[Abstract unavailable

This report describes the first human study of a novel amyloid-imaging positron emission tomography (PET) tracer, termed Pittsburgh Compound-B (PIB), in 16 patients with diagnosed mild AD and 9 controls. Compared with controls, AD patients typically showed marked retention of PIB in areas of association cortex known to contain large amounts of amyloid deposits in AD. In the AD patient group, PIB retention was increased most prominently in frontal cortex (1.94-fold, p = 0.0001). Large increases also were observed in parietal (1.71-fold, p = 0.0002), temporal (1.52-fold, p = 0.002), and occipital (1.54-fold, p = 0.002) cortex and the striatum (1.76-fold, p = 0.0001). PIB retention was equivalent in AD patients and controls in areas known to be relatively unaffected by amyloid deposition (such as subcortical white matter, pons, and cerebellum). Studies in three young (21 years) and six older healthy controls (69.5 +/- 11 years) showed low PIB retention in cortical areas and no significant group differences between young and older controls. In cortical areas, PIB retention correlated inversely with cerebral glucose metabolism determined with 18F-fluorodeoxyglucose. This relationship was most robust in the parietal cortex (r = -0.72; p = 0.0001). The results suggest that PET imaging with the novel tracer, PIB, can provide quantitative information on amyloid deposits in living subjects.

Peripheral blood neutrophils form highly decondensed chromatin structures, termed neutrophil extracellular traps (NETs), that have been implicated in innate immune response to bacterial infection. Neutrophils express high levels of peptidylarginine deiminase 4 (PAD4), which catalyzes histone citrullination. However, whether PAD4 or histone citrullination plays a role in chromatin structure in neutrophils is unclear. In this study, we show that the hypercitrullination of histones by PAD4 mediates chromatin decondensation. Histone hypercitrullination is detected on highly decondensed chromatin in HL-60 granulocytes and blood neutrophils. The inhibition of PAD4 decreases histone hypercitrullination and the formation of NET-like structures, whereas PAD4 treatment of HL-60 cells facilitates these processes. The loss of heterochromatin and multilobular nuclear structures is detected in HL-60 granulocytes after PAD4 activation. Importantly, citrullination of biochemically defined avian nucleosome arrays inhibits their compaction by the linker histone H5 to form higher order chromatin structures. Together, these results suggest that histone hypercitrullination has important functions in chromatin decondensation in granulocytes/neutrophils.

Soft and conformable wearable electronics require stretchable semiconductors, but existing ones typically sacrifice charge transport mobility to achieve stretchability. We explore a concept based on the nanoconfinement of polymers to substantially improve the stretchability of polymer semiconductors, without affecting charge transport mobility. The increased polymer chain dynamics under nanoconfinement significantly reduces the modulus of the conjugated polymer and largely delays the onset of crack formation under strain. As a result, our fabricated semiconducting film can be stretched up to 100% strain without affecting mobility, retaining values comparable to that of amorphous silicon. The fully stretchable transistors exhibit high biaxial stretchability with minimal change in on current even when poked with a sharp object. We demonstrate a skinlike finger-wearable driver for a light-emitting diode.

The synthesis and evaluation of a series of neutral analogues of thioflavin-T (termed BTA's) with high affinities for aggregated amyloid and a wide range of lipophilicities are reported. Radiolabeling with high specific activity [(11)C]methyl iodide provided derivatives for in vivo evaluation. Brain entry in control mice and baboons was high for nearly all of the analogues at early times after injection, but the clearance rate of radioactivity from brain tissue varied by more than 1 order of magnitude. Upon the basis of its rapid clearance from normal mouse and baboon brain tissues, [N-methyl-(11)C]2-(4'-methylaminophenyl)-6-hydroxybenzothiazole (or [(11)C]6-OH-BTA-1) was selected as the lead compound for further evaluation. The radiolabeled metabolites of [(11)C]6-OH-BTA-1 were polar and did not enter brain. The binding affinities of [N-methyl-(3)H]6-OH-BTA-1 for homogenates of postmortem AD frontal cortex and synthetic Abeta(1-40) fibrils were similar (K(d) = 1.4 nM and 4.7 nM, respectively), but the ligand-to-Abeta peptide binding stoichiometry was approximately 400-fold higher for AD brain than Abeta(1-40) fibrils. Staining of AD frontal cortex tissue sections with 6-OH-BTA-1 indicated the selective binding of the compound to amyloid plaques and cerebrovascular amyloid. The encouraging in vitro and in vivo properties of [(11)C]6-OH-BTA-1 support the choice of this derivative for further evaluation in human subject studies of brain Abeta deposition.