How Do Molecular Crowders Influence Ligand Binding Kinetics with G-Quadruplex DNA? The Role of Bound Water.

Understanding the kinetics of ligand interaction with G-quadruplex DNA (GqDNA) in a crowded cell-like environment is of paramount importance in biology and pharmacology, as it elucidates the effect of molecular crowders on reaction rates governing these interactions─a process that largely remains unexplored. In this study, we investigate the binding/unbinding kinetics of a G-quadruplex stabilizing benzophenoxazine ligand, cresyl violet (CV), with a human telomeric hybrid GqDNA structure using fluorescence correlation spectroscopy (FCS) and molecular dynamics (MD) simulations. Experiments are conducted with and without 10% and 20% (w/v) ethylene glycol (EG), PEG200 and PEG6000 crowders.

A same day α-synuclein RT-QuIC seed amplification assay for synucleinopathy biospecimens.

Parkinson's disease (PD), dementia with Lewy bodies (DLB), and other synucleinopathies are characterized by the accumulation of abnormal, self-propagating aggregates of α-synuclein. RT-QuIC or seed amplification assays are currently showing unprecedented diagnostic sensitivities and specificities for synucleinopathies even in prodromal phases years in advance of the onset of Parkinsonian signs or dementia. However, commonly used α-synuclein seed amplification assays take ≥48 h to perform as applied to patients' diagnostic biospecimens.

Elevated Cerebrospinal Fluid α-Synuclein Seeding Activity Predicts Central Lewy Body Diseases.

Background: Cerebrospinal fluid (CSF) α-synuclein seeding activity (SSA) via a seed amplification assay might predict central Lewy body diseases (LBD) in at-risk individuals.

Objective: The aim was to assess CSF SSA in a prospective, longitudinal study.

Methods: Participants self-reported risk factors were genetics, olfactory dysfunction, dream enactment behavior, orthostatic intolerance, or hypotension; individuals who had ≥3 confirmed risk factors underwent CSF sampling and were followed for up to 7.

Effect of Divalent Cations on Polarity and Hydration at the Lipid/Water Interface Probed by 4-Aminophthalimide-Based Dyes.

The ion binding to the lipid/water interface can substantially influence the structural, functional, and dynamic properties of the cell membrane. Despite extensive research on ion-lipid interactions, the specific effects of ion binding on the polarity and hydration at the lipid/water interface remain poorly understood. This study explores the influence of three biologically relevant divalent cations─Mg, Ca, and Zn─on the depth-dependent interfacial polarity and hydration of zwitterionic DPPC lipid in its gel phase at room temperature.

Cryo-EM structure of a natural prion: chronic wasting disease fibrils from deer.

Chronic wasting disease (CWD) is a widely distributed prion disease of cervids with implications for wildlife conservation and also for human and livestock health. The structures of infectious prions that cause CWD and other natural prion diseases of mammalian hosts have been poorly understood. Here we report a 2.

Ex vivo nanoscale abluminal mapping of putative cargo receptors at the blood-brain barrier of expanded brain capillaries.

Receptor mediated transport of therapeutic antibodies through the blood-brain barrier (BBB) give promise for drug delivery to alleviate brain diseases. We developed a low-cost method to obtain nanoscale localization data of putative cargo receptors. We combine existing ex vivo isolation methods with expansion microscopy (ExM) to analyze receptor localizations in brain microcapillaries.

Peristaltic Motion Enabled by Pneumatic Artificial Muscles (PAMs) as Structural "Soft-Stiff" Actuators in a Modular Worm-Inspired Robot.

This paper considers the design, manufacture, and testing of a prototype "soft-stiff" worm-inspired robot referred to herein, as the neumaticallyctuated Peristatic dvancing odular (PALAM) robot. The robot has a modular structure, mimicking the segmented nature of earthworms, and each segment is individually actuated by a set of three pneumatic artificial muscles (PAMs). The PAMs contract when inflated by pressurised air, generating a pulling force and fulfilling the role of biological muscles in the robot.

The ER-Resident Ras Inhibitor 1 (Eri1) of Inhibits Hyphal Morphogenesis via the Ras-Independent cAMP-PKA Pathway.

Ras signaling and glycosylphosphatidylinositol (GPI) biosynthesis are mutually inhibitory in (Sc). The inhibition is mediated via an interaction of yeast Ras2 with the Eri1 subunit of its GPI--acetylglucosaminyl transferase (GPI-GnT), the enzyme catalyzing the very first GPI biosynthetic step. In contrast, Ras signaling and GPI biosynthesis in (Ca) are mutually activated and together control the virulence traits of the human fungal pathogen.

Effect of molecular crowders on ligand binding kinetics with G-quadruplex DNA probed by fluorescence correlation spectroscopy.

Guanine-rich single-stranded DNA folds into G-quadruplex DNA (GqDNA) structures, which play crucial roles in various biological processes. These structures are also promising targets for ligands, potentially inducing antitumor effects. While thermodynamic parameters of ligand/DNA interactions are well-studied, the kinetics of ligand interaction with GqDNA, particularly in cell-like crowded environments, remain less explored.

Mode III Tear Resistance of Silk Cocoons.

This paper concerns the tear properties and behavior of () silk cocoons. The tear resistance of cocoon layers is found to increase progressively from the innermost layer to the outermost layer. Importantly, the increase in tear strength correlates with increased porosity, which itself affects fiber mobility.

Seeding activity of human superoxide dismutase 1 aggregates in familial and sporadic amyotrophic lateral sclerosis postmortem neural tissues by real-time quaking-induced conversion.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with average lifespan of 2-5 years after diagnosis. The identification of novel prognostic and pharmacodynamic biomarkers are needed to facilitate therapeutic development. Metalloprotein human superoxide dismutase 1 (SOD1) is known to accumulate and form aggregates in patient neural tissue with familial ALS linked to mutations in their SOD1 gene.

Hotspot site microenvironment in the deubiquitinase OTUB1 drives its stability and aggregation.

Lewy bodies (LB) are aberrant protein accumulations observed in the brain cells of individuals affected by Parkinson's disease (PD). A comprehensive analysis of LB proteome identified over a hundred proteins, many co-enriched with α-synuclein, a major constituent of LB. Within this context, OTUB1, a deubiquitinase detected in LB, exhibits amyloidogenic properties, yet the mechanisms underlying its aggregation remain elusive.

Discovery of potent inhibitors of α-synuclein aggregation using structure-based iterative learning.

Machine learning methods hold the promise to reduce the costs and the failure rates of conventional drug discovery pipelines. This issue is especially pressing for neurodegenerative diseases, where the development of disease-modifying drugs has been particularly challenging. To address this problem, we describe here a machine learning approach to identify small molecule inhibitors of α-synuclein aggregation, a process implicated in Parkinson's disease and other synucleinopathies.

Unusual similarity of DNA solvation dynamics in high-salinity crowding with divalent cations of varying concentrations.

Double-stranded DNA bears the highest linear negative charge density (2 per base-pair) among all biopolymers, leading to strong interactions with cations and dipolar water, resulting in the formation of a dense 'condensation layer' around DNA. Interactions involving proteins and ligands binding to DNA are primarily governed by strong electrostatic forces. Increased salt concentrations impede such electrostatic interactions - a situation that prevails in oceanic species due to their cytoplasm being enriched with salts.

The influence of claw morphology on gripping efficiency.

This paper considers the effects of claw morphology on the gripping efficiency of arboreal (Varanus varius) and burrowing (Varanus gouldii and Varanus panoptes) lizards. To ensure a purely morphological comparison between the lizards, we circumvent the material effects of claws from different species, by modelling and testing claw replicates of the same material properties. We correlate climbing efficiency to critical morphological features including; claw height (hc), width (wc), length (lc), curvature () and tip angle (γ), which are expressed as ratios to normalise mechanically beneficial claw structures.

Drug repurposing screens identify compounds that inhibit α-synuclein oligomers' membrane disruption and block antibody interactions.

Small soluble oligomers of the protein α-synuclein (αSO) have been linked to disruptions in neuronal homeostasis, contributing to the development of Parkinson's Disease (PD). While this makes αSO an obvious drug target, the development of effective therapeutics against αSO is challenged by its low abundance and structural and morphological complexity. Here, we employ two different approaches to neutralize toxic interactions made by αSOs with different cellular components.

From trash to treasure: Sourcing high-value, sustainable cellulosic materials from living bioreactor waste streams.

The appreciation of how conventional and fossil-based materials could be harmful to our planet is growing, especially when considering single-use and non-biodegradable plastics manufactured from fossil fuels. Accordingly, tackling climate change and plastic waste pollution entails a more responsible approach to sourcing raw materials and the adoption of less destructive end-of-life pathways. Livestock animals, in particular ruminants, process plant matter using a suite of mechanical, chemical and biological mechanisms through the act of digestion.

A penetratin-derived peptide reduces the membrane permeabilization and cell toxicity of α-synuclein oligomers.

Parkinson's disease is a neurodegenerative movement disorder associated with the intracellular aggregation of α-synuclein (α-syn). Cytotoxicity is mainly associated with the oligomeric species (αSOs) formed at early stages in α-syn aggregation. Consequently, there is an intense focus on the discovery of novel inhibitors such as peptides to inhibit oligomer formation and toxicity.

Cryo-EM of prion strains from the same genotype of host identifies conformational determinants.

Prion strains in a given type of mammalian host are distinguished by differences in clinical presentation, neuropathological lesions, survival time, and characteristics of the infecting prion protein (PrP) assemblies. Near-atomic structures of prions from two host species with different PrP sequences have been determined but comparisons of distinct prion strains of the same amino acid sequence are needed to identify purely conformational determinants of prion strain characteristics. Here we report a 3.

Polarized α-synuclein trafficking and transcytosis across brain endothelial cells via Rab7-decorated carriers.

Parkinson's disease is mainly caused by aggregation of α-synuclein (α-syn) in the brain. Exchange of α-syn between the brain and peripheral tissues could have important pathophysiological and therapeutic implications, but the trafficking mechanism of α-syn across the blood brain-barrier (BBB) remains unclear. In this study, we therefore investigated uptake and transport mechanisms of α-syn monomers and oligomers across an in vitro BBB model system.

RT-QuIC and Related Assays for Detecting and Quantifying Prion-like Pathological Seeds of α-Synuclein.

Various disease-associated forms or strains of α-synuclein (αSyn) can spread and accumulate in a prion-like fashion during synucleinopathies such as Parkinson's disease (PD), Lewy body dementia (DLB), and multiple system atrophy (MSA). This capacity for self-propagation has enabled the development of seed amplification assays (SAAs) that can detect αSyn in clinical samples. Notably, α-synuclein real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA) assays have evolved as ultrasensitive, specific, and relatively practical methods for detecting αSyn in a variety of biospecimens including brain tissue, CSF, skin, and olfactory mucosa from synucleinopathy patients.

The C-terminal tail of α-synuclein protects against aggregate replication but is critical for oligomerization.

Aggregation of the 140-residue protein α-synuclein (αSN) is a key factor in the etiology of Parkinson's disease. Although the intensely anionic C-terminal domain (CTD) of αSN does not form part of the amyloid core region or affect membrane binding ability, truncation or reduction of charges in the CTD promotes fibrillation through as yet unknown mechanisms. Here, we study stepwise truncated CTDs and identify a threshold region around residue 121; constructs shorter than this dramatically increase their fibrillation tendency.

Mixed-Mode Interlaminar Fracture Toughness of Glass and Carbon Fibre Powder Epoxy Composites-For Design of Wind and Tidal Turbine Blades.

Powder epoxy composites have several advantages for the processing of large composite structures, including low exotherm, viscosity and material cost, as well as the ability to carry out separate melting and curing operations. This work studies the mode I and mixed-mode toughness, as well as the in-plane mechanical properties of unidirectional stitched glass and carbon fibre reinforced powder epoxy composites. The interlaminar fracture toughness is studied in pure mode I by performing Double Cantilever Beam tests and at 25% mode II, 50% mode II and 75% mode II by performing Mixed Mode Bending testing according to the ASTM D5528-13 test standard.

The Impact Behaviour of Crab Carapaces in Relation to Morphology.

Brachyuran crab carapaces are protective, impact-resistant exoskeletons with elaborate material microstructures. Though several research efforts have been made to characterise the physical, material and mechanical properties of the crab carapace, there are no studies detailing how crab morphologies might influence impact resistance. The purpose of this paper is to characterise and compare Brachyuran crab carapace morphologies in relation to their impact properties, using opto-digital, experimental and numerical methods.