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INTRODUCTION: The morphological and molecular changes associated with the degeneration of arterioles in cerebral amyloid angiopathy (CAA) are incompletely understood. METHODS: Post mortem brains from 26 patients with CAA or neurological controls were analyzed using light-sheet microscopy, and morphological features of microvascular degeneration were quantified using surface volume rendering. Vascular stiffness was analyzed using atomic force microscopy. RESULT: Vascular smooth muscle cells (VSMCs) volume was reduced by ≈ 55% inCAA. This loss of VSMC volume correlated with increased arteriolar diameter, variability in diameter, and the volume of amyloid beta (Aβ) deposition in the vessel. Vessels with CAA were > 300% stiffer than controls. The volume of extracellular matrix cross-linking enzyme lysyl oxidase (LOX) correlated closely with vascular degenerative features. DISCUSSION: Our findings provide valuable insights into the connections among LOX, Aβ deposition, and vascular stiffness in CAA. Restoration of physiologic extracellular matrix properties in penetrating arteries may yield a novel therapeutic strategy for CAA. 

Abstract Potential G-quadruplex sites have been identified in the genomes of DNA and RNA viruses and proposed as regulatory elements. The genusOrthoflaviviruscontains arthropod-transmitted, positive-sense, single-stranded RNA viruses that cause significant human disease globally. Computational studies have identified multiple potential G-quadruplex sites that are conserved across members of this genus. Subsequent biophysical studies established that some G-quadruplexes predicted in Zika and tickborne encephalitis virus genomes can form and known quadruplex binders reduced viral yields from cells infected with these viruses. The susceptibility of RNA to degradation and the variability of loop regions have made structure determination challenging. Despite these difficulties, we report a high-resolution structure of the NS5-B quadruplex from the West Nile virus genome. Analysis reveals two stacked tetrads that are further stabilized by a stacked triad and transient noncanonical base pairing. This structure expands the landscape of solved RNA quadruplex structures and demonstrates the diversity and complexity of biological quadruplexes. We anticipate that the availability of this structure will assist in solving further viral RNA quadruplexes and provides a model for a conserved antiviral target inOrthoflavivirusgenomes. 

With the rising need for on-body biometric sensing, the development of wearable electrophysiological sensors has been faster than ever. Surface electrodes placed on the skin need to be robust in order to measure biopotentials from the body reliably and comfortable for extended wearability. The electrical stability of nonpolarizable silver/silver chloride (Ag/AgCl) and its low-cost, commercial production have made these electrodes ubiquitous health sensors in the clinical environment, where wet gels and long wires are accommodated by patient immobility. However, smaller, dry electrodes with wireless acquisition are essential for truly wearable, continuous health sensing. Currently, techniques for the robust fabrication of custom Ag/AgCl electrodes are lacking. Here, we present three methods for the fabrication of Ag/AgCl electrodes: oxidizing Ag in a chlorine solution, electroplating Ag, and curing Ag/AgCl ink. Each of these methods is then used to create three different electrode shapes for wearable application. Bench-top and on-body evaluation of the electrode techniques was achieved by electrochemical impedance spectroscopy (EIS), calculation of variance in electrocardiogram (ECG) measurements, and analysis of auditory steady-state response (ASSR) measurement. Microstructures produced on the electrode by each fabrication technique were also investigated with scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDX). The custom Ag/AgCl electrodes were found to be efficient in comparison with standard, commercial Ag/AgCl wet electrodes across all three of our presented techniques, with Ag/AgCl ink shown to be the better out of the three in bench-top and biometric recordings. 

Electrostatic protein/DNA interactions arise from the neutralization of the DNA phosphodiester backbone as well as coupled exchanges by charged protein residues as salt bridges or with mobile ions. Much focus has been and continues to be paid to interfacial ion pairs with DNA. The role of extra-interfacial ionic interactions, particularly as dynamic drivers of DNA sequence selectivity, remain poorly known. The ETS family of transcription factors represents an attractive model for addressing this knowledge gap given their diverse ionic composition in primary structures that fold to a tightly conserved DNA-binding motif. To probe the importance of extra-interfacial salt bridges in DNA recognition, we compared the salt-dependent binding by Elk1 with ETV6, two ETS homologs differing markedly in ionic composition. While both proteins exhibit salt-dependent binding with cognate DNA that corresponds to interfacial phosphate contacts, their nonspecific binding diverges from cognate binding as well as each other. Molecular dynamics simulations in explicit solvent, which generated ionic interactions in agreement with the experimental binding data, revealed distinct salt-bridge dynamics in the nonspecific complexes formed by the two proteins. Impaired DNA contact by ETV6 resulted in fewer backbone contacts in the nonspecific complex, while Elk1 exhibited a redistribution of extra-interfacial salt bridges via residues that are non-conserved between the two ETS relatives. Thus, primary structure variation in ionic residues can encode highly differentiated specificity mechanisms in a highly conserved DNA-binding motif. 

ABSTRACT In this work, we investigate the impact of uncertainties due to convective boundary mixing (CBM), commonly called ‘overshoot’, namely the boundary location and the amount of mixing at the convective boundary, on stellar structure and evolution. For this we calculated two grids of stellar evolution models with the MESA code, each with the Ledoux and the Schwarzschild boundary criterion, and vary the amount of CBM. We calculate each grid with the initial masses of 15, 20, and $$25\, \rm {M}_\odot$$. We present the stellar structure of the models during the hydrogen and helium burning phases. In the latter, we examine the impact on the nucleosynthesis. We find a broadening of the main sequence with more CBM, which is more in agreement with observations. Furthermore, during the core hydrogen burning phase there is a convergence of the convective boundary location due to CBM. The uncertainties of the intermediate convective zone remove this convergence. The behaviour of this convective zone strongly affects the surface evolution of the model, i.e. how fast it evolves redwards. The amount of CBM impacts the size of the convective cores and the nucleosynthesis, e.g. the 12C to 16O ratio and the weak s-process. Lastly, we determine the uncertainty that the range of parameter values investigated introduces and we find differences of up to $$70{{\ \rm per\ cent}}$$ for the core masses and the total mass of the star.