Psychometric outcome measures in beta-propeller protein-associated neurodegeneration (BPAN).

BACKGROUND: Beta-propeller protein-associated neurodegeneration (BPAN) is a rare neurodegenerative disorder characterized by iron accumulation in the brain with spectrum of neurodevelopmental and movement phenotypes. In anticipation of future clinical trials and to inform clinical care, there is an unmet need to capture the phenotypic diversity of this rare disorder and better define disease subtypes. METHODS: A total of 27 individuals with BPAN were included in our natural history study, from which traditional outcome measures were obtained in 18 subjects. Demographic and diagnostic information, along with acquisition of basic developmental skills and overall neurologic severity were extracted from the medical records. Functional outcome measures were administered at the time of the evaluation or applied retrospectively at the last clinical encounter for patients who were not able to travel for in person. Based on age and functional level, the following assessments were administered: Leiter-3, Gross Motor Function Measure (GMFM)-66 Item Sets, Vineland-3, and Peabody-2. RESULTS: Overall, cognitive function was more impaired compared to gross motor function. Onset of symptoms of BPAN within the first 6 months of life was associated with decreased gain of ambulation and gain of spoken language (ambulation: log-rank test p = 0.0015; gain of first word: p = 0.0015). There was no difference in age at seizure onset by age at initial symptom onset (p = 0.8823). Collection of prospective outcome measures was limited by attention and behavior in our patient population, reinforcing the complexity of phenotype assessment and inadequacy of available standardized tests. Overall, gross motor and adaptive behavior assessments were better able to capture the dynamic range of function across the BPAN population than the fine motor and non-verbal cognitive tests. Floor effects were noted across outcome measures in a subset of individuals for cognitive and adaptive behavior tests. CONCLUSION: Our data suggest the distinct phenotypes of BPAN: a severe, early onset form and an attenuated form with higher cognitive capabilities. Early age at onset was a key factor in predicting future neurologic impairment.

Hybrid adipose graft materials synthesized from chemically modified adipose extracellular matrix.

Decellularized extracellular matrix (ECM) from tissues is a promising biomaterial that can provide a complex 3D microenvironment capable of modulating cell response and tissue regeneration. In this study, we have integrated the decellularized thiolated adipose-derived ECM, at different concentrations, with polyethylene glycol (PEG) using Michael addition between thiol and acrylate moieties. The potential for this material to support adipogenic differentiation of human adipose-derived stem cells was evaluated by encapsulating cells in hydrogels with increasing concentrations of chemically modified ECM (mECM). Our results demonstrated a positive correlation between the ECM content in the hydrogels and cell proliferation, adipogenic marker expression, and lipid formation and accumulation. Furthermore, we have shown host cell infiltration and enhanced adipogenesis in vivo after implantation. These findings support the graft as a potential alternative for adipose tissue regeneration.

Alternating magnetic field mediated release of fluorophores from magnetic nanoparticles by hysteretic heating.

This study explores the use of differential heating of magnetic nanoparticles with different sizes and compositions (MFe2O4 (M = Fe, Co)) for heteroplexed temporal controlled release of conjugated fluorophores from the surface of nanoparticles. By exploiting these differences, we were able to control the amount of hysteretic heating occurring with the distinct sets of magnetic nanoparticles using the same applied alternating magnetic field radio frequency (AMF-RF). Using thermally labile retro-Diels-Alder linkers conjugated to the surface of nanoparticles, the fluorescent payload from the different nanoparticles disengaged when sufficient energy was locally generated during hysteretic heating. 1H, 13C NMR, ESI-MS, and SIMS characterized the thermally responsive fluorescent cycloadducts used in this study; the Diels Alder cycloadducts were modeled using density functional theory (DFT) computations. The localized point heating of the different nanoparticle compositions drove the retro-Diels-Alder reaction at different times resulting in higher release rates of fluorophores from the CoFe2O4 compared to the Fe3O4 nanoparticles.

Class IIa HDACs do not influence beta-cell function under normal or high glucose conditions.

Inhibiting Class IIa Histone Deacetylase (HDAC) function is a promising approach to therapeutically enhance skeletal and cardiac muscle metabolic health in several chronic diseases including type 2 diabetes. However, the importance of Class IIa HDACs in the beta-cell remains unknown. As beta-cell function is vital to maintaining glycaemia it is essential that the importance of Class IIa HDACs in the beta-cell is determined. Here we used the INS-1E cell line cultured in normal glucose (11.1 mM) or hyperglycaemic (20 mM) conditions for 48 hrs to represent cells in a normal and diabetic environment respectively. Cells cultured in high glucose showed significantly reduced insulin secretory function and increased apoptotic signalling compared to cells cultured in normal glucose. Class IIa HDACS, HDAC-4 and -5, were not regulated at the transcript or protein level under normal or hyperglycaemic conditions suggesting that they may not play a role in beta-cell dysfunction. Furthermore, overexpression of wild-type HDAC-4 and -5 or dominant negative HDAC-4 and -5 did not alter insulin secretion, insulin mRNA expression or apoptotic signalling under normal or hyperglycaemic conditions. This suggests that Class IIa Histone Deacetylases do not play an important physiological role in the beta-cell under normal or diabetic conditions. Thus, Class IIa Histone Deacetylase inhibitors are not likely to have a detrimental effect on beta-cells supporting the use of these inhibitors to treat metabolic diseases such as type 2 diabetes.

Hybrid Synthetic-Biological Hydrogel System for Adipose Tissue Regeneration.

Hydrogels are promising scaffolds for adipose tissue regeneration. Currently, the incorporation of bioactive molecules in hydrogel system is used, which can increase the cell proliferation rate or improve adipogenic differentiation performance of stromal stem cells but often suffers from high expense or cytotoxicity because of light/thermal curing used for polymerization. In this study, decellularized adipose tissue is incorporated, at varying concentrations, with a thiol-acrylate fraction that is then polymerized to produce hydrogels via a Michael addition reaction. The results reveal that the major component of isolated adipose-derived extracellular matrix (ECM) is Collagen I. Mechanical properties of ECM polyethylene glycol (PEG) are not negatively affected by the incorporation of ECM. Additionally, human adipose-derived stem cells (hASCs) are encapsulated in ECM PEG hydrogel with ECM concentrations varying from 0% to 1%. The results indicate that hASCs maintained the highest viability and proliferation rate in 1% ECM PEG hydrogel with most lipids formation when cultured in adipogenic conditions. Furthermore, more adipose regeneration is observed in 1% ECM group with in vivo study by Day 14 compared to other ECM PEG hydrogels with lower ECM content. Taken together, these findings suggest the ECM PEG hydrogel is a promising substitute for adipose tissue regeneration applications.