Biology subjects

Chen, L. Y.

Publications and source records attributed to Chen, L. Y..

6 recordsLinked to original sources

bioRxiv2018

Plasma metabolomics and incidence of atrial fibrillation: the Atherosclerosis Risk in Communities (ARIC) Study

We have previously identified associations of two circulating secondary bile acids (glycocholenate and glycolithocolate sulfate) with atrial fibrillation (AF) risk among blacks. We aimed to replicate these findings in an independent sample including both whites and blacks, and performed a new metabolomic analysis in the combined sample. We studied 3,922 participants from the ARIC cohort followed between 1987 and 2013. Of these, 1,919 had been included in the prior analysis and 2,003 were new samples. Metabolomic profiling was done in baseline serum samples using gas and liquid chromatography mass spectrometry. AF was ascertained from electrocardiograms, hospitalizations, and death certificates. We used multivariable Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (95%CI) of AF by one standard deviation difference of metabolite levels. Over a mean follow-up of 20 years, 608 participants developed AF. Glycocholenate sulfate was associated with AF in the replication and combined samples (HR 1.10, 95%CI 1.00, 1.21 and HR 1.13, 95%CI 1.04, 1.22, respectively). Glycolithocolate sulfate was not related to AF risk in the replication sample (HR 1.02, 95%CI 0.92, 1.13). An analysis of 245 metabolites in the combined cohort identified three additional metabolites associated with AF after multiple-comparison correction: pseudouridine (HR 1.18, 95%CI 1.10, 1.28), uridine (HR 0.86, 95%CI 0.79, 0.93) and acisoga (HR 1.17, 95%CI 1.09, 1.26). To conclude, we replicated a prospective association between a previously identified secondary bile acid, glycocholenate sulfate, and AF incidence, and identified new metabolites involved in nucleoside and polyamine metabolism as markers of AF risk.

epidemiology↗

bioRxiv2017

A Pilot Randomized Trial of Oral Magnesium Supplementation on Supraventricular Arrhythmias

BackgroundMagnesium is believed to have a physiologic role in cardiac contractility, and evidence from epidemiologic and clinical studies has suggested that low serum concentrations of magnesium may be associated with increased risk of atrial fibrillation (AF).\n\nObjectiveAs part of the planning effort for a large randomized trial to prevent AF with magnesium supplementation, we conducted a 12-week pilot study to assess adherence to oral magnesium supplementation and matching placebo, estimate the effect on circulating magnesium concentrations, and evaluate the feasibility of using an ambulatory monitoring device (ZioPatch) for assessing premature atrial contractions (PACs), a predictor of AF.\n\nDesignDouble-blind randomized pilot clinical trial comparing supplementation with 400 mg magnesium oxide daily (versus placebo) over 12 weeks of follow-up. The ZioPatch was applied for 14 days at baseline and the end of follow-up. Adherence to the assigned treatment, and changes in PACs, serum magnesium concentration, glucose and blood pressure were assessed.\n\nResultsA total of 59 participants, 73% women and average age 62 years, were randomized. 98% of participants completed follow-up. Those assigned to the magnesium supplement took 75% of tablets as compared to 83% for those in the placebo group. Change in magnesium concentrations was significantly greater for those given magnesium supplement compared to placebo (0.07; 95% confidence interval (CI): 0.03, 0.12 mEq/L; p = 0.002). ZioPatch was worn for an average of 13.0 of the requested 14 days at baseline; at the end of follow-up, the average number of days of monitoring was 13.0 days for the magnesium supplement group and 12.7 days for the placebo group. For log PAC burden (episodes per hour), the average change from baseline was -0.05 (95% CI: -0.31, 0.20) for those randomized to magnesium supplement and 0.04 (95% CI: -0.24, 0.31) for those randomized to placebo (p=0.79 for difference). Gastrointestinal problems were reported by 50% of participants in the magnesium supplement group and 7% in the placebo group. Only one person in the magnesium supplement group and none in the placebo group experienced adverse events which led to treatment discontinuation.\n\nConclusionsIn this pilot randomized clinic trial, although gastrointestinal side effects to the magnesium supplement were common, adherence, measured by pill counts, was very good and, as a consequence, magnesium concentrations were greater for those randomly assigned to the magnesium supplement compared to placebo. Participant acceptance of the planned monitoring with ZioPatch was also very good. While the difference in the change in PACs was not significant, this pilot study was small, short-term, and did not include participants at high risk of AF. Thus, we could not reliably evaluate the effect of magnesium supplementation on PACs.\n\nClinicaltrials.gov registrationNCT02837328

clinical trials↗

bioRxiv2017

Thermodynamic Integration in 3n Dimensions without Biases or Alchemy for Protein Interactions

Thermodynamic integration (TI), a powerful formalism for computing the Gibbs free energy, has been implemented for many biophysical processes characterized by one-dimensional order parameters with alchemical schemes that require delicate human efforts to choose/design biasing potentials for sampling the desired biophysical events and to remove their artifactitious consequences afterwards. Theoretically, an alchemical scheme is exact but practically, it causes error amplification. Small relative errors in the interaction parameters can be amplified many times in their propagation into the computed free energy [due to subtraction of similar numbers such as (105 {+/-} 5) - (100 {+/-} 5) = 5 {+/-} 7], which would render the results significantly less accurate than the input interaction parameters. In this paper, we present an unsophisticated implementation of TI in 3n dimensions (3nD) (n=1,2,3...) without alchemy or biasing potentials. In TI3nD, the errors in the interaction parameters will not be amplified and human efforts are not required to design biasing potentials that generate unphysical consequences. Using TI3nD, we computed the standard free energies of three protein complexes: trometamol in Salmonella effector SpvD (n=1), biotin in avidin (n=2), and Colicin E9 endonuclease with cognate immunity protein Im9 (n=3) and the hydration energies of ten biologically relevant compounds (n=1 for water, acetamide, urea, glycerol, trometamol, ammonium and n=2 for erythritol, 1,3-propanediol, xylitol, biotin). The computed results all agree with available experimental data. Each of the 13 computations is accomplishable within two (for a hydration problem) to ten (for the protein-recognition problem) days on an inexpensive workstation (two Xeon E5-2665 2.4GHz CPUs and one nVidia P5000 GPU).

biophysics↗

bioRxiv2017

Biologics-associated Risks for Incident Skin and Soft Tissue Infections in Psoriasis Patients: Results from Propensity Score-Stratified Survival Analysis

BackgroundHow biologics affect psoriasis patients risks for SSTIs in a pragmatic clinical setting remains unclear.\n\nMethodsIn a cohort of adult psoriasis outpatients (aged 20 years or older) who visited the Dermatology Clinic in 2010-2015, we compared incident SSTI risks between patients using biologics (users) versus nonbiologics (nonusers). We also estimated SSTI risks in biologics-associated time-periods relative to nonbiologics only in users. We applied random effects Cox proportional hazard models with propensity score-stratification to account for differential baseline hazards.\n\nResultsOver a median follow-up of 2.8 years (interquartile range: 1.5, 4.3), 172 of 922 patients ever received biologics (18.7%); 233 SSTI incidents occurred during 2518.3 person-years, with an overall incidence of 9.3/100 person-years (95% confidence interval [CI]: 8.1, 10.6). In univariate analysis, users showed an 89% lower risk for SSTIs than nonusers (hazard ratio [HR]: 0.11, 95%CI: 0.05, 0.26); the association persisted in a multivariable model (adjusted HR: 0.26, 95%CI: 0.12, 0.58). Among biologics users, biologics-exposed time-periods were associated with a nonsignificant 21% increased risk (adjusted HR: 1.21, 95%CI: 0.41, 3.59).\n\nConclusionsDespite of adjusting for the underlying risk profiles, risk comparisons between biologics users and nonusers remained confounded by treatment selection. By comparing time-periods being exposed versus unexposed to biologics among users, the current analysis did not find evidence for an increased SSTI risk that was associated with biologics use in psoriasis patients.

epidemiology↗

bioRxiv2017

Mupirocin-associated temporal changes in the nasal microbiota and host’s antimicrobial responses: A pilot study in healthy staphylococcal carriers

BackgroundHow mupirocin affects the human nasal microbiota over time remains uncharacterized.\n\nMethodsWe repeatedly sampled the anterior nares of four healthy staphylococcal carriers before and after mupirocin use. By sequencing bacterial 16S ribosomal cDNA, we characterized sequential changes in the carriage status, the nasal microbiota, and the hosts antimicrobial peptide expression up to 90 days after decolonization.\n\nResultsBefore mupirocin use, the nasal microbiota differed by the initial, culture-based staphylococcal carriage status, with Firmicutes (54.1%) being the most predominant in carriers and Proteobacteria (75.8%) in the only noncarrier. The nasal microbiota became less diverse (Shannon diversity: 1.33, 95% confidence interval [CI]: 1.06-1.54) immediately after decolonisation than that before decolonisation (1.78, 95%CI: 0.58-1.93). Based on results of differential abundance analysis, Firmicutes were significantly enriched (log2 fold changes [≥] 4, Benjamini-Hochberg adjusted P < .01) while Actinobacteria, particularly Corynbebacterium, were relatively depleted in samples from staphylococcal carriers. Results of nonmetric multidimensional scaling (NMDS) and constrained correspondence analysis (CCA) also suggested that the initial staphylococcal carriage status, human neutrophil peptide 1 levels, and sampling times were major contributors to the between-community dissimilarities (P for marginal permutation test: .014) though the significance attenuated when within-group correlation was considered (P for blocked permutation test: .047).\n\nConclusionThese findings suggest that large-scale investigations on antibiotic effects on the human nasal microbiota are warranted.

microbiology↗

bioRxiv2017

Computing Osmotic Permeabilities of Aquaporins AQP4, AQP5, and GlpF from Near-Equilibrium Simulations

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC=\"FIGDIR/small/102343_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (20K):\norg.highwire.dtl.DTLVardef@c57ff0org.highwire.dtl.DTLVardef@527a79org.highwire.dtl.DTLVardef@e6bde6org.highwire.dtl.DTLVardef@bd53cf_HPS_FORMAT_FIGEXP M_FIG C_FIG Measuring or computing the single-channel permeability of aquaporins/aquaglyceroporins (AQPs) has long been a challenge. The measured values scatter over an order of magnitude but the corresponding Arrhenius activation energies converge in the current literature. Osmotic flux through an AQP was simulated as water current forced through the channel by kilobar hydraulic pressure or theoretically approximated as single-file diffusion. In this paper, we report large scale simulations of osmotic current under sub M gradient through three water channels (the water-specific AQP4 and AQP5 along with aquaglyceroporin GlpF) using the mature particle mesh Ewald technique (PME) for which the established force fields have been optimized with known accuracy. These simulations were implemented with hybrid periodic boundary conditions devised to avoid the artifactitious mixing across the membrane in a regular PME simulation. The computed single-channel permeabilities at 5{degrees}C and 25{degrees}C are in agreement with recently refined experiments on GlpF. The Arrhenius activation energies extracted from our simulations for all the three AQPs agree with the in vitro measurements. The single-file diffusion approximations from our large-scale simulations are consistent with the current literature on smaller systems. From these unambiguous agreements among the in vitro and in silico studies, we observe the quantitative accuracy of the all-atom force fields of the current literature for water-channel biology. We also observe that AQP4, that is particularly rich in the central nervous system, is more efficient in water conduction and more temperature-sensitive than other water-specific channel proteins.

biophysics↗