Quantification of Lipoprotein Uptake in Vivo Using Magnetic Particle Imaging and Spectroscopy

Lipids are a major source of energy for most tissues, and lipid uptake and storage is therefore crucial for energy homeostasis. So far, quantification of lipid uptake in vivo has primarily relied on radioactive isotope labeling, exposing human subjects or experimental animals to ionizing radiation. Here, we describe the quantification of in vivo uptake of chylomicrons, the primary carriers of dietary lipids, in metabolically active tissues using magnetic particle imaging (MPI) and magnetic particle spectroscopy (MPS). We show that loading artificial chylomicrons (ACM) with iron oxide nanoparticles (IONPs) enables rapid and highly sensitive post hoc detection of lipid uptake in situ using MPS. Importantly, by utilizing highly magnetic Zn-doped iron oxide nanoparticles (ZnMNPs), we generated ACM with MPI tracer properties superseding the current gold-standard, Resovist, enabling quantification of lipid uptake from whole-animal scans. We focused on brown adipose tissue (BAT), which dissipates heat and can consume a large part of nutrient lipids, as a model for tightly regulated and inducible lipid uptake. High BAT activity in humans correlates with leanness and improved cardiometabolic health. However, the lack of nonradioactive imaging techniques is an important hurdle for the development of BAT-centered therapies for metabolic diseases such as obesity and type 2 diabetes. Comparison of MPI measurements with iron quantification by inductively coupled plasma mass spectrometry revealed that MPI rivals the performance of this highly sensitive technique. Our results represent radioactivity-free quantification of lipid uptake in metabolically active tissues such as BAT

Limited diversity in natal origins of immature anadromous fish during ocean residency

Author Posting. © The Authors, 2009. This is the author's version of the work. It is posted here by permission of NRC Research Press for personal use, not for redistribution. The definitive version was published in Canadian Journal of Fisheries and Aquatic Sciences. 67 (2010): 1699-1707, doi:10.1139/F10-086.Variable migration patterns can play a significant role in promoting diverse life history traits among populations. However, population and stage specific movement patterns are generally unknown yet crucial aspects of life history strategies in many highly migratory species. We used a natural tag approach using geochemical signatures in otoliths to identify natal origins of one-year-old anadromous American shad (Alosa sapidissima) during ocean residency. Otolith signatures of migrants were compared to a database of baseline signatures from 20 source populations throughout their spawning range. Samples were dominated by fish from only two rivers, while all other potential source populations were nearly or completely absent. These data support the hypothesis that American shad exhibit diverse migratory behaviors and immature individuals from populations throughout the native range do not all mix on northern summer feeding grounds. Rather, our results suggest populations of anadromous fish are distributed heterogeneously at sea in the first year of life and thus may encounter different ocean conditions at a critical early life history stage.This work was funded by National Science Foundation grants OCE-0215905 and OCE-0134998 to SRT and by a WHOI Ocean Life Institute grant to BDW

PRIMA1 mutation: A new cause of nocturnal frontal lobe epilepsy

Objective Nocturnal frontal lobe epilepsy (NFLE) can be sporadic or autosomal dominant; some families have nicotinic acetylcholine receptor subunit mutations. We report a novel autosomal recessive phenotype in a single family and identify the causative gene. Methods Whole exome sequencing data was used to map the family, thereby narrowing exome search space, and then to identify the mutation. Results Linkage analysis using exome sequence data from two affected and two unaffected subjects showed homozygous linkage peaks on chromosomes 7, 8, 13, and 14 with maximum LOD scores between 1.5 and 1.93. Exome variant filtering under these peaks revealed that the affected siblings were homozygous for a novel splice site mutation (c.93+2T>C) in the PRIMA1 gene on chromosome 14. No additional PRIMA1 mutations were found in 300 other NFLE cases. The c.93+2T>C mutation was shown to lead to skipping of the first coding exon of the PRIMA1 mRNA using a minigene system. Interpretation PRIMA1 is a transmembrane protein that anchors acetylcholinesterase (AChE), an enzyme hydrolyzing acetycholine, to membrane rafts of neurons. PRiMA knockout mice have reduction of AChE and accumulation of acetylcholine at the synapse; our minigene analysis suggests that the c.93+2T>C mutation leads to knockout of PRIMA1. Mutations with gain of function effects in acetylcholine receptor subunits cause autosomal dominant NFLE. Thus, enhanced cholinergic responses are the likely cause of the severe NFLE and intellectual disability segregating in this family, representing the first recessive case to be reported and the first PRIMA1 mutation implicated in disease

Repeat expansion disorders enriched in an Australian and New Zealand Epi25 Year 1 epilepsy cohort

Meeting abstract: 33rd International Epilepsy Congress Bangkok, Thailand 22 – 26 June 201

SCN1A Variants in vaccine-related febrile seizures: a prospective study

Objective: Febrile seizures may follow vaccination. Common variants in the sodium channel gene, SCN1A, are associated with febrile seizures, and rare pathogenic variants in SCN1A cause the severe developmental and epileptic encephalopathy Dravet syndrome. Following vaccination, febrile seizures may raise the specter of poor outcome and inappropriately implicate vaccination as the cause. We aimed to determine the prevalence of SCN1A variants in children having their first febrile seizure either proximal to vaccination or unrelated to vaccination compared to controls. Methods: We performed SCN1A sequencing, blind to clinical category, in a prospective cohort of children presenting with their first febrile seizure as vaccine proximate (n = 69) or as non–vaccine proximate (n = 75), and children with no history of seizures (n = 90) recruited in Australian pediatric hospitals. Results: We detected 2 pathogenic variants in vaccine‐proximate cases (p.R568X and p.W932R), both of whom developed Dravet syndrome, and 1 in a non–vaccine‐proximate case (p.V947L) who had febrile seizures plus from 9 months. All had generalized tonic–clonic seizures lasting >15 minutes. We also found enrichment of a reported risk allele, rs6432860‐T, in children with febrile seizures compared to controls (odds ratio = 1.91, 95% confidence interval = 1.31–2.81). Interpretation: Pathogenic SCN1A variants may be identified in infants with vaccine‐proximate febrile seizures. As early diagnosis of Dravet syndrome is essential for optimal management and outcome, SCN1A sequencing in infants with prolonged febrile seizures, proximate to vaccination, should become routine. ANN NEUROL 2019John A. Damiano, Lucy Deng, Wenhui Li, Rosemary Burgess, Amy L. Schneider ... Michael Gold ... et al