed disulfides with proteins, termed as S-bacillithiolations, which are reduced by bacilliredoxins (BrxA and BrxB). The NADPH-dependent flavin disulfide reductase YpdA is phylogenetically associated with the BSH synthesis and BrxA/B enzymes and was proposed to function as BSSB reductase. Here, we investigated the role of the bacilliredoxin BrxAB/BSH/YpdA pathway in S. aureus COL under oxidative stress and macrophage infection conditions in vivo and in biochemical assays in vitro. Using HPLC thiol metabolomics, a strongly enhanced BSSB level and a decreased BSH/BSSB ratio were measured in the S. aureus COL ypdA deletion mutant under control and NaOCl stress. Monitoring the BSH redox potential (EBSH) using the Brx-roGFP2 biosensor revealed that YpdA is required for regeneration of the reduced EBSH upon recovery from oxidative stress. In addition, the ypdA mutant was impaired in H2O2 detoxification as measured with the novel H2O2-specific Tpx-roGFP2 biosensor. Phenotype analyses further showed that BrxA and YpdA are required for survival under NaOCl and H2O2 stress in vitro and inside murine J-774A.1 macrophages in infection assays in vivo. Finally, NADPH-coupled electron transfer assays provide evidence for the function of YpdA in BSSB reduction, which depends on the conserved Cys14 residue. YpdA acts together with BrxA and BSH in de-bacillithiolation of S-bacilithiolated GapDH. In conclusion, our results point to a major role of the BrxA/BSH/YpdA pathway in BSH redox homeostasis in S. aureus during recovery from oxidative stress and under infections.

microbiology↗

bioRxiv2019

The Dialysis Procedure Triggers Autonomic Imbalance and Cardiac Arrhythmias: Insights from Continuous 14-day ECG Monitoring

BackgroundIn end-stage kidney disease the dialytic cycle relates to the rate of sudden cardiac death. We hypothesized that circadian, dialytic cycles, paroxysmal arrhythmias, and cardiovascular risk factors are associated with periodic changes in heart rate and heart rate variability (HRV) in incident dialysis patients.\n\nMethodsWe conducted a prospective ancillary study of the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease cohort (n=28; age 54{+/-}13 y; 57% men; 96% black; 33% with a history of structural heart disease; left ventricular ejection fraction 70{+/-}9%). Continuous ECG monitoring was performed using an ECG patch (Zio Patch, iRhythm) and short-term HRV was measured for three minutes every hour. HRV was measured by root mean square of the successive normal-to-normal intervals (rMSSD), high and low frequency power, Poincare plot, and sample and Renyi entropy.\n\nResultsArrhythmias were detected in 46% (n=13). Non-sustained ventricular tachycardia (VT) was more frequent during dialysis or within 6 hours post-dialysis, as compared to pre-or between-dialysis (63% vs. 37%, P=0.015), whereas supraventricular tachycardia was more frequent pre-/ between-dialysis, as compared to during-/ post-dialysis (84% vs. 16%, P=0.015). In adjusted for cardiovascular disease and its risk factors autoregressive conditional heteroscedasticity panel (ARCH) model, VT events were associated with increased heart rate by 11.2 (95%CI 10.1-12.3) bpm (P<0.0001). During regular dialytic cycle, rMSSD demonstrated significant circadian pattern (Mesor 10.6(0.9-11.2) ms; Amplitude 1.5(1.0-3.1) ms; Peak at 02:01(20:22-03:16) am; P<0.0001), which was abolished on a second day interdialytic extension (adjusted ARCH trend for rMSSD -1.41(-1.67 to -1.15) ms per 24h; P<0.0001).\n\nConclusionCardiac arrhythmias associate with dialytic phase. Regular dialytic schedule preserves physiological circadian rhythm, but the second day without dialysis is characterized by parasympathetic withdrawal and a steady increase in sympathetic predominance.\n\nSubject TermsArrhythmias, Autonomic Nervous System, Electrocardiology (ECG), Treatment.

epidemiology↗

bioRxiv2019

Dynamic Predictive Accuracy of Electrocardiographic Biomarkers of Sudden Cardiac Death within a Survival Framework: The Atherosclerosis Risk in Communities (ARIC) study

BackgroundThe risk of sudden cardiac death (SCD) is known to be dynamic. However, an accuracy of a dynamic SCD prediction, and \"expiration date\" of ECG biomarkers is unknown. Our goal was to measure dynamic predictive accuracy of ECG biomarkers of SCD and competing outcomes.\n\nMethodsAtherosclerosis Risk In Community study participants with analyzable digital ECGs were included (n=15,768; 55% female, 73% white, age 54.2{+/-}5.8 y). ECGs of 5 follow-up visits were analyzed. Global electrical heterogeneity (GEH) and traditional ECG metrics were measured. Adjudicated SCD served as the primary outcome; non-sudden cardiac death served as competing outcome. Time-dependent area under the (receiver operating characteristic) curve (AUC) analysis was performed to assess prediction accuracy of a continuous biomarker in a period of 3,6,9 months, and 1,2,3,5,10, and 15 years, using survival analysis framework.\n\nResultsOver a median 24.4 y follow-up, there were 581 SCDs (incidence 1.77 (95%CI 1.63-1.92)/1,000 person-years), and 838 nonSCDs [2.55 (95%CI 2.39-2.73)]. Resting heart rate was the strongest (AUC 0.930) short-term (3-month) non-specific SCD predictor, whereas spatial peak QRS-T angle predicted specifically SCD 15 years after ECG recording (AUC 0.719). QRS duration (AUC 0.885) and QTc (AUC 0.711) short-term predicted advanced structural heart disease better than SCD. \"Expiration date\" for most ECG biomarkers was two years after ECG recording. GEH significantly improved reclassification of SCD risk beyond age, sex, race, diabetes, hypertension, coronary heart disease and stroke.\n\nConclusionShort-term predictors of SCD, nonSCD, and biomarkers of long-term SCD risk differed, reflecting differences in transient vs. persistent SCD substrates.

epidemiology↗