Characterization of Borrelia Burgdorferi BlyA and BlyB Proteins: a Prophage-Encoded Holin-Like System

The conserved cp32 plasmid family of Borrelia burgdorferi was recently shown to be packaged into a bacteriophage particle (C. H. Eggers and D. S. Samuels, J. Bacteriol. 181:7308-7313, 1999), This plasmid encodes BlyA, a 7.4-kDa membrane-interactive protein, and BlyB, an accessory protein, which were previously proposed to comprise a hemolysis system. Our genetic and biochemical evidence suggests that this hypothesis is incorrect and that BlyA and BlyB function instead as a prophage-encoded holin or holin-like system for this newly described bacteriophage, An Escherichia coli mutant containing the blyAB locus that was defective for the normally cryptic host hemolysin SheA was found to be nonhemolytic, suggesting that induction of sheA by blyAB expression was responsible for the hemolytic activity observed previously, Analysis of the structural features of BlyA indicated greater structural similarity to bacteriophage-encoded holins than to hemolysins, Consistent with holin characteristics, subcellular localization studies with E. coli and B. burgdorferi indicated that BlyA is solely membrane associated and that BlyB is a soluble protein. Furthermore, BlyA exhibited a holin-like function by promoting the endolysin-dependent lysis of an induced lambda lysogen that was defective in the holin gene. Finally, induction of the cp32 prophage in B. burgdorferi dramatically stimulated blyAB expression. Our results provide the first evidence of a prophage-encoded holin within Borrelia

Diagnostic Utility of C4d by Direct Immunofluorescence in Bullous Pemphigoid

ABSTRACT: Bullous pemphigoid (BP) is an autoimmune blistering disease that commonly affects elderly patients. Direct immunofluorescence (DIF) for immunoglobulin G (IgG) and C3c on frozen skin biopsies is the gold standard for the diagnosis of BP. In a minority of cases, IgG and/or C3c are found negative, and in these situations, there is a need for a more stable diagnostic marker of BP. C4d is biologically inactive, but has a long half-life, rendering it a long-lived marker for antibody-mediated complement activation. Previous studies already demonstrated that C4d was diagnostically useful in formalin-fixed paraffin-embedded skin biopsies of patients with BP. We hypothesized that C4d detected by DIF could also be a promising diagnostic marker for BP, particularly in IgG and/or C3c DIF-negative cases. In this single-center retrospective study, 69 cases of BP were analyzed for linear deposition of C4d; of the 69 cases, n = 26 were IgG+/C3c-, n = 10 IgG+/C3c+, and n = 33 IgG-/C3c-. Results were compared with n = 39 negative controls. Seven of the 26 (27%) IgG+/C3c- and 3 of the 33 (9%) IgG-/C3c- BP cases were positive for C4d. All 10 IgG+/C3c+ cases were also C4d positive. In the negative control group, 2 of the 39 (5%) were found positive for C4d. In conclusion, the current study shows that C4d is a more sensitive but not a 100% specific marker of BP. We conclude that C4d by DIF could be an interesting diagnostic adjunct for BP, particularly in IgG-/C3c- double negative cases

Dynamic Monte Carlo Measurement of Critical Exponents

Based on the scaling relation for the dynamics at the early time, a new method is proposed to measure both the static and dynamic critical exponents. The method is applied to the two dimensional Ising model. The results are in good agreement with the existing results. Since the measurement is carried out in the initial stage of the relaxation process starting from independent initial configurations, our method is efficient.Comment: (5 pages, 1 figure) Siegen Si-94-1

Multiple-length-scale elastic instability mimics parametric resonance of nonlinear oscillators

Spatially confined rigid membranes reorganize their morphology in response to the imposed constraints. A crumpled elastic sheet presents a complex pattern of random folds focusing the deformation energy while compressing a membrane resting on a soft foundation creates a regular pattern of sinusoidal wrinkles with a broad distribution of energy. Here, we study the energy distribution for highly confined membranes and show the emergence of a new morphological instability triggered by a period-doubling bifurcation. A periodic self-organized focalization of the deformation energy is observed provided an up-down symmetry breaking, induced by the intrinsic nonlinearity of the elasticity equations, occurs. The physical model, exhibiting an analogy with parametric resonance in nonlinear oscillator, is a new theoretical toolkit to understand the morphology of various confined systems, such as coated materials or living tissues, e.g., wrinkled skin, internal structure of lungs, internal elastica of an artery, brain convolutions or formation of fingerprints. Moreover, it opens the way to new kind of microfabrication design of multiperiodic or chaotic (aperiodic) surface topography via self-organization.Comment: Submitted for publicatio

Impact of Renal Impairment on Beta-Blocker Efficacy in Patients With Heart Failure.

BACKGROUND: Moderate and moderately severe renal impairment are common in patients with heart failure and reduced ejection fraction, but whether beta-blockers are effective is unclear, leading to underuse of life-saving therapy. OBJECTIVES: This study sought to investigate patient prognosis and the efficacy of beta-blockers according to renal function using estimated glomerular filtration rate (eGFR). METHODS: Analysis of 16,740 individual patients with left ventricular ejection fraction <50% from 10 double-blind, placebo-controlled trials was performed. The authors report all-cause mortality on an intention-to-treat basis, adjusted for baseline covariates and stratified by heart rhythm. RESULTS: Median eGFR at baseline was 63 (interquartile range: 50 to 77) ml/min/1.73 m2; 4,584 patients (27.4%) had eGFR 45 to 59 ml/min/1.73 m2, and 2,286 (13.7%) 30 to 44 ml/min/1.73 m2. Over a median follow-up of 1.3 years, eGFR was independently associated with mortality, with a 12% higher risk of death for every 10 ml/min/1.73 m2 lower eGFR (95% confidence interval [CI]: 10% to 15%; p < 0.001). In 13,861 patients in sinus rhythm, beta-blockers reduced mortality versus placebo; adjusted hazard ratio (HR): 0.73 for eGFR 45 to 59 ml/min/1.73 m2 (95% CI: 0.62 to 0.86; p < 0.001) and 0.71 for eGFR 30 to 44 ml/min/1.73 m2 (95% CI: 0.58 to 0.87; p = 0.001). The authors observed no deterioration in renal function over time in patients with moderate or moderately severe renal impairment, no difference in adverse events comparing beta-blockers with placebo, and higher mortality in patients with worsening renal function on follow-up. Due to exclusion criteria, there were insufficient patients with severe renal dysfunction (eGFR <30 ml/min/1.73 m2) to draw conclusions. In 2,879 patients with atrial fibrillation, there was no reduction in mortality with beta-blockers at any level of eGFR. CONCLUSIONS: Patients with heart failure, left ventricular ejection fraction <50% and sinus rhythm should receive beta-blocker therapy even with moderate or moderately severe renal dysfunction

Urinary Sodium Profiling in Chronic Heart Failure to Detect Development of Acute Decompensated Heart Failure

OBJECTIVES This study sought to determine the relationship between urinary sodium (U-na) concentration and the pathophysiologic interaction with the development of acute heart failure (AHF) hospitalization. BACKGROUND No data are available on the longitudinal dynamics of U-na concentration in patients with chronic heart failure (HF), including its temporal relationship with AHF hospitalization. METHODS Stable, chronic HF patients with either reduced or preserved ejection fraction were prospectively included to undergo prospective collection of morning spot U-na samples for 30 consecutive weeks. Linear mixed modeling was used to assess the longitudinal changes in U-na concentration. Patients were followed for the development of the clinical endpoint of AHF. RESULTS A total of 80 chronic HF patients (71 +/- 11 years of age; an N-terminal pro-B-type natriuretic peptide [NT-proBNP] concentration of 771 [interquartile range: 221 to 1,906] ng/l; left ventricular ejection fraction [LVEF] 33 +/- 7%) prospectively submitted weekly pre-diuretic first void morning U-na samples for 30 weeks. A total of 1,970 U-na samples were collected, with mean U-na concentration of 81.6 +/- 41 mmol/l. Sodium excretion remained stable over time on a population level (time effect p = 0.663). However, interindividual differences revealed the presence of high (88 mmol/l U-na [n = 39]) and low (73 mmol/l U-na [n = 41]) sodium excreters. Only younger age was an independent predictor of high sodium excretion (odds ratio [OR]: 0.91; 95% confidence interval [CI]: 0.83 to 1.00; p = 0.045 per year). During 587 +/- 54 days of follow-up, 21 patients were admitted for AHF. Patients who developed AHF had significantly lower U-na concentrations (F-[1.80] = 24.063; p <0.001). The discriminating capacity of U-na concentration to detect AHF persisted after inclusion of NT-proBNP and estimated glomerular filtration rate (eGFR) measurements as random effects (p = 0.041). Furthermore, U-na concentration dropped (U-na = 46 +/- 16 mmol/l vs. 70 +/- 32 mmol/l, respectively; p = 0.003) in the week preceding the hospitalization and returned to the individual's baseline (U-na = 71 +/- 22 mmol/l; p = 0.002) following recompensation, while such early longitudinal changes in weight and dyspnea scores were not apparent in the week preceding decompensation. CONCLUSIONS Overall, U-na concentration remained relatively stable over time, but large interindividual differences existed in stable, chronic HF patients. Patients who developed AHF exhibited a chronically lower U-na concentration and exhibited a further drop in U-na concentration during the week preceding hospitalization. Ambulatory U-na sample collection is feasible and may offer additional prognostic and therapeutic information. (C) 2019 by the American College of Cardiology Foundation

Finite Size Scaling and Critical Exponents in Critical Relaxation

We simulate the critical relaxation process of the two-dimensional Ising model with the initial state both completely disordered or completely ordered. Results of a new method to measure both the dynamic and static critical exponents are reported, based on the finite size scaling for the dynamics at the early time. From the time-dependent Binder cumulant, the dynamical exponent $z$ is extracted independently, while the static exponents $\beta/\nu$ and $\nu$ are obtained from the time evolution of the magnetization and its higher moments.Comment: 24 pages, LaTeX, 10 figure