Sr isotopic composition of hydroxyapatite from recent and fossil salmon: the record of lifetime migration and diagenesis

By comparing the Sr isotopic composition of migratory fossil salmon, which lived in the ocean but died in continental regions, to the well established marine Sr isotopic record, the age of the continental deposit could be determined with high accuracy. This approach to marine-continental correlation and dating requires (1) that marine-resident salmon bear a marine 87Sr/86Sr value in their bones or teeth, and (2) that the original 87Sr/86Sr value of fossils is not overprinted by diagenesis. The vertebrae of modern, hatchery-reared salmon exhibit Sr isotopic variations indicative of freshwater to marine migration during bone growth. Modern marine 87Sr/86Sr values were preserved in growth layers formed later in life. Marine-phase growth layers in the bones and teeth of the late Miocene migratory salmon, Oncorhynchus rastrosus, were subjected to stepwise selective leaching to separate biogenic hydroxyapatite from diagenetic calcium carbonate and recrystallized hydroxyapatite. Although the procedure yielded leachates with Sr/Ca and Ca/P values characteristic of apatite, the leachates had 87Sr/86Sr values consistently less radiogenic than values for late Miocene seawater ( [superset or implies] 0.7087. The fossils were substantially contaminated by Sr from the hosting clastic sediments. Specimens in continental deposits differed in 87Sr/86Sr value from host sediments by 0.0002 to 0.0200, supporting the conclusion that these salmon were migrants from marine waters. However, because the original Sr isotopic composition of fossil bones and teeth cannot be determined with confidence, archaeological, paleobiological and stratigraphic applications of this technique may be limited.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30230/1/0000624.pd

The Ionic Charge of Copper-64 Complexes Conjugated to an Engineered Antibody Affects Biodistribution

The development of biomolecules as imaging probes requires radiolabeling methods that do not significantly influence their biodistribution. Sarcophagine (Sar) chelators form extremely stable complexes with copper and are therefore a promising option for labeling proteins with ⁶⁴Cu. However, initial studies using the first-generation sarcophagine bifunctional chelator SarAr to label the engineered antibody fragment ch14.18-ΔC_H2 (MW 120 kDa) with ⁶⁴Cu showed high tracer retention in the kidneys, presumably because the high local positive charge on the Cu^II-SarAr moiety resulted in increased binding of the labeled protein to the negatively charged basal cells of the glomerulus. To test this hypothesis, ch14.18-ΔC_H2 was conjugated with a series of Sar derivatives of decreasing positive charge and three commonly used macrocyclic polyaza polycarboxylate (PAC) bifunctional chelators (BFC). The immunoconjugates were labeled with ⁶⁴Cu and injected into mice, and PET/CT images were obtained at 24 and 48 h postinjection (p.i.). At 48 h p.i., <i>ex vivo</i> biodistribution was assessed. In addition, to demonstrate the potential of metastasis detection using ⁶⁴Cu-labeled ch14.18-ΔC_H2, a preclinical imaging study of intrahepatic neuroblastoma tumors was performed. Reducing the positive charge on the Sar chelators decreased kidney uptake of Cu-labeled ch14.18-ΔC_H2 by more than 6-fold, from >45 to <6% ID/g, whereas the uptake in most other tissues, including liver, was relatively unchanged. However, despite this dramatic decrease, the renal uptake of the PAC BFCs was generally lower than that of the Sar derivatives, as was the liver uptake. Uptake of ⁶⁴Cu-labeled ch14.18-ΔC_H2 in neuroblastoma hepatic metastases was detected using PET

Sleep deprivation impairs cAMP signalling in the hippocampus

Millions of people regularly obtain insufficient sleep1. Given the effect of sleep deprivation on our lives, understanding the cellular and molecular pathways affected by sleep deprivation is clearly of social and clinical importance. One of the major effects of sleep deprivation on the brain is to produce memory deficits in learning models that are dependent on the hippocampus2, 3, 4, 5. Here we have identified a molecular mechanism by which brief sleep deprivation alters hippocampal function. Sleep deprivation selectively impaired 3', 5'-cyclic AMP (cAMP)- and protein kinase A (PKA)-dependent forms of synaptic plasticity6 in the mouse hippocampus, reduced cAMP signalling, and increased activity and protein levels of phosphodiesterase 4 (PDE4), an enzyme that degrades cAMP. Treatment of mice with phosphodiesterase inhibitors rescued the sleep-deprivation-induced deficits in cAMP signalling, synaptic plasticity and hippocampus-dependent memory. These findings demonstrate that brief sleep deprivation disrupts hippocampal function by interfering with cAMP signalling through increased PDE4 activity. Thus, drugs that enhance cAMP signalling may provide a new therapeutic approach to counteract the cognitive effects of sleep deprivation

GBA Variants are associated with a distinct pattern of cognitive deficits in Parkinson's disease

BackgroundLoss-of-function mutations in the GBA gene are associated with more severe cognitive impairment in PD, but the nature of these deficits is not well understood and whether common GBA polymorphisms influence cognitive performance in PD is not yet known.MethodsWe screened the GBA coding region for mutations and the E326K polymorphism in 1,369 PD patients enrolled at eight sites from the PD Cognitive Genetics Consortium. Participants underwent assessments of learning and memory (Hopkins Verbal Learning Test-Revised), working memory/executive function (Letter-Number Sequencing Test and Trail Making Test A and B), language processing (semantic and phonemic verbal fluency), visuospatial abilities (Benton Judgment of Line Orientation), and global cognitive function (MoCA). We used linear regression to test for association between genotype and cognitive performance with adjustment for important covariates and accounted for multiple testing using Bonferroni's corrections.ResultsMutation carriers (n = 60; 4.4%) and E326K carriers (n = 65; 4.7%) had a higher prevalence of dementia (mutations, odds ratio = 5.1; P = 9.7 × 10(-6) ; E326K, odds ratio = 6.4; P = 5.7 × 10(-7) ) and lower performance on Letter-Number Sequencing (mutations, corrected P[Pc ] = 9.0 × 10(-4) ; E326K, Pc  = 0.036), Trail Making B-A (mutations, Pc  = 0.018; E326K, Pc  = 0.018), and Benton Judgment of Line Orientation (mutations, Pc  = 0.0045; E326K, Pc  = 0.0013).ConclusionsBoth GBA mutations and E326K are associated with a distinct cognitive profile characterized by greater impairment in working memory/executive function and visuospatial abilities in PD patients. The discovery that E326K negatively impacts cognitive performance approximately doubles the proportion of PD patients we now recognize are at risk for more severe GBA-related cognitive deficits