Biological Sciences

Permanent URI for this collectionhttps://hdl.handle.net/10323/11883

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Investigation of the effect of auranofin, cisplatin, and gliptins on the neurolysin catalytic activity
(2025-01-01) Aljarrah, Manar; Karamyan, Vardan T; Dembinski, Roman; Diaz, Luis Villa
Neurolysin is a zinc metallopeptidase belonging to the M3 family of endopeptidases. It can be found in different cellular components, such as the cytosol, mitochondria, and plasma membrane. It plays a crucial role in breaking down neurotoxic and cerebrotoxic neuropeptides. Neurolysin plays an important role in stroke and some cancer types. Enhancing neurolysin is deemed to be a promising therapeutic approach for stroke, while inhibiting neurolysin is believed to be a potential therapeutic approach for specific types of cancer.This study aimed to evaluate the effects of various approved drugs, such as auranofin, cisplatin, alogliptin, linagliptin, sitagliptin, and vildagliptin, on the activity of neurolysin and related enzymes. The majority of experiments were carried out using fluorometric enzyme assays and recombinant proteins. Our results show that auranofin selectively inhibits neurolysin at nanomolar concentrations, potentially offering a previously unrecognized mechanism of action for this drug.
Studying neurological impairment in IL-10 gene deficiency-induced mouse colitis
(2025-01-01) Nichols, Mackenzie Reese; Rhee, Sang H; Liu, Zijuan; Delorme-Axford, Elizabeth
Inflammatory Bowel Disease (IBD) is a group of diseases associated with chronic inflammation and mucosal immune responses within the gut. Elevated pro-inflammatory cytokines and chemokines drive this disease state, with loss of regulatory cytokines such as IL-10 exacerbating this response. The IL-10 Knockout (KO) mouse model replicates key pathological features of human IBD and provides an effective in vivo model for the study of intestinal inflammation and its systemic effects. Current research in the field highlights the link between IBD-associated inflammation and neurocognitive decline. CCL11 (eotaxin-1) is an age-related chemokine that has been linked to IBD and is an emerging biomarker and mediator in neurocognitive decline due to its stimulation of reactive oxygen species (ROS). Experimental evidence shows that CCL11 easily crosses the blood-brain barrier (BBB), accumulates in regions associated with memory formation and retention, and consequently enhances ROS production via the interaction with microglial cells. This study investigates how intestinal inflammation amplifies ROS production in the brain through CCL11 signaling, using IL-10 KO mice, and highlights a link between IBD and neurocognitive decline.
Temporal variation of elemental stoichiometry in freshwater plankton
(2025-01-01) Mersino, Hailee; Wagner, Nicole; Prater, Clay; Raffel, Tom
The balance of elements within aquatic food webs shapes ecosystem productivity, energy transfer, and nutrient cycling, yet how this balance varies across space and time in freshwater systems remain poorly understood. Much of stoichiometric research in freshwater communities has focused on how macronutrients such as carbon (C), nitrogen (N), and phosphorus (P) move through food webs. Far less is known about how environmental drivers shape consumer stoichiometry, and the entire elemental profile of freshwater communities (i.e. the ionome). To address this, we examined temporal dynamics of seston and zooplankton in Tree Top Pond, a small, dimictic, eutrophic lake located within Seven Ponds Nature Center (Dryden, MI, USA), from March to September 2024. Temperature profiles were obtained from loggers deployed from the surface to the bottom of the lake to capture thermal variation through time. Zooplankton were sampled weekly to quantify the elemental composition (C, N, and P) of two taxa, Daphnia and copepods, alongside community composition through time. Seston was sampled weekly at 1m intervals throughout the water column to characterize the ionomic profile. We found that seston composition had inconsistent influence on zooplankton stoichiometry, while temperature had a stronger effect on elemental composition, particularly in Daphnia. Notably, P in Daphnia and copepods converged over the season, suggesting that warming may alter biochemical allocation of nutrients. Seston ionomic dynamics, in contrast, were more strongly structured by spatiotemporal patterns and physical processes. Spring mixing characterized the seston ionome through geochemical influences of sediment-associated elements, such as aluminum (Al), manganese (Mn), and iron (Fe); whereas macronutrients, such as C, N, and P, were more influential. Across these dynamics, temperature significantly correlated with the concentration of many elements. These results demonstrate that consumer stoichiometry is differentially sensitive to temperature, while seston ionomes are largely shaped by temporal lake processes, with implications for nutrient dynamics and lake functioning under a warming climate.
Discovering the Genomic Architecture of Cell-Type Specific Gene Regulation Using Genetically Diverse Strains of Mice
(2025-01-01) Jurek, Adrianna Maria; Westrick, Randal; Madlambayan, Gerard; Lal, Shailesh; Washington, Valance
In developed nations, thrombosis remains the most common cause of death, with myocardial infarction (MI) and stroke causing the most fatalities in the United States. Hemostasis, the highly regulated process of clot formation and dissolution, involves the complex interactions of diverse cell types and regulatory molecules, including clotting factors, fibrinolytic proteins, as well as components packed into vascular cells such as platelets and endothelial cells. Proper balance of this system is vital to prevent blood loss and unwanted clotting. Although the mechanisms of coagulation have been well characterized, the genetic regulation of essential molecules in the cell types contributing to hemostasis has not been well understood.To address this gap, I investigated the genetic regulators of three important coagulation and fibrinolysis molecules: Coagulation Factor V (FV), Plasminogen Activator Inhibitor 1 (PAI-1), and Protein C (PC). The appropriate regulation of these molecules is necessary for promoting hemostasis and fibrinolysis (the process of dissolving a clot) in the correct balance to maintain the physiological “status-quo”. I used inbred mice with natural differences in their antigen levels to generate four genetically informative crosses. I measured the antigen levels for all three proteins in the plasma and platelets of the strains and received genotyping data using miniMUGA to use in Quantitative Trait Loci (QTL) analyses to discover unique genetic regulators. This approach revealed a significant locus on Chromosome 1 when analyzing the plasma FV in one cross, and one significant and one suggestive locus when sex was included as a covariate for platelet FV. For platelet PAI-1, a major locus on Chromosome 5 was identified in all 4 crosses with suggestive loci identified in three crosses. Lastly, a suggestive locus on Chromosome 7 when using sex as an additive covariate was found when analyzing PC levels in the plasma. My findings offer improved insight into the cell-type specific regulatory pathways of these essential coagulation molecules. Enhanced understanding of physiological and pathogenic regulatory pathways may lead to future novel therapeutic strategies for humans.
Scaling Temperature Dependence of Disease Dynamics from Individuals to Populations
(2025-01-01) Noelker, James Edward; Raffel, Thomas R.; Tiegs, Scott D.; Pell, Bruce
There is growing interest among ecologists to develop mechanistic models that can generate generalizable predictions across multiple levels of biological organization. A key question is whether and how host and parasite contributions to infection can be disentangled, and to what degree these separate contributions affect population level transmission dynamics. The Metabolic Theory of Ecology (MT) provides a framework to investigate physiological processes such as metabolism, reproductive rates, host defenses, and parasite infectivity. The amphibian fungal pathogen
Thermal Biology of Parasites and Their Hosts in the Laboratory and Classroom
(2024-01-01) Craig, Hunter Michael; Raffel, Thomas R.; Berven, Keith A.; Moore, Shaun A.
The threat of climate change makes it increasingly important for biologists and the public to understand how organisms respond to temperature. The Metabolic Theory of Ecology (MTE) predicts that temperature should affect organism performance, with implications for species interactions and ecosystems that span disciplines including mathematics, chemistry, and biology. Temperature strongly impacts parasitic diseases of ectothermic hosts, with important implications for diseases of humans and wildlife. It is thus vital to examine metabolic responses of hosts and parasites to temperature in research laboratories and classroom education. I used MTE-based models to describe thermal responses of the pathogen Batrachochytrium dendrobatidis (Bd) and its amphibian hosts (Notophthalmus viridescens, eastern red-spotted newts). I measured newt breath rate and oxygen consumption (Chapter 2), as well as Bd zoospore swimming speed and critical thermal maximum (Chapter 3), to parameterize MTE-based models of host and parasite thermal performance. I conducted a controlled-temperature Bd infection experiment with newts collected from different latitudes (Chapter 4). In all three experiments, I also used temperature shifts to test for thermal acclimation effects. I hypothesized that newts and Bd would exhibit beneficial acclimation, but that Bd would acclimate to a new temperature faster because of its smaller mass and faster metabolism. I found little evidence of thermal acclimation effects on host performance, but my results suggested that the Bd either shows no acclimation or very rapid (< 3 minutes) acclimation responses. I also combined scholarship of research with scholarship of learning by developing an online teaching lab activity that introduces students to MTE-based thermal models by contrasting thermal responses in humans versus frogs (Chapter 5). I conducted a controlled experiment to compare learning outcomes for the online versus the face-to-face version of the activity (Chapter 6). Results varied, but students generally achieved similar learning outcomes in both versions of this activity.
Studying the Role of PTEN in The Gut and Investigating the Gut-Brain Inflammatory Interaction
(2023-01-01) Howe, Cody Scott; Rhee, Sang H; Madlambayan, Gerard; Song, Mi Hye
Phosphatase and tensin homolog (Pten) deficiency causes tumorigenesis because Pten opposes PI3k-Akt signaling. However, correlation between Pten deficiency and colon cancer remains unclear due to contradicting studies. The first project examines this correlation by generating intestinal epithelial cell (IEC) – specific Pten knockout (KO) mice. However, IEC-Pten deficiency alone did not induce tumorigenesis in mice but maintained the tumor-driving potential. The expression of tumor-promoting and tumor-suppressing genes was decreased and increased, respectively, in the intestine of PtenΔIEC/ΔIEC mice compared to controls. The abundance of Akkermansia muciniphila, capable of inducing chronic intestinal inflammation, was reduced in PtenΔIEC/ΔIEC mice. These findings suggest that altered tumor-associated gene expression and changed gut microbiota shape a tumor-preventive microenvironment in PtenΔIEC/ΔIEC mice. It was recently suggested that PTEN regulates TLR5-induced immune and inflammatory responses in IECs, suggesting an immunomodulatory function of PTEN in the gut. However, this alternative function of PTEN has not been evaluated in an in vivo context of protection against enteropathogenic bacteria. In the second project, PtenΔIEC/ΔIEC mice were subjected to the streptomycin-pre-treated mouse model of Salmonella infection. The bacterial infection in PtenΔIEC/ΔIEC mice increased the mortality, induced gastrointestinal inflammation, up-regulated pro-inflammatory cytokines, and increased bacterial loads in extraintestinal tissues. This suggests that IEC-restricted Pten deficiency renders the host greatly susceptible to Salmonella infection and supports an immune-regulatory role of PTEN in the gut. Lastly, in the third project, chronic gut inflammation is associated with neurodegenerative diseases. However, the direct evidence for and the underlying mechanism of the gut-brain interaction remain obscure. An interleukin-10 (IL-10) KO mouse was fed piroxicam-mixed chow, where it found that the brain and gut had increased levels of IL-1β and IL-6 cytokines. These findings suggest an inflammatory link in the piroxicam-fed IL-10 KO mice. Pten is an important factor in maintaining gut homeostasis, which is important for neural function.
Leveraging Big Data for Bioinformatic Analysis in Modern Population Genomics
(2023-01-01) Wolfsberger, Walter; Oleksyk, Taras K; Battistuzzi, Fabia; Westrick, Randal
The technological advancements and the cost reduction of genomic sequencing provide novel capabilities to pose and answer biological questions on a grand scale. The initial efforts of establishing genomic references for many species of the globe serve as a foundation for the projects that aim to analyze the populations of said species. This expansion of the number of samples involved in individual studies is often connected with increased infrastructural costs for data storage and analysis. Population genomics methods are expanding on the existing genetic approaches, leveraging our ability to automate big data processing and introducing comparative methods to our collection of scientific instruments. It has extensive applications in animal and wildlife research, conservation, and human population analyses. These unique opportunities are associated with emerging challenges related to the nature of the approaches and their relative novelty in the field. Analysis of a multitude of individuals often increases requirements in terms of bioinformatics expertise and resources. An increase in complexity and data volume means researchers often need access to high-performance computing facilities and specific training to utilize them. The field still grows, with new instruments or tests frequently introduced and outdated approaches depreciating. This work reviews population genomics methods and their application related to wildlife research, conservation, and human populations research, employs them to provide answers in multiple studies, and presents a newly developed analysis suite. The suite is aimed to facilitate reproducible, accessible population genomic testing across various fields of application, seeking to address the growing expertise challenges in the field.
Medically Relevant Genome Diversity in Ukraine
(2023-01-01) Shchubelka, Khrystyna; Oleksyk, Taras K; Battistuzzi, Fabia; Raffel, Thomas
Ukraine, the second-largest country in Europe, has a rich history characterized by migrations, epidemics, famines, wars, and occupations, all of which have contributed to the formation of the modern Ukrainian population. However, the genetic composition of Ukraine remains understudied. Previous population genetic studies have largely overlooked the unique genetic makeup of Ukraine due to lack of publicly available genomic data. Yet, recent global assessments of genome diversity have highlighted the presence of numerous endemic variants, underscoring the significance of investigating genetic variation in underrepresented regions like Eastern Europe and, specifically, Ukraine. Such research is vital in the context of worldwide clinical trials and the development of personalized medicine. Local populations, shaped by their distinct histories, harbor a wealth of unexplored genomic variation, which may impact drug response, influence the risk of common and rare diseases, and shape lifestyle adaptations.Comprehensively understanding the genetic makeup of specific populations facilitates more effective identification of genetic markers for disease gene mapping, including family linkage and genome-wide association studies. These investigations aim to uncover susceptibility genes or loci for both Mendelian and complex diseases. Therefore, in this discovery-based study, our objective is to characterize the extensive genetic variation of medically relevant alleles in contemporary Ukraine across various levels of population structure: within major regions of Ukraine, and among the multiethnic population of Transcarpathia. Additionally, we will explore the relationship between lactose persistence genotypes and phenotypes, as well as the genetic factors underlying global developmental delay and intellectual disability in Ukraine.
Assessment of Taxon Sampling on Phylogenetic Reconstructions and Timetrees: A New Methodology And Application
(2023-01-01) Powell, Christopher Lowell Edward; Battistuzzi, Fabia Ursula; Oleksyk, Taras K; Blumer-Schuette, Sara E
Over the past three decades, computational capabilities have grown at such a rapid rate that they have given rise to many computationally heavy science fields such as phylogenomics. As increasingly more genomes are sequenced in the three domains of life, larger and more species-complete phylogenetic tree reconstructions are leading to a better understanding of the Tree of Life and the evolutionary histories in deep times. However, these large datasets pose unique challenges from a modeling and computational perspective: accurately describing the evolutionary process of thousands of species is still beyond the capability of current evolutionary models while the computational burden limits our ability to exhaustively explore and test multiple hypotheses. These limitations become even more problematic when attempting to estimate the absolute times within these phylogenetic reconstructions (timetrees). These time estimations are not only constrained computationally by run times and resource requirements but also bound by the availability of fossil data to estimate divergence times for the evolution of species (primary calibrations). All of these issues are particularly severe in prokaryotes, because of the high number of species available in databases, their large evolutionary variability, and the few primary calibrations available. Yet, they represent two out of the three domains of life and are therefore key to reconstructing the Tree of Life. This combination of computational and data constraints is forcing researchers to make choices on the datasets being analyzed without a clear understanding of the consequences of these choices on the accuracy of the results obtained. This work presents an in-depth analysis of the effects of dataset choices on the reconstruction of phylogenetic histories using a newly developed tool (Phylogenetic Assessment of Taxon Sampling) that will enable fast, simple, and reproducible testing of taxon sampling. The PATS pipeline is available on GitHub: https://github.com/BlabOaklandU/PATS
Analyzing the In Vivo Roles of Histone Acetyltransferases GCN5 And ESA1 in RSC Recruitment and Remodeling Activity Genome-Wide in Saccharomyces Cerevisiae
(2023-01-01) Biernat, Emily R.; Govind, Chhabi K; Chaudhry, Rasul; Blumer-Schuette, Sara
Transcription is important for gene expression and is a tightly-controlled process involving multiple mechanisms of regulation, including regulation by chromatin structure. Chromatin consists of nucleosomes, which are comprised of DNA wrapped around histone proteins. Chromatin remodelers such as the Remodels the Structure of Chromatin (RSC) complex play important roles in controlling DNA accessibility to the transcriptional machinery and organizing chromatin throughout the genome. Mutations in yeast and mammalian RSC orthologs have been linked to dysregulated cell cycle progression, chromosome segregation, stress response, and developmental processes. In this study, we investigated the mechanisms by which RSC associates with chromatin on a genome-wide scale and the impact of disrupted RSC-chromatin interactions on transcription. Previous studies have suggested that nucleosome acetylation via histone acetyltransferases (HATs) may facilitate RSC binding to chromatin. To explore this, we examined the effects of removing HATs Gcn5 and Esa1 on RSC occupancy. Surprisingly, our results revealed distinct effects of HAT loss on RSC occupancy at promoters and gene bodies. In promoters, the loss of HATs increased RSC association with promoter nucleosomes, particularly in promoters containing partially-unwrapped fragile nucleosomes. Additionally, we found that HAT-mediated acetylation is crucial for maintaining nucleosome depletion at promoters. Conversely, HAT loss decreased RSC occupancy in gene bodies of highly transcribed genes. This reduction in RSC binding was dependent on histone tails, as cells lacking these tails also showed a significant loss of RSC binding to gene bodies. High-resolution mapping and analyses demonstrated that RSC-bound nucleosomes, particularly in gene bodies, were highly accessible. Consistent with these findings, loss of HAT functions resulted in widespread transcriptional changes, impacting both transcription initiation and elongation. This work provides valuable insights into how HAT-mediated histone modifications regulate RSC association with chromatin and the consequent impact on global transcription.
Traumatic Brain Injury: Assessing The Pathogenic Impact Of Chronic Smoking And Potential Countermeasures
(2022-11-04) Sivandzade, Farzane; Cucullo, Luca; Al-Shabrawey, Mohamed; Liu Zijuan
Traumatic brain injury is among the most prevalent causes of cerebrovascular and neurological damage worldwide. Premorbid conditions such as smoking could exacerbate post-traumatic brain injury damage and impact recovery due to vascular endothelial dysfunction. Cigarette smoke produces reactive oxygen species (ROS) and oxidative stress (OS), driving endothelial dysfunction and damaging the blood-brain barrier (BBB) endothelium. Interestingly, these pathogenic modulators of BBB impairment are similar to those initiated by hyperglycemia. Thus, this work investigated the pathophysiological mechanisms underlying traumatic brain injury (TBI) exacerbation following chronic smoking and vaping exposure to determine key pathological parameters leading to loss of BBB function and integrity. I also assessed the effectiveness of metformin and rosiglitazone to prevent/reduce the loss of BBB function and integrity and protect the brain from the exacerbation of post-TBI likely promoted by the chronic exposure to tobacco smoke (TS) or electronic cigarette (EC) vape and unravel the corresponding mechanism (s) of action. For this purpose, I used both in vitro (primary brain microvascular endothelial cells) and in vivo mice models (male and C57BL/6J mice) subjected to TS/EC and TBI, with/without antidiabetic treatments. The outcomes of these studies would define the complex interplay between smoking and TBI and lead to new approaches for alleviating TBI outcomes.
The New Zealand Mud Snail (Potamopyrgus Antipodarum) Ecology And Management Of A Global Invader
(2022-07-28) Gist, Jeremy A.; Tiegs, Scott; Berven, Keith; Luttenton, Mark; Strayer, David
The New Zealand mud snail (Potamopyrgus antipodarum; NZMS) is among the most globally widespread aquatic invaders, colonizing at least 40 countries across 6 continents. NZMS have recently colonized rivers of the Laurentian Great Lakes region. where little is known about their impacts on the native communities of the ecosystems they invade. In chapter one, I present the results of a systematic review of 245 articles, and outline NZMS impacts, distribution, population dynamics, vectors of spread, and management. The invasion success of NZMS stems from their opportunistic traits allowing them to tolerate broad ranges of environmental conditions. However, optimal conditions for successful establishment are evident. NZMS can become exceptionally abundant and impact multiple facets of aquatic ecosystems, though populations can fluctuate seasonally and over longer time scales, likely due to environmental constraints. In chapter two, I tested the efficacy of three different chemical reagents for NZMS decontamination on recreational fishing gear and combined these results with results of a self-administered public survey gauging the level of willingness individuals have to participate in a given NZMS decontamination technique. The greatest mortality of NZMS was caused by Formula 409, and participants of the survey revealed Formula 409 to be the chemical they'd be most willing to use. Chapter three outlines an investigation of the effects of NZMS on the diets and condition of fish in a recently invaded stream, the Au Sable River (Michigan, USA). Trout consumed NZMS throughout the duration of the study, while sculpin minimally consumed NZMS. Of the 83 trout collected, 60% contained NZMS in their stomachs. Age 2 trout that consumed NZMS exhibited reduced condition relative to those that contained fewer NZMS. Lastly, chapter four consists of a study to characterize NZMS population dynamics and their effects on native benthic invertebrates in the Au Sable River. NZMS populations exhibited pronounced seasonality with peak densities typically occurring during the Summer and Autumn of each year. NZMS numerically dominated the benthic community and were associated with differences in the overall benthic community composition. The results of these studies highlight how NZMS can affect native communities and higher consumers in rivers of the Great Lakes region and contribute to a more robust understanding of the global NZMS invasion, such that undesired impacts can be minimized or averted.

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