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Molecular Genetics and Cell Biology of Yeast and Mammalian Cells
No full textIron and copper are essential transition metals involved in key biological processes, including enzyme co-factors, mitochondrial respiration, and ATP production. Their redox properties make them vital yet potentially harmful, as they can induce radical formation through Fenton chemistry. Consequently, stringent regulation of their cellular levels and compartmentalization is crucial. Iron homeostasis is managed by a network involving transferrin, DMT1, and iron regulatory proteins, while copper homeostasis relies on transporters like CTR1 and chaperones like ATOX1. Both metals are implicated in cell death pathways like ferroptosis and cuproptosis, with iron-induced lipid peroxidation and copper-triggered mitochondrial stress playing significant roles.
Lipoic acid is vital for multienzyme complexes involved in oxidative decarboxylation and glycine cleavage. In yeast, copper toxicity related to protein lipoylation was studied using knockout strains of lipoic acid pathway components and the pyruvate dehydrogenase complex. In our study growth tests revealed that lip2∆, lip5∆, and lat1∆ strains were resistant to copper and ES, indicating these deletions block copper-mediated cell death. Further analysis showed lip5∆ strains had lower heme synthesis and iron levels, which were linked to growth defects in the presence of succinyl-acetone. Supplementation with hemin and FeSO4 rescued the growth phenotype in lip5∆ strains, highlighting the critical interplay between copper, iron, lipoylation, and cell viability. Additionally, copper is crucial for cellular processes, but its toxicity necessitates tight regulation. Although previous studies indicated overexpression of YAH1 inferred copper resistance in wild type cells, but in our studies with lipoic acid knockout strains, it revealed a growth defect linked to the pRS415 (LEU2) vector. A genomic library screen identified ATP1 as a suppressor, indicating its role in mitochondrial morphology and growth defect rescue.
In another aspect of the research our structural analysis of IRES RNA of BVDV, crucial for cap-independent translation, it adopted a modular structure with three domains, including a tertiary H-type pseudoknot. This pseudoknot is evolutionarily conserved across Pestivirus species, revealed through SHAPE-MaP and computational modeling. In another study we utilized Enhanced darkfield hyperspectral microscopy (EDHM), a non-invasive diagnostic method, to identify human coronavirus strains (HCoV) OC43 and 229E. EDHM captured optical images with spectral and spatial details, revealing unique spectral patterns for HCoV-OC43 and HCoV-229E, differentiating them and detecting infections in mammalian cells
Evaluating Olfactory Decline in Aging Dogs
No full textAging is an important aspect of the dog life, impacting how dogs function in their roles as both companions and workers. However, the impact of dog aging upon key sensory modalities, such as olfaction, is not well understood. The current study utilized the Natural Detection Task, the Cylinder Reversal Task, and survey data to characterize age-related changes in dogs’ olfactory and cognitive abilities. We found that age did not have a significant impact upon Natural Detection Task performance. However, there was a significant impact of both age and training upon whether dogs completed the Natural Detection Task or not. Furthermore, age-related changes in performance were seen in the survey scales. This indicates that while the sample was sufficient to capture age-related changes in performance, aging had minimal to no impact on olfactory abilities. This study emphasizes the importance of olfaction to the canine and the need for further research in this realm of study
Contributions of Vimentin to Skeletal Muscle Hypertrophy
Get PDFOur laboratory has performed various experiments examining the proteomic alterations that coincide with mechanical overload (MOV)-induced skeletal muscle hypertrophy. With this same intent we first sought to determine how 10 weeks of resistance training in 15 college-aged females affected protein concentrations in different tissue fractions. Training, which promoted significant lower body muscle- and fiber-level hypertrophy, notably increased sarcolemmal/membrane protein content (+10.1%, p1.5-fold, p<0.05), and one of these targets (the intermediate filament vimentin, VIM) warranted further investigation. VIM expression was first examined in the plantaris muscles of 4-month-old C57BL/6 mice following 10- and 20-days of MOV via synergist ablation. Relative to Sham (control) mice, VIM mRNA and protein content significantly increased in MOV mice. Immunohistochemistry corroborated these findings and showed that VIM was localized to the extracellular matrix (ECM). The 10- and 20-day MOV experiment was replicated in Pax7-DTA mice, and results indicated satellite cell depletion significantly blunted the presence of VIM in the ECM. A series of follow-up cell culture experiments supported that myoblasts, rather than myofibers, likely produce VIM in response to anabolic stimuli. Finally, a third 10- and 20-day MOV experiment was performed in C57BL/6 mice intramuscularly injected with either AAV9-scrambled (control) or AAV9-VIM shRNA. While VIM shRNA injections significantly blunted the presence of VIM (~50%), plantaris masses were similar between injection groups in response to MOV. However, a leftward (smaller) myofiber size shift in response to MOV was observed in VIM shRNA mice, and this coincided with appreciably more myofibers presenting a regeneration phenotype (MyHCemb-positive fibers with centrally located nuclei). Using a highly integrative approach, we propose that skeletal muscle VIM is a mechanosensitive target predominantly localized to the ECM and produced by satellite cells. Moreover, a disruption in VIM expression during MOV leads to dysfunctional skeletal muscle hypertrophy
Evaluation of a Novel Poultry-Derived Fertilizer
No full textPoultry litter, a common soil amendment, can be applied to soils as a plant nutrient source. Due to a balanced N: P ratio, applying poultry liter based on N rates may result in an overapplication of phosphorous which leads to eutrophication within aquatic environments. To reduce contamination risks, poultry litter can be altered through several different processes, such as anaerobic or aerobic digestion, and can be pelletized for a more uniform product distribution. In a novel fertilizer produced through this method, assessments were conducted to determine both chemical and physical product quality and application results when applied to a variety of crops. Product assessments were made of a proprietary process which combines aerobic digestion and ammonification to physically and chemically alter poultry litter. Through this process, standard poultry litter is transformed from a 1.5-1-1.5 N-P-K chemical formulation to a 11.5-1-1.5 N-P-K granulated product (C&G fertilizer). Nutrient release rates were investigated using a soil incubation test and a rapid water incubation test. Nutrient release rates in soil were evaluated at a 0.89 kg m3 rate (C&G, Synthetic, or Poultry Litter) with soil maintained at 0.3 cm3/cm3 volumetric water content at 30 C over a 55-day period. Rapid water incubation was conducted by adding one gram of fertilizer (C&G, Synthetic, or Osmocote) to 100 mL of water for 24-hour period. Electric conductivity was monitored to evaluate nutrient release over time. In soil, significant and increasing quantities of potassium, ammonium, and nitrate were released in the first six days of incubation for C&G. After six days, nitrate and potassium continue to increase while phosphorus and ammonium plateaued in release. In plant assays, three crops were grown using four fertilizer treatments at four rates. The treatments were Synthetic uncoated fertilizer, C&G, a nutrient even blend (C&G + Synthetic), and Poultry litter. Fertilizers were applied on a N basis of at the rates 0 kg m3, 0.44 kg m3, 0.89 kg m3, and 1.78 kg m3. C&G preformed similarly to a synthetic fertilizer across pH & EC sampling, growth indices and nutrient tissue analysis. Final results suggest the C&G fertilizer may be utilized similarly to synthetic, uncoated fertilizers for quick nutrient release
The effects of chronic exposure to risperidone during adolescence on behavioral rigidity and impulsive choice in adulthood
Get PDFRisperidone is a second-generation antipsychotic that is commonly prescribed in children in adolescence. Its mechanism of action targets both serotonin and dopamine, both of which mediate different types of behavior, such as perseveration and impulsive choice. To test whether there was a long-term effect of chronic risperidone exposure on these behaviors, adolescent and adult mice were exposed to 2.5 mg/kg/day risperidone over a 28-day period, then tested on both a spatial discrimination reversal procedure and a delay discounting procedure 30 days after cessation of the drug. During the reversal procedure, adolescent exposed animals showed more behavioral rigidity. In the delay discounting procedure, both adolescent and adult exposed mice showed lower higher rates of discounting
Explainable and Interpretable Machine Learning of Structure-Function Relationships for Membrane-Active Peptides in Drug Discovery: Enhancing Therapeutic Specificity
No full textMembrane-active peptides, particularly those with antimicrobial, anticancer, and other thera peutic properties, offer a promising alternative to traditional drug treatments. However, accurate
predictive models are essential to maximize their effectiveness while minimizing undesirable effects
such as hemolysis and improving solubility. This dissertation focuses on developing data-driven
models for activity prediction of membrane-active peptides (MAPs), with the ultimate goal of
designing of therapeutics with enhanced specificity. A key innovation in this work is using Fourier
transform (FFT)-based features, which capture the periodicities and order of amino acids in peptide
sequences without requiring a sequence alignment, leading to a more detailed understanding of
sequence properties that enable these peptides to interact with biological membranes. These FFT based features are not specific to MAP activity and potentially broad utility for predicting peptide
properties, such as solubility and hemolytic potential, since these inherent structural periodicities
could contribute to various types of protein structures and activities.
To ensure our models are interpretable, we have incorporated a feature selection framework
that ensures the most contributive features are identified and used in the models, allowing for
high predictive accuracy while minimizing model complexity. By focusing on a small number
of critical features, these models offer valuable insights into the sequence characteristics that are
most influential in determining MAP activities, making them highly interpretable and practical for
therapeutic peptide design. Support vector machines (SVMs) were employed due to their ability to
handle complex, non-linear relationships, and the models developed in this work demonstrate high
performance, robustness, and reliability. Extensive cross-validation and blind test evaluations reveal
that the models achieve competitive performance when compared to state-of-the-art approaches,
while also being simple and interpretable. This enhanced interpretability sets them apart from
more complex models, offering a clear advantage in therapeutic peptide design. The performance of these models stands out for utilizing a minimal number of features while still outperforming or
matching more complex state-of-the-art models. This is particularly relevant in drug discovery,
where identifying meaningful predictive features directly influences both the speed and accuracy
of therapeutic development.
Although the ultimate goal of this research is to facilitate the design of MAPs with high speci ficity, the primary contribution lies in the development of powerful and computationally efficient
predictive models. These models offer a practical and effective solution for advancing peptide based drug discovery, enabling the identification of MAPs with optimal therapeutic potential while
minimizing undesired properties such as hemolytic activity and increasing solubility. The design
aspect of this dissertation is positioned as a long-term outcome, supported by the high performance
and reliability of the predictive models developed here
Semi-Supervised Multiclass Classification with Novelty Detection Using Support Vector Machines and Linear Discriminant Analysis
Get PDFSemi-supervised multi-class classification with novelty detection consists of one tool that can accurately define what class an instance belongs to from a set group of known classes while simultaneously detecting instances that do not belong to any of the classes. This field of machine learning has been studied for a decade or more, with many different algorithms and solutions tested. In this thesis, an algorithm built using One-Class Support Vector Machines (OCSVM) and Linear Discriminant Analysis (LDA) will be explored and demonstrated on data from simulated missile trajectories. Not only is this algorithm novel to the aerospace industry, but also to the computer science and machine learning industries as well. Its strengths and limitations will be explored, as well as techniques to increase accuracy and ideas for future work and other uses for this tool.
The data used is produced by the Auburn University Solid Rocket Code (AUSRC), a validated code which simulates the flight of a missile given its design parameters. The output data from the AUSRC is preprocessed using common techniques such as standardization, to eliminate the influence of units of measurement, and principal component analysis (PCA) as a method of data reduction. The data is then fed into an iterative OCSVM, during which necessary data is recorded to extract any outlier points. An objective threshold is used to differentiate between instances that are outliers of a known clean class and instances that are true novelties from an unknown class. The instances deemed 'true' novelties by the threshold are added to the training data to fit the LDA to. The data is then run through the LDA, which provides a higher classification accuracy than the OCSVM, cleaning up inter-class misclassifications as well as tracking the outliers back to their known class. Since the LDA was trained on the 'true' novelty class data, it acts as a novelty detector by extracting any other points the OCSVM missed.
This method works accurately (>90\% overall accuracy) on simulated missile trajectories across 3 different data sets and robustness tests. The data set features used are comprised of performance parameters, trajectory data, or derived features. The tests comprise of reduced time frames and random missing data. The OCSVM provides high accuracy novelty detection while the LDA provides high accuracy classification, exploiting the strengths of each machine learning algorithm. Further work should be done to improve the hybrid method and to investigate ways to eliminate the LDA's underlying assumption of the data set to have a multivariate Gaussian distribution
To War or Not to War: Sub-Conventional Warfare’s Effects on the Likelihood of Conventional War
Get PDFAs states seek to advance their interests in the international system, the threat of war is perpetually present. As a result, scholars have produced a rich body of literature that seeks to explain the causes of war. One explanation is the bargaining model of war. Fearon (1995) argues that the inefficiency of war gives states incentives to reach prewar bargains but notes that states still fail to reach bargains and go to war. To explain this, Fearon (1995) gives three logical, rationalist explanations for war: (1) information problems or private information and incentives to misrepresent that information, (2) commitment problems, and (3) issue indivisibility (pp. 381-382). Fearon (1995) and other scholars have made significant contributions to the literature on the causes of war, but these efforts have focused primarily on civil war and conventional war (CW) between states. A critique of Fearon’s (1995) work is that it does not explain why states may be able to reach a settlement in one context but not in another. As a result, this dissertation seeks to answer this question: Why do states fail to reach a war-avoiding bargain in one case but not another? Sub-conventional warfare (SCW) can answer this question. Due to the relative costs of war, states turn to SCW to advance their interests. This dissertation seeks to explain the effects of SCW on the likelihood of CW. Using the bargaining model of war and Fearon’s (1995) “rationalist explanations for war” as a foundation, this dissertation proposes a theoretical framework for the effects that SCW has on the likelihood of CW. Tests of this theory, using case studies of enduring rivals, demonstrate that SCW can make CW both more and less likely
In Spite of the Odds: Exploring How Black HBCU Graduates Successfully Navigated PWI Graduate Programs
Get PDFThis study explores the experiences of Black graduates from Historically Black Colleges and Universities (HBCUs) who transitioned to and successfully navigated Predominantly White Institutions (PWIs) for their graduate programs. Utilizing a qualitative research design focused on narrative inquiry and oral storytelling, this research centers the voices of the graduates as experts of their own experiences. Through semi-structured interviews conducted with fourteen graduates, the study examines how these individuals leveraged their HBCU backgrounds to foster resilience and achieve success in PWI environments. The data analysis, guided by Afrocentric constructivist principles and the Anti-Deficit Achievement Framework, highlights the agency, cultural affirmations, and support systems that facilitated their academic journeys. This research contributes to Black student success scholarship by presenting counternarratives that challenge deficit perspectives and underscore the importance of culturally responsive support structures in higher education, especially graduate education. The findings provide insights into effective strategies for supporting Black graduate students in diverse academic settings, emphasizing the critical role of community engagement and cultural identity in their success
Impact of thermal variation during early-stage incubation on muscle satellite cell heterogeneity and muscle development of broiler chicken embryos
No full textAlthough it has been known for some time that the use of multi-stage (MS) incubators results in broiler chicken embryos being exposed to sub-optimal incubation temperatures, they are still quite common in the commercial poultry industry. The impact of sub-optimal incubation temperatures, especially cold conditions, during early-stage incubation (ESI; embryonic day (ED) 4 to 11) while muscle fiber and satellite cell (SC) populations are being established are not well understood. Therefore, an experiment was conducted to determine the impact of hypothermic (COLD; 36.4 °C), standard (CTRL; 37.5 °C), and hyperthermic (HOT; 38.6 °C) incubation temperatures from ED 4 to 11 on muscle fiber hyperplasia and SC heterogeneity from 2 functionally different muscles, Pectoralis major (PM) and Biceps femoris (BF), on ED 18 and at hatch. Ross 708 × Yield Plus broiler breeder eggs (n = 2,160) were incubated at 37.5 °C from ED 0 to 3. On ED 4, COLD incubator setpoints were decreased to 36.4 °C, HOT incubator setpoints were increased to 38.6 °C, and CTRL incubators remained 37.5 °C (n = 2 incubators per treatment). On ED 11, all incubators were set to 37.5 °C until ED 18 when eggs were transferred to hatchers. At transfer (ED 18) and hatch (ED 21), PM and BF muscle samples were collected from 6 chicks per treatment. Samples from both muscles from each bird were immunofluorescence stained with two different primary antibody strategies to facilitate taxonomy of SC populations expressing the myogenic regulatory factors and SC markers, Myf5, MRF4, and MyoD or Myf5, Pax7, MyoD by fluorescence microscopy for strategy 1 and 2 respectively. Data were analyzed as a 1-way ANOVA with the GLIMMIX procedure of SAS. A complete pairwise mean comparison was performed using the PDIFF option and means were considered significantly different when P ≤ 0.05. The thermal variation (TV) treatments applied during ESI did not impact (P > 0.05) SC expression of Pax7(+), Myf5(+), MyoD(+),
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Pax7(+):Myf5(+), Pax7(+):MyoD(+), Myf5(+):MyoD(+), or Pax7(+):Myf5(+):MyoD(+) in the BF muscle of chicks on ED 18 or ED 21 nor in the PM muscle on ED 18. On ED 21, chicks from the HOT incubators had a higher number of MRF(-) external nuclei (P = 0.0431) in the PM muscle than chicks from the CTRL treatment. Although the Type 3 fixed-effects ANOVA P-value was not significant (P > 0.05), the pairwise means comparisons revealed that in the PM muscle, chicks from the HOT treatment had a higher number of total external nuclei (P = 0.0247) and Pax7(+) SC (P =0.0400) compared with CTRL chicks on ED 21. On ED 18, chicks from the COLD incubators had the highest number of Myf5(+):MyoD(+) SC (P = 0.0255) in the BF muscle. No differences were detected in SC expression of Myf5(+), MyoD(+), MRF4(+), Myf5(+):MyoD(+), Myf5(+):MRF4(+), MyoD(+):MRF4(+), or Myf5(+):MyoD(+):MRF4(+) or number of myonuclei in the PM muscle on ED18 or in the BF muscle at hatch (P > 0.05). Chicks from the HOT and CTRL incubators had a higher number of Myf5(+):MyoD(+):MRF4(+)in the PM muscle than the chicks from the COLD incubators at hatch SC (P = 0.0060). The pairwise mean comparison revealed that the chicks from the HOT incubators had more myonuclei per fiber than chicks from the CTRL treatment at hatch (P = 0.0392). The CTRL chicks had the highest number of muscle fibers per mm2 in the PM muscle at hatch indicating that CTRL chicks also had the smallest muscle fiber cross-sectional area (CSA; P = 0.0151). This data shows that myogenesis of 2 functionally different, economically important muscles of broiler chicken embryos is altered by TV during ESI and highlights the importance of proper incubation management. Further work is needed to better understand the mechanisms responsible for the observed changes in muscle fiber morphometrics and SC heterogeneity and how these changes may impact post-hatch muscle growth potential