Evolutionary and functional history of the Escherichia coli K1 capsule

Escherichia coli is a leading cause of invasive bacterial infections in humans. Capsule polysaccharide has an important role in bacterial pathogenesis, and the K1 capsule has been firmly established as one of the most potent capsule types in E. coli through its association with severe infections. However, little is known about its distribution, evolution and functions across the E. coli phylogeny, which is fundamental to elucidating its role in the expansion of successful lineages. Using systematic surveys of invasive E. coli isolates, we show that the K1-cps locus is present in a quarter of bloodstream infection isolates and has emerged in at least four different extraintestinal pathogenic E. coli (ExPEC) phylogroups independently in the last 500 years. Phenotypic assessment demonstrates that K1 capsule synthesis enhances E. coli survival in human serum independent of genetic background, and that therapeutic targeting of the K1 capsule re-sensitizes E. coli from distinct genetic backgrounds to human serum. Our study highlights that assessing the evolutionary and functional properties of bacterial virulence factors at population levels is important to better monitor and predict the emergence of virulent clones, and to also inform therapies and preventive medicine to effectively control bacterial infections whilst significantly lowering antibiotic usage

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Distributed Security-Constrained Unit Commitment for Large-Scale Power Systems

Independent system operators (ISOs) of electricity markets solve the security-constrained unit commitment (SCUC) problem to plan a secure and economic generation schedule. However, as the size of power systems increases, the current centralized SCUC algorithm could face critical challenges ranging from modeling accuracy to calculation complexity. This paper presents a distributed SCUC (D-SCUC) algorithm to accelerate the generation scheduling of large-scale power systems. In this algorithm, a power system is decomposed into several scalable zones which are interconnected through tie lines. Each zone solves its own SCUC problem and a parallel calculation method is proposed to coordinate individual D-SCUC problems. Several power systems are studied to show the effectiveness of the proposed algorithm

Distributed Security-Constrained Unit Commitment for Large-Scale Power Systems

Independent system operators (ISOs) of electricity markets solve the security-constrained unit commitment (SCUC) problem to plan a secure and economic generation schedule. However, as the size of power systems increases, the current centralized SCUC algorithm could face critical challenges ranging from modeling accuracy to calculation complexity. This paper presents a distributed SCUC (D-SCUC) algorithm to accelerate the generation scheduling of large-scale power systems. In this algorithm, a power system is decomposed into several scalable zones which are interconnected through tie lines. Each zone solves its own SCUC problem and a parallel calculation method is proposed to coordinate individual D-SCUC problems. Several power systems are studied to show the effectiveness of the proposed algorithm

Natural progression of childhood asthma symptoms and strong influence of sex and puberty.

Rationale: Asthma prevalence, onset, remission and relapse, and healthcare use have been intensively studied. However, asthma symptom progression through childhood and adolescence has not been well studied, in part due to the challenges in obtaining consistent and robust long-term follow-up data on a large series of subjects with asthma. Objectives: To use the asthma diary symptom data of the Childhood Asthma Management Program placebo group (5 yr, 418 subjects, and total 564,518 records) to establish sex-specific high-resolution time courses of the natural progression of asthma symptoms through childhood and adolescence. Methods: We used the asthma diary symptom code as a measure of daily disease severity. Annual records of Tanner stage were used to determine the influence of puberty on severity. A data alignment technique was used to derive 13-year time courses of mean symptoms and mean Tanner stage. Measurements and Main Results: Data analyses showed three age- and sex-related phases of asthma symptom progression: Phase 1 (ages 5 and 6 yr)—greater severity in boys; Phase 2 (ages 7 to 9 yr)—no sex difference in severity; and Phase 3 (age 10-17 yr)—greater severity in girls. The continuous decline of symptoms in both sexes stops abruptly at the onset of puberty. Conclusions: The severity of asthma symptoms varies through childhood and adolescence, and patterns differ by sex. Puberty has a strong influence on symptom progression in both sexes. Progression of symptoms is a distinct aspect of asthma epidemiology

Quercetin Is More Effective than Cromolyn in Blocking Human Mast Cell Cytokine Release and Inhibits Contact Dermatitis and Photosensitivity in Humans

Mast cells are immune cells critical in the pathogenesis of allergic, but also inflammatory and autoimmune diseases through release of many pro-inflammatory cytokines such as IL-8 and TNF. Contact dermatitis and photosensitivity are skin conditions that involve non-immune triggers such as substance P (SP), and do not respond to conventional treatment. Inhibition of mast cell cytokine release could be effective therapy for such diseases. Unfortunately, disodium cromoglycate (cromolyn), the only compound marketed as a mast cell “stabilizer”, is not particularly effective in blocking human mast cells. Instead, flavonoids are potent anti-oxidant and anti-inflammatory compounds with mast cell inhibitory actions. Here, we first compared the flavonoid quercetin (Que) and cromolyn on cultured human mast cells. Que and cromolyn (100 mu M) can effectively inhibit secretion of histamine and PGD(2). Que and cromolyn also inhibit histamine, leukotrienes and PGD(2) from primary human cord blood-derived cultured mast cells (hCBMCs) stimulated by IgE/Anti-IgE. However, Que is more effective than cromolyn in inhibiting IL-8 and TNF release from LAD2 mast cells stimulated by SP. Moreover, Que reduces IL-6 release from hCBMCs in a dose-dependent manner. Que inhibits cytosolic calcium level increase and NF-kappa B activation. Interestingly, Que is effective prophylactically, while cromolyn must be added together with the trigger or it rapidly loses its effect. In two pilot, open-label, clinical trials, Que significantly decreased contact dermatitis and photosensitivity, skin conditions that do not respond to conventional treatment. In summary, Que is a promising candidate as an effective mast cell inhibitor for allergic and inflammatory diseases, especially in formulations that permit more sufficient oral absorption

Quercetin Is More Effective than Cromolyn in Blocking Human Mast Cell Cytokine Release and Inhibits Contact Dermatitis and Photosensitivity in Humans

<div><p>Mast cells are immune cells critical in the pathogenesis of allergic, but also inflammatory and autoimmune diseases through release of many pro-inflammatory cytokines such as IL-8 and TNF. Contact dermatitis and photosensitivity are skin conditions that involve non-immune triggers such as substance P (SP), and do not respond to conventional treatment. Inhibition of mast cell cytokine release could be effective therapy for such diseases. Unfortunately, disodium cromoglycate (cromolyn), the only compound marketed as a mast cell “stabilizer”, is not particularly effective in blocking human mast cells. Instead, flavonoids are potent anti-oxidant and anti-inflammatory compounds with mast cell inhibitory actions. Here, we first compared the flavonoid quercetin (Que) and cromolyn on cultured human mast cells. Que and cromolyn (100 µM) can effectively inhibit secretion of histamine and PGD₂. Que and cromolyn also inhibit histamine, leukotrienes and PGD₂ from primary human cord blood-derived cultured mast cells (hCBMCs) stimulated by IgE/Anti-IgE. However, Que is more effective than cromolyn in inhibiting IL-8 and TNF release from LAD2 mast cells stimulated by SP. Moreover, Que reduces IL-6 release from hCBMCs in a dose-dependent manner. Que inhibits cytosolic calcium level increase and NF-kappa B activation. Interestingly, Que is effective prophylactically, while cromolyn must be added <u>together</u> with the trigger or it rapidly loses its effect. In two pilot, open-label, clinical trials, Que significantly decreased contact dermatitis and photosensitivity, skin conditions that do not respond to conventional treatment. In summary, Que is a promising candidate as an effective mast cell inhibitor for allergic and inflammatory diseases, especially in formulations that permit more sufficient oral absorption.</p> </div