In-vivo biodistribution and safety of 99mTc-LLP2A-HYNIC in canine non-Hodgkin lymphoma

Theranostic agents are critical for improving the diagnosis and treatment of non-Hodgkin Lymphoma (NHL). The peptidomimetic LLP2A is a novel peptide receptor radiotherapy candidate for treating NHL that expresses the activated α4β1 integrin. Tumor-bearing dogs are an excellent model of human NHL with similar clinical characteristics, behavior, and compressed clinical course. Canine in vivo imaging studies will provide valuable biodistribution and affinity information that reflects a diverse clinical population of lymphoma. This may also help to determine potential dose-limiting radiotoxicity to organs in human clinical trials. To validate this construct in a naturally occurring model of NHL, we performed in-vivo molecular targeted imaging and biodistribution in 3 normal dogs and 5 NHL bearing dogs. (99m)Tc-LLP2A-HYNIC-PEG and (99m)Tc-LLP2A-HYNIC were successfully synthesized and had very good labeling efficiency and radiochemical purity. (99m)Tc-LLP2A-HYNIC and (99m)Tc-LLP2A-HYNIC-PEG had biodistribution in keeping with their molecular size, with (99m)Tc-LLP2A-HYNIC-PEG remaining longer in the circulation, having higher tissue uptake, and having more activity in the liver compared to (99m)Tc-LLP2A-HYNIC. (99m)Tc-LLP2A-HYNIC was mainly eliminated through the kidneys with some residual activity. Radioactivity was reduced to near-background levels at 6 hours after injection. In NHL dogs, tumor showed moderately increased activity over background, with tumor activity in B-cell lymphoma dogs decreasing after chemotherapy. This compound is promising in the development of targeted drug-delivery radiopharmaceuticals and may contribute to translational work in people affected by non-Hodgkin lymphoma.     

Common and distinct patterns of terminal modifications to mirtrons and canonical microRNAs

Nucleotide modifications to microRNAs or their precursors can influence their processing and/or activity. A challenge to their analysis is the lack of independent references for the termini generated by primary processing; typically, these are empirically assigned as the most abundant mapped reads. Mirtrons offer such an independent measure since these microRNA hairpins are defined by splicing. Consequently, mirtron-derived reads that deviate from splice sites reflect modification following primary processing. Analysis in Drosophila revealed multiple modification patterns, including select alterations of 5' termini, many 3' resection events, and unexpectedly abundant 3' untemplated monouridylation. Resections occur on mature AGO1-loaded species, whereas uridylation occurs on pre-miRNAs but is compatible with dicing and AGO1 loading. Strikingly, we found many mirtrons whose modified reads are more abundant than those produced by primary processing. In some cases, these abundant modified reads matched the genome owing to fortuitous uridines in downstream flanking exons, thus highlighting the value of an independent reference for the primary-processed sequence. We could further extend the principle of abundant and preferred uridylation of mirtrons, relative to canonical pre-miRNAs, to Caenorhabditis elegans, mouse, and human. Finally, we found that 3' resection occurs broadly across AGO1-loaded canonical miRNA and star species. Altogether, these findings substantially broaden the complexity of terminal modification pathways acting upon small regulatory RNAs.     

Climate-driven changes in pollinator assemblages during the last 60?years in an Arctic mountain region in Northern Scandinavia

Climate change is occurring more rapidly in the Arctic than elsewhere, and is predicted to have a large impact on biodiversity, since entire cold-adapted ecosystems are likely to disappear. Here, we highlight changes in the insect species richness and community composition of wild bees, butterflies and moths over 60 years in an area situated above the tree limit (Padjelanta National Park) in northern Sweden. Although there were changes in habitat availability, indicated by a significant decrease in the area of a glacier (from 22 km² in 1898 to 7.5 km² in 2009), and an increase in the area of birch forest in the National Park, we nevertheless found relatively moderate changes in the insect communities. Indeed, the observed number of species increased from 52 in 1944 to 64 in 2008. Remarkably, the mean number of butterflies and moths per site, but not wild bee species, increased significantly. Among the species that were recorded in both periods, the average altitude of 17 species had shifted downhill, 12 shifted uphill, and the altitude of the remaining 17 had not changed. While alterations in community composition were greater at the highest altitudes, changes in the insect community were smaller than expected, indeed much smaller than those reported from agricultural landscapes in North-West Europe. Interestingly, our results suggest that lower alpine altitudes (600–800 m a.s.l.) have become colonized by southern species, but also that high alpine areas (above 1,000 m a.s.l.) have recently become colonized by high alpine species previously absent from these sites, likely as a result of increasing habitat availability. We conclude that wild bee, butterfly, and moth communities in Arctic areas in northern Sweden are in flux, as a result of climate change and suggest that increased attention must be given to conservation planning in cold areas. In addition, we propose that monitoring programs should be established, because more pronounced climate-driven changes can be expected in the future.     

Linaria dalmatica invades south-facing slopes and less grazed areas in grazing-tolerant mixed-grass prairie

Identifying environments where invasive plants are most invasive is key to understanding causes of invasion and developing effective management strategies. In mixed-grass prairie, invasive plants are often successful in relatively wet, nitrogen-rich areas, and areas protected from grazing. Dalmatian toadflax, a common invader of mixed-grass prairie, can also be favored by high water and nitrogen availability, but is thought to be relatively unpalatable to cattle, and therefore favored by grazing. We used spatially-adjusted model selection techniques to quantify relationships between toadflax cover (measured using very high-resolution aerial imagery), and relative snow deposition (estimated with a blowing snow model), slope, aspect, soil texture, and grazing intensity (estimated by proximity to water tanks). Toadflax was common throughout the 400 ha study site, occurring in 742 of 1,861 images. Toadflax cover was high on steeper slopes, particularly those with southern aspects. These two topographic variables were more effective in explaining toadflax distribution than modeled snow deposition, suggesting that factors other than snow deposition cause toadflax invasion on south-facing slopes. Toadflax cover was also high in areas further from water tanks, indicating that grazing may inhibit toadflax invasion. More broadly, this result suggests that grazing can reduce invasion of even relatively unpalatable species in ecosystems with long evolutionary histories of grazing.