Disease pathology signatures in a mouse model of Mucopolysaccharidosis type IIIB.

Mucopolysaccharidosis type IIIB (MPS IIIB) is a rare and devastating childhood-onset lysosomal storage disease caused by complete loss of function of the lysosomal hydrolase α-N-acetylglucosaminidase. The lack of functional enzyme in MPS IIIB patients leads to the progressive accumulation of heparan sulfate throughout the body and triggers a cascade of neuroinflammatory and other biochemical processes ultimately resulting in severe mental impairment and early death in adolescence or young adulthood. The low prevalence and severity of the disease has necessitated the use of animal models to improve our knowledge of the pathophysiology and for the development of therapeutic treatments. In this study, we took a systematic approach to characterizing a classical mouse model of MPS IIIB. Using a series of histological, biochemical, proteomic and behavioral assays, we tested MPS IIIB mice at two stages: during the pre-symptomatic and early symptomatic phases of disease development, in order to validate previously described phenotypes, explore new mechanisms of disease pathology and uncover biomarkers for MPS IIIB. Along with previous findings, this study helps provide a deeper understanding of the pathology landscape of this rare disease with high unmet medical need and serves as an important resource to the scientific community.

Modifying antibody-FcRn interactions to increase the transport of antibodies through the blood-brain barrier.

The blood-brain barrier (BBB) largely excludes antibodies from entering the central nervous system, thus limiting the potential of therapeutic antibodies to treat conditions such as neurodegenerative diseases and neuro-psychiatric disorders. Here, we demonstrate that the transport of human antibodies across the BBB in mice can be enhanced by modulating their interactions with the neonatal Fc receptor (FcRn). When M252Y/S254T/T246E substitutions are introduced on the antibody Fc domain, immunohistochemical assays reveal widespread distribution of the engineered antibodies throughout the mouse brain. These engineered antibodies remain specific for their antigens and retain pharmacological activity. We propose that novel brain-targeted therapeutic antibodies can be engineered to differentially engage FcRn for receptor-mediated transcytosis across the BBB in order to improve neurological disease therapeutics in the future.

Detection of PFAS and Fluorinated Surfactants Using Differential Behaviors at Interfaces of Complex Droplets.

Contamination of per- and polyfluoroalkyl substances (PFAS) in water supplies will continue to have serious health and environmental consequences. Despite the importance of monitoring the concentrations of PFAS at potential sites of contamination and at treatment plants, there are few suitable and rapid on-site methods. Many nonconventional techniques do not possess the necessary selectivity and sensitivity to distinguish PFAS from other surface-active components and to quantify the low concentrations in real-world conditions. Herein, we report a novel and rapid method for the detection of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) by leveraging their differential behaviors at the interfaces of emissive complex droplets. Measurement of surface and interfacial tensions via a force tensiometer reveals that PFAS preferentially self-assemble at the water-fluorocarbon oil interface (F/W) rather than the water-hydrocarbon oil interface (H/W). We also observe an opposite behavior for hydrocarbon surfactants. This difference in interfacial behavior produces distinct effects on the morphological change and optical emission of biphasic oil-in-water droplets. The change in the intensity of fluorescence emission, measured with a simple spectroscopic setup, correlates with the concentrations of PFAS. We also demonstrate that the range of detection and sensitivity can be tuned by adjusting the initial composition of the complex droplets. Our results illustrate an alternative mode of sensors that may provide a rapid and on-site detection of PFAS.