Enhancers activation by CRISPR/Cas9-based acetyltransferase rescues loss of function in CREBBP point mutant

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The role of lipid composition on the interaction between a tryptophan-rich protein and model bacterial membranes

The interaction between tryptophan-rich puroindoline proteins and model bacterial membranes at the air-liquid interface has been investigated by FTIR spectroscopy, surface pressure measurements and Brewster angle microscopy. The role of different lipid constituents on the interactions between lipid membrane and protein was studied using wild type (Pin-b) and mutant (Trp44 to Arg44 mutant, Pin-bs) puroindoline proteins. The results show differences in the lipid selectivity of the two proteins in terms of preferential binding to specific lipid head groups in mixed lipid systems. Pin-b wild type was able to penetrate mixed layers of phosphatidylethanolamine (PE) and phosphatidylglycerol (PG) head groups more deeply compared to the mutant Pin-bs. Increasing saturation of the lipid tails increased penetration and adsorption of Pin-b wild type, but again the response of the mutant form differed. The results provide insight as to the role of membrane architecture, lipid composition and fluidity, on antimicrobial activity of proteins. Data show distinct differences in the lipid binding behavior of Pin-b as a result of a single residue mutation, highlighting the importance of hydrophobic and charged amino acids in antimicrobial protein and peptide activity

Selected wheat seed defense proteins exhibit competitive binding to model microbial lipid interfaces

Puroindolines (Pins) and purothionins (Pths) are basic, amphiphilic, cysteine-rich wheat proteins that play a role in plant defense against microbial pathogens. We have examined the co-adsorption and sequential addition of Pins (Pin-a, Pin-b and a mutant form of Pin-b with Trp-44 to Arg-44 substitution) and β-purothionin (β-Pth) model anionic lipid layers, using a combination of surface pressure measurements, external reflection FTIR spectroscopy and neutron reflectometry. Results highlighted differences in the protein binding mechanisms, and in the competitive binding and penetration of lipid layers between respective Pins and β-Pth. Pin-a formed a blanket-like layer of protein below the lipid surface that resulted in the reduction or inhibition of β-Pth penetration of the lipid layer. Wild-type Pin-b participated in co-operative binding with β-Pth, whereas the mutant Pin-b did not bind to the lipid layer in the presence of β-Pth. The results provide further insight into the role of hydrophobic and cationic amino acid residues in antimicrobial activity

Tryptophan to arginine substitution in puroindoline b alters binding to model eukaryotic membranes

We have studied how puroindoline-b (PINB) mutants bind to model eukaryotic membranes dependent on binary composition of anionic:zwitterionic phospholipids and the presence of cholesterol and sphingomyelin in the model membrane. We have found that the trends in lipid binding behavior are different for wild-type PINB compared to its naturally occurring PINB(Trp44Arg) mutant form and have seen evidence of protein-induced domain formation within the lipid layer structure. Results show that selective binding of antimicrobial peptides to different membrane types is as a result of differences in lipid composition and the arrangement of lipids within the membrane surface. However, membrane-binding behavior is not easily predicted; it is determined by net charge, hydrophobicity, and the amphiphilicity of the protein/peptide lipid-binding domain

Variational water-wave model with accurate dispersion and vertical vorticity

A new water-wave model has been derived which is based on variational techniques and combines a depth-averaged vertical (component of) vorticity with depth-dependent potential flow. The model facilitates the further restriction of the vertical profile of the velocity potential to n-th order polynomials or a finite-element profile with a small number of elements (say), leading to a framework for efficient modeling of the interaction of steepening and breaking waves near the shore with a large-scale horizontal flow. The equations are derived from a constrained variational formulation which leads to conservation laws for energy, mass, momentum and vertical vorticity. It is shown that the potential-flow water-wave equations and the shallow-water equations are recovered in the relevant limits. Approximate shock relations are provided, which can be used in numerical schemes to model breaking waves

Panoramic Views of the Cygnus Loop

We present a complete atlas of the Cygnus Loop supernova remnant in the light of [O III] (5007), H alpha, and [S II] (6717, 6731). Despite its shell-like appearance, the Cygnus Loop is not a current example of a Sedov-Taylor blast wave. Rather, the optical emission traces interactions of the supernova blast wave with clumps of gas. The surrounding interstellar medium forms the walls of a cavity through which the blast wave now propagates, including a nearly complete shell in which non-radiative filaments are detected. The Cygnus Loop blast wave is not breaking out of a dense cloud, but is instead running into confining walls. The interstellar medium dominates not only the appearance of the Cygnus Loop but also the continued evolution of the blast wave. If this is a typical example of a supernova remnant, then global models of the interstellar medium must account for such significant blast wave deceleration.Comment: 28 pages AAS Latex, 28 black+white figures, 6 color figures. To be published in The Astrophysical Journal Supplement Serie

Modeling water waves beyond perturbations

In this chapter, we illustrate the advantage of variational principles for modeling water waves from an elementary practical viewpoint. The method is based on a `relaxed' variational principle, i.e., on a Lagrangian involving as many variables as possible, and imposing some suitable subordinate constraints. This approach allows the construction of approximations without necessarily relying on a small parameter. This is illustrated via simple examples, namely the Serre equations in shallow water, a generalization of the Klein-Gordon equation in deep water and how to unify these equations in arbitrary depth. The chapter ends with a discussion and caution on how this approach should be used in practice.Comment: 15 pages, 1 figure, 39 references. This document is a contributed chapter to an upcoming volume to be published by Springer in Lecture Notes in Physics Series. Other author's papers can be downloaded at http://www.denys-dutykh.com

Limited impact of adolescent meningococcal ACWY vaccination on Neisseria meningitides serogroup W carriage in university students

Background In the UK rising disease levels due to Neisseria meningitidis serogroup W clonal complex ST-11 (MenW:cc11) strains led to introduction of conjugate MenACWY vaccination for teenagers. We investigated the impact of immunization on carriage of targeted meningococci by whole genome sequencing of isolates recovered from a cohort of vaccinated university students. Methods Strain designation data were extracted from whole genome sequence data. Genomes from carried and invasive MenW:cc11 were compared using a gene-by-gene approach. Serogrouping identified isolates expressing capsule antigens targeted by the vaccine. Results Isolates with a W: P1.5,2: F1-1: ST-11 (cc11) designation, and belonging to the emerging ‘2013-strain’ of the South American-UK MenW:cc11 sub-lineage, were responsible for an increase in carried group W. A multifocal expansion was evident with close transmission networks extending beyond individual dormitories. Carried group Y isolates were predominantly from clonal complex 23, but showed significant heterogeneity and individual strain designations were only sporadically recovered. No shifts towards acapsulate phenotypes were detected in targeted meningococcal populations. Conclusions In a setting with high levels of conjugate MenACWY vaccination, expansion of capsule-expressing isolates from the 2013-strain of MenW:cc11, but not MenY:cc23 isolates, is indicative of differential susceptibilities to vaccine-induced immunity

Rapid Transmission of a Hyper-Virulent Meningococcal Clone Due to High Effective Contact Numbers and Super Spreaders

© Copyright © 2020 Holmes, Green, Oldfield, Turner and Bayliss. Rapid transmission, a critical contributory factor in outbreaks of invasive meningococcal disease, requires naïve populations of sufficient size and intermingling. We examined genomic variability and transmission dynamics in a student population subject to an 11-fold increase in carriage of a hypervirulent Neisseria meningitidis serogroup W ST-11 clone. Phylogenetic clusters, mutation and recombination rates were derived by bioinformatic analyses of whole-genome sequencing data. Transmission dynamics were determined by combining observed carriage rates, cluster sizes and distributions with simple SIS models. Between 9 and 15 genetically-distinct clusters were detected and associated with seven residential halls. Clusters had low mutation accumulation rates and infrequent recombination events. Modeling indicated that effective contacts decreased from 10 to 2 per day between the start and mid-point of the university term. Transmission rates fluctuated between 1 and 4% while the R(t) for carriage decreased from an initial rate of 47 to 1. Decreases in transmission values correlated with a rise in vaccine-induced immunity. Observed carriage dynamics could be mimicked by populations containing 20% of super spreaders with 2.3-fold higher effective contact rates. We conclude that spread of this hypervirulent ST-11 meningococcal clone depends on the levels of effective contacts and immunity rather than genomic variability. Additionally, we propose that super-spreaders enhance meningococcal transmission and that a 70% MenACWY immunization level is sufficient to retard, but not fully prevent, meningococcal spread in close-contact populations