Experimental Design: CB-TE2A and TETA were conjugated to the somatostatin analogue tyrosine-3-octreotate (Y3-TATE) for evaluation of CB-TE2A as a bifunctional chelator of 64 Cu. The in vitro affinity of each compound for SSTr was determined using a homologous competitive binding assay. In vivo characteristics of both radiolabeled compounds were examined in biodistribution and microPET studies of AR42J tumor-bearing rats.Results: Cu-CB-TE2A-Y3-TATE (K d ‫؍‬ 1.7 nmol/L) and Cu-TETA-Y3-TATE (K d ‫؍‬ 0.7 nmol/L) showed similar affinities for AR42J derived SSTr. In biodistribution studies, nonspecific uptake in blood and liver was lower for 64 Cu-CB-TE2A-Y3-TATE. Differences increased with time such that, at 4 hours, blood uptake was 4.3-fold higher and liver uptake was 2.4-fold higher for 64 Cu-TETA-Y3-TATE than for 64 Cu-CB-TE2A-Y3-TATE. In addition, 4.4-times greater tumor uptake was detected with 64 Cu-CB-TE2A-Y3-TATE than with 64 Cu-TETA-Y3-TATE at 4 hours postinjection. MicroPET imaging yielded similar results.Conclusions: CB-TE2A appears to be a superior in vivo bifunctional chelator of 64 Cu for use in molecular imaging by PET or targeted radiotherapy due to both improved nontarget organ clearance and higher target organ uptake of 64 Cu-CB-TE2A-Y3-TATE compared with 64 Cu-TETA-Y3-TATE.

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We develop a cross‐station method to detect and locate tremor and low‐frequency earthquakes (LFEs), based on the original work of Armbruster et al. (2014) that compares waveforms from the same time window at stations separated by roughly 10 km. To improve the signal‐to‐noise ratio, we first rotate the horizontal components into the empirical shear wave particle motion direction. The large‐scale “rapid tremor reversals” beneath southern Vancouver Island are best recorded by stations that exhibit pronounced shear wave splitting, which obscures this optimal direction. We correct for splitting using the stacked templates of 11 low‐frequency earthquake families obtained in this region by Bostock et al. (2012). We find that the style of rapid tremor migrations (RTMs) evolves as the main front passes over a region. Very close to the main front, numerous small‐scale migrations occur with recurrence intervals far shorter than tidal periods. These usually propagate along the main front even when that is not parallel to dip. Several larger RTMs propagating along the main front have prominent elongation orthogonal to the propagation direction, inconsistent with the interpretation that their large propagation speed is an “apparent” velocity caused by the slow main front intersecting a preexisting linear structure on the plate interface. Farther behind the main front, RTMs gradually progress to being tidally modulated and have generally slower propagation speeds. Many reversal‐like RTMs are observed, some of which evolve from fronts initially propagating along the main front. These reversals are sometimes coherent across regions of low tremor density.

Copper-64, a positron emitter suitable for positron emission tomography (PET), demonstrates improved in vivo clearance when chelated by the cross-bridged tetraazamacrocycle CB-TE2A compared to TETA. Good in vivo clearance was also observed for 64Cu-CB-TE2A conjugated to a peptide, which converts one coordinating carboxylate pendant arm to an amide. To better understand the in vivo stability of peptide- conjugated CB-TE2A, cross-bridged monoamides were synthesized. Crystal structures of natCu(II)-CB-TEAMA and natCu(II)-CB-PhTEAMA revealed hexadentate, distorted octahedral coordination geometry. In vivo biodistribution showed clearance of all 64Cu-radiolabeled cross-bridged monoamides from liver and bone marrow such that uptake at 24 h was <10% of uptake at 30 min. In contrast, >60% of 30 min uptake from 64Cu-TETA was retained in these tissues at 24 h. Clearance of 64Cu-cross-bridged monoamides from nontarget organs suggests good in vivo stability, thus supporting the use of CB-TE2A as a bifunctional chelator without modifications to the macrocycle backbone.

Rats with streptozotocin (STZ)-induced diabetes were studied in order to identify abnormal microRNA (miRNA) expression profiles in diabetic retinopathy (DR) and to ascertain miRNAs associated with DR. Histopathologically, we observed characteristic features of DR in rats at 10 weeks after STZ injection. Investigation of miRNA expression profiles in the retinas of control and diabetic rats using miRNA microarrays revealed that many miRNAs were abnormally expressed in DR. On the basis of their fold changes and probability values, a total of 37 miRNAs were selected for further validation by real-time PCR analysis. The results showed that 11 miRNAs were significantly upregulated and 6 miRNAs were notably downregulated in DR. Furthermore, these changes in retinal miRNA expression levels paralleled the course of DR. Levels of miR-182, miR-96, miR-183, miR-211, miR-204, and miR-124 were significantly increased during the progress of DR, whereas miR-10b, miR-10a, miR-219-2-3p, miR-144, miR-338, and miR-199a-3p were significantly decreased. Our data indicate that the aberrant miRNA expression profiles in DR are associated with the development of DR. Modulation of retinal miRNA expression levels may provide a potential therapeutic strategy for DRs.

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