Phage display library derived peptides that bind to human tumor melanin as potential vehicles for targeted radionuclide therapy of metastatic melanoma

Metastatic melanoma remains an incurable disease, and there is a great need for novel therapeutic modalities. We have recently identified melanin as a target for radionuclide therapy of melanoma and demonstrated the feasibility of this approach using a 188-rhenium ( (188)Re)-radiolabeled melanin-binding decapeptide to fungal melanin known as 4B4. Although the results indicated that radiolabeled melanin-binding decapeptide had activity against melanoma, that peptide also manifested high kidney uptake and this might become a concern during clinical trials. We hypothesized that by identifying peptides with different amino acid composition against tumor melanin we might be able to decrease their kidney uptake. Using the Heptapeptide Ph.D.-7 Phage Display Library, we identified three heptapeptides that bind to human tumor melanin. These peptides were radiolabeled with (188)Re via HYNIC ligand, and their comprehensive biodistribution in A2058 human metastatic melanoma tumor-bearing nude mice was compared to that of (188)Re-4B4 decapeptide. While tumor uptake of heptapeptides was quite similar to that of (188)Re-4B4 decapeptide, there was dramatically less uptake in the kidneys at both 3 h (6% ID/g vs 38%) and 24 h (2% ID/g vs 15%) postinjection. Administration of one of the generated heptapeptides, (188)Re-HYNIC-AsnProAsnTrpGlyProArg, to A2058 human metastatic melanoma-bearing nude mice resulted in significant retardation of the tumor growth. Immunofluorescence showed that in spite of their relatively small size heptapeptides were not able to penetrate through the membranes of viable melanoma cells and bound only to extracellular melanin, which provides assurance that they will be safe to healthy melanin-containing tissues during radionuclide therapy. Thus, these heptapeptides appear to have potentially significant advantages for targeted therapy of melanoma relative to existing melanin-binding peptides.     

Effects of gender and foot-landing techniques on lower extremity kinematics during drop-jump landings

The purpose of this study was to assess kinematic lower extremity motion patterns (hip flexion, knee flexion, knee valgus, and ankle dorsiflexion) during various foot-landing techniques (self-preferred, forefoot, and rear foot) between genders. 3-D kinematics were collected on 50 (25 male and 25 female) college-age recreational athletes selected from a sample of convenience. Separate repeated-measures ANOVAs were used to analyze each variable at three time instants (initial contact, peak vertical ground reaction force, and maximum knee flexion angle). There were no significant differences found between genders at the three instants for each variable. At initial contact, the forefoot technique (35.79 degrees +/- 11.78 degrees ) resulted in significantly (p = .001) less hip flexion than did the self-preferred (41.25 degrees +/- 12.89 degrees ) and rear foot (43.15 degrees +/- 11.77 degrees ) techniques. At peak vertical ground reaction force, the rear foot technique (26.77 degrees +/- 9.49 degrees ) presented significantly lower (p = .001) knee flexion angles as compared with forefoot (58.77 degrees +/- 20.00 degrees ) and self-preferred (54.21 degrees +/- 23.78 degrees ) techniques. A significant difference for knee valgus angles (p = .001) was also found between landing techniques at peak vertical ground reaction force. The self-preferred (4.12 degrees +/- 7.51 degrees ) and forefoot (4.97 degrees +/- 7.90 degrees ) techniques presented greater knee varus angles as compared with the rear foot technique (0.08 degrees +/- 6.52 degrees ). The rear foot technique created more ankle dorsiflexion and less knee flexion than did the other techniques. The lack of gender differences can mean that lower extremity injuries (e.g., ACL tears) may not be related solely to gender but may instead be associated with the landing technique used and, consequently, the way each individual absorbs jump-landing energy.     

Sclerosperma fossils from the late Oligocene of Chilga,north-western Ethiopia

The palm family, Arecaceae, is notoriously depauperate in Africa today, and its evolutionary, paleobiogeographic, and extinction history there are not well documented by fossils. In this article we report the pollen of two new extinct species of the small genus, Sclerosperma (Arecoideae), from a late Oligocene (27–28 Ma) stratum exposed along the Guang River in Chilga Wereda of north-western Ethiopia. The pollen are triporate, and the two taxa can be distinguished from each other and from modern species using a combination of light and scanning electron microscopy, which reveals variations in the finer details of their reticulate to perforate exine sculpture. We also report a palm leaf fragment from a stratum higher in the same section that is in the Arecoideae subfamily, and most likely belongs to Sclerosperma. The implications of these discoveries for the evolutionary history of this clade of African arecoid palms is that their diversification was well underway by the middle to late Oligocene, and they were much more widespread in Africa at that time than they are now, limited to West and Central Africa. Sclerosperma exhibits ecological conservatism, as today it occurs primarily in swamps and flooded forests, and the sedimentology of the Guang River deposits at Chilga indicate a heterogeneous landscape with a high water table. The matrix containing the fossil pollen is lignite, which itself indicates standing water, and a variety of plant macrofossils from higher in the section have been interpreted as representing moist tropical forest or seasonally inundated forest communities.     

No barrier breakdown between human and cattle schistosome species in the Senegal River Basin in the face of hybridisation

Schistosomiasis is widely distributed along the Senegal River Basin (SRB), affecting both the human population and their livestock. Damming of the Senegal River for irrigation purposes in the 1980s induced ecological changes that resulted in a large outbreak of Schistosoma mansoni, followed a few years later by an increase and spread of Schistosoma haematobium infections. The presence of hybrid crosses between the human and cattle schistosomes, S. haematobium and Schistosoma bovis, respectively, is adding complexity to the disease epidemiology in this area, and questions the strength of the species boundary between these two species. This study aimed to investigate the epidemiology of S. haematobium, S. bovis and their hybrids along the Senegal River basin using both microsatellite genetic markers and analysis of mitochondrial and nuclear DNA markers. Human schistosome populations with a S. haematobium cox1 mtDNA profile and those with a S. bovis cox1 mtDNA profile (the so-called hybrids) appear to belong to a single randomly mating population, strongly differentiated from the pure S. bovis found in cattle. These results suggest that, in northern Senegal, a strong species boundary persists between human and cattle schistosome species and there is no prolific admixing of the populations. In addition, we found that in the SRB S. haematobium was spatially more differentiated in comparison to S. mansoni. This may be related either to the presence and susceptibility of the intermediate snail hosts, or to the colonisation history of the parasite.     

Survival and growth of northern bobwhite offspring post-translocation

Continual population declines in northern bobwhites (Colinus virginianus) have prompted the use of population restoration techniques in conjunction with habitat management to restore their populations. We tested the site familiarity hypothesis to determine if translocation to new environments affected offspring survival and growth rates of bobwhites. We used bobwhites from north Florida and translocated them to a study site in Brunswick County, North Carolina, USA, and monitored birds during April−October 2016 and April−October 2017. We used the corral capture method and modified-suture technique to capture and radio-tag chicks to evaluate offspring growth and survival rates of resident and translocated bobwhites. Offspring survival varied by year and age. We did not find any difference in offspring survival rates of resident and translocated individuals, lending no support to the site familiarity hypothesis with regards to survival. Offspring of resident bobwhites did not grow at a faster rate than offspring of translocated bobwhites, indicating a lack of support for the site familiarity hypothesis in terms of physiological development. Survival, however, is a more important metric for determining post-translocation population dynamics, and our results indicated that translocated bobwhites can reproduce and raise offspring similar to resident counterparts, but both had low survival. © 2019 The Wildlife Society.     

Nitrite Reductase and Nitric-oxide Synthase Activity of the Mitochondrial Molybdopterin Enzymes mARC1 and mARC2

Mitochondrial amidoxime reducing component (mARC) proteins are molybdopterin-containing enzymes of unclear physiological function. Both human isoforms mARC-1 and mARC-2 are able to catalyze the reduction of nitrite when they are in the reduced form. Moreover, our results indicate that mARC can generate nitric oxide (NO) from nitrite when forming an electron transfer chain with NADH, cytochrome b₅, and NADH-dependent cytochrome b₅ reductase. The rate of NO formation increases almost 3-fold when pH was lowered from 7.5 to 6.5. To determine if nitrite reduction is catalyzed by molybdenum in the active site of mARC-1, we mutated the putative active site cysteine residue (Cys-273), known to coordinate molybdenum binding. NO formation was abolished by the C273A mutation in mARC-1. Supplementation of transformed Escherichia coli with tungsten facilitated the replacement of molybdenum in recombinant mARC-1 and abolished NO formation. Therefore, we conclude that human mARC-1 and mARC-2 are capable of catalyzing reduction of nitrite to NO through reaction with its molybdenum cofactor. Finally, expression of mARC-1 in HEK cells using a lentivirus vector was used to confirm cellular nitrite reduction to NO. A comparison of NO formation profiles between mARC and xanthine oxidase reveals similar K_cat and V_max values but more sustained NO formation from mARC, possibly because it is not vulnerable to autoinhibition via molybdenum desulfuration. The reduction of nitrite by mARC in the mitochondria may represent a new signaling pathway for NADH-dependent hypoxic NO production.