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Investigating Host-Pathogen Interactions during Macrophage Infections with Mycobacterium abscessus
No full textThesis (Ph.D.)--Michigan State University. Microbiology and Molecular Genetics - Doctor of Philosophy, 2024Mycobacterium abscessus (Mab) is a rapidly growing nontuberculous mycobacterium (NTM) that has been increasing in prevalence in patients with chronic or acquired lung disease for decades. Treatment strategies targeting Mab pulmonary infections largely rely on repurposed antibiotics commonly used for tuberculosis treatment. Unfortunately, Mab is intrinsically resistant to many of these antibiotic therapies, forcing health care professionals to use multiple antibiotics for longer periods of time to effectively treat infection. As such, cost of treatment, acquired antibiotic resistance and patient compliance rates are greatly affected. Notably, Mab pulmonary infections are rarely seen in patients with healthy lung environments, underscoring the requirement of a healthy pulmonary space and intact initial immune responses as key mediators in Mab control.Central to maintaining healthy lung environments are macrophages, key innate immune cells tasked with preserving healthy tissues, sensing the environment, and mounting initial immune responses upon pathogen exposure. Macrophages are the first immune cell Mab encounters following infection and, as such, represent an important intracellular niche where Mab must persist to survive. Although many elegant studies have begun to define Mab specific pathogenesis factors leveraged at this interface, few studies have investigated global macrophage responses upon Mab exposure. In this dissertation, I sought to address this gap in knowledge by using a combination of iterative genetic approaches and unique macrophage subset models to expand our understanding of macrophage biological responses during Mab infection. We first employ CRISPR-Cas9 genetics on a genome-wide scale to identify novel factors that contribute to Mab uptake by macrophages and pave the way for future genetic approaches to uncover previously undefined uptake mediators leveraged by macrophages following pathogen exposure. We then explore global transcriptional and cytokine profiles in unique macrophage subsets present in patients most at risk for Mab chronic infection and uncover a tendency for our Mab infected alveolar macrophage model (FLAMs) to remain hypoinflammatory. This study highlights the utility of our macrophage models to uncover key differences in macrophage immune responses that are most likely to impact upregulated immune mechanism during Mab infection. Combined, these studies explore macrophage immune responses at distinct points during early Mab infection. They underscore the importance of leveraging functional genetic approaches to broaden our current understanding of Mab-host interactions and contribute to the shared goal of improving therapeutic options for at-risk patients in the future.Description based on online resource. Title from PDF t.p. (Michigan State University Fedora Repository, viewed ).Includes bibliographical references
GENETIC AND BIOCHEMICAL ANALYSIS OF CUCUMBER FRUIT SURFACE PROPERTIES
No full textThesis (Ph.D.)--Michigan State University. Plant Breeding, Genetics and Biotechnology - Horticulture - Doctor of Philosophy, 2024The fruit surface is an important tissue that serves many functions including protection from abiotic and biotic stresses which can impact fruit development, post-harvest quality and subsequent storage. Variation in fruit surface properties has been observed among species, cultivars, and developmental stages. Genetic factors driving this natural variation are not well characterized in cucumber (Cucumis sativus). Morphological changes in the fruit epidermal properties of two breeding lines of cucumber were quantified in fruits ranging in age from anthesis (0 days post-pollination (dpp)) to maturity (~30 dpp). Pickling type \u2018Gy14\u2019, and Chinese fresh market type Chinese Long \u20189930\u2019 (CL9930) were chosen for this study based on epidermal properties differences and the availability of genomic resources. Thin sections from the mid-region of fruits were stained with red lipid stain Sudan IV and viewed using light microscopy. Measurements were taken for cuticle thickness and depth of cuticular intercalations between epidermal cells, epidermal cell height and width, and number and diameter of lipid droplets. These features increased in size coinciding with overall fruit growth, exhibiting rapid increase between 4 and 12 dpp and plateauing at ~16 dpp. Fruits from a genotyped Gy14xCL9930 recombinant inbred line (RIL) population were phenotyped at 16 dpp for epidermal traits for use in a quantitative trait loci (QTL) study. Strong QTL co-localized on chromosome 1 for epidermal cell height, cuticle thickness, intercalation depth, and diameter of lipid droplets. Fine mapping with SSR and KASP markers, transcriptomic analyses, and gene expression profiling identified transcription factor CsSHINE1/WIN1 as a source of natural variation for cucumber fruit epidermal traits. To explore additional sources of variation, a genome wide association study (GWAS) was done using the cucumber diversity panel, which varied greatly for cuticle thickness and lipid droplet number and size. GWAS identified several QTL that correspond with prior candidate genes for cuticle or lipid biosynthesis as well as suggesting new candidate genes of interest. Persistence of lipid droplets in number and size as fruits approached maturity indicated lipid droplets may have additional roles other than substrate transport for cuticular deposition. A protocol was devised to isolate and purify lipid droplets from cucumber fruit peel. Lipid droplets were analyzed using mass spectrometry and their contents shown to vary with genotype, developmental state, and environment.Description based on online resource. Title from PDF t.p. (Michigan State University Fedora Repository, viewed ).Includes bibliographical references
CHARACTERIZATION OF RESISTANCE MECHANISMS AND INHERITANCE OF THE FALL ARMYWORM Spodoptera frugiperda (J.E. SMITH) (LEPIDOPTERA : NOCTUIDAE) FROM PUERTO RICO TO SYNTHETIC AND BIOLOGICAL INSECTICIDES.
No full textThesis (Ph.D.)--Michigan State University. Entomology - Doctor of Philosophy, 2024The fall armyworm (FAW) (Spodoptera frugiperda J.E. Smith) poses a considerable challenge to global corn production owing to its remarkable ability to develop resistance to synthetic insecticides and insecticides derived from microorganisms, thereby undermining conventional pest management strategies. A remarkable FAW adaptation to pesticides was detected in Puerto Rico (PR). This region has one of the most strategic nurseries in the world for seed augmentation and research. However, a combination of factors including more than ten FAW generations per year, a high pest infestation, isolated geographical conditions, and 29 insecticide sprays per season prompt FAW to develop quick resistance. This doctoral thesis comprises three detailed studies that address the FAW inheritance and metabolic mechanism of resistance to synthetic insecticides and derived insecticides from microorganisms Saccharopolyspora spinosa. Diet overlay bioassays were conducted in all experiments, employing third early instar larvae.In the initial study, I characterized the resistance of the PR strain of FAW to the diamide insecticides chlorantraniliprole and flubendiamide, uncovering high resistance ratios (RR50 = 96-fold for chlorantraniliprole and RR50 = 2,762-fold for flubendiamide). This resistance exhibits distinct inheritance patterns, with chlorantraniliprole showing autosomal inheritance and flubendiamide demonstrating an X-linked inheritance mode. Additionally, the resistant strains exhibited cross-resistance to cyantraniliprole and cyclaniliprole. Synergist bioassays using DEF, DEM, PBO and verapamil reveal crucial role of detoxification enzymes as glutathione S-transferases, ABC transporters and esterases in resistance to flubendiamide and reduced metabolism for chlorantraniliprole. High levels of resistance from the PR strain to pyrethroid insecticides esfenvalerate (62-fold) and deltamethrin (15-fold) were detected. The inheritance of resistance exhibited an incompletely dominant resistance trait. Cytochrome P450 monooxygenases, esterases, glutathione S-transferases, and ABC transporters had an important role in the detoxification of the esfenvalerate. For deltamethrin, significant resistance was attributed to glutathione S-transferases, with lesser roles for ABC transporters and minor contributions from cytochrome P450 monooxygenases and esterases. This sheds light on the complex interplay of detoxification enzymes in pyrethroid resistance. The final study investigates resistance mechanisms in the PR strain to spinosyn insecticides. Very high levels of resistance were found for spinosad (214-fold) and spinetoram (63-fold), revealing an autosomal inheritance of resistance for spinosad and an X-linked for spinetoram. A higher role of esterases and glutathione S-transferases, followed by ABC transporters, and cytochrome P450 monooxygenases was observed in the Puerto Rican strain. Conversely, resistance to spinetoram was primarily mediated through by glutathione S-transferases, followed by ABC transporters, and lesser contributions from cytochrome P450 monooxygenases and esterases. These findings underscore the critical roles of detoxification enzymes, both individually and collectively, in conferring resistance. The synergist bioassays, employing both diet-overlay and topical applications, validated the hypothesis regarding the involvement of detoxification enzymes in resistance to spinosyns in the PR strain. These studies analyze the genetic and biochemical factors behind insecticide resistance in FAW, highlighting the complexity and cross-resistance. They emphasize the need for new, holistic pest management methods and insecticide rotation. This research enhances understanding and provides crucial knowledge to manage resistance, potentially mitigating FAW's impact on agriculture worldwide.Description based on online resource. Title from PDF t.p. (Michigan State University Fedora Repository, viewed ).Includes bibliographical references
DEVELOPMENT OF GENOMIC RESOURCES FOR UNDERSTANDING PLANT METABOLISM,GENOME DIVERSITY, AND TRAIT EVOLUTION
No full textThesis (Ph.D.)--Michigan State University. Plant Biology - Doctor of Philosophy, 2024Access to genome sequences and accompanying -omic data have revolutionized plant biology. In this dissertation, I report on generation of genome assemblies and associated analyses for Mitragyna speciosa (kratom), a medicinal plant species, Salvia hispanica (Chia pinta), a cultural food crop from Mesoamerica, and a comparative of species that produce tubers. Mitragyna speciosa produces monoterpene indole alkaloids with potential clinical use as opioid agonists. Through generation of a chromosome-scale chia genome and comparison to other chia genomes, structural variation in terpene biosynthetic pathway components was revealed. Additionally, the first population structure of chia was described with rampant introgressions from other Salvia species. Genomic assemblies of multiple tuber-producing species as well as their sister or closely related species were generated and compared to determine the evolutionary origin(s) of the trait of tuberization. The conserved expression of three transcription factors: POTH1, BRC1b, and BEL5 were found in tuberizing species suggesting co-option of these genes across angiosperms. A central role for POTH1 was also demonstrated in development of rhizomes, a parallel under-ground structure to the stolon.Description based on online resource. Title from PDF t.p. (Michigan State University Fedora Repository, viewed ).Includes bibliographical references
Movement and population dynamics of Great Lakes mallards
No full textThesis (Ph.D.)--Michigan State University. Fisheries and Wildlife - Doctor of Philosophy, 2024Mallard (Anas platyrhynchos) abundance in the Great Lakes states declined by 30% from 2000 to 2023 based on spring aerial surveys in Michigan, Minnesota, and Wisconsin. Concern among management agencies and uncertainty in the factors contributing to Great Lakes mallard decline led to a regional partnership which initiated this research project. The research objectives were to estimate Great Lakes mallard demographic parameters, determine which parameters had driven declines in abundance, and reduce uncertainty about the ecological and anthropogenic factors affecting movement and population dynamics. We captured, collected genetic and feather samples from, and marked 592 female mallards with GPS-GSM transmitters in Michigan, Wisconsin, Ohio, Indiana, and Illinois, USA from 2021\u20132023. We also used 32 years of banding, band recovery, and aerial survey data collected from mallards in Michigan and Wisconsin during 1991\u20132022 to develop an Integrated Population Model (IPM). Genetic ancestry analysis of GPS-marked female mallards via ddRAD sequencing revealed 44% were wild mallards and 56% were wild x domestic game-farm mallard hybrids. Hybrid mallards had shorter daily movement distances, were less likely to engage in autumn migration, and had higher use and selection of urban developed land cover than did wild mallards. Survival of female GPS-marked mallards was positively related to the proportion of locations in urban developed land cover, regardless of individual genotype, suggesting urban land cover use could be a source of individual heterogeneity in survival. Female mallards with greater domestic ancestry primarily used urban developed land cover, raising questions about their ability to survive in rural habitat types primarily used by wild mallards. Increasing proportion of domestic ancestry was associated with significantly lower probability of initiating nest incubation, indicating early generational hybrids had low productivity. Sedentary behavior, use and selection of urban areas, and low incubation incidence related to domestic ancestry raises concern regarding hybridization between wild and domestic game-farm mallards. Molting and natal origins estimated from stable hydrogen (\u3b42H) isotopes predicted 72%\u201384% of adult females molted and 59%\u201377% of juvenile females hatched at the latitudes of the Great Lakes region. Emigration likely contributed little to population decline as 98% of surviving female Great Lakes mallards remained in or returned to the Great Lakes region in subsequent breeding periods. The IPM identified declining productivity and increasing natural mortality in adult and juvenile female mallards as the primary demographic drivers of population decline. Productivity was lowest at urban developed banding sites in the southern Great Lakes region, where prevalence of hybrid mallards was greatest. Productivity declined with loss of area enrolled in the Conservation Reserve Program within Michigan and Wisconsin during 2000\u20132022. Natural mortality was 3.5\u20136.7 times and 1.3\u20134.2 times greater than harvest mortality for adult and juvenile female mallards, respectively, suggesting environmental factors during spring and summer, not harvest, drove annual mortality for female mallards. Attempts to increase or maintain Great Lakes mallard abundance should consider regional quantity and quality of nesting and brood-rearing habitat types and population genetics.Description based on online resource. Title from PDF t.p. (Michigan State University Fedora Repository, viewed ).Includes bibliographical references
Construction And Evaluation Of Data-Driven Learning Modules For EFL Writers\u2019 Hedging In Academic English
No full textThesis (Ph.D.)--Michigan State University. Linguistics - Doctor of Philosophy, 2024This experimental study, and partial replication of Sun and Hu (2020), examined how and to what extent direct (i.e., hands-on corpus use) or indirect (i.e., hands-off corpus use) online data-driven learning (DDL) modules were able to assist Chinese writers from an English as a foreign language (EFL) context in using more appropriate hedging (i.e., in patterns and frequencies closer to native English-speaking writers). Participants' perceptions regarding the challenges and benefits of the online corpus tools, as well as the online instructional modules, were assessed using Likert-scale surveys, open-ended survey responses, and interviews with select participants aided by a stimulated recall procedure. Students participated in four weeks of online DDL instruction, and a pre- and post- instruction writing task. Participants' hedging frequencies and patterns were statistically examined pre- and post- instruction, with log likelihood and mixed-effects modeling. Participants' Likert-scale survey responses were also examined with their open-ended survey responses and interview data. Results showed that, when both groups (direct and indirect DDL groups) were considered together, there was a significant difference across time (pre- and post- instruction) on the frequency of hedge use, indicating that DDL instruction, in general, helped to significantly increase hedge usage frequencies over time. When each group was examined separately, the direct DDL group showed a significant change over time, and the indirect DDL group showed non-significant changes over time. Therefore, while DDL instruction as a whole seemed beneficial, a more detailed analysis revealed that the direct instruction was statistically more effective. Results from the surveys and interviews identified larger patterns, and then more specific sub-themes, that participants found challenging and beneficial regarding the interface, functions, and texts, of the corpora. Challenges included, among others, the lack of easily accessible help information on the interfaces, error messages and account issues, a lack of understanding the role of certain functions, and issues with the compilation of the corpora. Benefits included, among others, the authenticity of the texts, the ability to do comparisons (i.e., across text types and learner English populations), and the ability to see keywords in larger contexts.Description based on online resource. Title from PDF t.p. (Michigan State University Fedora Repository, viewed ).Includes bibliographical references
ACCESSING CROP WILD RELATIVES OF POTATO WITH A FOCUS ON SOLANUM VERRUCOSUM AND THE 1EBN WILD SPECIES IN THE TERTIARY GENE POOL
No full textThesis (Ph.D.)--Michigan State University. Plant Breeding, Genetics and Biotechnology - Crop and Soil Sciences - Doctor of Philosophy, 2024ABSTRACTACCESSING CROP WILD RELATIVES OF POTATO WITH A FOCUS ON SOLANUM VERRUCOSUM AND THE 1EBN WILD SPECIES IN THE TERTIARY GENEPOOLByWilliam Behling Potato, Solanum tuberosum L. group Tuberosum (2n=4x=48), remains one of the most important crops worldwide and plays an integral role in global food security. Due to challenges with tetraploid breeding, the past century of potato breeding has struggled to make significant genetic gains or utilize valuable crop wild relatives effectively. A recent movement towards diploid breeding methods to develop commercial potato varieties aims to address these issues. Diploid breeding methods also offer new opportunities to leverage the immense potential of untapped genetic diversity in wild potato. However, the lack of broad self- and interspecific compatibility in diploid potato remains a substantial barrier to this effort. We characterized interspecific reproductive barriers which breeders are likely to encounter when using wild species in the genetic improvement of potato. The wild potato species S. verrucosum was selected for these experiments as it exhibits a desirable high level of self-compatibility and broad interspecific compatibility. We first examined the validity and consistency of the Endosperm Balance Number (EBN) hypothesis. Two experiments were used to examine the accuracy of the EBN hypothesis to predict normal seed development in interspecific crosses. Eleven 1EBN species and three S. verrucosum clones were used to elucidate significant inter- and intraspecific variation for effective ploidy and regular seed development. The variation observed could not be predicted or characterized by the EBN hypothesis, thus questioning the value and application of this classification system. Second, we sought to understand the genetic basis and heritability of the broad interspecific compatibility phenotype present in S. verrucosum, using an F2 population derived from a cross between the S. tuberosum doubled monoploid DM1s1 and the S. verrucosum clone MSII1813-02. The population was phenotyped using self-pollinations, pollen viability assays, and interspecific pollinations with S. pinnatisectum and S. tarnii. Biparental linkage mapping identified two major QTLs on chromosomes 1 and 11 together explaining 56.6% of the phenotypic variance in interspecific compatibility. We also identified three QTL associated with male fertility on chromosomes 3, 8, and 9 explaining, respectively: 27.1%, 26.5% and 16.2% of the phenotypic variance in male fertility. Third, breaking from the S. verrucosum focus, we evaluated a novel germplasm pool of advanced breeding clones of hybrids between the wild species S. ehrenbergii, S. jamesii, and S. stenophyllidium for their potential in 1EBN germplasm characterization and development. In a modest yield trial, advanced clones exhibited desirable cultivated traits and outperformed their wild species sources. These results, along with crossing experiments, evince the suitability of this material as a prebreeding resource and alternative germplasm worthy of further research. This work explores pathways to harness underutilized genetic resources of wild potato species, expanding the armamentarium available to breeders for the genetic improvement of diploid S. tuberosum for commercial variety development. The availability of diploid S. tuberosum germplasm with broad interspecific compatibility and high self-compatibility derived from S. verrucosum will facilitate further utilization and characterization of wild germplasm.Description based on online resource. Title from PDF t.p. (Michigan State University Fedora Repository, viewed ).Includes bibliographical references
Microbiome in Healthy Perivascular Adipose Tissue
No full textPerivascular adipose tissue (PVAT) is a novel target in the treatment of vascular pathologies such as atherosclerosis and hypertension. It has been reported that the functions of this tissue include functions in vasoprotective activity, anti-inflammatory roles, and anti-contractile effects on the vessels that it surrounds. The lack of detailed investigation into the form and function of this crucial tissue beckons further research into the composition of this tissue. Comparisons between the structure of other adipose tissue throughout the body and PVAT provide valuable information on the potential presence of bacteria, viruses or fungi within healthy PVAT. This knowledge would enable an understanding of the changes that occur during a disease state of the PVAT and further elucidate the function during the healthy state. Using this, we propose further study into identifying a presence of microbiome within healthy PVAT tissue, and argue that current evidence provides support for a presence of this microbiome.Thesis (M.S.)--Michigan State University. Basic Medical Science - Master of Science, 2024Includes bibliographical reference
CHEMOENZYMATIC SYNTHESIS AND ANALYSIS OF CHONDROITIN SULFATE GLYCOPEPTIDES AND PROTEOGLYCANS
No full textGlycosaminoglycans (GAGs) or mucopolysaccharides are a class of highly negatively charged polysaccharides, which are present in all mammalian cells and involved in various important biological events such as growth factor signaling, blood coagulation, brain development and neural stem cell migration. GAGs, except for hyaluronic acid, are commonly found covalently linked to proteoglycans (PGs). These PGs typically start with a common tetrasaccharide linkage region (GlcA\u3b21-3Gal\u3b21-3Gal\u3b21-4Xyl) that links to a serine residue on the core protein. The tetrasaccharide linkage region is then elongated to polysaccharides composed of disaccharide repeating units of chondroitin sulfate (CS) or heparan sulfate (HS). In this dissertation, we first discussthe recent advancesin the understanding of biosynthetic enzymes involved in the synthesis of the tetrasaccharide linkage region in chapter 1 and focus on the expression and the relationship between these enzymes. Building on the knowledge of these enzymes, in chapter 2, we report a new method using commercially available EAH Sepharose as the solid support to synthesize tetrasaccharide linkage region bearing glycopeptides. This method eliminates the tedious traditional glycosyl amino acid synthesis, greatly reducing the time need for tetrasaccharide linkage region construction. We further modified the synthesized linkage region with CS transferase and sulfotransferase to complete the synthesis of multiple CS-bearing glycopeptides. Notably, the dodecasaccahride bearing glycopeptide is the largest GAG-bearing glycopeptide synthesized to date. CSPG plays important roles in biological events, to better understand the mechanism, it is important to map the expression level and the types of CSPG. In chapter 3, an enzymatic method was developed to label and enrich CSPG in biospecimen and various fragmentation methods have been explored for quantitative CSPG mapping.Thesis (Ph.D.)--Michigan State University. Chemistry - Doctor of Philosophy, 2024Includes bibliographical reference
RISK MODELING, DECISION ANALYSIS, AND RISK COMMUNICATION FOR LISTERIOSIS IN CANCER PATIENTS WHO CONSUME FRESH SALAD
No full textListeria monocytogenes is a problematic pathogen for cancer patients, with morbidity and mortality rates higher than those in the general population. The neutropenic diet (ND), which is commonly employed to reduce infection risk by excluding raw foods, including fresh produce, remains a subject of controversy. Correspondingly, produce safety communication strategies are largely unstandardized, with patients and caretakers receiving widely different guidelines and materials depending on their institution. Data-driven food safety diets and communication strategies are needed to improve health and quality of life outcomes in this population.This dissertation aimed to resolve these issues: by (i) updating a previous listeriosis risk model to improve accuracy and define limitations, (ii) constructing decision models evaluating outcomes for the ND vs. three alternative produce safety diets, and determining parameters that justify the use of the ND, (iii) using quantitative and qualitative data to understand the produce safety beliefs, barriers, motivators, and behaviors of pediatric cancer patient caretakers, and their feedback on communication strategies, and (iv) combining literature and qualitative pediatric cancer patient caretaker data to formulate communication objectives and a resulting produce safety communication strategy prototype.A previously presented listeriosis risk model for fresh salads was updated to account for tomato contamination from soil, cross-contamination during dump tank washing, and conveyor and waxing surfaces. Main sources of uncertainty and variability and areas lacking data were highlighted, suggesting opportunities for future research. The risk model was then used to build decision models for cancer patients who consume ready-to-eat (RTE) salads. As measured in disability-adjusted life years (DALYs) per person per chemotherapy cycle, outcomes associated with the ND were consistently worse than for alternative, produce-inclusive food safety diets. Furthermore, when fluctuating uncertain and/or variable parameters were used to compute switchover points, the resulting values were unrealistic (e.g., negative probability), meaning that produce-inclusive food safety diets were the favored intervention for the scenarios examined.Subsequently, foodborne illness risk management strategies were explored. Quantitative surveys and qualitative interviews were conducted with pediatric cancer patient caretakers to assess their beliefs, barriers, motivators, and behaviors, with respect to produce safety guidelines. While no significant quantitative relationships were observed between demographic variables and produce safety behavior frequencies, qualitative grounded theory coding led to classification of five caretaker archetypes, with commonalities in guidelines received, child\u2019s health, food safety behaviors previously enacted, and concerns beyond microbial food safety. The existence of these archetypes underscored the prevalent adoption of the ND and the absence of uniformity in produce safety communication materials. Recommendations for information delivery, timing, and material organization were conceived based on caretaker feedback. These recommendations then were integrated with scientific communication literature to develop objectives conducive to a produce safety communication strategy endorsing safe produce preparation, storage, and dietary inclusion. A novel produce safety communication intervention was prototyped based on corresponding tactics.Overall, this work quantitatively and qualitatively supports the adoption of produce-inclusive food safety diets, such as those recommended by the U.S. Food and Drug Administration (FDA) and American Cancer Society (ACS), as a replacement for the ND. It also presents a feedback-driven risk communication strategy for imparting this information.Thesis (Ph.D.)--Michigan State University. Biosystems Engineering - Doctor of Philosophy, 2024Includes bibliographical reference