Genetic control of resistance to H. contortus was assessed in 198 ewes and 386 lambs of 50% Dorset, 25% Rambouillet and 25% Finnsheep breeding in fall and spring over 2 yr. After deworming, lambs that were approximately 120 d old and ewes that had weaned their lambs at 60 d and dried off were individually dosed with approximately 10,000 infective larvae. After infection, body weight (BW), fecal egg counts (FEC) and packed cell volume (PCV) were measured weekly for 7 wk in lambs and fortnightly for eleven wk in ewes. Summary traits were defined as initial PCV, mean BW (MBW) across all times, and means for FEC, log-transformed FEC (MLFEC), and PCV (MPCV) at wk 3 to 7 post-infection for lambs and wk 3 to 11 post-infection for ewes. No consistent seasonal variation in FEC was observed. Younger ewes were more susceptible to infection than older ewes. Sex differences in FEC were not observed in lambs. Heritabilities for summary traits were estimated from a REML analysis that included fixed effects of year and season plus effects of either sex (for lambs) or age category (for ewes). Heritability estimates for MBW, MPCV, and MLFEC were 0.74, 0.57, and 0.27 respectively (all P < 0.01), in lambs, and 0.24 (P < 0.1), 0.25 (P < 0.05) and 0.55 (P < 0.01), respectively, in ewes. Across-year repeatability estimates in ewes for MBW, MPCV, and MLFEC were 0.83, 0.54 and 0.56, respectively (all P < 0.01). Resistance was antagonistically associated with estimated breeding values for growth in ewes but not in lambs. Fertility and prolificacy in ewes were not related to resistance. Breed differences in resistance to H. contortus were also evaluated in 4 to 6-mo-old crossbred Dorset and Dorper, straightbred Katahdin, and Barbados Blackbelly x St. Croix lambs. Dorpers were not more resistant than Dorsets but appeared to cope better, with higher PCV and similar BW during infection compared to Dorsets. Katahdin and Barbados Blackbelly x St. Croix lambs were more resistant with lower FEC. / Master of Science

Terminal sire crossbreeding systems which improve growth performance while maintaining parasite resistance have the potential to enhance the profitability of hair sheep enterprises. Katahdin (KT, n = 4), Suffolk (SU, n = 3), and Texel (TX, n = 3) rams were randomly mated to KT ewes over two years (Y1, Y2) at the Virginia Tech Southwest Agricultural Research and Extension Center. Post-lambing until weaning (80 d), pairs were managed on fescue pasture. At weaning, lambs (n = 192) were moved to an ungrazed pasture and provided a concentrate pellet daily for a 90 d grazing trial. During this time, BW, strongylid egg count (FEC), FAMACHA score and packed cell volume (PCV) were collected every 14 d. FAMACHA score - 3 was utilized as the basis for anthelmintic treatment. Post-grazing, lambs were fed to approximately 50 kg BW. Lambs were harvested at the Virginia Tech Meat Center and carcass evaluation performed 1 d post-harvest. Statistical analyses were conducted using SAS (SAS Institute Inc., Cary, NC) with Proc MIXED for repeated measures analysis and Proc GLM with Tukey?s test for mean separation. No differences existed between sire breeds for adjusted number of lambs born or number of lambs weaned. Adjusted birth BW was greater for SU-sired lambs than KT-sired and TX-sired (P < 0.05) in Y2. Adjusted weaning BW was smallest for KT-sired lambs compared to SU- and TX-sired lambs (P < 0.05) in both years. During the grazing trials, BW, ADG, lnFEC, FAMACHA and PCV varied over time (P < 0.001) with lower FAMACHA scores for KT-sired lambs than SU- and TX-sired lambs in Y1 (P < 0.05). A greater proportion of SU-sired lambs tended to require deworming than KT-sired lambs (P = 0.08). Adjusted BW post weaning was greater for TX-sired lambs than KT-sired lambs (P < 0.05) in Y1. Post-grazing, BW and ADG varied over time (P < 0.01) with no sire breed differences for ADG. At harvest, SU-sired lambs were heavier than KT-sired lambs (P < 0.05). TX-sired lambs had greater LM area than KT-sired lambs (P = 0.05). KT-sired lambs had the smallest leg scores (P < 0.05). These results indicate the potential of terminal sires (SU- and TX-sires) to improve lamb growth and carcass merit. TX-sired lambs had more similar parasite resistance characteristics to KT-sired Iambs and may have potential as terminal sires in forage based hair sheep production systems. / Master of Science / Katahdin hair sheep have been developed as an easy-care breed adaptable to forage-based production systems. Their enhanced resistance to gastrointestinal parasites has resulted in their rise in popularity among sheep producers in the southeastern United States. However, their lower cutability (muscle to fat ratio) and lighter carcass weights have resulted in economic concerns. Therefore, other breeds (Texel and Suffolk) have been considered for crossbreeding to increase carcass size and muscle improving the market value of lambs produced. Here, Katahdin, Suffolk and Texel sires were mated to Katahdin ewes over two years at the Southwest Virginia Agriculture Research and Extension Center. Lambs were grazed with their dams until weaning at approximately 70 days of age. Post-weaning, lambs were grazed for approximately 90 days during which time body weights and parasite resistance indicators were recorded every two weeks. Lambs were dewormed based on anemia level measured by mucus membrane color (FAMACHA score). After grazing, lambs were fed until they reached approximately 50 kg. Lambs were harvested at the Virginia Tech Meat Center for carcass evaluation. There were no differences between the sire breeds for number of lambs born or weaned per ewe. Suffolk-sired lambs were heaviest at birth in year 2 and at weaning Suffolk- and Texel-sired lambs were heavier than Katahdin-sired in both years. In year 1, Texel-sired lambs were heaviest at the end of the grazing period. FAMACHA scores tended to be lower for Katahdin-sired lambs and Suffolk-sired lambs tended to require greater deworming. At harvest, Suffolk-sired lambs were heavier than Katahdin-sired lambs while the Texel-sired lambs had greater loin muscle area. These results indicate the potential of terminal-sires (Suffolk and Texel) to improve lamb growth. Texel-sired lambs were more similar to Katahdin-sired lambs for resistance traits while increasing carcass muscling and may be a potential terminal option for forage-based production systems.

Yes / Metastatic melanoma, a deadly form of skin cancer, often develops resistance to the BRAF inhibitor drug vemurafenib, highlighting the need for understanding the underlying mechanisms of resistance and exploring potential therapeutic strategies targeting integrins and TGF-β signalling. In this study, the role of integrins and TGF-β signalling in vemurafenib resistance in melanoma was investigated, and the potential of combining vemurafenib with cilengitide as a therapeutic strategy was investigated. In this study, it was found that the transcription of PAI1 and p21 was induced by acquired vemurafenib resistance, and ITGA5 levels were increased as a result of this resistance. The transcription of ITGA5 was mediated by the TGF-β pathway in the development of vemurafenib resistance. A synergistic effect on the proliferation of vemurafenib-resistant melanoma cells was observed with the combination therapy of vemurafenib and cilengitide. Additionally, this combination therapy significantly decreased invasion and colony formation in these resistant cells. In conclusion, it is suggested that targeting integrins and TGF-β signalling, specifically ITGA5, ITGB3, PAI1, and p21, may offer promising approaches to overcoming vemurafenib resistance, thereby improving outcomes for metastatic melanoma patients.

Antibiotics form the cornerstone of modern medicine, facilitating advancements in numerous healthcare fields and contributing to unprecedented increases in human life expectancy. However, the efficacy of these life-saving drugs is now jeopardized by the rise of antimicrobial resistance. This growing threat is exacerbated by the slow pace of new antibiotic discoveries. The drug discovery process is both time-consuming and costly, and efforts to identify novel antibiotics often result in the rediscovery of known antibiotics, further hindering progress. To combat antibiotic resistance and facilitate the discovery of novel drugs, several approaches can be employed. First, understanding the mechanisms of resistance found in environmental bacteria is crucial for preparing against the potential mobilization of these resistance mechanisms into pathogenic bacteria. Second, developing tools that make the drug discovery process less costly and time-consuming can accelerate the discovery rate and broaden participation in drug discovery efforts. Finally, understanding how bacteria synthesize natural product antibiotics provides invaluable information that can be leveraged in drug discovery efforts, including synthetic biology approaches. This thesis addresses efforts and challenges in the various aspects of drug discovery. To enhance our understanding of environmental resistance mechanisms, I conducted a screen for ciprofloxacin-inactivating enzymes and characterized the activity of a previously reported ciprofloxacin-inactivating enzyme, CrpP. These findings highlight the difficulties associated with discovering synthetic antibiotic-inactivating enzymes. To contribute to drug discovery, I expanded the Antibiotic Resistance Platform and developed a streamlined version to improve antibiotic dereplication efforts, thereby accelerating the natural product discovery process. Additionally, I investigated the mechanism of β-serine biosynthesis, a nonproteinogenic amino acid found in the antibiotic edeine. By elucidating how β-serine is synthesized, this information can be applied to synthetic biology approaches for drug discovery. / Thesis / Doctor of Philosophy (PhD) / Antibiotics used in medical treatments today often originate from natural sources like environmental bacteria and are known as natural product antibiotics. These natural product antibiotics are essential for treating bacterial infections and play a crucial role in modern medicine, including surgery and cancer treatment. However, the increasing problem of antimicrobial resistance and the lack of new drugs being discovered threatens the effectiveness of these life-saving medicines. To combat antibiotic resistance and protect the use of antibiotics, we need to understand how bacteria resist antibiotics, develop better methods for discovering new antibiotics, and gain insights into how bacteria produce natural product antibiotics. This thesis addresses these challenges by trying to find bacteria that can break down antibiotics, improving a tool for drug discovery, and understanding how bacteria make the antibiotic known as edeine. These efforts advance our understanding of antibiotic resistance and pave the way for developing new and effective antibiotics.

The purpose of this research was to investigate and create preliminary design aids for the determination of lateral resistance capacity and spacing requirements of deck tie fasteners in curved railroad bridges with smooth top girders. In railroad bridge design, required lateral resistance dictates the spacing of deck tie fasteners. Currently, no provisions exist to aid in the calculation of lateral resistance for systems that include bridge ties, fasteners, and girders which experience centrifugal or lateral forces. Thus, design practices specific to each railroad vary, producing inconsistent fastener spacing in existing railroad bridges. This project identified and quantified three factors contributing to lateral resistance through experimental testing: resistance due to friction at the tie-girder interface; resistance from the fastener; and resistance from dapped ties bearing against the girder flange. Three fastener types were studied in this research: Square body hook bolts, Lewis Forged hook bolts, and Quikset Anchors. Results indicated that frictional resistance is a product of the train wheel load and the friction coefficient. Fastener resistance was determined to be a function of fastener type and lateral track displacement. Finally, dap resistance was found to be a function of the area of the shear plane in a dapped tie. A preliminary equation for calculating the total lateral resistance capacity was developed utilizing superposition of all three resistance contributions. Lateral demand loads were compared with reported lateral capacity to create a preliminary design aid to determine fastener spacing. / Master of Science / Railroad bridges are constructed by securing wooden ties to I-shaped steel beams (girders) using deck tie fasteners. Curved railroad bridges should provide lateral resistance to resist lateral loads from trains negotiating the curve. Currently, there is no official practice for determining lateral strength, which is a function of fastener spacing. Thus, each railroad company uses a proprietary fastener spacing, producing inconsistencies in existing railroad bridges. The purpose of this research was to create a preliminary table or equation for determining the lateral strength and spacing requirements of deck tie fasteners through experimental testing. This project identified and quantified three factors contributing to lateral resistance: resistance due to friction at the tie-girder interface; resistance from the fastener; and resistance from dapped ties (ties that are notched to sit on the girder flanges). Three fastener types were studied. Results showed that frictional resistance was directly proportionate to the magnitude of the vertical wheel load. Fastener resistance was found to be a function of the type of fastener used. Finally, the dap was determined to be a function of the area of the shear plane in a dapped tie. A preliminary equation for calculating the total lateral resistance capacity was developed by summing the resistance contributions from all three resistance factors. Lateral loads were compared with lateral capacity to create a preliminary design aid to determine fastener spacing.

Evolution of Helicoverpa armigera resistance to Bacillus thuringiensis (Bt) cotton producing Cry1Ac is progressing in northern China, and replacement of Cry1Ac cotton by pyramided Bt cotton has been considered to counter such resistance. Here, we investigated four of the eight conditions underlying success of the refuge strategy for delaying resistance to Cry1Ac+Cry2Ab cotton, a pyramid that has been used extensively against H.armigera outside China. Laboratory bioassays of a Cry2Ab-selected strain (An2Ab) and a related unselected strain (An) reveal that resistance to Cry2Ab (130-fold) was nearly dominant, autosomally inherited, and controlled by more than one locus. Strong cross-resistance occurred between Cry2Ab and Cry2Aa (81-fold). Weaker cross-resistance (18- to 22-fold) between Cry2Ab and Cry1A toxins was also present and significantly increased survival of An2Ab relative to An on cotton cultivars producing the fusion protein Cry1Ac/Cry1Ab or Cry1Ac. Survival on Cry1Ac+Cry2Ab cotton was also significantly higher in An2Ab than in An, showing that redundant killing on this pyramid was incomplete. Survival on non-Bt cotton did not differ significantly between An2Ab and An, indicating an absence of fitness costs affecting this trait. These results indicate that a switch to three-toxin pyramided cotton could be valuable for increasing durability of Bt cotton in China.

No description available.

The effects of AC and DC on cooling rate, solute distribution and nugget shape after solidification, which are responsible for microstructure of the fusion zone, during resistance spot welding are realistically and extensively investigated. The finite difference method is used to predict transport variables in workpieces and electrodes during heating, melting, cooling and freezing periods. The model accounts for electromagnetic force, heat generations at the electrode-workpiece interface and faying surface between workpieces, and dynamic electrical resistance including bulk resistance and contact resistances at the faying surface and electrode-wokpiece interfaces, which are function of hardness, temperature, electrode force, and surface condition. The computed results show that in contrast to DC, using AC readily produces the nugget in an ellipse shape. Deficit and excess of solute content occur in a thin layer around the boundary and interior of the nugget, respectively. The effects of dynamic electrical resistance subject to AC (Alternative current) on transport variables, cooling rate, solute distribution and nugget shape after solidification during resistance spot welding are realistically and extensively investigated. The model accounts for electromagnetic force, heat generation and contact resistances at the faying surface and electrode-workpiece interfaces and bulk resistance in workpieces. Contact resistance are comprised of constriction and film resistances, which are functions of hardness, temperature, electrode force and surface condition. The computed results show that the weld nugget readily occurs by increasing constriction resistance and Curie temperature. High Curie temperature enhances convection and solute mixing, and readily melts through the workpiece surface near the electrode edge. Aside from finding the significant effect of Curie temperature on resistance spot welding, this study indicates that any mean (For example, adjusting solute content) to reduce Curie temperature can be a new way to control weld quality.

No description available.

Thesis (M.S.) -- University of Tennessee, Knoxville, 2005. / Title from title page screen (viewed on June 30, 2005). Thesis advisor: John Sorochan. Document formatted into pages (xiii, 124 p. : ill. (some col.), col. map). Vita. Includes bibliographical references (p. 59-68).