A History of the Men\u27s Physical Education Program at Utah State Agricultural College

This study will present a historical review of the men\u27s physical education program at Utah State Agricultural College from 1888 through 1954. Specifically, it will give special attention to: (1) philosophy, (2) organization and administration, (3) leadership, (4) equipment and facilities, and (5) program

3D in vitro cancer models for drug screening: A study of glucose metabolism and drug response in 2D and 3D culture models

Current drug screening protocols use in vitro cancer cell panels grown in 2D to evaluate drug response and select the most promising candidates for further in vivo testing. Most drug candidates fail at this stage, not showing the same efficacy in vivo as seen in vitro. An improved first screening that is more translatable to the in vivo tumor situation could aid in reducing both time and cost of cancer drug development. 3D cell cultures are an emerging standard for in vitro cancer cell models, being more representative of in vivo tumour conditions. To overcome the translational challenges with 2D cell cultures, 3D systems better model the more complex cell-to-cell contact and nutrient levels present in a tumour, improving our understanding of cancer complexity. Furthermore, cancer cells exhibit altered metabolism, a phenomenon described a century ago by Otto Warburg, and possibly related to changes in nutrient access. However, there are few reports on how 3D cultures differ metabolically from 2D cultures, especially when grown in physiological glucose conditions. Along with this, metabolic drug targeting is considered an underutilized and poorly understood area of cancer therapy. Therefore, the aim of this work was to investigate the effect of culture conditions on response to metabolic drugs and study the metabolism of 3D spheroid cultures in detail. To achieve this, multiple cancer cell lines were studied in high and low glucose concentrations and in 2D and 3D cultures. We found that glucose concentration is important at a basic level for growth properties of cell lines with different metabolic phenotypes and it affects sensitivity to metformin. Furthermore, metformin is able to shift metabolic phenotype away from OXPHOS dependency. There are significant differences in glucose metabolism of 3D cultures compared to 2D cultures, both related to glycolysis and oxidative phosphorylation. Spheroids have higher ATP-linked respiration in standard nutrient conditions and higher non-aerobic ATP production in the absence of supplemented glucose. Multi-round treatment of spheroids is able to show more robust response than standard 2D drug screening, including resistance to therapy. Results from 2D cultures both over and underestimate drug response at different concentrations of 5-fluorouracil (5-FU). A higher maximum effect of 5-FU is seen in models with lower OCR/ECAR ratios, an indication of a more glycolytic metabolic phenotype. In conclusion, both culture method and nutrient conditions are important consideration for in vitro cancer models. There is good reason to not maintain in vitro cultures in artificially high glucose conditions. It can have downstream affects on drug response and likely other important metrics. If possible, assays should also be implemented in 3D. If not in everyday assays, at least as a required increase in complexity to validate 2D results. Finally, metabolism even in the small scope presented here, is complex in terms of phenotypic variation. This shows the importance of metabolic screening in vitro to better understand the effects of these small changes and to model how a specific tumor may behave based on its complex metabolism

Pharmacology of DB844, an orally active aza analogue of pafuramidine, in a monkey model of second stage human African trypanosomiasis

Novel drugs to treat human African trypanosomiasis (HAT) are still urgently needed despite the recent addition of nifurtimox-eflornithine combination therapy (NECT) to WHO Model Lists of Essential Medicines against second stage HAT, where parasites have invaded the central nervous system (CNS). The pharmacology of a potential orally available lead compound, N-methoxy-6-{5-[4-(N-methoxyamidino) phenyl]-furan-2-yl}-nicotinamidine (DB844), was evaluated in a vervet monkey model of second stage HAT, following promising results in mice. DB844 was administered orally to vervet monkeys, beginning 28 days post infection (DPI) with Trypanosoma brucei rhodesiense KETRI 2537. DB844 was absorbed and converted to the active metabolite 6-[5-(4-phenylamidinophenyl)-furanyl-2-yl]-nicotinamide (DB820), exhibiting plasma C(max) values of 430 and 190 nM for DB844 and DB820, respectively, after the 14th dose at 6 mg/kg qd. A 100-fold reduction in blood trypanosome counts was observed within 24 h of the third dose and, at the end of treatment evaluation performed four days post the last drug dose, trypanosomes were not detected in the blood or cerebrospinal fluid of any monkey. However, some animals relapsed during the 300 days of post treatment monitoring, resulting in a cure rate of 3/8 (37.5%) and 3/7 (42.9%) for the 5 mg/kg×10 days and the 6 mg/kg×14 days dose regimens respectively. These DB844 efficacy data were an improvement compared with pentamidine and pafuramidine both of which were previously shown to be non-curative in this model of CNS stage HAT. These data show that synthesis of novel diamidines with improved activity against CNS-stage HAT was possible

Semiarid watershed response in central New Mexico and its sensitivity to climate variability and change

Hydrologic processes in the semiarid regions of the Southwest United States are considered to be highly susceptible to variations in temperature and precipitation characteristics due to the effects of climate change. Relatively little is known about the potential impacts of climate change on the basin hydrologic response, namely streamflow, evapotranspiration and recharge, in the region. In this study, we present the development and application of a continuous, semi-distributed watershed model for climate change studies in semiarid basins of the Southwest US. Our objective is to capture hydrologic processes in large watersheds, while accounting for the spatial and temporal variations of climate forcing and basin properties in a simple fashion. We apply the model to the Río Salado basin in central New Mexico since it exhibits both a winter and summer precipitation regime and has a historical streamflow record for model testing purposes. Subsequently, we use a sequence of climate change scenarios that capture observed trends for winter and summer precipitation, as well as their interaction with higher temperatures, to perform long-term ensemble simulations of the basin response. Results of the modeling exercise indicate that precipitation uncertainty is amplified in the hydrologic response, in particular for processes that depend on a soil saturation threshold. We obtained substantially different hydrologic sensitivities for winter and summer precipitation ensembles, indicating a greater sensitivity to more intense summer storms as compared to more frequent winter events. In addition, the impact of changes in precipitation characteristics overwhelmed the effects of increased temperature in the study basin. Nevertheless, combined trends in precipitation and temperature yield a more sensitive hydrologic response throughout the year

Mapping Water Availability, Cost and Projected Consumptive Use in the Eastern United States with Comparisons to the West

The availability of freshwater supplies to meet future demand is a growing concern. Water availability metrics are needed to inform future water development decisions. Furthermore, with the help of water managers, water availability was mapped for over 1300 watersheds throughout the 31-contiguous states in the eastern U.S. complimenting a prior study of the west. The compiled set of water availability data is unique in that it considers multiple sources of water (fresh surface and groundwater, wastewater and brackish groundwater); accommodates institutional controls placed on water use; is accompanied by cost estimates to access, treat and convey each unique source of water, and; is compared to projected future growth in consumptive water use to 2030. Although few administrative limits have been set on water availability in the east, water managers have identified 315 fresh surface water and 398 fresh groundwater basins (with 151 overlapping basins) as Areas of Concern (AOCs) where water supply challenges exist due to drought related concerns, environmental flows, groundwater overdraft, or salt water intrusion. This highlights a difference in management where AOCs are identified in the east which simply require additional permitting, while in the west strict administrative limits are established. Although the east is generally considered water rich roughly a quarter of the basins were identified as AOCs; however, this is still in strong contrast to the west where 78% of the surface water basins are operating at or near their administrative limit. There was little effort noted on the part of eastern or western water managers to quantify non-fresh water resource

Diets and Food Selection of Female Mallards and Blue-Winged Teal During Spring Migration

Waterfowl nutritional requirements and food availability at migration stopover habitats may differ from those at nesting or wintering areas. Although there is little information on factors that influence waterfowl diets and food selection during migration, we hypothesized that bird age and wetland density in the surrounding landscape would influence food selection. Thus, the objective of this study was to quantify mallard Anas platyrhynchos and blue-winged teal Anas discors diets during migration and evaluate effects of age and wetland density on waterfowl food selection. We collected 30 mallards and 29 blue-winged teal with food items present in esophagi from wetlands in south-central Nebraska during spring 2008 and 2009. Smartweed Polygonum spp. and barnyard grass Echinochloa spp. were the most common seeds found in both mallards and blue-winged teal, while Naididae and Chironomidae larvae were the most common invertebrates in mallard and blue-winged teal diets, respectively. Invertebrates were consumed by both species in greater proportion than available. Both mallards and blue-winged teal collected in wetland complexes selected some seeds over others, whereas birds in isolated wetlands foraged on foods in proportion to availability. After-hatch-year mallards also selected for some seeds over others, as compared with hatch-year birds, which foraged opportunistically on available foods. If after-hatch-year birds and birds in wetland complexes are able to be more selective in their diets relative to food availability at individual wetlands, they may be able to acquire and replenish lipids reserves more efficiently than hatch-year birds or birds in areas with lower wetland densities

The diamidine DB75 targets the nucleus of Plasmodium falciparum

Abstract Background DB289, [2,5-bis(4-amidinophenyl)furan bis-O-methylamidoxime], is a broad spectrum anti-parasitic compound which has been shown to be effective against malaria in recent clinical trials. DB75, [2,5-bis(4-amidinophenyl)furan], is the active metabolite of this drug. The objective of this study was to determine the mechanism of action of DB75 in Plasmodium falciparum. Methods Live parasites were observed by confocal microscopy after treatment with organelle specific dyes and DB75, an inherently fluorescent compound. Parasites were exposed to DB75 and assessed for growth and morphological changes over time using blood smears and light microscopy. Also, to determine if DB75 affects gene transcription, real time PCR was used to monitor transcript levels over time for six developmentally expressed genes, including trophozoite antigen R45-like (PFD1175w), lactate dehydrogenase (PF13_0141), DNA primase (PFI0530c), isocitrate dehydrogenase (PF13_0242), merozoite surface protein-1 (PFI1475w), and merozoite surface protein-7 (PF13_0197). Results The results show that DB75 localizes in the parasite nucleus but not in other organelles. Once rings are exposed, parasites mature to the trophozoite stage and stall. No stage-dependent or gene-specific inhibition of transcription was seen. However, DB75 delayed peak transcription of trophozoite-stage genes. Conclusion Taken together, DB75 appears to concentrate in the nucleus and delay parasite maturation

The Mitochondrion Is a Site of Trypanocidal Action of the Aromatic Diamidine DB75 in Bloodstream Forms of Trypanosoma brucei

Human African trypanosomiasis (HAT) is a fatal tropical disease caused by infection with protozoans of the species Trypanosoma brucei gambiense and T. b. rhodesiense. An oral prodrug, DB289, is a promising new therapy undergoing phase III clinical trials for early-stage HAT. DB289 is metabolically converted to the active trypanocidal diamidine DB75 [2,5-bis(4-amidinophenyl)furan]. We previously determined that DB75 inhibits yeast mitochondrial function (C. A. Lanteri, B. L. Trumpower, R. R. Tidwell, and S. R. Meshnick, Antimicrob. Agent Chemother. 48:3968-3974, 2004). The purpose of this study was to investigate if DB75 targets the mitochondrion of T. b. brucei bloodstream forms. DB75 rapidly accumulates within the mitochondria of living trypanosomes, as indicated by the fluorescent colocalization of DB75 with a mitochondrion-specific dye. Fluorescence-activated cell sorting analysis of rhodamine 123-stained living trypanosomes shows that DB75 and other trypanocidal diamidines (pentamidine and diminazene) collapse the mitochondrial membrane potential. DB75 inhibits ATP hydrolysis within T. brucei mitochondria and appears to inhibit the oligomycin-sensitive F1F0-ATPase and perhaps other ATPases. DB75 is most likely not an inhibitor of electron transport within trypanosome mitochondria, since DB75 fails to inhibit mitochondrial respiration when glycerol-3-phosphate is used as the respiratory substrate. However, DB75 inhibits whole-cell respiration (50% inhibitory concentration, 20 μM) at drug concentrations and incubation durations that also result in the dissipation of the mitochondrial membrane potential. Taken together, these findings suggest that the mitochondrion is a target of the trypanocidal action of DB75

Human African trypanosomiasis: pharmacological re-engagement with a neglected disease

This review discusses the challenges of chemotherapy for human African trypanosomiasis (HAT). The few drugs registered for use against the disease are unsatisfactory for a number of reasons. HAT has two stages. In stage 1 the parasites proliferate in the haemolymphatic system. In stage 2 they invade the central nervous system and brain provoking progressive neurological dysfunction leading to symptoms that include the disrupted sleep wake patterns that give HAT its more common name of sleeping sickness. Targeting drugs to the central nervous system offers many challenges. However, it is the cost of drug development for diseases like HAT, that afflict exclusively people of the world's poorest populations, that has been the principal barrier to new drug development and has led to them becoming neglected. Here we review drugs currently registered for HAT, and also discuss the few compounds progressing through clinical trials. Finally we report on new initiatives that might allow progress to be made in developing new and satisfactory drugs for this terrible disease

Metabolic flux analysis of 3D spheroids reveals significant differences in glucose metabolism from matched 2D cultures of colorectal cancer and pancreatic ductal adenocarcinoma cell lines

Background Most in vitro cancer cell experiments have been performed using 2D models. However, 3D spheroid cultures are increasingly favored for being more representative of in vivo tumor conditions. To overcome the translational challenges with 2D cell cultures, 3D systems better model more complex cell-to-cell contact and nutrient levels present in a tumor, improving our understanding of cancer complexity. Despite this need, there are few reports on how 3D cultures differ metabolically from 2D cultures. Methods Well-described cell lines from colorectal cancer (HCT116 and SW948) and pancreatic ductal adenocarcinoma (Panc-1 and MIA-Pa-Ca-2) were used to investigate metabolism in 3D spheroid models. The metabolic variation under normal glucose conditions were investigated comparing 2D and 3D cultures by metabolic flux analysis and expression of key metabolic proteins. Results We find significant differences in glucose metabolism of 3D cultures compared to 2D cultures, both related to glycolysis and oxidative phosphorylation. Spheroids have higher ATP-linked respiration in standard nutrient conditions and higher non-aerobic ATP production in the absence of supplemented glucose. In addition, ATP-linked respiration is significantly inversely correlated with OCR/ECAR (p = 0.0096). Mitochondrial transport protein, TOMM20, expression decreases in all spheroid models compared to 2D, and monocarboxylate transporter (MCT) expression increases in 3 of the 4 spheroid models. Conclusions In this study of CRC and PDAC cell lines, we demonstrate that glucose metabolism in 3D spheroids differs significantly from 2D cultures, both in terms of glycolytic and oxidative phosphorylation metrics. The metabolic phenotype shift from 2D to 3D culture in one cell line is greater than the phenotypic differences between each cell line and tumor source. The results herein emphasize the need to use 3D cell models for investigating nutrient utilization and metabolic flux for a better understanding of tumor metabolism and potential metabolic therapeutic targets.publishedVersio