Fractality of tics as a quantitative assessment tool for Tourette syndrome

Tics manifest as brief, purposeless and unintentional movements or noises that, for many individuals, can be suppressed temporarily with effort. Previous work has hypothesized that the chaotic temporal nature of tics could possess an inherent fractality, that is, have neighbour-to-neighbour correlation at all levels of timescale. However, demonstrating this phenomenon has eluded researchers for more than two decades, primarily because of the challenges associated with estimating the scale-invariant, power law exponent—called the fractal dimension D_f—from fractional Brownian noise. Here, we confirm this hypothesis and establish the fractality of tics by examining two tic time series datasets collected 6–12 months apart in children with tics, using random walk models and directional statistics. We find that D_f is correlated with tic severity as measured by the YGTTS total tic score, and that D_f is a sensitive parameter in examining the effect of several tic suppression conditions on the tic time series. Our findings pave the way for using the fractal nature of tics as a robust quantitative tool for estimating tic severity and treatment effectiveness, as well as a possible marker for differentiating typical from functional tics.     

Effect of two stage pressure molding on surface quality of sheet molding compounds

The goal of this work was to investigate the effect of two stage pressure molding on the compression molding of a sheet molding compound (SMC). It has been shown in previous studies that a rapid drop in pressure during SMC curing significantly reduced severity of sink marks. This study concentrated on a method of predicting the optimum time during curing to release pressure by examining material behavior through process data from in-mold sersors. A simple control scheme was them applied for automatic pressure release at the optimum time corresponding with the peak of the material expansion and the onset of the reaction exotherm.     

Evaluation of Oxidative Stress Biomarkers,Pro-Inflammatory Cytokines,and Histological Changes in Experimental Hypertension,Dyslipidemia, and Type 1 Diabetes Mellitus

The present study aims to compare the oxidative stress biomarkers, pro-inflammatory cytokines, and histological changes induced by three cardiovascular risk factors, namely, hypertension, dyslipidemia, and type 1 diabetes mellitus. Hypertension was induced with 40 mg/kg body weight (b.w.) of N omega-nitro-L-arginine-methyl (L-NAME) administered orally. Dyslipidemia was induced by the administration of a diet with a high cholesterol (2%) content. Diabetes mellitus was induced by intraperitoneal administration of a single dose of streptozocin (65 mg/kg). Malondialdehyde (MDA) and total oxidative status (TOS) are increased by all three cardiovascular risk factors (up to 207%). The indirect assessment of NO synthesis (NOx) is observed to be reduced after L-NAME administration (43%), and dyslipidemia induction (16%), while type 1 diabetes mellitus is associated with the highest levels of NOx (increased 112%). Hypertension, dyslipidemia, and type 1 diabetes reduced the total antioxidative capacity (TAC) and total thiol (SH) levels (up to 57%). The values of evaluated pro-inflammatory cytokines, tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β), assessed from the ascending aorta were elevated by all three cardiovascular risk factors, with the highest levels induced by type 1 diabetes mellitus (up to 259%). The histopathological examination of the ascending and descending aorta revealed reversible pro-atherogenic changes consisting of the accumulation of lipid droplets in the subendothelial connective tissue on rats with hypertension and dyslipidemia. Irreversible pro-atherogenic changes consisting of a reduction of the specific elasticity of the arteries were observed in rats with type 1 diabetes mellitus. Type 1 diabetes mellitus demonstrates an alteration of the oxidative stress parameters, the elevation of tissue levels of the pro-inflammatory cytokines and causing irreversible pro-atherogenic changes on the aortic wall.     

An Atomistic Understanding of Allosteric Inhibition of Glutamate Racemase: a Dampening of Native Activation Dynamics

Glutamate racemases (GR) are members of the family of bacterial enzymes known as cofactor-independent racemases and epimerases and catalyze the stereoinversion of glutamate. D-amino acids are universally important for the proper construction of viable bacterial cell walls, and thus have been repeatedly validated as attractive targets for novel antimicrobial drug design. Significant aspects of the mechanism of this challenging stereoinversion remain unknown. The current study employs a combination of MD and QM/MM computational approaches to show that the GR from H. pylori must proceed via a pre-activation step, which is dependent on the enzyme's flexibility. This mechanism is starkly different from previously proposed mechanisms. These findings have immediate pharmaceutical relevance, as the H. pylori GR enzyme is a very attractive allosteric drug target. The results presented in this study offer a distinctly novel understanding of how AstraZeneca's lead series of inhibitors cripple the H. pylori GR's native motions, via prevention of this critical chemical pre-activation step. Our experimental studies, using SPR, fluorescence and NMR WaterLOGSY, show that H. pylori GR is not inhibited by the uncompetitive mechanism originally put forward by Lundqvist et al.. The current study supports a deep connection between native enzyme motions and chemical reactivity, which has strong relevance to the field of allosteric drug discovery.     

CeO2−CoO Phase Diagram

Phase equilibria in the CeO₂−CoO system at temperatures above 1500°C were investigated. The microstructures and the phase compositions of the DTA (differential thermal analysis) samples and the quenched solid pellets were analyzed using SEM (scanning electron microscope), EDX (energy dispersive X-ray), and WDX (wavelength dispersive X-ray). A eutectic reaction was found at 1645 ± 5°C. The eutectic point was calculated to be at 82 ± 1.5 mol% CoO. The eutectic phases were the CeO₂-rich phase (containing <5 mol% CoO) and the CoO-rich phase (containing ∼0.5 mol% CeO₂). At 1580°C, the solubility of CoO in CeO₂ was ∼3 mol%.     

Prebiotic Origin of Pre-RNA Building Blocks in a Urea “Warm Little Pond” Scenario

Urea appears to be a key intermediate of important prebiotic synthetic pathways. Concentrated pools of urea likely existed on the surface of the early Earth, as urea is synthesized in significant quantities from hydrogen cyanide or cyanamide (widely accepted prebiotic molecules), it has extremely high water solubility, and it can concentrate to form eutectics from aqueous solutions. We propose a model for the origin of a variety of canonical and non-canonical nucleobases, including some known to form supramolecular assemblies that contain Watson-Crick-like base pairs.The dual nucleophilic-electrophilic character of urea makes it an ideal precursor for the formation of nitrogenous heterocycles. We propose a model for the origin of a variety of canonical and noncanonical nucleobases, including some known to form supramolecular assemblies that contain Watson-Crick-like base pairs. These reactions involve urea condensation with other prebiotic molecules (e. g., malonic acid) that could be driven by environmental cycles (e. g., freezing/thawing, drying/wetting). The resulting heterocycle assemblies are compatible with the formation of nucleosides and, possibly, the chemical evolution of molecular precursors to RNA. We show that urea eutectics at moderate temperature represent a robust prebiotic source of nitrogenous heterocycles. The simplicity of these pathways, and their independence from specific or rare geological events, support the idea of urea being of fundamental importance to the prebiotic chemistry that gave rise to life on Earth.     

The history and development of the helium ion microscope

The helium ion microscope has recently emerged as a commercially available instrument. However, its roots go back more than 60 years to the development of the field ion microscope in Berlin, first reported in 1951. Over the intervening years, numerous researchers have pursued the development of a gas field ionization source with the goal of producing a suitable source for an ion microscope. This proved to be an elusive goal until early in this century when a number of discoveries led to a successful source, and shortly thereafter, an instrument fully able to exploit its advantages. Many individuals and many technical advances have come together to make this new class of microscope. The long history of this quest is reviewed along with the recent advances that led to the achievement of this milestone. A brief summary of the current status of the technology and its applications are given.     

Diet-Induced Gut Barrier Dysfunction Is Exacerbated in Mice Lacking Cannabinoid 1 Receptors in the Intestinal Epithelium

The gut barrier provides protection from pathogens and its function is compromised in diet-induced obesity (DIO). The endocannabinoid system in the gut is dysregulated in DIO and participates in gut barrier function; however, whether its activity is protective or detrimental for gut barrier integrity is unclear. We used mice conditionally deficient in cannabinoid receptor subtype-1 (CB₁R) in the intestinal epithelium (intCB1−/−) to test the hypothesis that CB₁Rs in intestinal epithelial cells provide protection from diet-induced gut barrier dysfunction. Control and intCB1−/− mice were placed for eight weeks on a high-fat/sucrose Western-style diet (WD) or a low-fat/no-sucrose diet. Endocannabinoid levels and activity of their metabolic enzymes were measured in the large-intestinal epithelium (LI). Paracellular permeability was tested in vivo, and expression of genes for gut barrier components and inflammatory markers were analyzed. Mice fed WD had (i) reduced levels of endocannabinoids in the LI due to lower activity of their biosynthetic enzymes, and (ii) increased permeability that was exacerbated in intCB1−/− mice. Moreover, intCB1−/− mice fed WD had decreased expression of genes for tight junction proteins and increased expression of inflammatory markers in LI. These results suggest that CB₁Rs in the intestinal epithelium serve a protective role in gut barrier function in DIO.