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Pyrimidine catabolism is implicated in hepatic steatosis. Dihydropyrimidine dehydrogenase (DPYD) is an enzyme responsible for uracil and thymine catabolism, and DPYD human genetic variability affects clinically observed toxicity following 5-Fluorouracil administration. In an in vitro model of fatty acid-induced steatosis, the pharmacologic inhibition of DPYD resulted in protection from lipid accumulation. Additionally, a gain-of-function mutation of DPYD, created through clustered regularly interspaced short palindromic repeats associated protein 9 (CRISPR-Cas9) engineering, led to an increased lipid burden, which was associated with altered mitochondrial functionality in a hepatocarcionma cell line. The studies presented herein describe a novel role for DPYD in hepatocyte metabolic regulation as a modulator of hepatic steatosis. [ABSTRACT FROM AUTHOR]

During passive whole-body motion in the dark, the motion perceived by subjects may or may not be veridical. Either way, reflexive eye movements are typically compensatory for the perceived motion. However, studies are discovering that for certain motions, the perceived motion and eye movements are incompatible. The incompatibility has not been explained by basic differences in gain or time constants of decay. This paper uses three-dimensional modeling to investigate gondola centrifugation (with a tilting carriage) and off-vertical axis rotation. The first goal was to determine whether known differences between perceived motions and eye movements are true differences when all three-dimensional combinations of angular and linear components are considered. The second goal was to identify the likely areas of processing in which perceived motions match or differ from eye movements, whether in angular components, linear components and/or dynamics. The results were that perceived motions are more compatible with eye movements in three dimensions than the one-dimensional components indicate, and that they differ more in their linear than their angular components. In addition, while eye movements are consistent with linear filtering processes, perceived motion has dynamics that cannot be explained by basic differences in time constants, filtering, or standard GIF-resolution processes. [ABSTRACT FROM AUTHOR]

Understanding the organization and mechanical function of the extracellular matrix (ECM) is critical for the development of therapeutic strategies that regulate wound healing following disease or injury. However, these relationships are challenging to elucidate during remodeling following myocardial infarction (MI) due to rapid changes in cellularity and an inability to characterize both ECM microstructure and function non-destructively. In this study, we overcome those challenges through whole organ decellularization and non-linear optical microscopy to directly relate the microstructure and mechanical properties of myocardial ECM. We non-destructively quantify collagen organization, content, and cross-linking within decellularized healthy and infarcted myocardium using second harmonic generation (SHG) and two photon excited autofluorescence. Tensile mechanical testing and compositional analysis reveal that the cumulative SHG intensity within each image volume and the average collagen autofluorescence are significantly correlated with collagen content and elastic modulus of the ECM, respectively. Compared to healthy ECM, infarcted tissues demonstrate a significant increase in collagen content and fiber alignment, and a decrease in cross-linking and elastic modulus. These findings indicate that cross-linking plays a key role in stiffness at the collagen fiber level following infarction, and highlight how this non-destructive approach to assessing remodeling can be used to understand ECM structure-function relationships. [ABSTRACT FROM AUTHOR]