Browsing by Subject "Animal models"
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Item The Intersexual Genetic Correlation for Lifetime Fitness in the Wild and Its Implications for Sexual Selection(Public Library of Science, 2007-08-15) Brommer, Jon E.; Kirkpatrick, Mark; Qvarnström, Anna; Gustafsson, LarsBackground -- The genetic benefits of mate choice are limited by the degree to which male and female fitness are genetically correlated. If the intersexual correlation for fitness is small or negative, choosing a highly fit mate does not necessarily result in high fitness offspring. Methodology/Principal Finding -- Using an animal-model approach on data from a pedigreed population of over 7,000 collared flycatchers (Ficedula albicollis), we estimate the intersexual genetic correlation in Lifetime Reproductive Success (LRS) in a natural population to be negative in sign (−0.85±0.6). Simulations show this estimate to be robust in sign to the effects of extra-pair parentage. The genetic benefits in this population are further limited by a low level of genetic variation for fitness in males. Conclusions/Significance -- The potential for indirect sexual selection is nullified by sexual antagonistic fitness effects in this natural population. Our findings and the scarce evidence from other studies suggest that the intersexual genetic correlation for lifetime fitness may be very low in nature. We argue that this form of conflict can, in general, both constrain and maintain sexual selection, depending on the sex-specific additive genetic variances in lifetime fitness.Item Modeling ultrasonic vocalization profiles as predictive biomarkers for alcohol consumption susceptibility(2018-01-24) Mittal, Nitish; Duvauchelle, Christine L.; Schallert, Timothy; Gonzales, Rueben A; Harris, R. Adron; Vasquez, KarenThe overarching goal of this dissertation project is to characterize the ultrasonic vocalization profiles associated with sex differences and predisposition for alcohol consumption in rodents. In order to accomplish this goal we pursued the following specific aims: 1) to investigate potential sex differences in the USV profiles of 50 – 55 kHz frequency modulated (FM) and 22 – 28 kHz calls in male and female high-alcohol-drinking (HAD-1) rats, 2) to investigate potential differences in the counts and acoustic characteristics of 50 – 55 kHz FM and 22 – 28 kHz USVs between HAD-1 and low-alcohol-drinking (LAD-1) rats, and 3) to determine whether USV profiles can serve as biomarkers for the predisposition to consume high levels of alcohol in Long-Evans rats. The results from the studies assessing the first aim are described in chapters 2 and 3. We found that male and female HAD-1 rats spontaneously emit large amounts of unprovoked 50 – 55 kHz FM and 22 – 28 kHz USVs with distinct acoustic properties, which are further susceptible to modulation by ethanol. We also found that female HAD-1 rats show enhanced exploratory activity in an object recognition task, and that these exploratory behaviors predict future alcohol consumption levels in male and female HAD-1 rats. The results for the second aim are described in chapter 4, where we show that USV acoustic profiles can be used to generate machine learning classification models, which can discriminate between HAD-1 and LAD-1 rats with very high accuracy. The results for the third aim are described in chapter 5, where we show that USV data from alcohol-naïve rats across five different rat lines is significantly correlated with predisposition alcohol consumption. Here we provide direct evidence that USV data collected from alcohol-naïve, adult, male Long-Evans rats can be used to predict future alcohol consumption in these rats. In chapter 6, we further characterize changes in the total counts and acoustic characteristics of spontaneously emitted USVs due to age and ethanol exposure in adult, male Long-Evans rats. We finish in chapter 7 by summarizing the results and discussing the implications, as well as, potential future directions of this work.Item Repurposing niclosamide : oral and inhaled delivery of niclosamide using hot-melt extrusion and thin film freezing technologies(2023-03-29) Jara Gonzalez, Miguel Orlando; Williams, Robert O., III, 1956-; Smyth, Hugh D; Zhang, Feng; Maniruzzaman, Mohammed; Morales, Javier OThis research aims to enable the repurposing of niclosamide as a viable pharmaceutical product for treating cancer and viral infections, including COVID-19. Niclosamide is a unique drug candidate because although it was approved for use over 60 years ago as an anthelmintic medication, several studies have shown its potential as a multi-targeted cancer therapy, broad-spectrum antiviral (including COVID-19), and antibacterial, among several others. There have previously been several attempts to repurpose niclosamide in clinical trials. Unfortunately, niclosamide is a poorly water-soluble molecule with low bioavailability, which has negatively affected the outcomes of these studies. To overcome this challenge, we developed two different niclosamide formulations based on the targeted disease state as well as the intended route of administration. We prepared an amorphous solid dispersion of niclosamide (Niclosamide ASD) as an oral therapy for prostate cancer and a dried powder inhaler to treat COVID-19 infection. Niclosamide ASD was manufactured using hot-melt extrusion. This ASD generates nanoparticles during its dissolution, increasing niclosamide’s apparent 5 solubility by more than 60-fold (i.e. from 6.6 ± 0.4 to 481.7 ± 22.2 μg/mL) and its oral bioavailability in Sprague–Dawley rats. This formulation generates amorphous nanoparticles during its dissolution, confirmed by cryo-TEM and Wide-angle X-ray scattering. Nevertheless, niclosamide ASD undergoes recrystallization in acidic media, and an enteric oral dosage form of niclosamide ASD was formulated without hindering the generation of nanoparticles while maintaining the increase in the niclosamide’s apparent solubility. The formulation successfully increased niclosamide’s plasma levels in dogs when compared to a niclosamide solution prepared using organic solvents. Niclosamide dried powder inhaler was prepared using the Thin Film Freezing technology (TFF). This formulation proved to be safe after an acute three-day, multi-dose pharmacokinetic study in rats, as evidenced by histopathology analysis. In addition, it achieved lung concentrations above the required IC90 levels of SARS-CoV-2 for at least 24 h after a single administration in Syrian golden hamsters. Efficacy studies confirmed that the formulation effectively reduces viral load in infected hamsters that had been inoculated 24 hours prior with intranasal SARS-CoV-2. This formulation was transferred to a pharmaceutical company and has successfully completed phase 1 clinical trials.